CN116745325A

CN116745325A - BCMA targeting antibody, chimeric antigen receptor and application thereof

Info

Publication number: CN116745325A
Application number: CN202180005555.3A
Authority: CN
Inventors: 赵阳兵; 潘伟
Original assignee: Shanghai Youtijisheng Biomedical Co ltd
Current assignee: Shanghai Youtijisheng Biomedical Co ltd
Priority date: 2021-08-16
Filing date: 2021-08-16
Publication date: 2023-09-12
Also published as: WO2023019398A1

Abstract

The present invention discloses anti-BCMA antibodies and antigen binding fragments, chimeric antigen receptors ("CARs") having these anti-BCMA antibodies and antigen binding fragments ("BCMA CARs") and genetically engineered immune effector cells having these BCMA CARs. The invention also provides polynucleotides encoding anti-BCMA antibodies and antigen binding fragments, as well as BCMACARs. The invention also provides compositions comprising anti-BCMA antibodies and antigen binding fragments, as well as BCMA CARs. The invention also relates to the use of said anti-BCMA antibodies and antigen binding fragments, and genetically engineered immune effector cells having such BCMA CARs in the treatment of cancer.

Description

BCMA targeting antibody, chimeric antigen receptor and application thereof

1. Technical field

The present invention relates to molecular biology, cell biology and immunooncology. In particular, the invention provides genetically engineered immune effector cells comprising anti-BCMA antibodies, chimeric antigen receptors ("BCMACARs") comprising such anti-BCMA antibodies, expressing such BCMACARs, and their use in the treatment of tumors or cancers.

2. Background art

B Cell Maturation Antigen (BCMA) is a transmembrane glycoprotein expressed on mature B lymphocytes. BCMA expression is associated with a variety of diseases including cancer and infectious diseases. However, current therapies for BCMA, including BCMA binding Chimeric Antigen Receptors (CARs) and cells expressing such CARs, have met with limited success. Thus, the selection of other BCMA targeted therapies represents an unmet need. The compositions and methods provided herein meet these needs and have other related advantages.

3. Summary of the invention

The present invention provides antibodies or antigen binding fragments thereof capable of specifically binding BCMA (e.g., human BCMA), comprising: (a) A light chain variable region (VL) comprising (1) a light chain CDR1 (VL CDR 1) having an amino acid sequence selected from the group consisting of the sequences set forth in SEQ ID NOs 1-10; (2) A light chain CDR2 (VL CDR 2) having an amino acid sequence selected from the group consisting of the sequences shown in SEQ ID NOS 11-21; and (3) a light chain CDR3 (VL CDR 3) having an amino acid sequence selected from the group consisting of the sequences shown in SEQ ID NOS 22-32; or a variant thereof having up to about 5 amino acid substitutions, additions and/or deletions in the VL CDRs; and/or (b) a heavy chain variable region (VH) comprising (1) a heavy chain CDR1 (VH CDR 1) having an amino acid sequence selected from the group consisting of the sequences set forth in SEQ ID NOs 33-43; (2) Heavy chain CDR2 (VH CDR 2) having an amino acid sequence selected from the group consisting of the sequences shown in SEQ ID NOS 44-55; and (3) a heavy chain CDR3 (VH CDR 3) having an amino acid sequence selected from the group consisting of the sequences shown in SEQ ID NOS: 56-67; or a variant thereof having up to about 5 amino acid substitutions, additions and/or deletions in the VH CDRs.

In some embodiments of the antibodies and antigen binding fragments provided herein, (a) the VL CDR1, CDR2 and CDR3 have the amino acid sequences shown in (1) SEQ ID NOs 1, 11 and 22, respectively; (2) the amino acid sequences shown in SEQ ID NOs 2, 12 and 23; (3) the amino acid sequences shown in SEQ ID NOs 3, 13 and 24; (4) the amino acid sequences shown in SEQ ID NOS.4, 14 and 24; (5) the amino acid sequences shown in SEQ ID NOs 5, 15 and 25; (6) the amino acid sequences shown in SEQ ID NOS.6, 16 and 26; (7) the amino acid sequences shown in SEQ ID NOS.7, 17 and 27; (8) the amino acid sequences shown in SEQ ID NOS.8, 18 and 28; (9) the amino acid sequences shown in SEQ ID NOS.2, 19 and 29; (10) the amino acid sequences shown in SEQ ID NOs 2, 20 and 30; (11) the amino acid sequences shown in SEQ ID NOS.9, 21 and 31; or (12) the amino acid sequences shown in SEQ ID NOS 10, 14 and 32; or a variant thereof having up to about 5 amino acid substitutions, additions and/or deletions in the VL CDRs; and/or, (b) said VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in (1) SEQ ID NOs 33, 44 and 56, respectively; (2) the amino acid sequences shown in SEQ ID NOS.34, 45 and 57; (3) the amino acid sequences shown in SEQ ID NOs 35, 46 and 58; (4) the amino acid sequences shown in SEQ ID NOS.36, 47 and 59; (5) the amino acid sequences shown in SEQ ID NOS.37, 48 and 60; (6) the amino acid sequences shown in SEQ ID NOS.38, 49 and 61; (7) the amino acid sequences shown in SEQ ID NOS.35, 50 and 62; (8) the amino acid sequences shown in SEQ ID NOS: 39, 51 and 63; (9) the amino acid sequences shown in SEQ ID NOS.40, 52 and 64; (10) the amino acid sequences shown in SEQ ID NOS.41, 53 and 65; (11) the amino acid sequences shown in SEQ ID NOS.42, 54 and 66; or (12) the amino acid sequences shown in SEQ ID NOS.43, 55 and 67; or a variant thereof having up to about 5 amino acid substitutions, additions and/or deletions in the VH CDRs.

In some embodiments of the antibodies and antigen-binding fragments provided herein, (1) the VL CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOs 1, 11 and 22, respectively; and/or, the VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOs 33, 44 and 56, respectively; (2) The VL CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NO 2, 12 and 23 respectively; and/or, the VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOs 34, 45 and 57, respectively; (3) The VL CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NO 3, 13 and 24 respectively; and/or, the VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOs 35, 46 and 58, respectively; (4) The VL CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOS 4, 14 and 24, respectively; and/or, the VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOs 36, 47 and 59, respectively; (5) The VL CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOS 5, 15 and 25, respectively; and/or, the VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOs 37, 48 and 60, respectively; (6) The VL CDR1, CDR2 and CDR3 respectively have amino acid sequences shown in SEQ ID NO 6, 16 and 26; and/or, the VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOs 38, 49 and 61, respectively; (7) The VL CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOS 7, 17 and 27, respectively; and/or the VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOs 35, 50 and 62, respectively; (8) The VL CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOS 8, 18 and 28, respectively; and/or the VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOs 39, 51 and 63, respectively; (9) The VL CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NO 2, 19 and 29 respectively; and/or the VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOs 40, 52 and 64, respectively; (10) The VL CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NO 2, 20 and 30 respectively; and/or the VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOs 41, 53 and 65, respectively; (11) The VL CDR1, CDR2 and CDR3 have the amino sequences shown in SEQ ID NOS 9, 21 and 31, respectively; and/or the VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOs 42, 54 and 66, respectively; or, (12) the VL CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOS 10, 14 and 32, respectively; and/or the VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOS 43, 55 and 67, respectively.

In some embodiments, the antibodies and antigen-binding fragments provided herein include VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3, wherein (a) the VL CDR1, CDR2, and CDR3 have the amino acid sequences shown in SEQ ID NOs 4, 14, and 24, respectively; and (b) said VH CDR1, CDR2 and CDR3 have the amino acid sequences of SEQ ID NOS 36, 47 and 59, respectively.

In some embodiments, the antibodies and antigen-binding fragments provided herein include VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3, wherein (a) the VL CDR1, CDR2, and CDR3 have the amino acid sequences shown in SEQ ID NOs 8, 18, and 28, respectively; and (b) said VH CDR1, CDR2 and CDR3 have the amino acid sequences of SEQ ID NOS 39, 51 and 63, respectively.

In some embodiments, the antibodies and antigen-binding fragments provided herein include VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3, wherein (a) the VL CDR1, CDR2, and CDR3 have the amino acid sequences shown in SEQ ID NOs 2, 20, and 30, respectively; and (b) said VH CDR1, CDR2 and CDR3 have the amino acid sequences of SEQ ID NOS 41, 53 and 65, respectively.

The invention provides antibodies, or antigen binding fragments thereof, capable of specifically binding BCMA (e.g., human BCMA), comprising: (a) VL having at least 85%, at least 90%, at least 95%, at least 98% or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs 68-79; and/or (b) a VH having at least 85%, at least 90%, at least 95%, at least 98% or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs 80-91.

In some embodiments, antibodies and antigen-binding fragments provided herein include a VL and a VH, wherein the VL and VH have (1) the amino acid sequences set forth in SEQ ID NOs 68 and 80, respectively; (2) the amino acid sequences shown in SEQ ID NOS 69 and 81; (3) the amino acid sequences shown in SEQ ID NOS.70 and 82; (4) the amino acid sequences shown in SEQ ID NOS: 71 and 83; (5) the amino acid sequences shown in SEQ ID NOS: 72 and 84; (6) the amino acid sequences shown in SEQ ID NOS: 73 and 85; (7) the amino acid sequences shown in SEQ ID NOS 74 and 86; (8) the amino acid sequences shown in SEQ ID NOS 75 and 87; (9) the amino acid sequences shown in SEQ ID NOS 76 and 88; (10) the amino acid sequences shown in SEQ ID NOS 77 and 89; (11) the amino acid sequences shown in SEQ ID NOS.78 and 90; or (12) the amino acid sequences shown in SEQ ID NOS 79 and 91.

In some embodiments, the antibodies and antigen-binding fragments provided herein include a VL and a VH, wherein the VL and VH have the amino acid sequences shown in SEQ ID NOs 71 and 83, respectively. In some embodiments, antibodies and antigen-binding fragments provided herein include a VL and a VH, wherein the VL and VH have the amino acid sequences set forth in SEQ ID NOs 75 and 87, respectively. In some embodiments, the antibodies and antigen-binding fragments provided herein include a VL and a VH, wherein the VL and VH have the amino acid sequences set forth in SEQ ID NOs 77 and 89, respectively.

The invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA), comprising (a) a VL comprising VL CDR1, CDR2, and CDR3, said VL CDR1, CDR2, and CDR3 being derived from a VL having an amino acid sequence selected from the group consisting of SEQ ID NOs 68-79; and/or, (b) a VH comprising VH CDR1, CDR2 and CDR3, said VH CDR1, CDR2 and CDR3 being derived from a VH having an amino acid sequence selected from the group consisting of SEQ ID NOs 80-91.

In some embodiments, the antibodies and antigen-binding fragments provided herein include (1) a VL comprising a VL CDR1, a CDR2 and a CDR3, said VL CDR1, CDR2 and CDR3 derived from a VL having the amino acid sequence shown in SEQ ID NO:68 and/or a VH comprising a VH CDR1, CDR2 and CDR3, said VH CDR1, CDR2 and CDR3 derived from a VH having the amino acid sequence shown in SEQ ID NO: 80; (2) A VL comprising VL CDR1, CDR2 and CDR3, said VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence shown in SEQ ID No. 69 and/or a VH comprising VH CDR1, CDR2 and CDR3, said VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID No. 81; (3) A VL comprising VL CDR1, CDR2 and CDR3, said VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence shown in SEQ ID No. 70, and/or a VH comprising VH CDR1, CDR2 and CDR3, said VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID No. 82; (4) A VL comprising VL CDR1, CDR2 and CDR3, said VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence shown in SEQ ID NO:71 and/or a VH comprising VH CDR1, CDR2 and CDR3, said VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID NO: 83; (5) A VL comprising VL CDR1, CDR2 and CDR3, said VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence shown in SEQ ID No. 72 and/or a VH comprising VH CDR1, CDR2 and CDR3, said VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID No. 84; (6) A VL comprising VL CDR1, CDR2 and CDR3, said VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence shown in SEQ ID NO:73 and/or a VH comprising VH CDR1, CDR2 and CDR3, said VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID NO: 85; (7) A VL comprising VL CDR1, CDR2 and CDR3, said VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence shown in SEQ ID No. 74 and/or a VH comprising VH CDR1, CDR2 and CDR3, said VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID No. 86; (8) A VL comprising VL CDR1, CDR2 and CDR3, said VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence shown in SEQ ID No. 75 and/or a VH comprising VH CDR1, CDR2 and CDR3, said VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID No. 87; (9) A VL comprising VL CDR1, CDR2 and CDR3, said VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence shown in SEQ ID No. 76 and/or a VH comprising VH CDR1, CDR2 and CDR3, said VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID No. 88; (10) A VL comprising VL CDR1, CDR2 and CDR3, said VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence shown in SEQ ID NO:77, and/or a VH comprising VH CDR1, CDR2 and CDR3, said VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID NO: 89; (11) A VL comprising VL CDR1, CDR2 and CDR3, said VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence shown in SEQ ID No. 78 and/or a VH comprising VH CDR1, CDR2 and CDR3, said VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID No. 90; or (12) a VL comprising a VL CDR1, a CDR2 and a CDR3, said VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence shown in SEQ ID NO:79 and/or a VH comprising a VH CDR1, CDR2 and CDR3, said VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID NO: 91.

In some embodiments of the antibodies or antigen-binding fragments provided herein, the VL comprises VL CDR1, CDR2 and CDR3, the VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence shown in SEQ ID NO: 71; and, the VH includes a VH CDR1, a CDR2 and a CDR3, the VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID NO 83. In some embodiments, the VL comprises VL CDR1, CDR2 and CDR3, the VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence of SEQ ID NO:75 and the VH comprises VH CDR1, CDR2 and CDR3, the VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence of SEQ ID NO: 87. In some embodiments, the VL comprises VL CDR1, CDR2 and CDR3, the VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence of SEQ ID NO. 77; and, the VH includes a VH CDR1, a CDR2 and a CDR3, the VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID NO 89.

In some embodiments, the invention provides antibodies or antigen binding fragments that compete with the antibodies or antigen binding fragments described herein for binding to BCMA.

In some embodiments, the antibodies or antigen-binding fragments provided herein are monoclonal antibodies or antigen-binding fragments. In some embodiments, the antibodies or antigen binding fragments provided herein are bispecific or multispecific antibodies. In some embodiments, the antibodies provided herein are bispecific T cell engagers (bites). In some embodiments, the antibodies provided herein are selected from the group consisting of IgG1 antibodies, igG2 antibodies, igG3 antibodies, and IgG4 antibodies. In some embodiments, the antibodies or antigen binding fragments provided herein are selected from the group consisting of Fab, fab ', F (ab') ₂ 、Fv、scFv、(scFv) ₂ A single domain antibody (sdAb) and a heavy chain antibody (HCAb). In some embodiments, the antibodies or antigen binding fragments provided herein are scFv.

In some embodiments, the antibodies or antigen-binding fragments provided herein are chimeric antibodies or antigen-binding fragments, humanized antibodies or antigen-binding fragments, or human antibodies or antigen-binding fragments. In some embodiments, the antibodies or antigen-binding fragments provided herein are human antibodies or antigen-binding fragments.

The invention also provides polynucleotides encoding the antibodies or antigen binding fragments of the invention. In some embodiments, the polynucleotide is messenger RNA (mRNA). In some embodiments, the invention provides vectors comprising the polynucleotides of the invention. In some embodiments, the invention provides a host cell comprising a polynucleotide of the invention or a vector of the invention.

The invention also provides a Chimeric Antigen Receptor (CAR) that specifically binds BCMA comprising, from N-terminus to C-terminus: (a) BCMA binding domains comprising an antibody or antigen binding fragment of the invention; (b) a transmembrane domain; and (c) a cytoplasmic domain. In some embodiments, the transmembrane domain is derived from CD8, CD28, CD3ζ, CD4, 4-1BB, OX40, ICOS, CTLA-4, PD-1, LAG-3, 2B4, BTLA, TCR alpha chain, TCR beta chain, or TCR zeta chain, CD3 ε, CD45, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, or CD154.

In some embodiments of the CARs provided herein, the transmembrane domain comprises a CD8 transmembrane region or a CD28 transmembrane region. In some embodiments, the cytoplasmic domain comprises a signaling domain derived from cd3ζ, fcrγ, fcγriia, fcrβ, cd3γ, cd3δ, cd3ε, CD5, CD22, CD79a, CD79b, DAP10, DAP12, or any combination thereof. In some embodiments, the cytoplasmic domain further comprises a costimulatory domain derived from CD28, 4-1BB (CD 137), OX40, ICOS, DAP10, 2B4, CD27, CD30, CD40, CD2, CD7, LIGHT, GITR, TLR, DR3, CD43, or any combination thereof, in some embodiments, the cytoplasmic domain comprises a CD3 zeta signaling domain and a 4-1BB costimulatory domain. In some embodiments, the cytoplasmic domain comprises a CD3 zeta signaling domain and a CD28 costimulatory domain.

In some embodiments, the CARs provided herein further comprise a CD8 hinge, the CD8 hinge being located between the antibody or antigen binding fragment and the transmembrane domain.

In some embodiments, the invention provides a CAR that specifically binds BCMA comprising: an amino acid sequence selected from the group consisting of SEQ ID NOS.131-142.

The invention also provides polynucleotides encoding the CARs of the invention. In some embodiments, the polynucleotide is mRNA. The invention also provides a vector comprising the polynucleotide of the invention or the vector of the invention.

In some embodiments, the cells provided herein are immune effector cells. In some embodiments, the cells are derived from cells isolated from peripheral blood or bone marrow. In some embodiments, the cells are derived from cells differentiated in vitro from stem or progenitor cells selected from the group consisting of T cell progenitor cells, hematopoietic stem/progenitor cells, hematopoietic multipotent progenitor cells, embryonic stem cells, and induced multipotent cells. In some embodiments, the cell is a T cell or NK cell. In some embodiments, the cell is a cytotoxic T cell, helper T cell, γδ T cell, cd4+/cd8+ double positive T cell, cd4+ T cell, cd8+ T cell, CD4/CD8 double negative T cell, cd3+ T cell, naive T cell, effector T cell, helper T cell, memory T cell, regulatory T cell, th0 cell, th1 cell, th2 cell, th3 (Treg) cell, th9 cell, th17 cell, thαβ helper cell, tfh cell, stem cell memory TSCM cell, central memory TCM cell, effector memory TEM cell, or effector memory TEMRA cell. In some embodiments, the cell is a cytotoxic T cell.

In some embodiments, the invention provides a population of cells according to the invention, wherein the population of cells is derived from Peripheral Blood Mononuclear Cells (PBMCs), peripheral Blood Lymphocytes (PBLs), tumor-infiltrating lymphocytes (TILs), cytokine-induced killer Cells (CIKs), lymphokine-activated killer cells (LAKs), or bone marrow-infiltrating lymphocytes (MILs).

In some embodiments, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of an antibody or antigen-binding fragment of the invention, and a pharmaceutically acceptable carrier. In some embodiments, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a cell or cell population described herein, and a pharmaceutically acceptable carrier.

In some embodiments, the invention provides the use of an antibody or antigen binding fragment of the invention, a cell or population of cells of the invention, or a pharmaceutical composition of the invention in the treatment of cancer. In some embodiments, the invention provides the use of an antibody or antigen binding fragment of the invention, a cell or population of cells of the invention, or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of cancer. In some embodiments, the cell, cell population, or pharmaceutical composition is used in combination with an additional therapy.

In some embodiments, the invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an antibody or antigen binding fragment of the invention, or a pharmaceutical composition of the invention.

In some embodiments, the invention provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a cell or population of cells described herein. In some embodiments, the cell population is a cell population of the subject's own. In some embodiments, the methods provided herein further comprise obtaining T cells from the subject.

In some embodiments, the methods provided herein further comprise administering an additional treatment to the subject.

In some embodiments, the subject is a human.

In some embodiments of the use or method provided herein, the cancer is a BCMA-expressing cancer. In some embodiments, the cancer is a solid tumor or a hematological cancer. In some embodiments, the cancer is a B cell malignancy. In some embodiments, the cancer is a lymphoma, leukemia, or plasma cell malignancy. In some embodiments, the cancer is Multiple Myeloma (MM), fahrenheit macroglobulinemia, hodgkin's lymphoma or non-hodgkin's lymphoma. In some embodiments, the cancer is MM. In some embodiments, the MM is non-secretory multiple myeloma, or smoldering multiple myeloma.

The invention also provides a method of making a cell capable of expressing a CAR that specifically binds BCMA, comprising transferring a polynucleotide of the invention into the cell. In some embodiments, the cell is selected from the group consisting of a T cell, NK cell, NKT cell, macrophage, neutrophil, and granulocyte. In some embodiments, the polynucleotide is transferred by electroporation. In some embodiments, the polynucleotide is transferred by viral transduction. In some embodiments, the invention provides methods comprising using lentiviruses, retroviruses, adenoviruses, or adeno-associated viruses for viral transduction. In some embodiments, the polynucleotide is transferred by a transposon system. In some embodiments, the transposon system is Sleeping Beauty (Sleeping Beauty) or PiggyBac. In some embodiments, the polynucleotide is transferred by gene editing. In some embodiments, the polynucleotide is transferred by a CRISPR-Cas system, ZFN system, or TALEN system.

4. Description of the drawings

FIGS. 1A-1B provide flow cytometry data for anti-BCMAAR-T cells stained with CD19-Fc (FIG. 1A) or BCMA-Fc (FIG. 1B).

Fig. 2A provides the frequency of car+ cells in T cells transduced with the specified BCMACARs.

Figure 2B provides the Mean Fluorescence Intensity (MFI) of CAR expression in T cells transduced with the specified BCMACARs.

Figure 3 provides the frequency of car+cd8 cells in T cells transduced with the specified BCMACARs.

FIG. 4 provides phenotypes of designated CART cells characterized by CCR7 expression and CD45RO expression.

FIGS. 5A-5B provide expression of BCMA in tumor cell lines. Fig. 5A provides FACS results. Fig. 5B provides relative expression levels compared to a549 cells.

FIGS. 6A-6B provide ELISA results showing the production of INF-gamma and IL-2 by designated CART cells. FIG. 6A shows the production of INF-gamma. FIG. 6B shows IL-2 production.

FIGS. 7A-7D provide the results of tumor killing assays showing cytolytic activity of designated CART cells against Jeko-1 cells at different E (T cells): T (tumor cells) ratios. Fig. 7A: e: t=0.1: 1, a step of; fig. 7B: e: t=0.5: 1, a step of; fig. 7C: e: t=2: 1, a step of; fig. 7D: e: t=2: 1 (enlarged view).

FIGS. 8A-8E provide tumor killing assay results showing cytolytic activity of designated CART cells against RPMI-8226 cells. Fig. 8a: e: t=0.1:1; fig. 8b, e: t=0.5:1; fig. 8c: e: t=0.5:1 (enlarged view); fig. 8d: e: t=2:1; fig. 8d: e: t=2:1 (enlarged view).

5. Detailed description of the preferred embodiments

Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described herein, and that this invention is not limited to particular examples, which are intended as such.

B-cell maturation antigen (BCMA), also known as tumor necrosis factor receptor superfamily member 17 (TNFRSF 17), is a member of the TNF-receptor superfamily. BCMA is preferentially expressed in mature B lymphocytes and plays an important role in B cell development and autoimmune response. BCMA has been shown to specifically bind to tumor necrosis factor (ligand) superfamily member 13B (TNFSF 13B/tal-1/BAFF) and result in activation of NF- κb and MAPK 8/JNK. BCMA has also been shown to bind to a variety of TRAF family members and switch signals for cell survival and proliferation.

Excessive expression and activation of BCMA is associated with human tumors such as Multiple Myeloma (MM), shah et al, leukemia,34:985-1005 (2020), MM is a hematological malignancy characterized by uncontrolled proliferation of plasma cells in the bone marrow. There are about 16 ten thousand new diagnosed cases annually worldwide, and 11 ten thousand patients die. This disease is incurable, although survival is increasing with the development of new treatments.

The present invention provides novel antibodies, including antigen binding fragments that specifically bind BCMA (e.g., human BCMA). Furthermore, the present invention provides Chimeric Antigen Receptors (CARs) comprising such antibodies or antigen binding fragments that specifically bind BCMA (e.g., human BCMA), as well as genetically engineered immune effector cells (e.g., T cells) and cell populations whose cells are cells (e.g., CART) that recombinantly express CARs that specifically bind BCMA (e.g., human BCMA). Also disclosed are pharmaceutical compositions comprising a therapeutically effective amount of such antibodies or antigen binding fragments, as well as pharmaceutical compositions comprising a therapeutically effective amount of cells or cell populations. The invention also discloses the use of such pharmaceutical compositions in the treatment of diseases and conditions associated with BCMA expression (e.g., BCMA expressing cancers) and related methods of treatment.

5.1 definition

Unless defined otherwise herein, scientific and technical terms used herein shall have the meanings commonly understood by one of ordinary skill in the art. Furthermore, unless the context requires otherwise, singular terms shall include the plural and plural terms shall include the singular. Generally, the terms and techniques used in connection with cell and tissue culture, molecular biology, immunology, microbiology, genetics, and protein and nucleic acid chemistry and hybridization are well known and commonly used in the art.

The present invention provides novel antibodies comprising antigen binding fragments that specifically bind BCMA (e.g., human BCMA). The term "BCMA" includes any variant or subtype of BCMA that is naturally expressed by cells. Thus, the antibodies of the invention are capable of cross-reacting with BCMA of a species other than human (e.g., cynomolgus BCMA). Alternatively, the antibody can be specific for human BCMA and not have any cross-reactivity with other species. BCMA or any variant or subtype thereof may be isolated from cells or tissues that naturally express them or recombinantly produced using techniques well known in the art and/or techniques described herein.

The term "antibody" and grammatical equivalents thereof as used herein refers to an immunoglobulin molecule that recognizes and specifically binds a target, such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or a combination of any of the foregoing, through at least one antigen binding site, typically within the variable region of the immunoglobulin molecule. As used herein, the term includes intact polyclonal antibodies, intact monoclonal antibodies, single domain antibodies (sdabs, e.g., camelid antibodies, alpaca antibodies), single chain Fv (scFv) antibodies, heavy chain antibodies (HCAbs), light chain antibodies (LCAbs), multispecific antibodies, bispecific antibodies, monospecific antibodies, monovalent antibodies, and any other modified immunoglobulin molecule comprising an antigen binding site (e.g., a double variable region immunoglobulin molecule), so long as the antibody exhibits the desired biological activity. The antibodies also include, but are not limited to, mouse antibodies, camelid antibodies, chimeric antibodies, humanized antibodies, and humanized antibodies. Antibodies can be any of five major immunoglobulins: igA, igD, igE, igG and IgM or subclasses (isotypes) thereof (e.g., igG1, igG2, igG3, igG4, igA1, and IgA 2) based on the identity of their heavy chain constant regions (referred to as α, δ, ε, γ, and μ, respectively). The term "antibody" as used herein includes "antigen binding fragments" of whole antibodies, unless explicitly stated otherwise. The term "antigen-binding fragment" as used herein refers to an epitope that is part or fragment of an intact antibody, i.e., an epitope variable region of an intact antibody. Examples of antigen binding fragments include, but are not limited to, fab ', F (ab') 2, fv, linear antibodies, single chain antibody molecules (e.g., scFv), heavy chain antibodies (HCAbs), light chain antibodies (LCAbs), disulfide-linked scFv (dsscFv), diabodies, triabodies, tetrabodies, minibodies, diabody (DVD), single variable region antibodies (sdAb, e.g., camelid, alpaca) and single variable region (VHH) of heavy chain antibodies, and bispecific or multispecific antibodies formed from antibody fragments.

The term "humanized antibody" as used herein refers to a form of non-human (e.g., mouse) antibody that is a specific immunoglobulin chain, chimeric immunoglobulin or fragment thereof that contains minimal non-human sequences. Typically, the humanized antibody is a human immunoglobulin. In some cases, fv framework region residues of the human immunoglobulin are replaced by corresponding residues in antibodies from non-human species. In certain instances, CDR residues are replaced with CDR residues from a non-human species (e.g., mouse, rat, hamster, camel) that have the desired specificity, affinity, and/or binding capacity. The humanized antibodies can be further modified by substitution of additional residues in the Fv framework region and/or substituted non-human residues to refine and optimize antibody specificity, affinity, and/or binding capacity. The term "human antibody" as used herein refers to an antibody produced by a human or an antibody having an amino acid sequence corresponding to an antibody produced by a human, wherein the antibody produced by a human can be made using any technique known in the art.

When used in reference to an antibody, the term "heavy chain" refers to a polypeptide chain of about 50-70kDa, wherein the amino-terminal portion includes a variable region of about 120-130 or more amino acids and the carboxy-terminal portion includes a constant region. Depending on the amino acid sequence of the heavy chain constant region, the constant region may be one of five different types, called alpha (a), delta (delta), epsilon (epsilon), gamma (gamma), and mu (mu). Different heavy chains vary in size: alpha, delta and gamma comprise about 450 amino acids, while mu and epsilon comprise about 550 amino acids. When combined with light chains, these different types of heavy chains produce five well known classes of antibodies, igA, igD, igE, igG and IgM, respectively, including four subclasses of IgG, called IgGl, igG2, igG3 and IgG4. The heavy chain may be a human heavy chain.

When used in reference to an antibody, the term "light chain" refers to a polypeptide chain of about 25kDa, wherein the amino-terminal portion includes a variable region of about 100 to about 110 or more amino acids and the carboxy-terminal portion includes a constant region. The length of the light chain is about 211 to 217 amino acids. Depending on the amino acid sequence of the constant region, there are two different types of light chains, known as kappa (kappa) and lambda (lambda). The amino acid sequence of the light chain is well known in the art. The light chain may be a human light chain.

The term "variable domain" or "variable region" refers to a portion of the light or heavy chain of an antibody that is typically at the amino terminus of the light or heavy chain and has a length of about 120 to 130 amino acids in the heavy chain and about 100 to 110 amino acids in the light chain for binding and specificity of each particular antibody for its particular antigen. The variable domains vary greatly in sequence between different antibodies. The variability of the sequence is concentrated in the CDRs, while the less variable parts of the variable domains are called Framework Regions (FR). The CDRs of the light and heavy chains are primarily responsible for the interaction between the antibody and antigen. Amino acid position numbers used in the present invention are according to EU index, kabat et al (1991) Sequences of proteins of immunological intermediate (u.s.device of Health and Human Services, washington, d.c.) 5 the. The variable region may be a human variable region.

One CDR refers to one of the three hypervariable regions (H1, H2 or H3) in the non-framework region of the β -sheet framework in an immunoglobulin (Ig or antibody) VH, or one of the three hypervariable regions (L1, L2 or L3) in the non-framework region of the β -sheet framework of an antibody VL. Thus, CDRs are variable region sequences interspersed with framework region sequences. CDR regions are well known to those skilled in the art and have been defined by a variety of methods/systems. These systems and/or definitions have evolved and perfected over many years, including Kabat, chothia, IMGT, abM and contacts. For example, kabat defines the region of highest variability within the variable (V) domain of an antibody ((Kabat et Al, J. Biol. Chem.252:6609-6616 (1977); in addition, the IMGT system is based on sequence variability and positions within the variable region structure AbM definition is a compromise between Kabat and Chothia.Contact definition is based on analysis of variable antibody crystal structure software programs for analyzing antibody sequences and determining CDRs (e.g., abYsis) are available and known to those skilled in the art to be able to accommodate different conformations (Chothia and Lesk, J. Mol. Biol.196:901-917 (1987)). Both terms are well known in the art. Furthermore, the IMGT system is based on sequence variability and positions within the variable region structure AbM definition is a compromise between Kabat and Chothia.Contact definition is based on analysis of variable antibody crystal structure software programs for analyzing antibody sequences and determining CDRs (e.g., abYsis) the positions of CDRs within a standard antibody variable structure have been determined by comparison of a number of structures (Al-Laziani et Al, J. Mol. Biol. 273-1997) and J. Mol. Bio7-8 (1997) the same numbering scheme is carried out for residues within the same domain as that of the standard antibody variable structure, amino acid sequence numbers used by the same technical scheme as that is commonly known to those skilled in the art, amino acid residues used in the specification (see the specification, amino acid sequence numbers of amino acid sequence numbers) and variable region sequences used in the variable region sequence numbers used in the variable region sequence domain).

For example, CDRs defined according to Kabat (high variability) or Chothia (structure) nomenclature are listed in the table below.

	Kabat ¹	Chothia ²	Loop Location
				VH CDRl	31-35	26-32	linking B and C strands
VH CDR2	50-65	53-55	linking C’and C”strands
				VH CDR3	95-102	96-101	linking F and G strands
VL CDRl	24-34	26-32	linking B and C strands
				VL CDR2	50-56	50-52	linking C’and C”strands
VL CDR3	89-97	91-96	linking F and G strands

¹ Residue numbering follows the nomenclature of Kabat et al, supra

² Residue numbering follows the nomenclature of Chothia et al, supra

One or more CDRs may also be covalently or non-covalently incorporated into a molecule making it an immunoadhesin. Immunoadhesins can have a CDR as part of a larger polypeptide chain, can covalently link the CDR to another polypeptide chain, or can non-covalently bind the CDR. CDRs enable immunoadhesins to bind to specific antigens. CDR regions can be obtained, for example, via the abysis website @, for examplehttp:// abysis.org/) Analysis was performed.

Thus, unless otherwise specified, a CDR or a separately specified CDR (e.g., VL CDR1, VL CDR2, VL CDR 3) of a given antibody or region thereof, e.g., a variable region thereof, is understood to comprise any one (or a particular) complementarity determining region of the above schemes or other known schemes. For example, where a particular CDR (e.g., VH CDR 3) is stated to contain the amino acid sequence of the corresponding CDR in a given VH or VL region, it is to be understood that such CDR has the sequence of the corresponding CDR (e.g., CDR-H3) within the variable region as defined in any one of the schemes described above or other known schemes. In some embodiments, although specific CDR sequences are specified, it is to be understood that the provided antibodies may include CDRs according to the above or other numbering schemes known to those of skill in the art. Likewise, unless otherwise specified, reference to an FR or individually specified FR (e.g., VH FRl, VH FR2, VH FR3, VH FR 4) for a given antibody or region thereof (e.g., variable region thereof) should be understood to include a (or specific) framework region defined by any known scheme.

The terms "epitope" and "antigenic determinant" are used interchangeably herein to refer to a site on the surface of a target molecule to which an antibody or antigen binding fragment binds, e.g., a localized region on the surface of an antigen. The target molecule may comprise a protein, peptide, nucleic acid, carbohydrate or lipid. An immunologically active epitope is part of a target molecule that induces an immune response in an animal. An epitope of a target molecule that has antigenic activity is part of an antibody-bound target molecule, as determined by any method known in the art, including, for example, by immunoassay. Epitopes are not necessarily immunogenic. Epitopes are generally composed of chemically active surface groups of molecules such as amino acids or sugar side chains, and have specific three-dimensional structural features as well as specific charge characteristics. The term "epitope" includes both linear and conformational epitopes. One region of the target molecule (e.g., a polypeptide) that may serve as an epitope may be contiguous amino acids of the polypeptide, or may result from aggregation of two or more non-contiguous regions of the target molecule. The epitope may or may not be a three-dimensional surface feature of the target molecule. Epitopes formed by consecutive amino acids (also referred to as linear epitopes) are typically retained upon protein denaturation, whereas epitopes formed by tertiary folding (also referred to as conformational epitopes) are typically lost upon protein denaturation. An epitope in a unique spatial conformation typically comprises at least 3, more typically at least 5, 6, 7 or 8-10 amino acids.

The term "specific binding" as used herein refers to a polypeptide or molecule that interacts more frequently and more rapidly with an epitope, protein, or target molecule than other substances (including related and unrelated proteins) with longer duration, greater affinity, or binding as described above. Binding moieties (e.g., antibodies) that specifically bind to a target molecule (e.g., antigen) can be determined, for example, by immunoassay, ELISA, SPR (e.g., biacore), or other techniques known to those of skill in the art. Typically, the specified response is at least twice the background signal or noise, and may be more than 10 times the background. See, e.g., paul, ed.,1989,Fundamental Immunology Second Editionraven Press, new York at pages 332-336, discussion of antibody specificity. Binding moieties that specifically bind target moleculesIts affinity for the target molecule can be higher than its affinity for other molecules. In some embodiments, the binding moiety that specifically binds to a target molecule may have an affinity for the target molecule that is at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, or at least 100-fold higher than its affinity for other molecules. In some embodiments, the binding moiety that specifically binds to a particular target molecule binds with such low affinity to other molecules that the binding cannot be detected by assays described herein or known in the art. In some embodiments, "specifically binds" means, for example, that the binding moiety is at about 0.1mM or less K _D Values bind to molecular targets. In some embodiments, "specifically binds" means that the polypeptide or molecule has a K of about 10. Mu.M or less, or about 1. Mu.M or less _D Values bind the target. In some embodiments, "specifically binds" means that the polypeptide or molecule binds at a K of about 0.1. Mu.M or less, about 0.01. Mu.M or less, or about 1nM or less _D Values bind the target. Due to sequence identity between homologous proteins in different species, specific binding may include a polypeptide or molecule that recognizes a protein or target in multiple species. Also, due to homology within certain regions of polypeptide sequences of different proteins, specific binding may include polypeptides or molecules that recognize multiple proteins or targets. It will be appreciated that in some embodiments, a binding moiety (e.g., an antibody) that specifically binds a first target molecule may or may not bind a second target. As such, "specific binding" is not necessarily (although it may include) binding alone, i.e., binding to a single target. Thus, in some embodiments, a binding moiety (e.g., an antibody) can specifically bind to multiple targets. For example, in some cases, an antibody may comprise two identical antigen binding sites, each site specifically binding to the same epitope on two or more proteins. In certain alternative embodiments, the antibody may be bispecific and include at least two antigen binding sites with different specificities.

The term "binding affinity" as used herein generally refers to the non-binding between a binding moiety and a target molecule (e.g., antigen)The intensity of the sum of the covalent interactions. Binding of the binding moiety to the target molecule is a reversible process, and the affinity of the binding is generally reported as the equilibrium dissociation constant (K _D )。K _D Is the dissociation rate (k) _off Or k _d ) And binding rate (k) _on Or k _a ) Is a ratio of (2). K of binding pair _D The lower the affinity, the higher. A variety of methods for measuring binding affinity are known in the art, any of which may be used in the present invention. Specific illustrative embodiments include the following. In some embodiments, "K _D "or" K _D The value "may be determined by assays known in the art, for example by binding assays. K (K) _D Can be measured in a radiolabeled antigen binding assay (RIA) (Chen, et al, (1999) J.mol Biol 293:865-881). The K is _D Or K _D Values may also be analyzed by surface plasmon resonance using Biacore, for example using BIacore TM-2000 or BIacore TM-3000 (Biacore, inc., piscataway, N.J.), or using biological layer interferometry, for example the OctetQK384 system (ForteBio, menlo Park, calif.).

The term "variant" as used herein relates to a protein or polypeptide having a particular sequence characteristic (a "reference protein" or "reference polypeptide") and refers to a different protein or polypeptide having one or more (e.g., about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) amino acid substitutions, deletions, and/or additions as compared to the reference protein or reference polypeptide. The change in amino acid sequence may be an amino acid substitution. The amino acid sequence changes may be conservative amino acid substitutions. Functional fragments or functional variants of a protein or polypeptide retain the basic structural and functional properties of the reference protein or polypeptide.

The terms "polypeptide", "peptide", "protein" and grammatical equivalents thereof used interchangeably herein refer to polymers of amino acids of any length, which may be linear or branched. It may include unnatural or modified amino acids, or be interrupted by non-amino acids. The polypeptide, peptide or protein may also be modified, for example by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation or any other manipulation or modification.

The terms "polynucleotide", "nucleic acid" and grammatical equivalents thereof used interchangeably herein refer to polymers of nucleotides of any length, including DNA and RNA. The nucleotide may be a deoxyribonucleotide, a ribonucleotide, a modified nucleotide or base, and/or an analogue thereof, or may be any substrate that can be incorporated into a polymer by a DNA or RNA polymerase.

In the context of two or more polynucleotides or polypeptides, the term "identity", percent "identity" and grammatical equivalents thereof, refers to two or more sequences or subsequences that are the same or have a specified percentage of the same nucleotide or amino acid residues, regardless of any conservative amino acid substitution, as part of sequence identity, when compared and aligned (introducing gaps, if necessary) to obtain maximum correspondence. The percentage of sequence may be measured using sequence comparison software or algorithms or by visual inspection. Various algorithms and software are well known in the art that can be used to obtain amino acid or nucleotide sequence alignments. Such algorithms or software include, but are not limited to BLAST, ALIGN, megalign, bestFit, GCG Wisconsin Package and variants thereof. In some embodiments, the two polynucleotides or polypeptides provided herein are substantially identical, meaning that they have at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, and in some embodiments at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% nucleotide or amino acid residue identity when compared and aligned using a sequence comparison algorithm or by visual inspection to obtain maximum correspondence. In some embodiments, identity exists over a region of the amino acid sequence that is at least about 10 residues in length, at least about 20 residues, at least about 40-60 residues, at least about 60-80 residues, or any integer value in between. In some embodiments, the identity exists over a region longer than 60-80 residues, such as at least about 80-100 residues, and in some embodiments, the sequences are substantially identical over the entire length of the compared sequences, such as the coding region of a protein or antibody of interest. In some embodiments, identity exists over a region of the nucleotide sequence that is at least about 10 bases in length, at least about 20 bases, at least about 40-60 bases, at least about 60-80 bases, or any integer value in between. In some embodiments, identity exists over a region longer than 60-80 bases, such as at least about 80-1000 bases or more, and in some embodiments, these sequences are substantially identical over the entire length of the sequences being compared (e.g., nucleotide sequences encoding the protein of interest).

The term "vector" and grammatical equivalents thereof as used herein refers to a vector for carrying genetic material (e.g., polynucleotide sequences) that can be introduced into a host cell where it can be replicated and/or expressed. Vectors that may be used include, for example, expression vectors, plasmids, phage vectors, viral vectors, episomes, and artificial chromosomes, which may include selection sequences or markers operable for stable integration into a host cell chromosome. In addition, the vector may include one or more selectable marker genes and appropriate expression control sequences. The selectable marker gene that may be included can, for example, provide resistance to antibiotics or toxins, supplement auxotrophs, or provide critical nutrients not present in the medium. The expression control sequences may include constitutive and inducible promoters, transcriptional enhancers, transcriptional terminators, and the like, as are known in the art. When two or more polynucleotides are to be co-expressed, both polynucleotides may be inserted, for example in a single expression vector or in separate expression vectors. For single vector expression, the encoded polynucleotides may be operably linked to a common expression control sequence, or may be linked to different expression control sequences, such as an inducible promoter and a constitutive promoter. The introduction of the polynucleotide into the host cell may be confirmed using methods well known in the art. Those of skill in the art understand that polynucleotides are expressed in sufficient amounts to produce the desired product (e.g., the invention described herein includes anti-CD 40BCMA antibodies or antigen binding fragments thereof), and further understand that expression levels can be optimized to obtain sufficient expression using methods well known in the art.

The term "chimeric antigen receptor" or "CAR" as used herein refers to an artificially constructed hybrid protein or polypeptide that contains a binding moiety (e.g., an antibody) linked to an immune cell (e.g., T cell) signaling or activation domain. In some embodiments, the CAR is a synthetic receptor capable of re-targeting T cells to tumor surface antigens (Sadelain et al, nat. Rev. Cancer.3 (1): 35-45 (2003); sadelain et al, cancer Discovery 3 (4): 388-398 (2013)). The CAR can provide antigen binding and immune cell activation functions to immune cells (e.g., T cells). CARs are able to utilize the antigen binding properties of monoclonal antibodies to redirect T cell specificity and reactivity to a selected target in a non-MHC-restricted manner. non-MHC-restricted antigen recognition can provide CAR-expressing T cells with antigen recognition capability independent of antigen processing, thereby avoiding tumor escape mechanisms.

The term "genetic engineering" or grammatical equivalents thereof, when used in reference to a cell, means a change in the genetic material of the cell that is not normally present in a naturally occurring cell. Genetic alterations include, for example, modifications that introduce expressible polynucleotides, other additions, mutations/alterations, deletions, and/or other functional disruptions of cellular genes. Such modifications may be made, for example, in the coding region of the gene and functional fragments thereof. Additional modifications may be made, for example, in non-coding regulatory regions, wherein the modifications alter the expression of the gene.

The terms "transfer," "transduction," "transfection," and grammatical equivalents thereof, as used herein, refer to the process of introducing an exogenous polynucleotide into a host cell. A "transferred," "transfected" or "transduced" cell refers to a cell that has been transferred, transduced or transfected with an exogenous polynucleotide. The cells include primary receptor cells and their progeny. The polynucleotide may be "transferred" into the host cell using any type of method known in the art, including chemical, physical, or biological methods. Polynucleotides are typically "transduced" into host cells using viruses. In contrast, polynucleotides are typically "transfected" into host cells using non-viral methods. These terms are sometimes used interchangeably and, when used in context, the meaning will be readily understood by one of ordinary skill in the art.

As used herein, the term "encoding" and grammatical equivalents thereof refers to the inherent nature of a particular nucleotide sequence in a polynucleotide or nucleic acid, such as a gene, cDNA or mRNA, that serves as a template for the synthesis of other polymers and macromolecules having the particular nucleotide sequence (i.e., rRNA, tRNA and mRNA) or a particular amino acid sequence, and the biological properties resulting therefrom, in a biological process. Thus, if transcription and translation of mRNA corresponding to the gene produces a protein, the gene encodes the protein. Unless otherwise indicated, a "nucleotide sequence encoding an amino acid sequence" includes all nucleotide sequences that are degenerate to each other or encode the same amino acid sequence. Nucleotide sequences encoding proteins and RNAs may include introns.

An "isolated" polypeptide, peptide, protein, antibody, polynucleotide, vector, cell, or composition is one that is not found in nature. Isolated polypeptides, proteins, antibodies, polynucleotides, vectors, cells or compositions include those that have been purified to such an extent that they are no longer in the form found in nature. In some embodiments, the isolated polypeptide, peptide, protein, antibody, polynucleotide, vector, cell, or composition is substantially purified.

As used herein and as understood in the art, an "immune effector cell" refers to a cell that has hematopoietic origin and plays a direct role in an immune response against a target (e.g., a pathogen, cancer cell, or foreign substance). Immune effector cells include T cells, B cells, natural Killer (NK) cells, NKT cells, macrophages, granulocytes, neutrophils, eosinophils, mast cells, and basophils.

The term "treatment" and grammatical equivalents thereof as used herein relates to a disease or disorder, or a subject suffering from a disease or disorder, that refers to an act of inhibiting, eliminating, alleviating, and/or ameliorating symptoms, severity of symptoms, and/or frequency of symptoms associated with the disease or disorder being treated. For example, when referring to a cancer or tumor, the term "treat" and grammatical equivalents thereof refers to the act of reducing the severity of the cancer or tumor, or slowing the progression of the cancer or tumor, including (a) inhibiting the growth or arresting the progression of the cancer or tumor, (b) causing regression of the cancer or tumor, or (c) slowing, ameliorating, or minimizing one or more symptoms associated with the presence of the cancer or tumor.

The term "administration" and grammatical equivalents thereof as used herein refers to the act of delivering or causing the delivery of a therapeutic agent or pharmaceutical composition to the body of a subject by methods described herein or other methods known in the art. The therapeutic agent may be a compound, polypeptide, cell, or cell population. Administering a therapeutic agent or pharmaceutical composition comprises prescribing delivery of a therapeutic agent or pharmaceutical composition into a subject. Typical forms of administration include oral dosage forms such as tablets, capsules, syrups, suspensions; injectable dosage forms such as Intravenous (IV), intramuscular (IM) or Intraperitoneal (IP); transdermal dosage forms, including creams, gels, powders or patches; oral dosage forms; inhalation powders, sprays, suspensions, and rectal suppositories.

The terms "effective amount," "therapeutically effective amount," and grammatical equivalents thereof, as used herein, refer to an amount of an agent administered to a subject, alone or as part of a pharmaceutical composition, in a single dose, or as part of a series of doses, that is capable of producing any detectable positive effect on any symptom, aspect, or feature of a disease, disorder, or condition upon administration. The therapeutically effective amount can be determined by measuring the relevant physiological effects. The exact amount required will vary from subject to subject, depending on the age, weight and general condition of the subject, the severity of the symptoms being treated, the judgment of the clinician, and the like. In any individual case, an appropriate "effective amount" can be determined by one of ordinary skill in the art using routine experimentation.

The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to a material suitable for administration to an individual with an active agent without causing adverse biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition.

The term "subject" as used herein refers to any animal (e.g., mammal), including but not limited to humans, non-human primates, dogs, felines, rodents, etc., which is an animal to be treated specifically. The subject may be a human. The subject may be a patient suffering from a particular disease or disorder.

The term "autologous" as used herein refers to any material that is derived from the same individual and subsequently reintroduced into that individual.

The term "variant" as used herein refers to grafts derived from different individuals of the same species.

The range is as follows: throughout this disclosure, various aspects of the invention may be presented in a range format. It should be understood that the description of the range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention.

Accordingly, the description of a range should be considered to have specifically disclosed all possible sub-ranges as well as individual values within that range. For example, a description of a range from 1 to 6 should be considered to have disclosed subranges such as from 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within the range, e.g., 1, 2, 2.7, 3, 4, 5, 5.3, and 6. Regardless of the breadth of the range, is applicable thereto.

Exemplary genes and polypeptides are described herein with reference to GenBank accession numbers, GI accession numbers, and/or SEQ ID NOs. It will be appreciated that homologous sequences can be readily identified by those skilled in the art by reference to sequence sources including, but not limited to, genBank (ncbi.lm.nih.gov/GenBank /) and EMBL (EMBL org /).

5.2 anti-BCMA antibodies and antigen binding fragments

The present invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA). In some embodiments, the invention provides anti-BCMA antibodies. In some embodiments, the antibody is a IgA, igD, igE, igG or IgM antibody. In some embodiments, the antibody is an IgA antibody. In some embodiments, the antibody is an IgD antibody. In some embodiments, the antibody is an IgE antibody. In some embodiments, the antibody is an IgG antibody. In some embodiments, the antibody is an IgM antibody. In some embodiments, the antibodies provided herein can be IgG1 antibodies, igG2 antibodies, igG3 antibodies, or IgG4 antibodies. In some embodiments, the antibody is an IgG1 antibody. In some embodiments, the antibody is an IgG2 antibody. In some embodiments, the antibody is an IgG3 antibody. In some embodiments, the antibody is an IgG4 antibody.

In some embodiments, the invention provides antigen binding fragments of anti-BCMA antibodies. In some embodiments, the antigen binding fragments provided herein can be single domain antibodies (sdabs), heavy chain antibodies (hcabs), fab ', F (ab') ₂ Fv, single chain variable fragment (scFv) or (scFv) ₂ . In some embodiments, the antigen binding fragment of the anti-BCMA antibody is a single domain antibody (sdAb). In some embodiments, the antigen binding fragment of the anti-BCMA antibody is a heavy chain antibody (HCAb). In some embodiments, the antigen binding fragment of the anti-BCMA antibody is a Fab. In some embodiments, the antigen binding fragment of the anti-BCMA antibody is Fab'. In some embodiments, the antigen binding fragment of the anti-BCMA antibody is F (ab') ₂ . In some embodiments, the antigen binding fragment of the anti-BCMA antibody is an Fv. In some embodiments, the antigen binding fragment of the anti-BCMA antibody is an scFv. In some embodiments, the antigen binding fragment of the anti-BCMA antibody is a disulfide-linked scFv [ (scFv) ₂ ]. In some embodiments, the antigen binding fragment of the anti-BCMA antibody is a bispecific antibody (dAb).

In some embodiments, the anti-BCMA antibodies or antigen binding fragments provided herein include recombinant antibodies or antigen binding fragments. In some embodiments, the anti-BCMA antibodies or antigen binding fragments provided herein include monoclonal antibodies or antigen binding fragments. In some embodiments, the anti-BCMA antibodies or antigen binding fragments provided herein include polyclonal antibodies or antigen binding fragments. In some embodiments, the anti-BCMA antibodies or antigen binding fragments provided herein include camelidae (e.g., camel, dromedary, and llama) antibodies or antigen binding fragments. In some embodiments, the anti-BCMA antibodies or antigen binding fragments provided herein include chimeric antibodies or antigen binding fragments. In some embodiments, the anti-BCMA antibodies or antigen binding fragments provided herein include humanized antibodies or antigen binding fragments. In some embodiments, the anti-BCMA antibodies or antigen binding fragments provided herein comprise human antibodies or antigen binding fragments. In some embodiments, the invention provides a human scFv against BCMA.

In some embodiments, the anti-BCMA antibodies or antigen binding fragments provided herein are isolated antibodies or antigen binding fragments. In some embodiments, the anti-BCMA antibodies or antigen binding fragments provided herein are substantially purified.

In some embodiments, the anti-BCMA antibodies or antigen binding fragments provided herein include multispecific antibodies or antigen binding fragments. In some embodiments, the anti-BCMA antibodies or antigen binding fragments provided herein include bispecific antibodies or antigen binding fragments. In some embodiments, the invention provides a bispecific T cell engager (BiTE). BiTE is a bispecific antibody that binds to T cell antigens (e.g., CD 3) and tumor antigens. BiTE has been demonstrated to induce directed lysis of targeted tumor cells, providing a tremendous potential therapy for cancer and other diseases. In some embodiments, the invention provides BiTE that specifically binds CD3 and BCMA. In some embodiments, the BiTE comprises an anti-BCMA antibody or antigen binding fragment provided herein. In some embodiments, the BiTE comprises an scFv against BCMA provided herein.

In some embodiments, the anti-BCMA antibodies or antigen binding fragments provided herein comprise a monovalent antigen binding site. In some embodiments, the anti-BCMA antibody or antigen binding fragment comprises a monospecific binding site. In some embodiments, the anti-BCMA antibody or antigen binding fragment comprises a bivalent binding site.

In some embodiments, the anti-BCMA antibody or antigen binding fragment is a monoclonal antibody or antigen binding fragment. Monoclonal antibodies may be prepared by any method known to those skilled in the art. One exemplary method is to screen a protein expression library, such as a phage or ribosome display library. Phage display is described, for example, in Ladner et al, U.S. Pat. nos. 5,223,409; smith (1985) Science 228:1315-1317; and WO 92/18619. In some embodiments, the recombinant monoclonal antibodies are isolated from phage display libraries capable of expressing variable regions or CDRs of the desired species. Screening of phage libraries can be accomplished by a variety of techniques known in the art.

In some embodiments, monoclonal antibodies are prepared using hybridoma methods known to those skilled in the art. For example, mice, rats, rabbits, hamsters or other suitable host animals are immunized as described above using a hybridoma method. In some embodiments, the lymphocyte is immunized in vitro. In some embodiments, the immune antigen is a human protein or fragment thereof. In some embodiments, the immune antigen is a human protein or fragment thereof.

Following immunization, lymphocytes are isolated and fused with a suitable myeloma cell line using, for example, polyethylene glycol. Hybridoma cells were selected using a dedicated medium known in the art, unfused lymphocytes and myeloma cells being unable to survive the selection process. Hybridomas producing monoclonal antibodies to the selected antigen can be identified by a variety of methods, including, but not limited to, immunoprecipitation, immunoblotting, and in vitro binding assays (e.g., flow cytometry, FACS, ELISA, SPR (e.g., biacore), and radioimmunoassay). Once hybridoma cells that produce antibodies of the desired specificity, affinity, and/or activity are identified, the clones can be subcloned by limiting dilution or other techniques. Hybridomas can be propagated in vitro culture using standard methods, and can also be propagated in vivo as animal ascites tumors. The monoclonal antibodies may be purified from the culture medium or ascites fluid according to methods standard in the art, including but not limited to, affinity chromatography, ion exchange chromatography, gel electrophoresis, and dialysis.

In some embodiments, monoclonal antibodies are prepared using recombinant DNA techniques known to those skilled in the art. For example, polynucleotides encoding antibodies are isolated from mature B cells or hybridoma cells, and the genes encoding the heavy and light chains of the antibodies are specifically amplified by, for example, RT-PCR using oligonucleotide primers and their sequences are determined using standard techniques. The isolated polynucleotides encoding the heavy and light chains are then cloned into suitable expression vectors that produce monoclonal antibodies when transfected into host cells such as e.coli, simian COS cells, chinese Hamster Ovary (CHO) cells, or myeloma cells, which otherwise do not produce immunoglobulins.

In some embodiments, the monoclonal antibody is modified by using recombinant DNA techniques to produce an alternative antibody. In some embodiments, the light and heavy chain constant regions of the mouse monoclonal antibody are replaced with the constant regions of the human antibody to generate a chimeric antibody. In some embodiments, the constant region is truncated or removed to generate an antibody fragment of the desired monoclonal antibody. In some embodiments, site-directed or high-density mutations in the variable regions are used to optimize the specificity and/or affinity of the monoclonal antibody.

In some embodiments, the anti-BCMA antibody or antigen binding fragment is a humanized antibody or antigen binding fragment. Various methods of preparing humanized antibodies are known in the art. Methods for achieving high affinity binding to humanized antibodies are known in the art. One non-limiting example of such a method is the hypermutation of the variable region and the selection of cells expressing such high affinity antibodies (affinity maturation). In addition to using a display library, specific antigens (e.g., recombinant BCMA or epitopes thereof) can be used to immunize non-human animals, such as rodents. In certain embodiments, rodent antigen-binding fragments (e.g., mouse antigen-binding fragments) can be prepared and isolated using methods known in the art and/or disclosed herein. In some embodiments, the mice can be immunized with an antigen (e.g., recombinant BCMA or an epitope thereof).

In some embodiments, the anti-BCMA antibody or antigen binding fragment is a human antibody or antigen binding fragment. Human antibodies can be prepared using a variety of techniques known in the art. In some embodiments, the human antibody is produced by an immortalized human B lymphocyte immunized in vitro. In some embodiments, the human antibody is produced by lymphocytes isolated from an immunized individual. In any case, antibody-producing cells can be prepared and isolated, the antibody being directed against the target antigen. In some embodiments, the human antibody is selected from a phage library, wherein the phage library expresses the human antibody. Alternatively, phage display technology can be used to produce human antibodies and antibody fragments in vitro, from immunoglobulin variable region gene libraries of non-immunized donors. Techniques for generating and using antibody phage libraries are well known in the art. Once the antibodies are identified, affinity maturation techniques known in the art can be used to generate higher affinity human antibodies, including but not limited to chain replacement and site-directed mutagenesis. In some embodiments, the human antibodies are produced in transgenic mice containing human immunoglobulin loci. After immunization, these mice were able to produce fully human antibodies without endogenous immunoglobulin production.

The specific CDR sequences defined in the present invention are generally based on a combination of Kabat and Chothia definitions. However, it is understood that references to one or more heavy chain CDRs, and/or one or more light chain CDRs, of a specific antibody include all CDR definitions known to those of skill in the art.

The anti-BCMA antibodies or antigen binding fragments provided by the invention include the following clones: BCMA21, BCMA22, BCMA23, BCMA24, BCMA27, BCMA28, BCMA30, BCMA31, BCMA32, BCMA33, BCMA34, and BCMA35. The sequence features are as follows.

In some embodiments, the anti-BCMA antibodies or antigen binding fragments provided herein comprise one, two, three, four, five, and/or six CDRs in any one of the antibodies described herein. In some embodiments, an anti-BCMA antibody or antigen binding fragment provided by the present invention includes a VL comprising one, two, and/or three VL CDRs in table 1. In some embodiments, an anti-BCMA antibody or antigen binding fragment provided by the present invention comprises a VH comprising one, two, and/or three VH CDRs in table 2. In some embodiments, the anti-BCMA antibodies or antigen binding fragments provided herein include one, two, and/or three VL CDRs from table 1 and one, two, and/or three VH CDRs from table 2.

TABLE 1 amino acid sequence of the light chain variable region CDR (VL CDR) of anti-BCMA Abs

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TABLE 2 amino acid sequences of heavy chain variable region CDRs (VH CDRs) of BCMA Abs

In some embodiments, the anti-BCMA antibody or antigen binding fragment thereof comprises a humanized antibody or antigen binding fragment. In some embodiments, an anti-BCMA antibody or antigen binding fragment thereof comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and/or a VH CDR3 of an antibody or antigen binding fragment of the invention. In some embodiments, an anti-BCMA antibody or antigen binding fragment thereof comprises variants of the antibodies or antigen binding fragments described herein. In some embodiments, the variants of the anti-BCMA antibody or antigen binding fragment include substitutions, additions, and/or deletions of 1 to 30 amino acids in the anti-BCMA antibody or antigen binding fragment. In some embodiments, the variants of the anti-BCMA antibody or antigen binding fragment include substitutions, additions, and/or deletions of 1 to 25 amino acids in the anti-BCMA antibody or antigen binding fragment. In some embodiments, the variants of the anti-BCMA antibody or antigen binding fragment include substitutions, additions, and/or deletions of 1 to 20 amino acids in the anti-BCMA antibody or antigen binding fragment. In some embodiments, the variants of the anti-BCMA antibody or antigen binding fragment include substitutions, additions, and/or deletions of 1 to 15 amino acids in the anti-BCMA antibody or antigen binding fragment. In some embodiments, the variants of the anti-BCMA antibody or antigen binding fragment include substitutions, additions, and/or deletions of 1 to 10 amino acids in the anti-BCMA antibody or antigen binding fragment. In some embodiments, the variants of the anti-BCMA antibody or antigen binding fragment include substitutions, additions, and/or deletions of 1 to 5 conserved amino acids in the anti-BCMA antibody or antigen binding fragment. In some embodiments, the variants of the anti-BCMA antibody or antigen binding fragment include substitutions, additions, and/or deletions of 1 to 3 amino acids in the anti-BCMA antibody or antigen binding fragment. In some embodiments, the amino acid substitutions, additions and/or deletions are conservative amino acid substitutions. In some embodiments, the conservative amino acid substitutions are located in CDRs of the antibody or antigen binding fragment. In some embodiments, the conservative amino acid substitutions are not in the CDRs of the antibody or antigen binding fragment. In some embodiments, the conservative amino acid substitutions are located in the framework region of the antibody or antigen binding fragment.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA), comprising a light chain variable region (VL) comprising (1) a light chain CDR1 (VL CDR 1) having an amino acid sequence selected from the group consisting of SEQ ID NOs 1-10; (2) A light chain CDR2 (VL CDR 2) having an amino acid sequence selected from the group consisting of SEQ ID NOS 11-21; or (3) a light chain CDR3 (VL CDR 3) having an amino acid sequence selected from the group consisting of SEQ ID NOS: 22-32; or a variant thereof having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and/or deletions in the VL CDRs. In some embodiments, the variants have about 5 amino acid substitutions, additions and/or deletions in the VL CDRs.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA), comprising VL comprising (1) VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs 1-10; (2) VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOS.11-21; and (3) VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOS.22-32; or a variant thereof having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and/or deletions in the VL CDRs. In some embodiments, the variants have up to about 5 amino acid substitutions, additions and/or deletions in the VL CDRs.

In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) comprising a heavy chain variable region (VH) comprising (1) a heavy chain CDR1 (VH CDR 1) having an amino acid sequence selected from the group consisting of SEQ ID NOs 33-43; (2) Heavy chain CDR2 (VH CDR 2) having an amino acid sequence selected from the group consisting of SEQ ID NOS 44-55; or (3) a heavy chain CDR3 (VH CDR 3) having an amino acid sequence selected from the group consisting of SEQ ID NOS: 56-67; or a variant thereof having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions, and/or deletions in the VH CDRs. In some embodiments, the variants have up to about 5 amino acid substitutions, additions and/or deletions in the VH CDRs.

In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) comprising a VH comprising (1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs 33-43; (2) VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs 44-55; and (3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 56-67; or a variant thereof having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and/or deletions in the VH CDRs. In some embodiments, the variants have up to about 5 amino acid substitutions, additions and/or deletions in the VH CDRs.

In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) comprising (a) a VL comprising (1) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs 1-10; (2) VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOS.11-21; and (3) VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOS.22-32; or a variant thereof having up to about 5 amino acid substitutions, additions and/or deletions; and (b) a VH comprising (1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs 33-43; (2) VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs 44-55; and (3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 56-67; or a variant thereof having up to about 5 amino acid substitutions, additions and/or deletions in the VH CDRs.

In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) having a VL, wherein said VL comprises VL CDR1, CDR2, and CDR3, said VL CDR1, CDR2, and CDR3 having the amino acid sequences shown in (1) SEQ ID NOs 1, 11, and 22, respectively; (2) the amino acid sequences shown in SEQ ID NOs 2, 12 and 23; (3) the amino acid sequences shown in SEQ ID NOs 3, 13 and 24; (4) the amino acid sequences shown in SEQ ID NOS.4, 14 and 24; (5) the amino acid sequences shown in SEQ ID NOs 5, 15 and 25;

(6) Amino acid sequences shown in SEQ ID NOS.6, 16 and 26; (7) the amino acid sequences shown in SEQ ID NOS.7, 17 and 27; (8) the amino acid sequences shown in SEQ ID NOS.8, 18 and 28; (9) the amino acid sequences shown in SEQ ID NOS.2, 19 and 29; (10) the amino acid sequences shown in SEQ ID NOs 2, 20 and 30; (11) the amino acid sequences shown in SEQ ID NOS.9, 21 and 31; or (12) the amino acid sequences shown in SEQ ID NOS 10, 14 and 32; or a variant thereof having up to about 3, 5, 8, 10, 12, or 15 amino acid substitutions, additions, and/or deletions in the VL CDRs. In some embodiments, the variants have up to about 5 amino acid substitutions, additions and/or deletions in the VL CDRs.

In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) having a VH, wherein said VH comprises VH CDR1, CDR2, and CDR3, said VH CDR1, CDR2, and CDR3 having the amino acid sequences shown in (1) SEQ ID NOs 33, 44, and 56, respectively; (2) the amino acid sequences shown in SEQ ID NOS.34, 45 and 57; (3) the amino acid sequences shown in SEQ ID NOs 35, 46 and 58;

(4) The amino acid sequences shown in SEQ ID NOS.36, 47 and 59; (5) the amino acid sequences shown in SEQ ID NOS.37, 48 and 60; (6) the amino acid sequences shown in SEQ ID NOS.38, 49 and 61; (7) the amino acid sequences shown in SEQ ID NOS.35, 50 and 62; (8) the amino acid sequences shown in SEQ ID NOS: 39, 51 and 63; (9) the amino acid sequences shown in SEQ ID NOS.40, 52 and 64; (10) the amino acid sequences shown in SEQ ID NOS.41, 53 and 65; (11) the amino acid sequences shown in SEQ ID NOS.42, 54 and 66; or (12) the amino acid sequences shown in SEQ ID NOS.43, 55 and 67; or a variant thereof having up to about 3, 5, 8, 10, 12 or 15 amino acid substitutions, additions and/or deletions in the VH CDRs. In some embodiments, the variants have up to about 5 amino acid substitutions, additions and/or deletions in the VH CDRs.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having VL and VH. In some embodiments, the VL and VH are linked by a linker. The connector may be a flexible connector or a rigid connector. In some embodiments, the linker has an amino acid sequence of (GGGGS) n, n=1, 2, 3, 4, or 5 (SEQ ID NO: 155). In some embodiments, the linker has an amino acid sequence of (EAAAK) n, n=1, 2, 3, 4, or 5 (SEQ ID NO: 156). In some embodiments, the linker has an amino acid sequence of (PA) nP, n=1, 2, 3, 4, or 5 (SEQ ID NO: 157). In some embodiments, the linker has the amino acid sequence of GGGGSGGGGSGGGGS (SEQ ID NO: 158).

In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) having VL and VH, wherein (a) the VL comprises VL CDR1, CDR2, and CDR3, the VL CDR1, CDR2, and CDR3 having (1) the amino acid sequences shown in SEQ ID NOs 1, 11, and 22, respectively; (2) the amino acid sequences shown in SEQ ID NOs 2, 12 and 23; (3) the amino acid sequences shown in SEQ ID NOs 3, 13 and 24; (4) the amino acid sequences shown in SEQ ID NOS.4, 14 and 24; (5) the amino acid sequences shown in SEQ ID NOs 5, 15 and 25; (6) the amino acid sequences shown in SEQ ID NOS.6, 16 and 26; (7) the amino acid sequences shown in SEQ ID NOS.7, 17 and 27; (8) the amino acid sequences shown in SEQ ID NOS.8, 18 and 28; (9) the amino acid sequences shown in SEQ ID NOS.2, 19 and 29; (10) the amino acid sequences shown in SEQ ID NOs 2, 20 and 30; (11) the amino acid sequences shown in SEQ ID NOS.9, 21 and 31; or (12) the amino acid sequences shown in SEQ ID NOS 10, 14 and 32; or a variant thereof having up to about 5 amino acid substitutions, additions and/or deletions in the VL CDRs; and (b) the VH comprises VH CDR1, CDR2 and CDR3, the VH CDR1, CDR2 and CDR3 having the amino acid sequences set forth in (1) SEQ ID NOs 33, 44 and 56, respectively; (2) the amino acid sequences set forth in SEQ ID NOS.34, 45 and 57; (3) the amino acid sequences set forth in SEQ ID NOs 35, 46 and 58; (4) the amino acid sequences shown in SEQ ID NOS.36, 47 and 59; (5) the amino acid sequences shown in SEQ ID NOS.37, 48 and 60; (6) the amino acid sequences shown in SEQ ID NOS.38, 49 and 61; (7) the amino acid sequences shown in SEQ ID NOS.35, 50 and 62; (8) the amino acid sequences shown in SEQ ID NOS: 39, 51 and 63; (9) the amino acid sequences shown in SEQ ID NOS.40, 52 and 64; (10) the amino acid sequences shown in SEQ ID NOS.41, 53 and 65; (11) the amino acid sequences shown in SEQ ID NOS.42, 54 and 66; or (12) the amino acid sequences shown in SEQ ID NOS.43, 55 and 67; or a variant thereof having up to about 5 amino acid substitutions, additions and/or deletions in the VH CDRs.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having VL and VH, wherein the VL comprises VL CDR1, CDR2, and CDR3, and the VH comprises VH CDR1, CDR2, and CDR3, wherein the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 have the amino acid sequences shown in (1) SEQ ID NOs 1, 11, 22, 33, 44, and 56, respectively; (2) Amino acid sequences shown in SEQ ID NOs 2, 12, 23, 34, 45 and 57; (3) Amino acid sequences shown in SEQ ID NOs 3, 13, 24, 35, 46 and 58; (4) Amino acid sequences shown in SEQ ID NOs 4, 14, 24, 36, 47 and 59;

(5) Amino acid sequences shown in SEQ ID NOs 5, 15, 25, 37, 48 and 60; (6) Amino acid sequences shown in SEQ ID NOS.6, 16, 26, 38, 49 and 61; (7) Amino acid sequences shown in SEQ ID NOs 7, 17, 27, 35, 50 and 62; (8) Amino acid sequences shown in SEQ ID NOS 8, 18, 28, 39, 51 and 63; (9) Amino acid sequences shown in SEQ ID NOs 2, 19, 29, 40, 52 and 64; (10) Amino acid sequences shown in SEQ ID NOs 2, 20, 30, 41, 53 and 65; (11) Amino acid sequences shown in SEQ ID NOs 9, 21, 31, 42, 54 and 66; or (12) the amino acid sequences shown in SEQ ID Nos. 10, 14, 32, 43, 55 and 67; or variants thereof having up to about 5 amino acid substitutions, additions and/or deletions in these CDRs.

In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) having a VL comprising (1) VL CDR1 having the amino acid sequence shown in SEQ ID No. 1; (2) VL CDR2 having the amino acid sequence shown in SEQ ID NO. 11, or (3) VL CDR3 having the amino acid sequence shown in SEQ ID NO. 22. The VL may have a VL CDR1, a VL CDR2 and a VL CDR3, the VL CDR1, the VL CDR2 and the VL CDR3 having the amino acid sequences shown in SEQ ID NOS 1, 11 and 22, respectively. In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) having a VH comprising (1) a VH CDR1 having the amino acid sequence shown in SEQ ID No. 33; (2) A VH CDR2 having the amino acid sequence shown in SEQ ID NO 44; or (3) a VH CDR3 having the amino acid sequence shown in SEQ ID NO: 56. The VH may have a VH CDR1, a VH CDR2 and a VH CDR3, the VH CDR1, VH CDR2 and VH CDR3 having the amino acid sequences shown in SEQ ID NOs 33, 44 and 56 respectively. In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA), comprising (a) a VL comprising VL CDR1, VL CDR2, and VL CDR3, the VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences shown in SEQ ID NOs 1, 11, and 22, respectively; and (b) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3, said VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences set forth in SEQ ID NOs 33, 44, and 56, respectively.

In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) having a VL comprising (1) a VL CDR1 having the amino acid sequence shown in SEQ ID No. 2, (2) a VL CDR2 having the amino acid sequence shown in SEQ ID No. 12, or (3) a VL CDR3 having the amino acid sequence shown in SEQ ID No. 23. The VL may have a VL CDR1, a VL CDR2 and a VL CDR3, the VL CDR1, the VL CDR2 and the VL CDR3 having the amino acid sequences shown in SEQ ID NOS 2, 12 and 23, respectively. In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) having a VH comprising (1) a VH CDR1 having the amino acid sequence shown in SEQ ID No. 34; (2) A VH CDR2 having the amino acid sequence shown in SEQ ID NO. 45; or (3) a VH CDR3 having the amino acid sequence shown in SEQ ID NO 57. The VH may have a VH CDR1, a VH CDR2 and a VH CDR3, the VH CDR1, VH CDR2 and VH CDR3 having the amino acid sequences shown in SEQ ID NOs 34, 45 and 57 respectively. In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) comprising (a) a VL comprising VL CDR1, VL CDR2, and VL CDR3, said VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences shown in SEQ ID NOs 2, 12, and 23, respectively; and (b) a VH comprising a VH CDR1, a VH CDR2 and a VH CDR3, said VH CDR1, VH CDR2 and VH CDR3 having the amino acid sequences shown in SEQ ID NOS 34, 45 and 57 respectively.

In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) having a VL comprising (1) a VL CDR1 having the amino acid sequence shown in SEQ ID No. 3, (2) a VL CDR2 having the amino acid sequence shown in SEQ ID No. 13, or (3) a VL CDR3 having the amino acid sequence shown in SEQ ID No. 24. The VL may have a VL CDR1, a VL CDR2 and a VL CDR3, the VL CDR1, the VL CDR2 and the VL CDR3 having the amino acid sequences shown in SEQ ID NOS 3, 13 and 24, respectively. In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) having a VH comprising (1) a VH CDR1 having the amino acid sequence shown in SEQ ID No. 35; (2) A VH CDR2 having the amino acid sequence shown in SEQ ID NO. 46; or (3) a VH CDR3 having the amino acid sequence shown in SEQ ID NO 58. The VH may have a VH CDR1, a VH CDR2 and a VH CDR3, the VH CDR1, VH CDR2 and VH CDR3 having the amino acid sequences shown in SEQ ID NOs 35, 46 and 58 respectively. In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA), comprising (a) a VL comprising VL CDR1, VL CDR2, and VL CDR3, the VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences shown in SEQ ID NOs 3, 13, and 24, respectively; and (b) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3, said VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences set forth in SEQ ID NOs 35, 46, and 58, respectively.

In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) having a VL comprising (1) a VL CDR1 having the amino acid sequence shown in SEQ ID No. 4, (2) a VL CDR2 having the amino acid sequence shown in SEQ ID No. 14, or (3) a VL CDR3 having the amino acid sequence shown in SEQ ID No. 24. The VL may have a VL CDR1, a VL CDR2 and a VL CDR3, the VL CDR1, the VL CDR2 and the VL CDR3 having the amino acid sequences shown in SEQ ID NOS 4, 14 and 24, respectively. In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) having a VH comprising (1) a VH CDR1 having the amino acid sequence shown in SEQ ID No. 36; (2) A VH CDR2 having the amino acid sequence shown in SEQ ID NO. 47; or (3) a VH CDR3 having the amino acid sequence shown in SEQ ID NO 59. The VH may have a VH CDR1, a VH CDR2 and a VH CDR3, the VH CDR1, VH CDR2 and VH CDR3 having the amino acid sequences shown in SEQ ID NO's 36, 47 and 59 respectively. In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA), comprising (a) a VL comprising VL CDR1, VL CDR2, and VL CDR3, the VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences shown in SEQ ID NOs 4, 14, and 24, respectively; and (b) a VH comprising a VH CDR1, a VH CDR2 and a VH CDR3, said VH CDR1, VH CDR2 and VH CDR3 having the amino acid sequences shown in SEQ ID NO's 36, 47 and 59 respectively.

In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) having a VL comprising (1) a VL CDR1 having the amino acid sequence shown in SEQ ID No. 5, (2) a VL CDR2 having the amino acid sequence shown in SEQ ID No. 15, or (3) a VL CDR3 having the amino acid sequence shown in SEQ ID No. 25. The VL may have a VL CDR1, a VL CDR2 and a VL CDR3, the VL CDR1, the VL CDR2 and the VL CDR3 having the amino acid sequences shown in SEQ ID NOS 5, 15 and 25, respectively. In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) having a VH comprising (1) a VH CDR1 having the amino acid sequence shown in SEQ ID No. 37;

(2) A VH CDR2 having the amino acid sequence shown in SEQ ID NO. 48; or (3) a VH CDR3 having the amino acid sequence shown in SEQ ID NO: 60. The VH may have a VH CDR1, a VH CDR2 and a VH CDR3, the VH CDR1, VH CDR2 and VH CDR3 having the amino acid sequences shown in SEQ ID NO 37, 48 and 60 respectively. In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA), comprising (a) a VL comprising VL CDR1, VL CDR2, and VL CDR3, the VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences shown in SEQ ID NOs 5, 15, and 25, respectively; and (b) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3, said VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences set forth in SEQ ID NOs 37, 48, and 60, respectively.

In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) having a VL comprising (1) a VL CDR1 having the amino acid sequence shown in SEQ ID No. 6, (2) a VL CDR2 having the amino acid sequence shown in SEQ ID No. 16, or (3) a VL CDR3 having the amino acid sequence shown in SEQ ID No. 26. The VL may have a VL CDR1, a VL CDR2 and a VL CDR3, the VL CDR1, the VL CDR2 and the VL CDR3 having the amino acid sequences shown in SEQ ID NOS 6, 16 and 26, respectively. In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) having a VH comprising (1) a VH CDR1 having the amino acid sequence shown in SEQ ID No. 38; (2) A VH CDR2 having the amino acid sequence shown in SEQ ID No. 49; or (3) a VH CDR3 having the amino acid sequence shown in SEQ ID NO. 61. The VH may have a VH CDR1, a VH CDR2 and a VH CDR3, the VH CDR1, VH CDR2 and VH CDR3 having the amino acid sequences shown in SEQ ID NO's 38, 49 and 61 respectively. In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA), comprising (a) a VL comprising VL CDR1, VL CDR2, and VL CDR3, the VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences shown in SEQ ID NOs 6, 16, and 26, respectively; and (b) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3, said VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences set forth in SEQ ID NOs 38, 49, and 61, respectively.

In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) having a VL comprising (1) a VL CDR1 having the amino acid sequence shown in SEQ ID No. 7, (2) a VL CDR2 having the amino acid sequence shown in SEQ ID No. 17, or (3) a VL CDR3 having the amino acid sequence shown in SEQ ID No. 27. The VL may have a VL CDR1, a VL CDR2 and a VL CDR3, the VL CDR1, the VL CDR2 and the VL CDR3 having the amino acid sequences shown in SEQ ID NOS 7, 17 and 27, respectively. In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) having a VH comprising (1) a VH CDR1 having the amino acid sequence shown in SEQ ID No. 35; (2) A VH CDR2 having the amino acid sequence shown in SEQ ID NO. 50; or (3) a VH CDR3 having the amino acid sequence shown in SEQ ID NO. 62. The VH may have a VH CDR1, a VH CDR2 and a VH CDR3, the VH CDR1, VH CDR2 and VH CDR3 having the amino acid sequences shown in SEQ ID NOs 35, 50 and 62 respectively. In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA), comprising (a) a VL comprising VL CDR1, VL CDR2, and VL CDR3, the VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences shown in SEQ ID NOs 7, 17, and 27, respectively; and (b) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3, said VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences set forth in SEQ ID NOs 35, 50, and 62, respectively.

In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) having a VL comprising (1) a VL CDR1 having the amino acid sequence shown in SEQ ID No. 8, (2) a VL CDR2 having the amino acid sequence shown in SEQ ID No. 18, or (3) a VL CDR3 having the amino acid sequence shown in SEQ ID No. 28. The VL may have a VL CDR1, a VL CDR2 and a VL CDR3, the VL CDR1, the VL CDR2 and the VL CDR3 having the amino acid sequences shown in SEQ ID NOS 8, 18 and 28, respectively. In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) having a VH comprising (1) a VH CDR1 having the amino acid sequence shown in SEQ ID No. 39; (2) A VH CDR2 having the amino acid sequence shown in SEQ ID NO. 51; or (3) a VH CDR3 having the amino acid sequence shown in SEQ ID NO. 63. The VH may have a VH CDR1, a VH CDR2 and a VH CDR3, the VH CDR1, VH CDR2 and VH CDR3 having the amino acid sequences shown in SEQ ID NO 39, 51 and 63 respectively. In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA), comprising (a) a VL comprising VL CDR1, VL CDR2, and VL CDR3, the VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences shown in SEQ ID NOs 8, 18, and 28, respectively; and (b) a VH comprising a VH CDR1, a VH CDR2 and a VH CDR3, said VH CDR1, VH CDR2 and VH CDR3 having the amino acid sequences shown in SEQ ID NOs 39, 51 and 63, respectively.

In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) having a VL comprising (1) a VL CDR1 having the amino acid sequence shown in SEQ ID No. 2, (2) a VL CDR2 having the amino acid sequence shown in SEQ ID No. 19, or (3) a VL CDR3 having the amino acid sequence shown in SEQ ID No. 29. The VL may have a VL CDR1, a VL CDR2 and a VL CDR3, the VL CDR1, the VL CDR2 and the VL CDR3 having the amino acid sequences shown in SEQ ID NOS 2, 19 and 29, respectively. In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) having a VH comprising (1) a VH CDR1 having the amino acid sequence shown in SEQ ID No. 40; (2) A VH CDR2 having the amino acid sequence shown in SEQ ID NO. 52; or (3) a VH CDR3 having the amino acid sequence shown in SEQ ID NO. 64. The VH may have a VH CDR1, a VH CDR2 and a VH CDR3, the VH CDR1, VH CDR2 and VH CDR3 having the amino acid sequences shown in SEQ ID NO's 40, 52 and 64 respectively. In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA), comprising (a) a VL comprising VL CDR1, VL CDR2, and VL CDR3, the VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences shown in SEQ ID NOs 2, 19, and 29, respectively; and (b) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3, said VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences set forth in SEQ ID NOs 40, 52, and 64, respectively.

In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) having a VL comprising (1) a VL CDR1 having the amino acid sequence shown in SEQ ID No. 2, (2) a VL CDR2 having the amino acid sequence shown in SEQ ID No. 20, or (3) a VL CDR3 having the amino acid sequence shown in SEQ ID No. 30. The VL may have a VL CDR1, a VL CDR2 and a VL CDR3, the VL CDR1, the VL CDR2 and the VL CDR3 having the amino acid sequences shown in SEQ ID NOS 2, 20 and 30, respectively. In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) having a VH comprising (1) a VH CDR1 having the amino acid sequence shown in SEQ ID No. 41; (2) A VH CDR2 having the amino acid sequence shown in SEQ ID NO 53; or (3) a VH CDR3 having the amino acid sequence shown in SEQ ID NO. 65. The VH may have a VH CDR1, a VH CDR2 and a VH CDR3, the VH CDR1, the VH CDR2 and the VH CDR3 having the amino acid sequences shown in SEQ ID NOs 41, 53 and 65 respectively. In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA), comprising (a) a VL comprising VL CDR1, VL CDR2, and VL CDR3, the VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences shown in SEQ ID NOs 2, 20, and 30, respectively; and (b) a VH comprising a VH CDR1, a VH CDR2 and a VH CDR3, said VH CDR1, VH CDR2 and VH CDR3 having the amino acid sequences shown in SEQ ID NOS 41, 53 and 65 respectively.

In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) having a VL comprising (1) a VL CDR1 having the amino acid sequence shown in SEQ ID No. 9, (2) a VL CDR2 having the amino acid sequence shown in SEQ ID No. 21, or (3) a VL CDR3 having the amino acid sequence shown in SEQ ID No. 31. The VL may have a VL CDR1, a VL CDR2 and a VL CDR3, the VL CDR1, the VL CDR2 and the VL CDR3 having the amino acid sequences shown in SEQ ID NOS 9, 21 and 31, respectively. In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) having a VH comprising (1) a VH CDR1 having the amino acid sequence shown in SEQ ID No. 42; (2) A VH CDR2 having the amino acid sequence shown in SEQ ID NO. 54; or (3) a VH CDR3 having the amino acid sequence shown in SEQ ID NO: 66. The VH may have a VH CDR1, a VH CDR2 and a VH CDR3, the VH CDR1, VH CDR2 and VH CDR3 having the amino acid sequences shown in SEQ ID NOs 42, 54 and 66 respectively. In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA), comprising (a) a VL comprising VL CDR1, VL CDR2, and VL CDR3, said VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences shown in SEQ ID NOs 9, 21, and 31, respectively; and (b) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3, said VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences set forth in SEQ ID NOs 42, 54, and 66, respectively.

In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) having a VL comprising (1) a VL CDR1 having the amino acid sequence shown in SEQ ID No. 10, (2) a VL CDR2 having the amino acid sequence shown in SEQ ID No. 14, or (3) a VL CDR3 having the amino acid sequence shown in SEQ ID No. 32. The VL may have a VL CDR1, a VL CDR2 and a VL CDR3, the VL CDR1, the VL CDR2 and the VL CDR3 having the amino acid sequences shown in SEQ ID NOS 10, 14 and 32, respectively. In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) having a VH comprising (1) a VH CDR1 having the amino acid sequence shown in SEQ ID No. 43; (2) A VH CDR2 having the amino acid sequence shown in SEQ ID NO. 55; or (3) a VH CDR3 having the amino acid sequence shown in SEQ ID NO: 67. The VH may have a VH CDR1, a VH CDR2 and a VH CDR3, the VH CDR1, VH CDR2 and VH CDR3 having the amino acid sequences shown in SEQ ID NO 43, 55 and 67 respectively. In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA), comprising (a) a VL comprising VL CDR1, VL CDR2, and VL CDR3, the VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences shown in SEQ ID NOs 10, 14, and 32, respectively; and (b) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3, said VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences set forth in SEQ ID NOs 43, 55, and 67, respectively.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA), comprising a VL having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs 68-79. In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA), comprising a VH having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs 80-91.

TABLE 3 amino acid sequences of anti-BCMA antibody light chain variable regions (VLs) and heavy chain variable regions (VHs)

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In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA), comprising: (a) VL having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs 68-79; and (b) a VH having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs 80-91.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising VL wherein said VL has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence shown in SEQ ID No. 68. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 85% sequence identity to the sequence set forth in SEQ ID NO. 68. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 90% sequence identity to the sequence set forth in SEQ ID NO. 68. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 95% sequence identity to the sequence set forth in SEQ ID NO. 68. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 98% sequence identity to the sequence set forth in SEQ ID NO. 68. In some embodiments, an anti-BCMA (e.g., human BCMA) antibody or antigen binding fragment thereof provided herein includes a VL having the amino acid sequence shown in SEQ ID No. 68.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising VL wherein said VL has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence shown in SEQ ID No. 69. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 85% sequence identity to the sequence set forth in SEQ ID NO. 69. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 90% sequence identity to the sequence set forth in SEQ ID NO. 69. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 95% sequence identity to the sequence set forth in SEQ ID NO. 69. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 98% sequence identity to the sequence set forth in SEQ ID NO. 69. In some embodiments, an anti-BCMA (e.g., human BCMA) antibody or antigen binding fragment thereof provided herein includes a VL having an amino acid sequence shown in SEQ ID No. 69.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising VL wherein said VL has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence set forth in SEQ ID No. 70. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 85% sequence identity to the sequence set forth in SEQ ID NO. 70. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 90% sequence identity to the sequence set forth in SEQ ID NO. 70. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 95% sequence identity to the sequence set forth in SEQ ID NO. 70. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 98% sequence identity to the sequence set forth in SEQ ID NO. 70. In some embodiments, an anti-BCMA (e.g., human BCMA) antibody or antigen binding fragment thereof provided herein includes a VL having an amino acid sequence shown in SEQ ID No. 70.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind to BCMA (e.g., human BCMA), comprising VL wherein said VL has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence shown in SEQ ID NO: 71. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 85% sequence identity to the sequence set forth in SEQ ID NO. 71. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 90% sequence identity to the sequence set forth in SEQ ID NO. 71. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 95% sequence identity to the sequence set forth in SEQ ID NO. 71. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 98% sequence identity to the sequence set forth in SEQ ID NO. 71. In some embodiments, an anti-BCMA (e.g., human BCMA) antibody or antigen binding fragment thereof provided herein includes a VL having an amino acid sequence shown in SEQ ID No. 71.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising VL wherein said VL has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence shown in SEQ ID NO: 72. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 85% sequence identity to the sequence set forth in SEQ ID NO. 72. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 90% sequence identity to the sequence set forth in SEQ ID NO. 72. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 95% sequence identity to the sequence set forth in SEQ ID NO. 72. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 98% sequence identity to the sequence set forth in SEQ ID NO. 72. In some embodiments, an anti-BCMA (e.g., human BCMA) antibody or antigen binding fragment thereof provided herein includes a VL having an amino acid sequence shown in SEQ ID No. 72.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising VL wherein said VL has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence shown in SEQ ID No. 73. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 85% sequence identity to the sequence set forth in SEQ ID NO. 73. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 90% sequence identity to the sequence set forth in SEQ ID NO. 73. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 95% sequence identity to the sequence set forth in SEQ ID NO. 73. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 98% sequence identity to the sequence set forth in SEQ ID NO. 73. In some embodiments, an anti-BCMA (e.g., human BCMA) antibody or antigen binding fragment thereof provided herein includes a VL having an amino acid sequence shown in SEQ ID No. 73.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising VL wherein said VL has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence shown in SEQ ID No. 74. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 85% sequence identity to the sequence set forth in SEQ ID NO. 74. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 90% sequence identity to the sequence set forth in SEQ ID NO. 74. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 95% sequence identity to the sequence set forth in SEQ ID NO. 74. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 98% sequence identity to the sequence set forth in SEQ ID NO. 74. In some embodiments, an anti-BCMA (e.g., human BCMA) antibody or antigen binding fragment thereof provided herein includes a VL having an amino acid sequence shown in SEQ ID No. 74.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising VL wherein said VL has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence set forth in SEQ ID No. 75. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 85% sequence identity to the sequence set forth in SEQ ID NO. 75. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 90% sequence identity to the sequence set forth in SEQ ID NO. 75. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 95% sequence identity to the sequence set forth in SEQ ID NO. 75. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 98% sequence identity to the sequence set forth in SEQ ID NO. 75. In some embodiments, an anti-BCMA (e.g., human BCMA) antibody or antigen binding fragment thereof provided herein includes a VL having an amino acid sequence shown in SEQ ID No. 75.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising VL wherein said VL has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence shown in SEQ ID No. 76. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 85% sequence identity to the sequence set forth in SEQ ID NO. 76. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 90% sequence identity to the sequence set forth in SEQ ID NO. 76. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 95% sequence identity to the sequence set forth in SEQ ID NO. 76. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 98% sequence identity to the sequence set forth in SEQ ID NO. 76. In some embodiments, an anti-BCMA (e.g., human BCMA) antibody or antigen binding fragment thereof provided herein includes a VL having the amino acid sequence shown in SEQ ID No. 76.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising VL wherein said VL has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence set forth in SEQ ID No. 77. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 85% sequence identity to the sequence set forth in SEQ ID NO. 77. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 90% sequence identity to the sequence set forth in SEQ ID NO. 77. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 95% sequence identity to the sequence set forth in SEQ ID NO. 77. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 98% sequence identity to the sequence set forth in SEQ ID NO. 77. In some embodiments, an anti-BCMA (e.g., human BCMA) antibody or antigen binding fragment thereof provided herein includes a VL having the amino acid sequence shown in SEQ ID No. 77.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising VL wherein said VL has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence shown in SEQ ID NO: 78. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 85% sequence identity to the sequence set forth in SEQ ID NO: 78. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 90% sequence identity to the sequence set forth in SEQ ID NO: 78. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 95% sequence identity to the sequence set forth in SEQ ID NO: 78. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 98% sequence identity to the sequence set forth in SEQ ID NO: 78. In some embodiments, an anti-BCMA (e.g., human BCMA) antibody or antigen binding fragment thereof provided herein includes a VL having an amino acid sequence shown in SEQ ID No. 78.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising VL wherein said VL has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence shown in SEQ ID No. 79. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 85% sequence identity to the sequence set forth in SEQ ID NO. 79. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 90% sequence identity to the sequence set forth in SEQ ID NO. 79. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 95% sequence identity to the sequence set forth in SEQ ID NO. 79. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VL that has at least 98% sequence identity to the sequence set forth in SEQ ID NO. 79. In some embodiments, an anti-BCMA (e.g., human BCMA) antibody or antigen binding fragment thereof provided herein includes a VL having an amino acid sequence shown in SEQ ID No. 79.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH wherein said VH has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence set forth in SEQ ID No. 80. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 85% sequence identity to the sequence set forth in SEQ ID NO. 80. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 90% sequence identity to the sequence set forth in SEQ ID NO. 80. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 95% sequence identity to the sequence set forth in SEQ ID NO. 80. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 98% sequence identity to the sequence set forth in SEQ ID NO. 80. In some embodiments, an anti-BCMA (e.g., human BCMA) antibody or antigen binding fragment thereof provided herein includes a VH having an amino acid sequence shown in SEQ ID No. 80.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH wherein said VH has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence set forth in SEQ ID No. 81. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 85% sequence identity to the sequence set forth in SEQ ID NO. 81. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 90% sequence identity to the sequence set forth in SEQ ID NO. 81. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 95% sequence identity to the sequence set forth in SEQ ID NO. 81. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 98% sequence identity to the sequence set forth in SEQ ID NO. 81. In some embodiments, an anti-BCMA (e.g., human BCMA) antibody or antigen binding fragment thereof provided herein includes a VH having an amino acid sequence shown in SEQ ID No. 81.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH wherein said VH has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence set forth in SEQ ID No. 82. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 85% sequence identity to the sequence set forth in SEQ ID NO. 82. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 90% sequence identity to the sequence set forth in SEQ ID NO. 82. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 95% sequence identity to the sequence set forth in SEQ ID NO. 82. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 98% sequence identity to the sequence set forth in SEQ ID NO. 82. In some embodiments, an anti-BCMA (e.g., human BCMA) antibody or antigen binding fragment thereof provided herein includes a VH having the amino acid sequence shown in SEQ ID No. 82.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH wherein said VH has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence set forth in SEQ ID NO 83. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 85% sequence identity to the sequence set forth in SEQ ID NO. 83. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 90% sequence identity to the sequence set forth in SEQ ID NO. 83. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 95% sequence identity to the sequence set forth in SEQ ID NO. 83. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 98% sequence identity to the sequence set forth in SEQ ID NO. 83. In some embodiments, an anti-BCMA (e.g., human BCMA) antibody or antigen binding fragment thereof provided by the present invention includes a VH having the amino acid sequence shown in SEQ ID No. 83.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind to BCMA (e.g., human BCMA) comprising a VH, wherein said VH has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence set forth in SEQ ID NO: 84. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 85% sequence identity to the sequence set forth in SEQ ID NO. 84. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 90% sequence identity to the sequence set forth in SEQ ID NO. 84. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 95% sequence identity to the sequence set forth in SEQ ID NO. 84. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 98% sequence identity to the sequence set forth in SEQ ID NO. 84. In some embodiments, an anti-BCMA (e.g., human BCMA) antibody or antigen binding fragment thereof provided herein includes a VH having an amino acid sequence shown in SEQ ID No. 84.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH wherein said VH has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence set forth in SEQ ID NO: 85. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 85% sequence identity to the sequence set forth in SEQ ID NO. 85. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 90% sequence identity to the sequence set forth in SEQ ID NO. 85. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 95% sequence identity to the sequence set forth in SEQ ID NO. 85. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 98% sequence identity to the sequence set forth in SEQ ID NO. 85. In some embodiments, an anti-BCMA (e.g., human BCMA) antibody or antigen binding fragment thereof provided herein includes a VH having the amino acid sequence shown in SEQ ID No. 85.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH wherein said VH has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence set forth in SEQ ID No. 86. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 85% sequence identity to the sequence set forth in SEQ ID NO. 86. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 90% sequence identity to the sequence set forth in SEQ ID NO. 86. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 95% sequence identity to the sequence set forth in SEQ ID NO. 86. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 98% sequence identity to the sequence set forth in SEQ ID NO. 86. In some embodiments, an anti-BCMA (e.g., human BCMA) antibody or antigen binding fragment thereof provided herein includes a VH having the amino acid sequence shown in SEQ ID No. 86.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH wherein said VH has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence set forth in SEQ ID No. 87. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 85% sequence identity to the sequence set forth in SEQ ID NO. 87. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 90% sequence identity to the sequence set forth in SEQ ID NO. 87. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 95% sequence identity to the sequence set forth in SEQ ID NO. 87. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 98% sequence identity to the sequence set forth in SEQ ID NO. 87. In some embodiments, an anti-BCMA (e.g., human BCMA) antibody or antigen binding fragment thereof provided herein includes a VH having the amino acid sequence shown in SEQ ID No. 87.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH wherein said VH has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence set forth in SEQ ID No. 88. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 85% sequence identity to the sequence set forth in SEQ ID NO. 88. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 90% sequence identity to the sequence set forth in SEQ ID NO. 88. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 95% sequence identity to the sequence set forth in SEQ ID NO. 88. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 98% sequence identity to the sequence set forth in SEQ ID NO. 88. In some embodiments, an anti-BCMA (e.g., human BCMA) antibody or antigen binding fragment thereof provided herein includes a VH having an amino acid sequence shown in SEQ ID No. 88.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH wherein said VH has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence set forth in SEQ ID No. 89. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 85% sequence identity to the sequence set forth in SEQ ID NO. 89. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 90% sequence identity to the sequence set forth in SEQ ID NO. 89. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 95% sequence identity to the sequence set forth in SEQ ID NO. 89. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 98% sequence identity to the sequence set forth in SEQ ID NO. 89. In some embodiments, an anti-BCMA (e.g., human BCMA) antibody or antigen binding fragment thereof provided herein includes a VH having an amino acid sequence shown in SEQ ID No. 89.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH wherein said VH has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence set forth in SEQ ID No. 90. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 85% sequence identity to the sequence set forth in SEQ ID NO. 90. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 90% sequence identity to the sequence set forth in SEQ ID NO. 90. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 95% sequence identity to the sequence set forth in SEQ ID NO. 90. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 98% sequence identity to the sequence set forth in SEQ ID NO. 90. In some embodiments, an anti-BCMA (e.g., human BCMA) antibody or antigen binding fragment thereof provided herein includes a VH having an amino acid sequence shown in SEQ ID No. 90.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH wherein said VH has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence set forth in SEQ ID No. 91. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 85% sequence identity to the sequence set forth in SEQ ID NO. 91. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 90% sequence identity to the sequence set forth in SEQ ID NO. 91. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 95% sequence identity to the sequence set forth in SEQ ID NO. 91. In some embodiments, the anti-BCMA antibody, or antigen binding fragment thereof, includes a VH that has at least 98% sequence identity to the sequence set forth in SEQ ID NO. 91. In some embodiments, an anti-BCMA (e.g., human BCMA) antibody or antigen binding fragment thereof provided herein includes a VH having an amino acid sequence shown in SEQ ID No. 91.

The anti-BCMA antibody or antigen binding fragment thereof may comprise a combination of any VL disclosed herein and any VH disclosed herein. In some embodiments, the VL and VH are linked by a linker. The connector may be a flexible connector or a rigid connector. In some embodiments, the linker has an amino acid sequence of (GGGGS) n, n=1, 2, 3, 4, or 5 (SEQ ID NO: 155). In some embodiments, the linker has an amino acid sequence of (EAAAK) n, n=1, 2, 3, 4, or 5 (SEQ ID NO: 156). In some embodiments, the linker has an amino acid sequence of (PA) nP, n=1, 2, 3, 4, or 5 (SEQ ID NO: 157). In some embodiments, the linker has the amino acid sequence of GGGGSGGGGSGGGGS (SEQ ID NO: 158).

In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA), comprising VL and VH, wherein said VL has the amino acid sequence shown in SEQ ID No. 68, and said VH has an amino acid sequence selected from the group consisting of SEQ ID nos. 80-91. In some embodiments, the VL has the amino acid sequence shown as SEQ ID NO. 69 and the VH has an amino acid sequence selected from the group consisting of SEQ ID NO. 80-91. In some embodiments, the VL has an amino acid sequence set forth in SEQ ID NO. 70 and the VH has an amino acid sequence selected from the group consisting of SEQ ID NO. 80-91. In some embodiments, the VL has an amino acid sequence set forth in SEQ ID NO. 71 and the VH has an amino acid sequence selected from the group consisting of SEQ ID NO. 80-91. In some embodiments, the VL has an amino acid sequence set forth in SEQ ID NO. 72 and the VH has an amino acid sequence selected from the group consisting of SEQ ID NO. 80-91. In some embodiments, the VL has an amino acid sequence set forth in SEQ ID NO. 73 and the VH has an amino acid sequence selected from the group consisting of SEQ ID NO. 80-91. In some embodiments, the VL has an amino acid sequence set forth in SEQ ID NO. 74 and the VH has an amino acid sequence selected from the group consisting of SEQ ID NO. 80-91. In some embodiments, the VL has an amino acid sequence set forth in SEQ ID NO. 75 and the VH has an amino acid sequence selected from the group consisting of SEQ ID NO. 80-91. In some embodiments, the VL has an amino acid sequence set forth in SEQ ID NO. 76 and the VH has an amino acid sequence selected from the group consisting of SEQ ID NO. 80-91. In some embodiments, the VL has the amino acid sequence shown in SEQ ID NO. 77 and the VH has an amino acid sequence selected from the group consisting of SEQ ID NO. 80-91. In some embodiments, the VL has an amino acid sequence set forth in SEQ ID NO:78 and the VH has an amino acid sequence selected from the group consisting of SEQ ID NO: 80-91. In some embodiments, the VL has an amino acid sequence set forth in SEQ ID NO. 79 and the VH has an amino acid sequence selected from the group consisting of SEQ ID NO. 80-91.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA), comprising VL and VH, wherein the VL has an amino acid sequence selected from the group consisting of SEQ ID nos. 68-79, and the VH has an amino acid sequence set forth in SEQ ID No. 80. In some embodiments, the VL has an amino acid sequence selected from the group consisting of SEQ ID NOS: 68-79 and the VH has an amino acid sequence shown in SEQ ID NO: 81. In some embodiments, the VL has an amino acid sequence selected from the group consisting of SEQ ID NOS: 68-79 and the VH has the amino acid sequence shown in SEQ ID NO: 82. In some embodiments, the VL has an amino acid sequence selected from the group consisting of SEQ ID NOS: 68-79 and the VH has the amino acid sequence shown in SEQ ID NO: 83. In some embodiments, the VL has an amino acid sequence selected from the group consisting of SEQ ID NOS: 68-79 and the VH has the amino acid sequence shown in SEQ ID NO: 84. In some embodiments, the VL has an amino acid sequence selected from the group consisting of SEQ ID NOS: 68-79 and the VH has the amino acid sequence shown in SEQ ID NO: 85. In some embodiments, the VL has an amino acid sequence selected from the group consisting of SEQ ID NOS: 68-79 and the VH has the amino acid sequence shown in SEQ ID NO: 86. In some embodiments, the VL has an amino acid sequence selected from the group consisting of SEQ ID NOS: 68-79 and the VH has the amino acid sequence shown in SEQ ID NO: 87. In some embodiments, the VL has an amino acid sequence selected from the group consisting of SEQ ID NOS: 68-79 and the VH has the amino acid sequence shown in SEQ ID NO: 88. In some embodiments, the VL has an amino acid sequence selected from the group consisting of SEQ ID NOS: 68-79, and the VH has the amino acid sequence shown in SEQ ID NO: 89. In some embodiments, the VL has an amino acid sequence selected from the group consisting of SEQ ID NOS: 68-79 and the VH has an amino acid sequence shown in SEQ ID NO: 90. In some embodiments, the VL has an amino acid sequence selected from the group consisting of SEQ ID NOS: 68-79 and the VH has an amino acid sequence shown in SEQ ID NO: 91.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA), comprising VL and VH, wherein the VL and VH have the amino acid sequences shown in SEQ ID NOs 68 and 80, respectively. In some embodiments, the VL and VH have the amino acid sequences shown in SEQ ID NOS 69 and 81, respectively. In some embodiments, the VL and VH have the amino acid sequences shown in SEQ ID NOS 70 and 82, respectively. In some embodiments, the VL and VH have the amino acid sequences shown in SEQ ID NOS 71 and 83, respectively. In some embodiments, the VL and VH have the amino acid sequences shown in SEQ ID NOS 72 and 84, respectively. In some embodiments, the VL and VH have the amino acid sequences shown in SEQ ID NOS 73 and 85, respectively. In some embodiments, the VL and VH have the amino acid sequences shown in SEQ ID NOS 74 and 86, respectively. In some embodiments, the VL and VH have the amino acid sequences shown in SEQ ID NOS 75 and 87, respectively. In some embodiments, the VL and VH have the amino acid sequences shown in SEQ ID NOS 76 and 88, respectively. In some embodiments, the VL and VH have the amino acid sequences shown in SEQ ID NOS 77 and 89, respectively. In some embodiments, the VL and VH have the amino acid sequences shown in SEQ ID NOS 78 and 90, respectively. In some embodiments, the VL and VH have the amino acid sequences shown in SEQ ID NOS 79 and 91, respectively.

In some embodiments, the invention provides antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA), comprising (a) a VL comprising VL CDRs 1, 2 and 3, said VL CDRs 1, 2 and 3 being derived from a VL having an amino acid sequence selected from the group consisting of SEQ ID NOs 68-79; and/or (b) a VH comprising VH CDRs 1, 2 and 3, said VH CDRs 1, 2 and 3 being derived from a VH having an amino acid sequence selected from the group consisting of SEQ ID NOs 80-91.

In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) comprising VL, wherein said VL comprises VL CDRs 1, 2 and 3, wherein said VL CDRs 1, 2 and 3 are derived from a VL having the amino acid sequence shown in SEQ ID No. 68. In some embodiments, the VL comprises VL CDRs 1, 2 and 3, the VL CDRs 1, 2 and 3 being derived from a VL having the amino acid sequence set forth in SEQ ID NO. 69. In some embodiments, the VL comprises VL CDRs 1, 2 and 3, the VL CDRs 1, 2 and 3 being derived from a VL having the amino acid sequence set forth in SEQ ID NO. 70. In some embodiments, the VL comprises VL CDRs 1, 2 and 3, the VL CDRs 1, 2 and 3 being derived from a VL having the amino acid sequence set forth in SEQ ID NO. 71. In some embodiments, the VL comprises VL CDRs 1, 2 and 3, the VL CDRs 1, 2 and 3 being derived from a VL having the amino acid sequence set forth in SEQ ID NO. 72. In some embodiments, the VL comprises VL CDRs 1, 2 and 3, the VL CDRs 1, 2 and 3 being derived from a VL having the amino acid sequence set forth in SEQ ID NO. 73. In some embodiments, the VL comprises VL CDRs 1, 2 and 3, the VL CDRs 1, 2 and 3 being derived from a VL having the amino acid sequence set forth in SEQ ID NO. 74. In some embodiments, the VL comprises VL CDRs 1, 2 and 3, the VL CDRs 1, 2 and 3 being derived from a VL having the amino acid sequence set forth in SEQ ID NO. 75. In some embodiments, the VL comprises VL CDRs 1, 2 and 3, the VL CDRs 1, 2 and 3 being derived from a VL having the amino acid sequence set forth in SEQ ID NO. 76. In some embodiments, the VL comprises VL CDRs 1, 2 and 3, the VL CDRs 1, 2 and 3 being derived from a VL having the amino acid sequence set forth in SEQ ID NO. 77. In some embodiments, the VL comprises VL CDRs 1, 2 and 3, the VL CDRs 1, 2 and 3 being derived from a VL having the amino acid sequence set forth in SEQ ID NO: 78. In some embodiments, the VL comprises VL CDRs 1, 2 and 3, the VL CDRs 1, 2 and 3 being derived from a VL having the amino acid sequence set forth in SEQ ID NO. 79.

In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA) comprising a VH, wherein said VH comprises VH CDRs 1, 2 and 3, said VH CDRs 1, 2 and 3 being derived from a VH having the amino acid sequence shown in SEQ ID No. 80. In some embodiments, the VH comprises VH CDRs 1, 2 and 3, the VH CDRs 1, 2 and 3 being derived from a VH having the amino acid sequence shown in SEQ ID NO. 81. In some embodiments, the VH comprises VH CDRs 1, 2 and 3, the VH CDRs 1, 2 and 3 being derived from a VH having the amino acid sequence shown in SEQ ID NO. 82. In some embodiments, the VH comprises VH CDRs 1, 2 and 3, the VH CDRs 1, 2 and 3 being derived from a VH having the amino acid sequence shown in SEQ ID NO. 83. In some embodiments, the VH comprises VH CDRs 1, 2 and 3, the VH CDRs 1, 2 and 3 being derived from a VH having the amino acid sequence shown in SEQ ID NO 84. In some embodiments, the VH comprises VH CDRs 1, 2 and 3, the VH CDRs 1, 2 and 3 being derived from a VH having the amino acid sequence shown in SEQ ID NO. 85. In some embodiments, the VH comprises VH CDRs 1, 2 and 3, the VH CDRs 1, 2 and 3 being derived from a VH having the amino acid sequence shown in SEQ ID NO 86. In some embodiments, the VH comprises VH CDRs 1, 2 and 3, the VH CDRs 1, 2 and 3 being derived from a VH having the amino acid sequence shown in SEQ ID NO. 87. In some embodiments, the VH comprises VH CDRs 1, 2 and 3, the VH CDRs 1, 2 and 3 being derived from a VH having the amino acid sequence shown in SEQ ID NO. 88. In some embodiments, the VH comprises VH CDRs 1, 2 and 3, the VH CDRs 1, 2 and 3 being derived from a VH having the amino acid sequence shown in SEQ ID NO. 89. In some embodiments, the VH comprises VH CDRs 1, 2 and 3, the VH CDRs 1, 2 and 3 being derived from a VH having the amino acid sequence shown in SEQ ID NO. 90. In some embodiments, the VH comprises VH CDRs 1, 2 and 3, the VH CDRs 1, 2 and 3 being derived from a VH having the amino acid sequence shown in SEQ ID NO. 91.

In some embodiments, the invention provides an antibody or antigen-binding fragment thereof that specifically binds BCMA (e.g., human BCMA), comprising VL and VH, wherein the VL comprises VL CDR1, CDR2, and CDR3, the VL CDR1, CDR2, and CDR3 are derived from a VL having the amino acid sequence set forth in SEQ ID No. 68, and the VH comprises VH CDR1, CDR2, and CDR3, the VH CDR1, CDR2, and CDR3 are derived from a VH having the amino acid sequence set forth in SEQ ID No. 80. In some embodiments, the VL comprises VL CDR1, CDR2 and CDR3, the VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence of SEQ ID NO:69 and the VH comprises VH CDR1, CDR2 and CDR3, the VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence of SEQ ID NO: 81. In some embodiments, the VL comprises VL CDR1, CDR2 and CDR3, the VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence of SEQ ID NO:70 and the VH comprises VH CDR1, CDR2 and CDR3, the VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence of SEQ ID NO: 82. In some embodiments, the VL comprises VL CDR1, CDR2 and CDR3, the VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence of SEQ ID NO:71 and the VH comprises VH CDR1, CDR2 and CDR3, the VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence of SEQ ID NO: 83. In some embodiments, the VL comprises VL CDR1, CDR2 and CDR3, the VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence of SEQ ID NO:72 and the VH comprises VH CDR1, CDR2 and CDR3, the VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence of SEQ ID NO: 84. In some embodiments, the VL comprises VL CDR1, CDR2 and CDR3, the VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence of SEQ ID NO:73 and the VH comprises VH CDR1, CDR2 and CDR3, the VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence of SEQ ID NO: 85. In some embodiments, the VL comprises VL CDR1, CDR2 and CDR3, the VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence of SEQ ID NO:74 and the VH comprises VH CDR1, CDR2 and CDR3, the VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence of SEQ ID NO: 86. In some embodiments, the VL comprises VL CDR1, CDR2 and CDR3, the VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence of SEQ ID NO:75 and the VH comprises VH CDR1, CDR2 and CDR3, the VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence of SEQ ID NO: 87. In some embodiments, the VL comprises VL CDR1, CDR2 and CDR3, the VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence of SEQ ID NO:76 and the VH comprises VH CDR1, CDR2 and CDR3, the VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence of SEQ ID NO: 88. In some embodiments, the VL comprises VL CDR1, CDR2 and CDR3, the VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence of SEQ ID NO:77 and the VH comprises VH CDR1, CDR2 and CDR3, the VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence of SEQ ID NO: 89. In some embodiments, the VL comprises VL CDR1, CDR2 and CDR3, the VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence of SEQ ID NO:78 and the VH comprises VH CDR1, CDR2 and CDR3, the VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence of SEQ ID NO: 90. In some embodiments, the VL comprises VL CDR1, CDR2 and CDR3, the VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence of SEQ ID NO:79 and the VH comprises VH CDR1, CDR2 and CDR3, the VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence of SEQ ID NO: 91.

In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein are scFv labeled BCMA21 (SEQ ID NO: 116). In some embodiments, the anti-BCMA antibodies, or antigen binding fragments thereof, provided herein have at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the sequence shown in SEQ ID NO. 116. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein, have a VL (SEQ ID NO: 68) derived from BCMA 21. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein, have a VH (SEQ ID NO: 80) derived from BCMA 21. The anti-BCMA antibodies or antigen binding fragments thereof provided herein may have both VL and VH derived from BCMA 21. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein have a VL comprising VL CDRs 1, 2 and 3, the VL CDRs 1, 2 and 3 being derived from a VL (SEQ ID NO: 68) derived from BCMA 21. In some embodiments, the anti-BCMA antibodies or antigen binding fragments thereof provided herein have a VH comprising VH CDRs 1, 2, and 3, the VH CDRs 1, 2, and 3 being derived from VH from BCMA21 (SEQ ID NO: 80). The anti-BCMA antibodies or antigen-binding fragments thereof provided herein have a VL comprising VL CDRs 1, 2 and 3 and a VH comprising VH CDRs 1, 2 and 3, wherein the VL CDRs 1, 2 and 3, and VH CDRs 1, 2 and 3 can be derived from VL and VH, respectively, from BCMA 21. In some embodiments, an anti-BCMA antibody or antigen binding fragment thereof provided herein is a variant of BCMA 21. The BCMA21 variant may have a VL that is a variant of BCMA21 VL having up to about 5 amino acid substitutions, additions and/or deletions in the sequence shown in SEQ ID No. 68. The BCMA21 variant may have a VH, which is a variant of BCMA21 VH having up to about 5 amino acid substitutions, additions and/or deletions in the sequence shown in SEQ ID No. 80. The amino acid substitutions, additions and/or deletions may occur in the VH CDRs or VL CDRs. In some embodiments, the amino acid substitutions, additions and/or deletions are not in the CDRs. In some embodiments, variants of BCMA21 have up to about 5 conservative amino acid substitutions. In some embodiments, variants of BCMA21 have up to about 3 conservative amino acid substitutions.

In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein are scFv labeled BCMA22 (SEQ ID NO: 117). In some embodiments, the anti-BCMA antibodies, or antigen binding fragments thereof, provided herein have at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the sequence set forth in SEQ ID NO. 117. In some embodiments, the anti-BCMA antibodies, or antigen binding fragments thereof, provided herein, have a VL (SEQ ID NO: 69) derived from BCMA 22. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein, have a VH (SEQ ID NO: 81) derived from BCMA 22. The anti-BCMA antibodies or antigen binding fragments thereof provided herein may have both VL and VH derived from BCMA 22. In some embodiments, the anti-BCMA antibodies or antigen binding fragments thereof provided herein have a VL comprising VL CDRs 1, 2, and 3, the VL CDRs 1, 2, and 3 being derived from a VL from BCMA22 (SEQ ID NO: 69). In some embodiments, the anti-BCMA antibodies or antigen binding fragments thereof provided herein have a VH comprising VH CDRs 1, 2, and 3, the VH CDRs 1, 2, and 3 being derived from VH from BCMA22 (SEQ ID NO: 81). The anti-BCMA antibodies or antigen-binding fragments thereof provided herein have a VL comprising VL CDRs 1, 2 and 3 and a VH comprising VH CDRs 1, 2 and 3, wherein the VL CDRs 1, 2 and 3, and VH CDRs 1, 2 and 3 can be derived from a VL and VH, respectively, from BCMA 22. In some embodiments, an anti-BCMA antibody or antigen binding fragment thereof provided herein is a variant of BCMA 22. The BCMA22 variant may have a VL that is a variant of BCMA22 VL having up to about 5 amino acid substitutions, additions and/or deletions in the sequence shown in SEQ ID No. 69. The BCMA22 variant may have a VH which is a variant of BCMA22 VH having up to about 5 amino acid substitutions, additions and/or deletions in the sequence shown in SEQ ID No. 81. The amino acid substitutions, additions and/or deletions may occur in the VH CDRs or VL CDRs. In some embodiments, the amino acid substitutions, additions and/or deletions are not in the CDRs. In some embodiments, variants of BCMA22 have up to about 5 conservative amino acid substitutions. In some embodiments, variants of BCMA22 have up to about 3 conservative amino acid substitutions.

In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein are scFv labeled BCMA23 (SEQ ID NO: 118). In some embodiments, the anti-BCMA antibodies, or antigen binding fragments thereof, provided herein have at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the sequence shown in SEQ ID NO. 118. In some embodiments, the anti-BCMA antibodies, or antigen binding fragments thereof, provided herein, have a VL (SEQ ID NO: 70) derived from BCMA 23. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein, have a VH (SEQ ID NO: 82) derived from BCMA 23. The anti-BCMA antibodies or antigen binding fragments thereof provided herein may have both VL and VH derived from BCMA 23. In some embodiments, the anti-BCMA antibodies or antigen binding fragments thereof provided herein have a VL comprising VL CDRs 1, 2, and 3, the VL CDRs 1, 2, and 3 being derived from a VL from BCMA23 (SEQ ID NO: 70). In some embodiments, the anti-BCMA antibodies or antigen binding fragments thereof provided herein have a VH comprising VH CDRs 1, 2, and 3 derived from VH from BCMA23 (SEQ ID NO: 82). The anti-BCMA antibodies or antigen-binding fragments thereof provided herein have a VL comprising VL CDRs 1, 2 and 3 and a VH comprising VH CDRs 1, 2 and 3, wherein the VL CDRs 1, 2 and 3, and VH CDRs 1, 2 and 3 can be derived from VL and VH, respectively, from BCMA 23. In some embodiments, an anti-BCMA antibody or antigen binding fragment thereof provided herein is a variant of BCMA 23. The BCMA23 variant may have a VL that is a variant of BCMA23 VL having up to about 5 amino acid substitutions, additions and/or deletions in the sequence shown in SEQ ID No. 70. The BCMA23 variant may have a VH which is a variant of BCMA23 VH having up to about 5 amino acid substitutions, additions and/or deletions in the sequence shown in SEQ ID No. 82. The amino acid substitutions, additions and/or deletions may occur in the VH CDRs or VL CDRs. In some embodiments, the amino acid substitutions, additions and/or deletions are not in the CDRs. In some embodiments, variants of BCMA23 have up to about 5 conservative amino acid substitutions. In some embodiments, variants of BCMA23 have up to about 3 conservative amino acid substitutions.

In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein are scFv labeled BCMA24 (SEQ ID NO: 119). In some embodiments, the anti-BCMA antibodies, or antigen binding fragments thereof, provided herein have at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the sequence shown in SEQ ID NO 119. In some embodiments, the anti-BCMA antibodies, or antigen binding fragments thereof, provided herein, have a VL (SEQ ID NO: 71) derived from BCMA 24. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein, have a VH (SEQ ID NO: 83) derived from BCMA 24. The anti-BCMA antibodies or antigen binding fragments thereof provided herein may have both VL and VH derived from BCMA 24. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein have a VL comprising VL CDRs 1, 2 and 3, the VL CDRs 1, 2 and 3 being derived from a VL (SEQ ID NO: 71) from BCMA 24. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein have a VH that includes VH CDRs 1, 2, and 3, the VH CDRs 1, 2, and 3 being derived from a VH (SEQ ID NO: 83) from BCMA 24. The anti-BCMA antibodies or antigen-binding fragments thereof provided herein have a VL comprising VL CDRs 1, 2 and 3 and a VH comprising VH CDRs 1, 2 and 3, wherein the VL CDRs 1, 2 and 3, and VH CDRs 1, 2 and 3 can be derived from VL and VH, respectively, from BCMA 24. In some embodiments, an anti-BCMA antibody or antigen binding fragment thereof provided herein is a variant of BCMA 24. The BCMA24 variant may have a VL that is a variant of BCMA24 VL having up to about 5 amino acid substitutions, additions and/or deletions in the sequence shown in SEQ ID NO: 71. The BCMA24 variant may have a VH which is a variant of BCMA24 VH having up to about 5 amino acid substitutions, additions and/or deletions in the sequence shown in SEQ ID No. 83. The amino acid substitutions, additions and/or deletions may occur in the VH CDRs or VL CDRs. In some embodiments, the amino acid substitutions, additions and/or deletions are not in the CDRs. In some embodiments, variants of BCMA24 have up to about 5 conservative amino acid substitutions. In some embodiments, variants of BCMA24 have up to about 3 conservative amino acid substitutions.

In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein are scFv labeled BCMA27 (SEQ ID NO: 120). In some embodiments, the anti-BCMA antibodies, or antigen binding fragments thereof, provided herein have at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the sequence set forth in SEQ ID NO. 120. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein, have a VL (SEQ ID NO: 72) derived from BCMA 27. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein, have a VH (SEQ ID NO: 84) derived from BCMA 27. The anti-BCMA antibodies or antigen binding fragments thereof provided herein may have both VL and VH derived from BCMA 27. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein have a VL comprising VL CDRs 1, 2 and 3, the VL CDRs 1, 2 and 3 being derived from a VL (SEQ ID NO: 72) derived from BCMA 27. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein have a VH that includes VH CDRs 1, 2, and 3, the VH CDRs 1, 2, and 3 being derived from a VH (SEQ ID NO: 84) from BCMA 24. The anti-BCMA antibodies or antigen-binding fragments thereof provided herein have a VL comprising VL CDRs 1, 2 and 3 and a VH comprising VH CDRs 1, 2 and 3, wherein the VL CDRs 1, 2 and 3, and VH CDRs 1, 2 and 3 can be derived from VL and VH, respectively, from BCMA 27. In some embodiments, an anti-BCMA antibody or antigen binding fragment thereof provided herein is a variant of BCMA 27. The BCMA27 variant may have a VL that is a variant of BCMA27 VL having up to about 5 amino acid substitutions, additions and/or deletions in the sequence shown in SEQ ID NO: 72. The BCMA27 variant may have a VH, which is a variant of BCMA27 VH having up to about 5 amino acid substitutions, additions and/or deletions in the sequence shown in SEQ ID No. 84. The amino acid substitutions, additions and/or deletions may occur in the VH CDRs or VL CDRs. In some embodiments, the amino acid substitutions, additions and/or deletions are not in the CDRs. In some embodiments, variants of BCMA27 have up to about 5 conservative amino acid substitutions. In some embodiments, variants of BCMA27 have up to about 3 conservative amino acid substitutions.

In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein are scFv labeled BCMA28 (SEQ ID NO: 121). In some embodiments, the anti-BCMA antibodies, or antigen binding fragments thereof, provided herein have at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the sequence set forth in SEQ ID NO. 121. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein, have a VL (SEQ ID NO: 73) derived from BCMA 28. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein, have a VH (SEQ ID NO: 85) derived from BCMA 28. The anti-BCMA antibodies or antigen binding fragments thereof provided herein may have both VL and VH derived from BCMA 28. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein have a VL comprising VL CDRs 1, 2 and 3, the VL CDRs 1, 2 and 3 being derived from a VL (SEQ ID NO: 73) from BCMA 28. In some embodiments, the anti-BCMA antibodies or antigen binding fragments thereof provided herein have a VH comprising VH CDRs 1, 2, and 3 derived from VH from BCMA28 (SEQ ID NO: 85). The anti-BCMA antibodies or antigen-binding fragments thereof provided herein have a VL comprising VL CDRs 1, 2 and 3 and a VH comprising VH CDRs 1, 2 and 3, wherein the VL CDRs 1, 2 and 3, and VH CDRs 1, 2 and 3 can be derived from a VL and VH, respectively, from BCMA 28. In some embodiments, an anti-BCMA antibody or antigen binding fragment thereof provided herein is a variant of BCMA 28. The BCMA28 variant may have a VL that is a variant of BCMA28 VL having up to about 5 amino acid substitutions, additions and/or deletions in the sequence shown in SEQ ID No. 73. The BCMA28 variant may have a VH which is a variant of BCMA28 VH having up to about 5 amino acid substitutions, additions and/or deletions in the sequence shown in SEQ ID No. 85. The amino acid substitutions, additions and/or deletions may occur in the VH CDRs or VL CDRs. In some embodiments, the amino acid substitutions, additions and/or deletions are not in the CDRs. In some embodiments, variants of BCMA28 have up to about 5 conservative amino acid substitutions. In some embodiments, variants of BCMA28 have up to about 3 conservative amino acid substitutions.

In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein are scFv labeled BCMA30 (SEQ ID NO: 122). In some embodiments, the anti-BCMA antibodies, or antigen binding fragments thereof, provided herein have at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the sequence set forth in SEQ ID NO. 122. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein, have a VL (SEQ ID NO: 74) derived from BCMA 30. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein, have a VH (SEQ ID NO: 86) derived from BCMA 30. The anti-BCMA antibodies or antigen binding fragments thereof provided herein may have both VL and VH derived from BCMA 30. In some embodiments, the anti-BCMA antibodies or antigen binding fragments thereof provided herein have a VL comprising VL CDRs 1, 2, and 3, the VL CDRs 1, 2, and 3 being derived from a VL from BCMA30 (SEQ ID NO: 74). In some embodiments, the anti-BCMA antibodies or antigen binding fragments thereof provided herein have a VH comprising VH CDRs 1, 2, and 3, the VH CDRs 1, 2, and 3 being derived from VH from BCMA30 (SEQ ID NO: 86). The anti-BCMA antibodies or antigen-binding fragments thereof provided herein have a VL comprising VL CDRs 1, 2 and 3 and a VH comprising VH CDRs 1, 2 and 3, wherein the VL CDRs 1, 2 and 3, and VH CDRs 1, 2 and 3 can be derived from a VL and VH, respectively, from BCMA 30. In some embodiments, an anti-BCMA antibody or antigen binding fragment thereof provided herein is a variant of BCMA 30. The BCMA30 variant may have a VL that is a variant of BCMA30 VL having up to about 5 amino acid substitutions, additions and/or deletions in the sequence shown in SEQ ID No. 74. The BCMA30 variant may have a VH which is a variant of BCMA30 VH having up to about 5 amino acid substitutions, additions and/or deletions in the sequence shown in SEQ ID No. 86. The amino acid substitutions, additions and/or deletions may occur in the VH CDRs or VL CDRs. In some embodiments, the amino acid substitutions, additions and/or deletions are not in the CDRs. In some embodiments, variants of BCMA30 have up to about 5 conservative amino acid substitutions. In some embodiments, variants of BCMA30 have up to about 3 conservative amino acid substitutions.

In some embodiments, the anti-BCMA antibodies or antigen binding fragments thereof provided herein are labeled as

The scFv of BCMA31 (SEQ ID NO: 123). In some embodiments, the anti-BCMA antibodies, or antigen binding fragments thereof, provided herein have at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the sequence shown as SEQ ID NO. 123. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein, have a VL (SEQ ID NO: 75) derived from BCMA 31. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein, have a VH (SEQ ID NO: 87) derived from BCMA 31. The anti-BCMA antibodies or antigen binding fragments thereof provided herein may have both VL and VH derived from BCMA 31. In some embodiments, the anti-BCMA antibodies or antigen binding fragments thereof provided herein have a VL comprising VL CDRs 1, 2, and 3, the VL CDRs 1, 2, and 3 being derived from a VL from BCMA31 (SEQ ID NO: 75). In some embodiments, the anti-BCMA antibodies or antigen binding fragments thereof provided herein have a VH comprising VH CDRs 1, 2, and 3, the VH CDRs 1, 2, and 3 being derived from VH from BCMA31 (SEQ ID NO: 87). The anti-BCMA antibodies or antigen-binding fragments thereof provided herein have a VL comprising VL CDRs 1, 2 and 3 and a VH comprising VH CDRs 1, 2 and 3, wherein the VL CDRs 1, 2 and 3, and VH CDRs 1, 2 and 3 can be derived from VL and VH, respectively, from BCMA 31. In some embodiments, an anti-BCMA antibody or antigen binding fragment thereof provided herein is a variant of BCMA 31. The BCMA31 variant may have a VL that is a variant of BCMA31 VL having up to about 5 amino acid substitutions, additions and/or deletions in the sequence shown in SEQ ID No. 75. The BCMA31 variant may have a VH which is a variant of BCMA31 VH having up to about 5 amino acid substitutions, additions and/or deletions in the sequence shown in SEQ ID No. 87. The amino acid substitutions, additions and/or deletions may occur in the VH CDRs or VL CDRs. In some embodiments, the amino acid substitutions, additions and/or deletions are not in the CDRs. In some embodiments, variants of BCMA31 have up to about 5 conservative amino acid substitutions. In some embodiments, variants of BCMA31 have up to about 3 conservative amino acid substitutions.

In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein are scFv labeled BCMA32 (SEQ ID NO: 124). In some embodiments, the anti-BCMA antibodies, or antigen binding fragments thereof, provided herein have at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the sequence shown as SEQ ID NO. 124. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein, have a VL (SEQ ID NO: 76) derived from BCMA 32. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein, have a VH (SEQ ID NO: 88) derived from BCMA 32. The anti-BCMA antibodies or antigen binding fragments thereof provided herein may have both VL and VH derived from BCMA 32. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein have a VL comprising VL CDRs 1, 2 and 3, the VL CDRs 1, 2 and 3 being derived from a VL (SEQ ID NO: 76) derived from BCMA 32. In some embodiments, the anti-BCMA antibodies or antigen binding fragments thereof provided herein have a VH comprising VH CDRs 1, 2, and 3, the VH CDRs 1, 2, and 3 being derived from VH from BCMA32 (SEQ ID NO: 88). The anti-BCMA antibodies or antigen-binding fragments thereof provided herein have a VL comprising VL CDRs 1, 2 and 3 and a VH comprising VH CDRs 1, 2 and 3, wherein the VL CDRs 1, 2 and 3, and VH CDRs 1, 2 and 3 can be derived from a VL and VH, respectively, from BCMA 32. In some embodiments, an anti-BCMA antibody or antigen binding fragment thereof provided herein is a variant of BCMA 32. The BCMA32 variant may have a VL that is a variant of BCMA32 VL having up to about 5 amino acid substitutions, additions and/or deletions in the sequence shown in SEQ ID No. 76. The BCMA32 variant may have a VH which is a variant of BCMA32 VH having up to about 5 amino acid substitutions, additions and/or deletions in the sequence shown in SEQ ID No. 88. The amino acid substitutions, additions and/or deletions may occur in the VH CDRs or VL CDRs. In some embodiments, the amino acid substitutions, additions and/or deletions are not in the CDRs. In some embodiments, variants of BCMA32 have up to about 5 conservative amino acid substitutions. In some embodiments, variants of BCMA32 have up to about 3 conservative amino acid substitutions.

In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein are scFv labeled BCMA33 (SEQ ID NO: 125). In some embodiments, the anti-BCMA antibodies, or antigen binding fragments thereof, provided herein have at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the sequence set forth in SEQ ID NO. 125. In some embodiments, the anti-BCMA antibodies, or antigen binding fragments thereof, provided herein, have a VL (SEQ ID NO: 77) derived from BCMA 33. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein, have a VH (SEQ ID NO: 89) derived from BCMA 33. The anti-BCMA antibodies or antigen binding fragments thereof provided herein may have both VL and VH derived from BCMA 33. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein have a VL comprising VL CDRs 1, 2 and 3, the VL CDRs 1, 2 and 3 being derived from a VL (SEQ ID NO: 77) from BCMA 33. In some embodiments, the anti-BCMA antibodies or antigen binding fragments thereof provided herein have a VH comprising VH CDRs 1, 2, and 3, the VH CDRs 1, 2, and 3 being derived from VH from BCMA33 (SEQ ID NO: 89). The anti-BCMA antibodies or antigen-binding fragments thereof provided herein have a VL comprising VL CDRs 1, 2 and 3 and a VH comprising VH CDRs 1, 2 and 3, wherein the VL CDRs 1, 2 and 3, and VH CDRs 1, 2 and 3 can be derived from VL and VH, respectively, from BCMA 33. In some embodiments, an anti-BCMA antibody or antigen binding fragment thereof provided herein is a variant of BCMA 33. The BCMA33 variant may have a VL that is a variant of BCMA33 VL having up to about 5 amino acid substitutions, additions and/or deletions in the sequence shown in SEQ ID NO: 77. The BCMA33 variant may have a VH which is a variant of BCMA33 VH having up to about 5 amino acid substitutions, additions and/or deletions in the sequence shown in SEQ ID No. 89. The amino acid substitutions, additions and/or deletions may occur in the VH CDRs or VL CDRs. In some embodiments, the amino acid substitutions, additions and/or deletions are not in the CDRs. In some embodiments, variants of BCMA33 have up to about 5 conservative amino acid substitutions. In some embodiments, variants of BCMA33 have up to about 3 conservative amino acid substitutions.

In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein are scFv labeled BCMA34 (SEQ ID NO: 126). In some embodiments, the anti-BCMA antibodies, or antigen binding fragments thereof, provided herein have at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the sequence shown as SEQ ID NO. 126. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein, have a VL (SEQ ID NO: 78) derived from BCMA 34. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein, have a VH (SEQ ID NO: 90) derived from BCMA 34. The anti-BCMA antibodies or antigen binding fragments thereof provided herein may have both VL and VH derived from BCMA 34. In some embodiments, the anti-BCMA antibodies or antigen binding fragments thereof provided herein have a VL comprising VL CDRs 1, 2, and 3, the VL CDRs 1, 2, and 3 being derived from a VL from BCMA34 (SEQ ID NO: 78). In some embodiments, the anti-BCMA antibodies or antigen binding fragments thereof provided herein have a VH comprising VH CDRs 1, 2, and 3, the VH CDRs 1, 2, and 3 being derived from VH from BCMA34 (SEQ ID NO: 90). The anti-BCMA antibodies or antigen-binding fragments thereof provided herein have a VL comprising VL CDRs 1, 2 and 3 and a VH comprising VH CDRs 1, 2 and 3, wherein the VL CDRs 1, 2 and 3, and VH CDRs 1, 2 and 3 can be derived from VL and VH, respectively, from BCMA 34. In some embodiments, an anti-BCMA antibody or antigen binding fragment thereof provided herein is a variant of BCMA 34. The BCMA34 variant may have a VL that is a variant of BCMA34 VL having up to about 5 amino acid substitutions, additions and/or deletions in the sequence shown in SEQ ID NO: 78. The BCMA34 variant may have a VH which is a variant of BCMA34 VH having up to about 5 amino acid substitutions, additions and/or deletions in the sequence shown in SEQ ID No. 90. The amino acid substitutions, additions and/or deletions may occur in the VH CDRs or VL CDRs. In some embodiments, the amino acid substitutions, additions and/or deletions are not in the CDRs. In some embodiments, variants of BCMA34 have up to about 5 conservative amino acid substitutions. In some embodiments, variants of BCMA34 have up to about 3 conservative amino acid substitutions.

In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein are scFv labeled BCMA35 (SEQ ID NO: 127). In some embodiments, the anti-BCMA antibodies, or antigen binding fragments thereof, provided herein have at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the sequence set forth in SEQ ID NO. 127. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein, have a VL (SEQ ID NO: 79) derived from BCMA 35. In some embodiments, the anti-BCMA antibodies, or antigen-binding fragments thereof, provided herein, have a VH (SEQ ID NO: 91) derived from BCMA 35. The anti-BCMA antibodies or antigen binding fragments thereof provided herein may have both VL and VH derived from BCMA 35. In some embodiments, the anti-BCMA antibodies or antigen binding fragments thereof provided herein have a VL comprising VL CDRs 1, 2, and 3, the VL CDRs 1, 2, and 3 being derived from a VL from BCMA35 (SEQ ID NO: 79). In some embodiments, the anti-BCMA antibodies or antigen binding fragments thereof provided herein have a VH comprising VH CDRs 1, 2, and 3 derived from VH from BCMA35 (SEQ ID NO: 91). The anti-BCMA antibodies or antigen-binding fragments thereof provided herein have a VL comprising VL CDRs 1, 2 and 3 and a VH comprising VH CDRs 1, 2 and 3, wherein the VL CDRs 1, 2 and 3, and VH CDRs 1, 2 and 3 can be derived from a VL and VH, respectively, from BCMA 35. In some embodiments, an anti-BCMA antibody or antigen binding fragment thereof provided herein is a variant of BCMA 35. The BCMA35 variant may have a VL that is a variant of BCMA35 VL having up to about 5 amino acid substitutions, additions and/or deletions in the sequence shown in SEQ ID No. 79. The BCMA35 variant may have a VH which is a variant of BCMA35 VH having up to about 5 amino acid substitutions, additions and/or deletions in the sequence shown in SEQ ID No. 91. The amino acid substitutions, additions and/or deletions may occur in the VH CDRs or VL CDRs. In some embodiments, the amino acid substitutions, additions and/or deletions are not in the CDRs. In some embodiments, variants of BCMA35 have up to about 5 conservative amino acid substitutions. In some embodiments, variants of BCMA35 have up to about 3 conservative amino acid substitutions.

In some embodiments, the invention also provides antibodies or antigen-binding fragments that compete with the antibodies or antigen-binding fragments provided above for binding to BCMA (e.g., human BCMA). An antibody that "competes with another antibody for binding to a target" refers to an antibody that inhibits (partially or fully) the binding of another antibody to the target. Whether or not two antibodies compete with each other to bind to a target, i.e., whether or not and to what extent one antibody inhibits binding of the other antibody to the target, known competition assays (e.g.,surface Plasmon Resonance (SPR) analysis). In some embodiments, an anti-BCMA antibody or antigen binding fragment competes at least 50%, 60%, 70%, 80%, 90% or 100% with another antibody or antigen binding fragment and inhibits binding of the other antibody or antigen binding fragment to BCMA. Competition assays may be performed as described, for example, in Ed Harlow and David Lane, cold Spring Harb Protoc;2006; doi.l0.H0l/pdb.prot4277 or "Using Antibodies" Chapter 11,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY,USA 1999 written by Ed Harlow and David Lane.

In some embodiments, the invention provides antibodies or antigen binding fragments that compete with BCMA21 for binding to BCMA. In some embodiments, the invention provides antibodies or antigen binding fragments that compete with BCMA22 for binding to BCMA. In some embodiments, the invention provides antibodies or antigen binding fragments that compete with BCMA23 for binding to BCMA. In some embodiments, the invention provides antibodies or antigen binding fragments that compete with BCMA24 to bind BCMA. In some embodiments, the invention provides antibodies or antigen binding fragments that compete with BCMA27 for binding to BCMA. In some embodiments, the invention provides antibodies or antigen binding fragments that compete with BCMA28 for binding to BCMA. In some embodiments, the invention provides antibodies or antigen binding fragments that compete with BCMA30 for binding to BCMA. In some embodiments, the invention provides antibodies or antigen binding fragments that compete with BCMA31 for binding to BCMA. In some embodiments, the invention provides antibodies or antigen binding fragments that compete with BCMA32 for binding to BCMA. In some embodiments, the invention provides antibodies or antigen binding fragments that compete with BCMA33 for binding to BCMA. In some embodiments, the invention provides antibodies or antigen binding fragments that compete with BCMA34 for binding to BCMA. In some embodiments, the invention provides antibodies or antigen binding fragments that compete with BCMA35 for binding to BCMA.

The invention further contemplates other variants and equivalents substantially homologous to the recombinant, monoclonal, chimeric, humanized and human antibodies or antibody fragments thereof described herein. In some embodiments, it is desirable to increase the binding affinity of the antibody. In some embodiments, it is desirable to modulate biological properties of antibodies, including but not limited to specificity, thermostability, expression levels, effector function, glycosylation, immunogenicity, and/or solubility. Those skilled in the art will appreciate that amino acid changes may alter the post-translational processes of the antibody, e.g., alter the number or position of glycosylation sites or alter membrane anchoring properties.

A variant may be a substitution, deletion, or insertion of one or more nucleotides encoding an antibody or polypeptide that results in a change in the amino acid sequence relative to the native antibody or polypeptide sequence. In some embodiments, the amino acid substitution is a result of substituting one amino acid for another amino acid having similar structure and/or chemical properties, such as substituting serine for leucine, e.g., a conservative amino acid substitution. Insertions or deletions may be in the range of about 1 to 5 amino acids. In some embodiments, substitutions, deletions, or insertions include fewer than 25 amino acid substitutions, fewer than 20 amino acid substitutions, fewer than 15 amino acid substitutions, fewer than 10 amino acid substitutions, fewer than 5 amino acid substitutions, fewer than 4 amino acid substitutions, fewer than 3 amino acid substitutions, or fewer than 2 amino acid substitutions relative to the parent molecule. In some embodiments, variations in biologically useful and/or related amino acid sequences can be determined by systematically making insertions, deletions, or substitutions in the sequence, and detecting the activity of the resulting variant protein as compared to the parent protein.

The constant regions of antibodies are known in the art to mediate a number of effector functions, and these effector functions may vary depending on the isotype of the antibody. For example, the C1 region of complement binds to the Fc region of an IgG or IgM antibody (binds to an antigen) to activate the complement system. Activation of complement plays an important role in the opsonization and lysis of cellular pathogens. Activation of the complement also stimulates inflammatory responses and is involved in autoimmune hypersensitivity reactions. Furthermore, the Fc region of an antibody may bind to cells expressing Fc receptors (FcR). There are many Fc receptors specific for different classes of antibodies, including IgG (gamma receptor), igE (epsilon receptor), igA (alpha receptor), and IgM (mu receptor). Binding of antibodies to cell surface Fc receptors initiates a number of important and diverse biological responses including phagocytosis and destruction of antibody-coated particles, clearance of immune complexes, killing of cytolytic antibody-coated target cells (known as antibody-dependent cellular cytotoxicity or ADCC), release of inflammatory mediators, placental transfer, and control of immunoglobulin production. In some embodiments, an anti-BCMA antibody or antigen binding fragment of the invention comprises at least one constant region of a human IgA antibody. In some embodiments, an anti-BCMA antibody or antigen binding fragment of the invention comprises at least one constant region of a human IgD antibody. In some embodiments, an anti-BCMA antibody or antigen binding fragment of the invention comprises at least one constant region of a human IgE antibody. In some embodiments, an anti-BCMA antibody or antigen binding fragment of the invention comprises at least one constant region of a human IgG antibody. In some embodiments, an anti-BCMA antibody or antigen binding fragment of the invention comprises at least one constant region of a human IgM antibody. In some embodiments, an anti-BCMA antibody or antigen binding fragment of the invention comprises at least one constant region of a human IgG1 antibody. In some embodiments, an anti-BCMA antibody or antigen binding fragment of the invention comprises at least one constant region of a human IgG2 antibody. In some embodiments, an anti-BCMA antibody or antigen binding fragment of the invention comprises at least one constant region of a human IgG3 antibody. In some embodiments, an anti-BCMA antibody or antigen binding fragment of the invention comprises at least one constant region of a human IgG4 antibody.

In some embodiments, at least one or more constant regions in an anti-BCMA antibody or antigen binding fragment of the invention have been modified or deleted. In some embodiments, the antibody comprises modifications to one or more of the three heavy chain constant regions (CH 1, CH2, or CH 3), and/or modifications to the light chain constant region (CL). In some embodiments, the heavy chain constant region of the modified antibody comprises at least one human constant region. In some embodiments, the heavy chain constant region of the modified antibody comprises more than one human constant region. In some embodiments, the modification to the constant region comprises the addition, deletion, or substitution of one or more amino acids in one or more domains. In some embodiments, one or more domains are partially or completely deleted from the constant region of the modified antibody. In some embodiments, the entire CH2 domain (Δch2 construct) is removed from the antibody. In some embodiments, the deleted constant regions are replaced with short amino acid spacers to provide some of the molecular flexibility normally afforded by deleted constant regions. In some embodiments, the modified antibody comprises a CH3 domain fused directly to the antibody hinge region. In some embodiments, the modified antibodies include a peptide spacer interposed between the hinge region and the modified CH2 and/or CH3 domains.

In some embodiments, the anti-BCMA antibody or antigen binding fragment comprises one Fc region. In some embodiments, the Fc region is fused by a hinge. The hinge may be an IgG1 hinge, an IgG2 hinge or an IgG3 hinge. The amino acid sequences of the Fc regions of human IgG1, igG2, igG3, and IgG4 are known to those of ordinary skill in the art. In some cases, fc regions with amino acid variations are found in natural antibodies. In some embodiments, modified antibodies (e.g., modified Fc regions) provide altered effector functions, which in turn affect the biological properties of the antibodies. For example, in some embodiments, deletion or inactivation of the constant region (by point mutation or other means) reduces binding of the modified antibody to the Fc receptor upon circulation. In some embodiments, the constant region modification reduces the immunogenicity of the antibody. In some embodiments, the constant region modification increases the serum half-life of the antibody. In some embodiments, the constant region modification reduces the serum half-life of the antibody. In some embodiments, the constant region modification reduces or eliminates ADCC and/or Complement Dependent Cytotoxicity (CDC) of the antibody. In some embodiments, substitution of a particular amino acid in the human IgG1 Fc region with a corresponding IgG2 or IgG4 residue reduces effector functions (e.g., ADCC and CDC) in the modified antibody. In some embodiments, the antibody does not have one or more effector functions (e.g., a null-response antibody). In some embodiments, the antibody has no ADCC activity and/or no CDC activity. In some embodiments, the antibody does not bind to Fc receptors and/or complement factors. In some embodiments, the antibody lacks effector function. In some embodiments, the constant region modification increases or enhances ADCC and/or CDC of the antibody. In some embodiments, the constant region is modified to eliminate disulfide bonds or oligosaccharide moieties. In some embodiments, the constant region is modified to add/replace one or more amino acids, thereby providing one or more cytotoxin, oligosaccharide, or carbohydrate attachment sites. In some embodiments, an anti-BCMA antibody or antigen binding fragment comprises a variant Fc region that is genetically engineered by substitution at a particular amino acid position as compared to the native Fc region. In some embodiments, an anti-BCMA antibody or antigen binding fragment of the invention comprises an IgG1 heavy chain constant region comprising one or more amino acid substitutions selected from the group consisting of K214R, L234A, L235E, G237A, D356E and L358M (EU numbering). In some embodiments, the IgG1 heavy chain constant region comprises one or more amino acid substitutions selected from the group consisting of K214R, L234A, L235E, G237A, A S, P331S, D356E and L358M (EU numbering). In some embodiments, the IgG1 heavy chain constant region comprises one or more amino acid substitutions selected from the group consisting of K214R, C226S, C S and P238S (EU numbering). In some embodiments, the IgG1 heavy chain constant region comprises one or more amino acid substitutions selected from the group consisting of K214R, D356E and L358M (EU numbering). In some embodiments, the IgG1 heavy chain constant region comprises one or more amino acid substitutions selected from the group consisting of S131C, K133R, G137E, G S, Q196K, I199T, N203D, K214R, C226S, C229S and P238S (EU numbering).

In some embodiments, variants may include the addition of amino acid residues at the amino and/or carboxy terminus of an antibody or polypeptide. The length of the added amino acid residues may range from one to one hundred or more residues. In some embodiments, the variant comprises an N-terminal methionyl residue. In some embodiments, the variants comprise other polypeptides/proteins (e.g., fc regions) to produce fusion proteins. In some embodiments, the variants are designed to be detectable and may include a detectable label and/or protein (e.g., a fluorescent label or enzyme).

The variant antibodies or antigen binding fragments of the invention may be produced using methods known in the art, including, but not limited to, site-directed mutagenesis, alanine-scanning mutagenesis, and PCR mutagenesis.

In some embodiments, variants of the disclosed anti-BCMA antibodies or antigen binding fragments can retain BCMA binding ability to a similar degree, the same degree, or a higher degree than the parent antibody or antigen binding fragment. In some embodiments, the variant may have at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or more identity in amino acid sequence to the parent antibody or antigen binding fragment. In some embodiments, variants of an anti-BCMA antibody or antigen binding fragment include amino acid sequences of a parent anti-BCMA antibody or antigen binding fragment having one or more conservative amino acid substitutions. Conservative amino acid substitutions are known in the art, and include those in which one amino acid having a particular physical and/or chemical property is replaced with another amino acid having the same or similar chemical or physical property.

In some embodiments, variants of an anti-BCMA antibody or antigen binding fragment include the amino acid sequence of a parent antibody or antigen binding fragment having one or more non-conservative amino acid substitutions. In some embodiments, variants of an anti-BCMA antibody or antigen binding fragment include an amino acid sequence of a parent binding antibody or antigen binding fragment having one or more non-conservative amino acid substitutions, wherein the one or more non-conservative amino acid substitutions do not interfere with or inhibit one or more biological activities (e.g., BCMA binding) of the variant. In certain embodiments, the one or more conservative amino acid substitutions, and/or the one or more non-conservative amino acid substitutions, may enhance the biological activity of the variant, such that the biological activity of the functional variant is increased as compared to the parental binding moiety.

In some embodiments, the variants can have 1, 2, 3, 4, or 5 amino acid substitutions in the binding portion of the CDRs (e.g., VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR 3).

In some embodiments, an anti-BCMA antibody or antigen binding fragment of the present invention is chemically modified naturally or by intervention. In some embodiments, the anti-BCMA antibody or antigen binding fragment is chemically modified by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, and/or attachment to a cellular ligand or other protein. Any of a number of chemical modifications may be made by known techniques. The anti-BCMA antibody or antigen binding fragment may include one or more amino acid analogs (including, for example, unnatural amino acids), as well as other modifying groups known in the art.

In some embodiments, an anti-BCMA antibody or antigen binding fragment (e.g., an antibody) is administered at a dissociation constant (K) of about 1 μm or less, about 100nM or less, about 40nM or less, about 20nM or less, about 10nM or less, about 1nM or less, about 0.1nM or less, about 50pM or less, about 10pM or less, or about 1pM or less _D ) BCMA (e.g., human BCMA) is bound. In some embodiments, the anti-BCMA antibody or antigen binding fragment has a K of about 20nM or less _D BCMA (e.g., human BCMA) is bound. In some embodiments, the anti-BCMA antibody or antigen binding fragment has a K of about 10nM or less _D BCMA (e.g., human BCMA) is bound. In some embodiments, the anti-BCMA antibody or antigen binding fragment has a K of about 1nM or less _D BCMA (e.g., human BCMA) is bound. In some embodiments, the anti-BCMA antibody or antigen binding fragment has a K of about 0.5nM or less _D BCMA (e.g., human BCMA) is bound. In some embodiments, the anti-BCMA antibody or antigen binding fragment has a K of about 0.1nM or less _D BCMA (e.g., human BCMA) is bound. In some embodiments, the anti-BCMA antibody or antigen binding fragment binds to a protein at a K of about 50pM or less _D BCMA (e.g., human BCMA) is bound. In some embodiments, the anti-BCMA antibody or antigen binding fragment has a K of about 25pM or less _D BCMA (e.g., human BCMA) is bound. In some embodiments, the anti-BCMA antibody or antigen binding fragment has a K of about 10pM or less _D BCMA (e.g., human BCMA) is bound. In some embodiments, the anti-BCMA antibody or antigen binding fragment has a K of about 1pM or less _D BCMA (e.g., human BCMA) is bound. In some embodiments, the dissociation constant of the binding agent (e.g., antibody) for BCMA is the dissociation constant determined using BCMA protein immobilized on a Biacore chip and the binding agent flowing through the chip. In some casesIn embodiments, the dissociation constant of a binding agent (e.g., antibody) for BCMA is the dissociation constant determined using the binding agent captured by the anti-human IgG antibody on the Biacore chip and the soluble BCMA flowing through the chip.

The anti-BCMA antibodies or antigen binding fragments of the invention may be analyzed for their physical, chemical, and/or biological properties by various methods known in the art. In some embodiments, an anti-BCMA antibody is tested for its ability to bind BCMA (e.g., human BCMA). Binding assays include, but are not limited to, SPR (e.g., biacore), ELISA, and FACS. Furthermore, antibodies can be evaluated in terms of solubility, stability, thermostability, viscosity, expression level, expression quality, and/or purification efficiency.

Epitope identification is a method of recognizing a binding site, region or epitope on a target protein to which an antibody binds. Various methods are known in the art for mapping epitopes to target proteins. These methods include mutations including, but not limited to, shotgun mutations, site-directed mutagenesis, and alanine scanning; these methods also include domain or fragment scanning; peptide scanning (e.g., pepscan technology); display methods (e.g., phage display, microbial display, and ribosome/mRNA display); methods involving proteolysis and mass spectrometry; structural measurements (e.g., X-ray crystallography and NMR). In some embodiments, the anti-BCMA antibodies or antigen binding fragments of the present invention are characterized by assays including, but not limited to, N-terminal sequencing, amino acid analysis, HPLC, mass spectrometry, ion exchange chromatography, and papain digestion.

In some embodiments, the anti-BCMA antibody or antigen binding fragment binds to a cytotoxic agent or cytotoxic moiety. In some embodiments, an anti-BCMA antibody or antigen binding fragment is conjugated to a cytotoxic agent to form an ADC (antibody-drug conjugate). In some embodiments, the cytotoxic moiety is a chemotherapeutic agent, including but not limited to methotrexate, doxorubicin (adriamycin/doxorubicin), melphalan, mitomycin C, chlorambucil, duocarmycin (duocarmycin), daunomycin, pyrrolobenzodiazepines (PBDs), or other intercalating agents. In some embodiments, the cytotoxic moiety is a microtubule inhibitor, including, but not limited to, auristatins, maytansinoids (e.g., DM1 and DM 4), and tubulin (tubulysins). In some embodiments, the cytotoxic moiety is an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or a fragment thereof, including but not limited to diphtheria chain, non-binding active fragments of diphtheria toxin, exotoxin a chain, ricin a chain, abrin a chain, pristina root toxin a chain, α -sarcins, aleurone, carnosine, pokeweed protein (PAPI, PAPII, and PAP-S), balsam pear inhibitors, curcin (curcin), crotin (crotin), soapbark (Sapaonaria officinalis) inhibitors, gelonin, mitomycin, restrictocin, phenomycin, ionomycin, and trichothecenes. In some embodiments, the antibodies bind to one or more small molecule toxins, such as card Li Jimei, maytansinoids, trichothenes, and CC1065.

In some embodiments, the anti-BCMA antibodies or antigen binding fragments of the present invention are conjugated to a detectable substance or molecule that enables the agent to be used for diagnosis and/or detection. The detectable substance may include, but is not limited to, enzymes such as horseradish peroxidase, alkaline phosphatase, beta-galactosidase, and acetylcholinesterase; also included are prosthetic groups such as biotin and flavins; fluorescent substances such as umbelliferone, fluorescein Isothiocyanate (FITC), rhodamine, tetramethylrhodamine isothiocyanate (TRITC), dichlorotriazinylamine fluorescein, dansyl chloride, anthocyanin (Cy 3) and phycoerythrin; bioluminescent materials such as luciferase; radioactive materials, e.g. ²¹² Bi、 ¹⁴ C、 ⁵⁷ Co、 ⁵¹ Cr、 ⁶⁷ Cu、 ¹⁸ F、 ⁶⁸ Ga、 ⁶⁷ Ga、 ¹⁵³ Gd、 ¹⁵⁹ Gd、 ⁶⁸ Ge、 ³ H、 ¹⁶⁶ Ho、 ¹³¹ I、 ¹²⁵ I、 ¹²³ I、 ¹²¹ I、 ¹¹⁵ In、 ¹¹³ In、 ¹¹² In、 ¹¹¹ In、 ¹⁴⁰ La、 ¹⁷⁷ Lu、 ⁵⁴ Mn、 ⁹⁹ Mo、 ³² P、 ¹⁰³ Pd、 ¹⁴⁹ Pm、 ¹⁴² Pr、 ¹⁸⁶ Re、 ¹⁸⁸ Re、 ¹⁰⁵ Rh、 ⁹⁷ Ru、 ³⁵ S、 ⁴⁷ Sc、 ⁷⁵ Se、 ¹⁵³ Sm、 ¹¹³ Sn、 ¹¹⁷ Sn、 ⁸⁵ Sr、 ^99m Tc、 ²⁰¹ Ti、 ¹³³ XE、 ⁹⁰ Y、 ⁶⁹ Yb、 ¹⁷⁵ Yb、 ⁶⁵ Zn; a positron emitting metal; and a magnetic metal ion positron emitting metal; and magnetic metal ions.

The anti-BCMA antibodies or antigen binding fragments of the present invention may be attached to a solid support. Such solid supports include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride or polypropylene. In some embodiments, the immobilized anti-BCMA antibody or antigen binding fragment is used in an immunoassay. In some embodiments, the immobilized anti-BCMA antibody or antigen binding fragment is used to purify an antigen of interest (e.g., human BCMA).

5.3CAR, TCR and genetically engineered immune effector cells

The anti-BCMA antibodies or antigen binding fragments of the invention can be used as part of a Chimeric Antigen Receptor (CAR) or T Cell Receptor (TCR), which can be expressed in immune effector cells for the treatment of cancer. As such, the invention also provides CARs and TCRs that specifically bind BCMA (e.g., human BCMA), immune effector cells expressing such CARs or TCRs, and uses of such cells.

5.3.1TCRs

The present invention provides T Cell Receptors (TCRs) that specifically bind BCMA ("BCMA TCRs"). TCRs are antigen-specific molecules responsible for recognizing antigenic peptides that occur in the context of MHC products on the surface of APCs or any nucleated cells. The system confers to T cells, through their TCR, the potential ability to recognize an array of whole intracellular antigens (including viral proteins) expressed by the cells, which are processed into short peptides, bound to intracellular MHC molecules, and delivered to the surface as peptide-MHC complexes. This system allows foreign proteins (such as mutated cancer antigens or viral proteins) or aberrantly expressed proteins to serve as targets for T cells (e.g., davis and Bjorkman (1988) Nature,334,395-402; davis et al (1998) Annu Rev Immunol,16, 523-544).

The interaction of TCR and peptide-MHC complexes can drive T cells into different activation states, depending on the affinity (or dissociation rate) of the binding. TCR recognition processes allow T cells to distinguish between normal and healthy cells and cells transformed, for example, by viruses or malignancies, by providing a diverse library of TCRs, where there is a high probability that one or more TCRs will be present with binding affinity to foreign peptides bound to MHC molecules above the threshold for stimulating T cell activity (Manning and Kranz (1999) Immunology Today,20, 417-422).

Wild-type TCRs isolated from human or mouse T cell clones identified by in vitro culture have been shown to have relatively low binding affinities (K _D =1-300 μΜ) (Davis et al (1998) Annu Rev Immunol,16, 523-544). This is due in part to the negative selection of self peptide-MHC ligands by T cells developing within the thymus (tolerance induction), thus allowing T cells with too high an affinity to be cleared (Starr et al (2003) Annu Rev Immunol,21,139-76). To compensate for these relatively low affinities, T cells evolved a co-receptor system in which cell surface molecules CD4 and CD8 bind to MHC molecules (class II and class I, respectively) and mediate signaling activity in concert with TCRs. CD8 is particularly effective in this process, allowing TCRs with very low affinity (e.g., K _D =300 μm) mediate strong antigen-specific activity.

Directed evolution can be used to generate TCRs with higher affinity for specific peptide-MHC complexes. Methods that may be used include yeast display (Holler et al (2003) Nat Immunol,4,55-62; holler et al (2000) Proc Natl Acad Sci U S A,97,5387-92). Phage display (Li et al (2005) Nat Biotechnol,23,349-54), and T cell display ((Chervin et al (2008) J Immunol Methods,339,175-84)) all three methods involve engineering or modifying a common, low affinity TCR that exhibits a wild-type TCR to increase affinity to the cognate peptide-MHC complex (T cell specific original antigen).

Also, in some embodiments, the TCRs provided herein include an anti-BCMA antibody or antigen binding fragment of the invention. The anti-BCMA antibody or antigen binding fragment may be any anti-BCMA antibody or antigen binding fragment described herein. For illustrative purposes, in some embodiments, the TCRs provided herein include anti-BCMA antibodies or antigen binding fragments that may have a VL and a VH, wherein the VL includes VL CDR1, CDR2, and CDR3, and the VH includes VH CDR1, CDR2, and CDR3, and wherein the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 have the amino acid sequences shown in (1) SEQ ID NOs 1, 11, 22, 33, 44, and 56, respectively; (2) Amino acid sequences shown in SEQ ID NOs 2, 12, 23,34, 45 and 57; (3) Amino acid sequences shown in SEQ ID NOs 3, 13, 24, 35, 46 and 58; (4) Amino acid sequences shown in SEQ ID NOs 4, 14, 24, 36, 47 and 59; (5) Amino acid sequences shown in SEQ ID NOs 5, 15, 25, 37, 48 and 60; (6) Amino acid sequences shown in SEQ ID NOS.6, 16, 26, 38, 49 and 61; (7) Amino acid sequences shown in SEQ ID NOs 7, 17, 27, 35, 50 and 62; (8) Amino acid sequences shown in SEQ ID NOS 8, 18, 28, 39, 51 and 63; (9) Amino acid sequences shown in SEQ ID NOs 2, 19, 29, 40, 52 and 64; (10) Amino acid sequences shown in SEQ ID NOs 2, 20, 30, 41, 53 and 65; (11) Amino acid sequences shown in SEQ ID NOs 9, 21, 31, 42, 54 and 66; or (12) the amino acid sequences shown in SEQ ID NOS 10, 14, 32, 43, 55 and 67.

In some embodiments, TCRs provided herein may include an anti-BCMA antibody or antigen binding fragment that is an scFv labeled BCMA21, BCMA22, BCMA23, BCMA24, BCMA27, BCMA28, BCMA30, BCMA31, BCMA32, BCMA33, BCMA34, or BCMA 35. In some embodiments, TCRs provided by the present invention may include BCMA24. In some embodiments, TCRs provided herein may include BCMA31. In some embodiments, TCRs provided herein may include BCMA33.

In some embodiments, the TCRs provided herein include an alpha chain and a beta chain. The constant regions of the TCR alpha and beta chains are encoded by TRAC and TRBC, respectively. Human TRAC may have a number corresponding to UniProtKB/Swiss-Prot: p01848.2 (accession number: P01848.2 GI: 1431906459). Human TRBC may have an amino acid sequence corresponding to the GenBank sequence (accession number: ALC78509.1 GI: 924924895). In some embodiments, the TCRs provided herein include a TCR a chain comprising an anti-BCMA antibody or antigen binding fragment provided herein. In some embodiments, the TCRs provided herein include a TCR β chain comprising an anti-BCMA antibody or antigen binding fragment provided herein. In some embodiments, the TCR comprises a gamma chain and a delta chain. The constant regions of the TCR gamma and delta chains are encoded by TRGC and TRDC, respectively. Human TRGC can have a sequence corresponding to UniProtKB/Swiss-Prot: P0CF51.1 (accession number: P0CF51.1 GI: 294863156), or corresponds to UniProtKB/Swiss-Prot: p03986.2 (accession number P03986.2GI: 1531253869). Human TRDC may have a sequence corresponding to UniProtKB/Swiss-Prot: B7Z8K6.2 (accession number: B7Z8K6.2 GI: 294863191). In some embodiments, the TCRs provided herein include a TCR gamma chain comprising an anti-BCMA antibody or antigen binding fragment provided herein. In some embodiments, the TCRs provided herein include a TCR delta chain comprising an anti-BCMA antibody or antigen binding fragment provided herein.

5.3.2CARs

CARs are engineered receptors that provide antigen binding and immune effector cell activation functions. The CAR can be used to specifically transplant an antibody (e.g., a monoclonal antibody) onto an immune effector cell (e.g., a T cell, NK cell, or macrophage). The CARs re-target immune effector cells (e.g., T cells) to tumor surface antigens in an HLA-independent manner (Sadelain et al, nat. Rev. Cancer.3 (1): 35-45 (2003); sadelain et al, cancer Discovery 3 (4): 388-398 (2013); rafiq and Brentjens (2016). Nat Rev Clin Oncol (6): 370-383). Typical structures of CAR molecules include extracellular antigen binding domains (e.g., scFv), transmembrane domains (TM), and intracellular signaling domains. The extracellular antigen binding domain of a CAR is typically derived from a monoclonal antibody (mAb) or receptor or ligand thereof. Binding of the CAR to the antigen can trigger phosphorylation of immune receptor tyrosine activation motifs (ITAMs) in the intracellular domain, thereby initiating the signaling cascade required for cytolytic induction, cytokine secretion and proliferation. T Cells (CART) expressing CARs can be divided into three generations, depending on the presence of intracellular co-stimulatory signals.

In some embodiments, the invention provides a CAR that specifically binds BCMA ("BCMACAR"). In some embodiments, the CAR may be a "first generation", "second generation" or "third generation" CAR (see, e.g., sadelain et al, cancer Discov.3 (4): 388-398 (2013); jensen et al, immunol. Rev.257:127-133 (2014); sharpe et al, dis. Model Mech.8 (4): 337-350 (2015); june et al (2018), science 359 (6382): 1361-1365).

"first generation" CARs typically consist of an extracellular antigen-binding domain, e.g., a single chain variable region fragment (scFv), fused to a transmembrane domain, which is fused to the cytoplasmic/intracellular domain of a T cell receptor chain. "first generation" CARs typically have an intracellular domain from the cd3ζ -chain, which is the primary transmitter of endogenous T Cell Receptor (TCRs) signals. "first generation" CARs can provide de novo antigen recognition and elicit CD4 through the CD3 zeta chain signaling domain in a single fusion molecule ⁺ T cells and CD8 ⁺ Activation of T cells is independent of HLA-mediated antigen presentation. A "second generation" CAR comprises a Cancer antigen binding domain fused to an intracellular signaling domain capable of activating an immune effector cell (e.g., a T cell) and a co-stimulatory domain intended to enhance the efficacy and persistence of the immune effector cell (e.g., a T cell) (Sadelain et al, cancer discovery.3:388-398 (2013)). 3:388-398 (2013)). Thus, CAR design can combine antigen recognition and signal transduction, both functions being physiologically assumed by two independent complexes (TCR heterodimer and CD3 complex). The "second generation" CARs include intracellular domains from various co-stimulatory receptors, such as CD28, 4-1BB, ICOS, OX, etc., located at the cytoplasmic tail of the CAR to provide additional signals to the cell. The "second generation" CAR provides both costimulatory (e.g., through the CD28 or 4-1BB domain) and activation (e.g., through the CD3 zeta signaling domain) functions. Studies have shown that "second generation" CARs can increase the anti-tumor activity of T cells. In 2017, the FDA approved two anti-CD 19 CAR T cell productions The product is used for treating recurrent B cell precursor acute lymphoblastic leukemia (B-ALL) and B cell non-Hodgkin lymphoma. The "third generation" CARs provide a variety of co-stimulatory (e.g., by comprising domains of both CD28 and 4-1 BB) and activating (e.g., by comprising a cd3δ activating domain) functions.

Thus, provided by the present invention is a CAR that specifically binds BCMA, comprising, from N-terminus to C-terminus: (a) a BCMA binding domain comprising an anti-BCMA antibody or antigen binding fragment provided by the invention, (b) a transmembrane domain, and (c) a cytoplasmic domain. The anti-BCMA antibody or antigen binding fragment may be any anti-BCMA antibody or antigen binding fragment described herein. For illustrative purposes, in some embodiments, the CARs provided by the invention include a CAR that can include an anti-BCMA antibody or antigen binding fragment that can have a VL and a VH, wherein the VL includes a VL CDR1, a CDR2, and a CDR3, and the VH includes a VH CDR1, a CDR2, and a CDR3, and wherein the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 have the amino acid sequences shown in (1) SEQ ID NOs 1, 11, 22, 33, 44, and 56, respectively; (2) Amino acid sequences shown in SEQ ID NOs 2, 12, 23, 34, 45 and 57; (3) Amino acid sequences shown in SEQ ID NOs 3, 13, 24, 35, 46 and 58; (4) Amino acid sequences shown in SEQ ID NOs 4, 14, 24, 36, 47 and 59; (5) Amino acid sequences shown in SEQ ID NOs 5, 15, 25, 37, 48 and 60; (6) Amino acid sequences shown in SEQ ID NOS.6, 16, 26, 38, 49 and 61; (7) Amino acid sequences shown in SEQ ID NOs 7, 17, 27, 35, 50 and 62; (8) Amino acid sequences shown in SEQ ID NOS 8, 18, 28, 39, 51 and 63; (9) Amino acid sequences shown in SEQ ID NOs 2, 19, 29, 40, 52 and 64; (10) Amino acid sequences shown in SEQ ID NOs 2, 20, 30, 41, 53 and 65; (11) Amino acid sequences shown in SEQ ID NOs 9, 21, 31, 42, 54 and 66; or (12) the amino acid sequences shown in SEQ ID NOS 10, 14, 32, 43, 55 and 67.

In some embodiments, the CARs provided herein can include an anti-BCMA antibody or antigen binding fragment that is an scFv labeled BCMA21, BCMA22, BCMA23, BCMA24, BCMA27, BCMA28, BCMA30, BCMA31, BCMA32, BCMA33, BCMA34, or BCMA 35. In some embodiments, the CARs of the invention may include BCMA24. In some embodiments, the CARs of the invention may include BCMA31. In some embodiments, a CAR of the present invention may comprise BCMA33.

The transmembrane domain of the CAR provided herein includes a hydrophobic alpha helix that spans at least a portion of the membrane. Different transmembrane domains lead to different receptor stabilities. Following antigen recognition, the receptor aggregates and transmits a signal to the cell. In one embodiment, the transmembrane domain of a CAR provided herein can be derived from a protein or polypeptide naturally expressed in immune effector cells. By a transmembrane domain derived from a protein or polypeptide is meant that the transmembrane domain includes the entire transmembrane region of the protein or polypeptide or a fragment thereof. In some embodiments, the invention provides a CAR having a transmembrane domain that can be from CD8, CD28, CD3 zeta, CD4, 4-1BB, OX40, ICOS, CTLA-4, PD-1, LAG-3, 2B4, BTLA, T Cell Receptor (TCR) alpha chain, TCR beta chain, TCR zeta chain, CD3 epsilon, CD45, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD154, or other polypeptide expressed in an immune effector cell. In some embodiments, the transmembrane domain of a CAR provided herein includes a transmembrane region that is the transmembrane region of CD8, CD28, CD3 ζ, CD4, 4-1BB, OX40, ICOS, CTLA-4, PD-1, LAG-3, 2B4, BTLA, T Cell Receptor (TCR) alpha chain, TCR beta chain, TCR zeta chain, CD3 epsilon, CD45, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD154, or other polypeptide expressed in an immune effector cell.

In some embodiments, the transmembrane domain of a CAR provided herein is derived from CD8. In some embodiments, the transmembrane domain comprises the transmembrane region of CD8. In some embodiments, the transmembrane domain is derived from CD28. In some embodiments, the transmembrane domain comprises the transmembrane region of CD28. In some embodiments, the transmembrane domain is derived from cd3ζ. In some embodiments, the transmembrane domain comprises a transmembrane region of cd3ζ. In some embodiments, the transmembrane domain is derived from CD4. In some embodiments, the transmembrane domain comprises the transmembrane region of CD4. In some embodiments, the transmembrane domain is derived from 4-1BB. In some embodiments, the transmembrane domain includes a transmembrane region of 4-1BB. In some embodiments, the transmembrane domain is derived from OX40. In some embodiments, the transmembrane domain comprises a transmembrane region of OX40. In some embodiments, the transmembrane domain is derived from ICOS. In some embodiments, the transmembrane domain comprises a transmembrane region of ICOS. In some embodiments, the transmembrane domain is derived from CTLA-4. In some embodiments, the transmembrane domain comprises a transmembrane region of CTLA-4. In some embodiments, the transmembrane domain is derived from PD-1. In some embodiments, the transmembrane domain comprises a transmembrane region of PD-1. In some embodiments, the transmembrane domain is derived from LAG-3. In some embodiments, the transmembrane domain comprises a transmembrane region of LAG-3. In some embodiments, the transmembrane domain is derived from 2B4. In some embodiments, the transmembrane domain comprises a transmembrane region of 2B4. In some embodiments, the transmembrane domain is derived from BTLA. In some embodiments, the transmembrane domain comprises a transmembrane region of BTLA. In some embodiments, the transmembrane domain is derived from a TCR a chain. In some embodiments, the transmembrane domain comprises a transmembrane region of a TCR a chain. In some embodiments, the transmembrane domain is derived from a TCR β chain. In some embodiments, the transmembrane domain comprises a transmembrane region of a TCR β chain. In some embodiments, the transmembrane domain is derived from a tcrζ chain. In some embodiments, the transmembrane domain comprises the transmembrane region of the TCR ζ chain. In some embodiments, the transmembrane domain is derived from CD3 epsilon. In some embodiments, the transmembrane domain comprises a transmembrane region of CD3 epsilon. In some embodiments, the transmembrane domain is derived from CD45. In some embodiments, the transmembrane domain comprises the transmembrane region of CD45. In some embodiments, the transmembrane domain is derived from CD5. In some embodiments, the transmembrane domain comprises the transmembrane region of CD5. In some embodiments, the transmembrane domain is derived from CD8. In some embodiments, the transmembrane domain comprises the transmembrane region of CD8. In some embodiments, the transmembrane domain is derived from CD9. In some embodiments, the transmembrane domain comprises the transmembrane region of CD9. In some embodiments, the transmembrane domain is derived from CD16. In some embodiments, the transmembrane domain comprises the transmembrane region of CD16. In some embodiments, the transmembrane domain is derived from CD22. In some embodiments, the transmembrane domain comprises the transmembrane region of CD22. In some embodiments, the transmembrane domain is derived from CD33. In some embodiments, the transmembrane domain comprises the transmembrane region of CD33. In some embodiments, the transmembrane domain is derived from CD37. In some embodiments, the transmembrane domain comprises the transmembrane region of CD37. In some embodiments, the transmembrane domain is derived from CD64. In some embodiments, the transmembrane domain comprises the transmembrane region of CD64. In some embodiments, the transmembrane domain is derived from CD80. In some embodiments, the transmembrane domain comprises a transmembrane region of CD80. In some embodiments, the transmembrane domain is derived from CD86. In some embodiments, the transmembrane domain comprises the transmembrane region of CD86. In some embodiments, the transmembrane domain is derived from CD134. In some embodiments, the transmembrane domain comprises the transmembrane region of CD134. In some embodiments, the transmembrane domain is derived from CD154. In some embodiments, the transmembrane domain comprises a transmembrane region of CD154. Exemplary transmembrane domains are described in more detail below.

In some embodiments, the transmembrane domain may be synthetic, in which case it comprises predominantly hydrophobic residues, such as leucine and valine. Optionally, the transmembrane domain may be derived from a polypeptide that is not naturally expressed in an immune effector cell, provided that the transmembrane domain is capable of transducing a signal from an antigen bound to the CAR to an intracellular signaling domain and/or a co-stimulatory domain. In some embodiments, the transmembrane domain may include a triplet of phenylalanine, tryptophan, and valine at each end. Optionally, a short oligonucleotide or polypeptide linker, preferably between 2 and 10 amino acids in length, can form a linkage between the transmembrane domain and cytoplasmic signaling domain of the CAR. Glycine-serine conjugates provide a very suitable linker.

As described above, the cytoplasmic domain of a CAR provided by the invention can contain a signaling domain that functions in an immune effector cell expressing the CAR. Such signaling domains may be derived, for example, from cd3ζ, fc receptor γ, fcγriia, fcrβ (fcεr1b), cd3γ, cd3δ, cd3ε, CD79a, CD79b, DAP10, or DAP12. The signaling domain may also be a combination of signaling domains derived from cd3ζ, fc receptor γ, fcγriia, fcrβ (fcεr1b), cd3γ, cd3δ, cd3ε, CD79a, CD79b, DAP10, or DAP12. A signaling domain derived from a protein or polypeptide refers to a domain of a protein or polypeptide responsible for activating immune effector cells (e.g., T cells), or a fragment thereof that retains its activating function. In general, the signaling domain induces persistence, transport and/or effector functions in transduced immune effector cells, such as T cells (Sharpe et al, dis. Model Mech.8:337-350 (2015); finney et al, J. Immunol.161:2791-2797 (1998); krause et al, J. Exp. Med.188:619-626 (1998)). The signaling domain of a protein or polypeptide may be an intracellular domain of the protein or polypeptide. In some embodiments, the signaling domain comprises an intracellular domain of cd3ζ, fcrγ, fcγriia, fcrβ, cd3γ, cd3δ, cd3ε, CD5, CD22, CD79a, CD79b, DAP10, DAP12, or any combination thereof.

In some embodiments, the cytoplasmic domain of the CARs provided herein comprises a signaling domain derived from cd3ζ. In some embodiments, the signaling domain comprises an intracellular domain of cd3ζ. In some embodiments, the cytoplasmic domain comprises a signaling domain derived from fcrγ. In some embodiments, the signaling domain comprises an intracellular domain of fcrγ. In some embodiments, the cytoplasmic domain comprises a signaling domain derived from fcyriia. In some embodiments, the signaling domain comprises an intracellular domain of fcyriia. In some embodiments, the cytoplasmic domain comprises a signaling domain derived from fcrβ. In some embodiments, the signaling domain comprises an intracellular domain of fcrβ. In some embodiments, the cytoplasmic domain comprises a signaling domain derived from cd3γ. In some embodiments, the signaling domain comprises an intracellular domain of cd3γ. In some embodiments, the cytoplasmic domain comprises a signaling domain derived from cd3δ. In some embodiments, the signaling domain comprises an intracellular domain of cd3δ. In some embodiments, the cytoplasmic domain comprises a signaling domain derived from CD3 epsilon. In some embodiments, the signaling domain comprises an intracellular domain of CD3 epsilon. In some embodiments, the cytoplasmic domain comprises a signaling domain derived from CD 5. In some embodiments, the signaling domain comprises an intracellular domain of CD 5. In some embodiments, the cytoplasmic domain comprises a signaling domain derived from CD 22. In some embodiments, the signaling domain comprises an intracellular domain of CD 22. In some embodiments, the cytoplasmic domain comprises a signaling domain derived from CD79 a. In some embodiments, the signaling domain comprises an intracellular domain of CD79 a. In some embodiments, the cytoplasmic domain comprises a signaling domain derived from CD79 b. In some embodiments, the signaling domain comprises an intracellular domain of CD79 b. In some embodiments, the cytoplasmic domain comprises a signaling domain derived from DAP 10. In some embodiments, the signaling domain comprises an intracellular domain of DAP 10. In some embodiments, the cytoplasmic domain comprises a signaling domain derived from DAP 12. In some embodiments, the signaling domain comprises an intracellular domain of DAP 12. Exemplary signaling domains are described in more detail below.

In some embodiments, the cytoplasmic domain of the CARs provided herein further comprises a costimulatory domain. In some embodiments, the cytoplasmic domain of the CARs provided herein further comprises two co-stimulatory domains. Such co-stimulatory domains may provide for enhanced activation of immune effector cells (e.g., T cells). The costimulatory signaling domain can be derived, for example, from CD28, 4-1BB (CD 137), OX40, ICOS, DAP10, 2B4, CD27, CD30, CD40, CD2, CD7, LIGHT, TIGIT, GITR, TLR, DR3, or CD43. Costimulatory domains derived from proteins or polypeptides refer to domains of proteins or polypeptides that are responsible for providing enhanced activation of immune effector cells (e.g., T cells), or fragments that retain their activation function. In some embodiments, the CAR co-stimulatory domains provided herein include the intracellular domains of CD28, 4-1BB (CD 137), OX40, ICOS, DAP10, 2B4, CD27, CD30, CD40, CD2, CD7, LIGHT, TIGIT, GITR, TLR, DR3, or CD43. In some embodiments, the invention provides a CAR cytoplasmic domain comprising a co-stimulatory domain derived from CD 28. In some embodiments, the co-stimulatory domain comprises an intracellular domain of CD 28. In some embodiments, the cytoplasmic domain comprises a costimulatory domain derived from 4-1 BB. In some embodiments, the costimulatory domain comprises the intracellular domain of 4-1 BB. In some embodiments, the cytoplasmic domain comprises a co-stimulatory domain derived from OX 40. In some embodiments, the co-stimulatory domain comprises an intracellular domain of OX 40. In some embodiments, the cytoplasmic domain comprises a costimulatory domain derived from ICOS. In some embodiments, the co-stimulatory domain comprises an intracellular domain of ICOS. In some embodiments, the cytoplasmic domain comprises a costimulatory domain derived from DAP 10. In some embodiments, the co-stimulatory domain comprises an intracellular domain of DAP 10. In some embodiments, the cytoplasmic domain comprises a costimulatory domain derived from 2B 4. In some embodiments, the co-stimulatory domain comprises an intracellular domain of 2B 4. In some embodiments, the cytoplasmic domain comprises a co-stimulatory domain derived from CD 27. In some embodiments, the co-stimulatory domain comprises an intracellular domain of CD 27. In some embodiments, the cytoplasmic domain comprises a co-stimulatory domain derived from CD 30. In some embodiments, the co-stimulatory domain comprises an intracellular domain of CD 30. In some embodiments, the cytoplasmic domain comprises a co-stimulatory domain derived from CD 40. In some embodiments, the co-stimulatory domain comprises an intracellular domain of CD 40. In some embodiments, the cytoplasmic domain comprises a co-stimulatory domain derived from CD 2. In some embodiments, the co-stimulatory domain comprises an intracellular domain of CD 2. In some embodiments, the cytoplasmic domain comprises a co-stimulatory domain derived from CD 7. In some embodiments, the co-stimulatory domain comprises an intracellular domain of CD 7. In some embodiments, the cytoplasmic domain comprises a costimulatory domain derived from LIGHT. In some embodiments, the co-stimulatory domain comprises an intracellular domain of LIGHT. In some embodiments, the cytoplasmic domain comprises a costimulatory domain derived from TIGIT. In some embodiments, the co-stimulatory domain comprises an intracellular domain of TIGIT. In some embodiments, the cytoplasmic domain comprises a costimulatory domain derived from GITR. In some embodiments, the co-stimulatory domain comprises an intracellular domain of GITR. In some embodiments, the cytoplasmic domain comprises a costimulatory domain derived from a TLR. In some embodiments, the co-stimulatory domain comprises an intracellular domain of a TLR. In some embodiments, the cytoplasmic domain comprises a co-stimulatory domain derived from DR 3. In some embodiments, the co-stimulatory domain comprises an intracellular domain of DR 3. In some embodiments, the cytoplasmic domain comprises a co-stimulatory domain derived from CD43. In some embodiments, the co-stimulatory domain comprises an intracellular domain of CD43. Exemplary co-stimulatory domains are described in more detail below.

CARs comprising an intracellular domain comprising a costimulatory domain derived from 4-1BB, ICOS, or DAP-10 have been described (see U.S.7,446,190, which is incorporated herein by reference, which also describes representative sequences of 4-1BB, ICOS, and DAP-10). In some embodiments, the cytoplasmic domain of the CAR can include two co-stimulatory domains derived from two co-stimulatory receptors, e.g., CD28 and 4-1BB (see Sadelain et al, cancer discover.3 (4): 388-398 (2013)), or CD28 and OX40, or a combination of other co-stimulatory ligands disclosed herein.

The extracellular domain of the CAR may be fused to a leader peptide or signal peptide that directs the nascent protein into the endoplasmic reticulum and subsequently transported to the cell surface. It will be appreciated that once a polypeptide containing a signal peptide is expressed on the cell surface, the signal peptide has typically been proteolytically removed during processing and transport of the polypeptide to the cell surface in the endoplasmic reticulum. Thus, a polypeptide, such as a CAR, is typically expressed on the cell surface as a mature protein lacking the signal peptide, whereas a precursor form of the polypeptide includes the signal peptide. If the CAR is to be glycosylated and/or anchored to the cell membrane, a signal peptide or leader peptide may be necessary. The signal or leader sequence is a peptide sequence, typically present at the N-terminus of the newly synthesized protein, that directs the protein into the secretory pathway. The signal peptide is covalently linked to the N-terminus of the extracellular antigen-binding domain of the CAR, forming a fusion protein. Any suitable signal peptide, as is well known in the art, can be used in the CAR to provide cell surface expression in immune cells (see Gierasch biochem.28:923-930 (1989); von Heijne, J. Mol. Biol.184 (1): 99-105 (1985)). Particularly useful signal peptides may be derived from any signal peptide provided herein that is naturally expressed in immune cells, including polypeptides disclosed herein. Thus, any suitable signal peptide may be utilized to direct expression of the CAR at the cell surface of an immune effector cell provided by the present invention.

In some embodiments, the CAR may further comprise a spacer or sequence that interconnects the domains of the CAR. For example, a spacer may be included between the signal peptide and the antigen binding domain, between the antigen binding domain and the transmembrane domain, between the transmembrane domain and the intracellular domain, and/or between domains within the intracellular domain, such as between the stimulation domain and the co-stimulation domain. The spacer can be flexible enough to allow interaction of various domains with other polypeptides, e.g., to allow anti-tumorThe primary binding domain has flexibility in orientation to facilitate antigen recognition. The spacer may be, for example, a hinge region from an IgG, CH of an immunoglobulin ₂ CH ₃ (constant) regions, and/or portions of CD3 (cluster 3) or some other sequence suitable as a spacer. In some embodiments, the presently disclosed CARs include a hinge domain that connects the BCMA binding domain and the transmembrane domain. In some embodiments, the hinge domain comprises a CD8 hinge structure. In some embodiments, the hinge domain comprises a CD28 hinge structure.

Some of the exemplary molecules provided below, the domains of the CARs provided herein can be derived therefrom.

CD 3ζCd3ζ comprises 3 immunoreceptor tyrosine-based activation motifs (ITAMs) and upon antigen binding, transmits activation signals to cells, e.g. cells of the lymphoid lineage, such as T cells. The CD3 zeta polypeptide may have an amino acid sequence corresponding to the sequence of GenBank accession NP-932170 (NP-932170.1, GI:37595565; shown below) or a fragment thereof. In some embodiments, the CD3 zeta signaling domain has the sequence of amino acids 52 to 164 of the CD3 zeta polypeptide sequence provided below, or a fragment thereof sufficient for signaling activity. See GenBank np_932170 for reference to domains within cd3ζ, such as the signal peptide of amino acids 1-21; an extracellular domain of amino acids 22-30; the transmembrane region of amino acids 31-51; an intracellular domain of amino acids 52-164. In some embodiments, the CAR can have a transmembrane domain derived from cd3ζ. The transmembrane domain may comprise the transmembrane region of cd3ζ (e.g. amino acids 31 to 51 of the sequence below) or a fragment thereof. In some embodiments, the CAR cytoplasmic domain can comprise a signaling domain derived from cd3ζ. In some embodiments, the signaling domain of cd3ζ may comprise an intracellular domain of cd3ζ (e.g., amino acids 52 to 164 of the following sequence) or fragment thereof. It will be appreciated that CD3 zeta sequences shorter or longer than the particular description domain may be included in the CAR if desired.

FcRγ，The activated class of IgG receptor fcγr forms a multimeric complex comprising an fcreceptor γ chain (fcrγ) containing an Intracellular Tyrosine Activation Motif (ITAM) whose activation triggers reactive oxygen species burst, cytokine release, phagocytosis, antibody dependent cell mediated cytotoxicity and degranulation. The FcR gamma polypeptide may have an amino acid sequence corresponding to the amino acid sequence of NCBI reference sequence np_004097.1 (GI: 4758344) (shown below) or a fragment thereof. See GenBank np_004097 for reference to domains within fcrγ, e.g., signal peptides such as amino acids 1-18; an extracellular domain of amino acids 19-23; a transmembrane domain of amino acids 24-44; an intracellular domain of amino acids 45-86. In some embodiments, the CAR may include a transmembrane domain derived from fcrγ. In some embodiments, the CAR transmembrane domain comprises a transmembrane region of fcrγ (e.g., amino acids 24 to 44 of the following sequence) or a fragment thereof. In some embodiments, the CAR cytoplasmic domain can include a signaling domain derived from fcrγ. In some embodiments, the signaling domain comprises an intracellular domain of fcrγ (e.g., amino acids 45 to 86 of the following sequence) or a fragment thereof. It will be appreciated that FcR gamma sequences shorter or longer than the particular description domain may be included in the CAR if desired.

FcγRiiaIs a cell surface receptor found on phagocytes such as macrophages, neutrophils, etc., which is involved in the phagocytosis and clearance process of immune complexes. By binding to IgG, it initiates a cellular response to pathogens and soluble antigens. Fcγriia also promotes phagocytosis of regulatory antigens. The fcyriia polypeptide may have an amino acid sequence corresponding to the sequence having NCBI reference sequence np_001129691.1 (shown below) or a fragment thereof. See NCBI reference sequence NP-001129691.1 for reference to a domain within FcgammaRIIa, e.g., amino acids 1-33A signal peptide of a base acid; an extracellular domain of amino acids 34-217; a transmembrane domain of amino acids 218-240; 241-317. In some embodiments, the CAR can include a transmembrane domain derived from fcyriia. In some embodiments, the CAR transmembrane domain comprises a transmembrane region of fcyriia (e.g., amino acids 218 to 240 of the following sequence) or a fragment thereof. In some embodiments, the CAR cytoplasmic domain can comprise a signaling domain derived from fcyriia. In some embodiments, the signaling domain comprises an intracellular domain of fcyriia (e.g., amino acids 241 to 317 of the following sequence) or a fragment thereof. It will be appreciated that fcγriia sequences shorter or longer than the particular description domain may be included in the CAR, if desired.

MTMETQMSQNVCPRNLWLLQPLTVLLLLASADSQAAAPPKAVLKLEPPWINVLQEDSVTLTCQGARSPESDSIQWFHNGNLIPTHTQPSYRFKANNNDSGEYTCQTGQTSLSDPVHLTVLSEWLVLQTPHLEFQEGETIMLRCHSWKDKPLVKVTFFQNGKSQKFSHLDPTFSIPQANHSHSGDYHCTGNIGYTLFSSKPVTITVQVPSMGSSSPMGIIVAVVIATAVAAIVAAVVALIYCRKKRISANSTDPVKAAQFEPPGRQMIAIRKRQLEETNNDYETADGGYMTLNPRAPTDDDKNIYLTLPPNDHVNSNN(SEQ ID NO:161)

FcRβ(FcεR1b)Is a high affinity receptor that binds to the Fc region of immunoglobulin epsilon. Complete mast cell responses require aggregation of fcrβ by multivalent antigens, including de novo production by degranulation releasing preformed mediators (such as histamine) as well as lipid mediators and cytokines. Fcrβ also mediates secretion of important lymphokines. Binding of allergen to receptor-bound IgE results in cell activation and mediator release responsible for allergic manifestations. The fcrβ polypeptide may have an amino acid sequence corresponding to an amino acid sequence having the NCBI reference sequence (np_ 000130.1, shown below) or a fragment thereof. See NCBI reference sequence: np_000130.1 references domains within fcrβ, such as the intracellular domains of amino acids 1-59, 118-130 and 201-244; transmembrane domains of amino acids 60-79, 98-117, 131-150 and 181-200; extracellular domains of amino acids 80-97 and 151-180. In some embodiments, the CAR cytoplasmic domain can include a signaling domain derived from fcrβ. In some embodiments, the signaling structureThe domain includes the intracellular domain of fcrβ (e.g., amino acids 1 to 59, 118 to 130, or 201 to 244 of the following sequences, or combinations thereof) or fragments thereof. It will be appreciated that fcrβ sequences shorter or longer than the particular description domain may be included in the CAR if desired.

CD3 gamma (T cell surface glycoprotein CD3 gamma chain)Is part of the TCR-CD3 complex present on the surface of T lymphocytes and plays an important role in the adaptive immune response. The cytoplasmic domain of CD3 gamma contains the Immunoreceptor Tyrosine Activation Motifs (ITAMs). In addition to signal transduction in T cell activation, cd3γ plays an important role in the dynamic regulation of cell surface TCR expression. The CD3 gamma polypeptide may have an amino acid sequence corresponding to the sequence having the NCBI reference sequence: NP-004097.1 (GI: 4758344) (shown below) or a fragment thereof. See GenBank np_004097 for reference to domains within CD3 gamma, such as the signal peptide of amino acids 1-22; an extracellular domain of amino acids 23-116; 117-137 amino acids; 138-182 amino acids. In some embodiments, the CAR can include a transmembrane domain derived from cd3γ. In some embodiments, the CAR transmembrane domain comprises a transmembrane region of cd3γ (e.g., amino acids 117 to 137 of the following sequence) or fragment thereof. In some embodiments, the CAR cytoplasmic domain can include a signaling domain derived from cd3γ. In some embodiments, the signaling domain comprises an intracellular domain of cd3γ (e.g., amino acids 138 to 182 of the following sequence) or fragment thereof. It will be appreciated that, if desired, a CD3 gamma sequence shorter or longer than the particular description domain may be included in the CAR.

CD3 delta (T cell surface glycoprotein CD3 delta chain)Is part of the TCR-CD3 complex on the surface of T lymphocytes and plays an important role in the adaptive immune response. The cytoplasmic domain of CD3δ contains the Immunoreceptor Tyrosine Activation Motif (ITAMs). In addition to signaling in T cell activation, cd3δ plays an important role in thymic cell differentiation and is involved in the correct assembly and surface expression of intracellular TCR-CD3 complex. The interaction of cd3δ with CD4 and CD8, thus serves to establish a functional link between TCR and CD4 and CD8 co-receptors, which is necessary for CD4 or CD 8T cell activation and positive selection. The CD3 delta polypeptide may have an amino acid sequence corresponding to the amino acid sequence of NCBI reference sequence np_000723.1 (shown below) or a fragment thereof. See BCBI reference sequence: np_000723.1 refers to domains within cd3δ, such as the signal peptide of amino acids 1-21; an extracellular domain of amino acids 22-105; a transmembrane region of amino acids 106-126; 127-171, and a pharmaceutically acceptable carrier. In some embodiments, the CAR can include a transmembrane domain derived from cd3δ. In some embodiments, the CAR transmembrane domain comprises a transmembrane region of cd3δ (e.g., amino acids 106 to 126 of the following sequence) or fragment thereof. In some embodiments, the CAR cytoplasmic domain can include a signaling domain derived from cd3δ. In some embodiments, the signaling domain comprises an intracellular domain of cd3δ (e.g., amino acids 127 to 171 of the following sequence) or fragment thereof. It will be appreciated that CD3 delta sequences shorter or longer than the particular description domain may be included in the CAR, if desired.

CD3 epsilon (T cell surface glycoprotein CD3 epsilon chain)Is part of the TCR-CD3 complex present on the surface of T lymphocytes and plays an important role in the adaptive immune response. The cytoplasmic domain of CD3 epsilon contains the Immunoreceptor Tyrosine Activation Motif (ITAMs). In addition to signal transduction in T cell activation,CD3 epsilon plays an important role in the proper development of T cells. CD3 epsilon triggers the assembly of the TCR-CD3 complex by the formation of two heterodimers, cd3δ/cd3γ and cd3γ/cd3γ. The CD3 epsilon polypeptide may have an amino acid sequence corresponding to the amino acid sequence of NCBI reference sequence np_000724.1 (shown below) or a fragment thereof. See BCBI reference sequence: NP-000724.1 is a signal peptide referencing a domain within CD3 epsilon, such as amino acids 1-22; an extracellular domain of amino acids 23-126; 127-152 amino acid transmembrane region; 153-207. In some embodiments, the CAR can include a transmembrane domain derived from CD3 epsilon. In some embodiments, the CAR transmembrane domain comprises a transmembrane region of CD3 epsilon (e.g., amino acids 127 to 152 of the sequence below) or a fragment thereof. In some embodiments, the CAR cytoplasmic domain can include a signaling domain derived from CD3 epsilon. In some embodiments, the signaling domain comprises the intracellular domain of CD3 epsilon (e.g., amino acids 153 to 207 of the following sequence) or a fragment thereof. It will be appreciated that CD3 epsilon sequences shorter or longer than the particular description domain can be included in the CAR, if desired.

CD79a (B-cell antigen receptor complex related protein alpha chain)Is required for the following process: in conjunction with CD79B, initiates a signaling cascade that is activated by binding of antigen to the B-cell antigen receptor complex (BCR), which results in internalization of the complex, transport to secondary endosomes, and antigen presentation. CD79a stimulates SYK autophosphorylation and activation. CD79a also binds to BLNK, approaching BLNK to SYK and phosphorylating SYK to BLNK, and interacts with some Src family tyrosine kinases, enhancing its activity. The CD79a polypeptide may have an amino acid sequence corresponding to the amino acid sequence of NCBI reference sequence np_001774.1 (shown below) or a fragment thereof. See NCBI reference sequence: np_001774.1 refers to domains within CD79a, such as the signal peptide of amino acids 1-32; an extracellular domain of amino acids 33-143; a transmembrane region of amino acids 144-165; 166-226 bitsAn intracellular domain of an amino acid. In some embodiments, the CAR can include a transmembrane domain derived from CD79 a. In some embodiments, the CAR transmembrane domain comprises the transmembrane region of CD79a (e.g., amino acids 144 to 165 of the following sequence) or a fragment thereof. In some embodiments, the CAR cytoplasmic domain can comprise a signaling domain derived from CD79 a. In some embodiments, the signaling domain comprises an intracellular domain of CD79a (e.g., amino acids 166 to 226 of the following sequence) or a fragment thereof. It will be appreciated that CD79a sequences shorter or longer than the particular description domain may be included in the CAR, if desired.

CD79B (B-cell antigen receptor complex related protein beta chain)Is required for the following process: in conjunction with CD79a, a signaling cascade is initiated that is activated by binding of antigen to the B-cell antigen receptor complex (BCR), which results in internalization of the complex, translocation to the secondary endosome, and antigen presentation. CD79b promotes phosphorylation of CD79 a. The CD79b polypeptide may have an amino acid sequence corresponding to the amino acid sequence of NCBI reference sequence np_000617.1 (shown below) or a fragment thereof. See NCBI reference sequence: np_000617.1 refers to domains within CD79b, such as the signal peptide of amino acids 1-28; 29-159; a transmembrane region of amino acids 160-180; 181-229. In some embodiments, the CAR may comprise a transmembrane domain derived from CD79 b. In some embodiments, the CAR transmembrane domain comprises the transmembrane region of CD79b (e.g., amino acids 160 to 180 of the following sequence) or a fragment thereof. In some embodiments, the CAR cytoplasmic domain can include a signaling domain derived from CD79 b. In some embodiments, the signaling domain comprises an intracellular domain of CD79b (e.g., amino acids 181 to 229 of the following sequence) or a fragment thereof. It will be appreciated that CD79b sequences shorter or longer than the specific description domain may be included if desired Is bracketed in the CAR.

DAP10DAP10, also known as hematopoietic cell signaling transducer, is a signaling subunit associated with the large family of receptors in hematopoietic cells. The DAP10 polypeptide can have an amino acid sequence corresponding to the sequence provided below with GenBank No. NP-055081.1 (GI: 15826850) or a fragment thereof. See GenBank np_055081 for reference to domains within DAP10, such as signal peptides of amino acids 1-18; an extracellular domain of amino acids 19-48; a transmembrane region of amino acids 49-69; an intracellular domain of amino acids 70-93. In some embodiments, the CAR cytoplasmic domain can comprise a signaling domain derived from DAP 10. In some embodiments, the signaling domain comprises an intracellular domain of DAP10 (e.g., amino acids 70 to 93 of the following sequence) or a fragment thereof. In some embodiments, the cytoplasmic domain comprises a costimulatory domain derived from DAP 10. In some embodiments, the costimulatory domain comprises the intracellular domain of DAP10 (e.g., amino acids 70 to 93 of the following sequence) or a fragment thereof. It is to be understood that DAP10 sequences shorter or longer than the particular description domain can be included in the CAR, if desired.

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DAP12，DAP12 is present in myeloid cells, such as macrophages and granulocytes, where it is associated with, for example, trigger receptors expressed on myeloid cell members (TREM) and MDL1 (myeloid DAP 12-related lectin 1/CLEC 5A), both of which are involved in the inflammatory response against pathogens, such as viruses and bacteria. In lymphoid cells, DAP12 is expressed in NK cells and is associated with the activating receptor (e.g.the C-type lectin receptor NKG2C), the natural cytotoxic receptor NKp44, short tail type KIR3DS1 and KIR2DS1/2/5, respectively. In particular, NGK2C is used to control CMV in humans and miceThe primary activation of NK cell receptors by infection. It was found that DAP12 containing CARs cross-linked with their Ag produced sufficient activation signals in NK cells.J Immunol 194:3201-12 (2015). The DAP12 polypeptide can have an amino acid sequence corresponding to a sequence having GenBank No. AAD09437.1 (GI: 2905996) or a fragment thereof, provided below. See GenBank No. aad09437.1 for reference to domains within DAP12, such as the signal peptide of amino acids 1-21; an extracellular domain of amino acids 22-40; the transmembrane region of amino acids 41-61; an intracellular domain of amino acids 62-113. In some embodiments, the CAR cytoplasmic domain can comprise a signaling domain derived from DAP 12. In some embodiments, the signaling domain comprises an intracellular domain of DAP12 (e.g., amino acids 62 to 113 of the following sequence) or a fragment thereof. In some embodiments, the cytoplasmic domain comprises a costimulatory domain derived from DAP 12. In some embodiments, the costimulatory domain comprises the intracellular domain of DAP12 (e.g., amino acids 62 to 113 of the following sequence) or a fragment thereof. It is to be understood that DAP12 sequences shorter or longer than the particular description domain can be included in the CAR, if desired.

CD28，Cluster of differentiation 28 (CD 28) is a protein expressed on T cells that provides a costimulatory signal for T cell activation and survival. CD28 is a receptor for CD80 (B7.1) and CD86 (B7.2) proteins. The CD28 polypeptide may have an amino acid sequence corresponding to a sequence having GenBank No. P10747 (P10747.1, GI: 115973) or NP-006130 (NP-006130.1, GI: 5453611) or a fragment thereof, as described below. See GenBank np_006130 to reference domains within CD28, e.g., signal peptides of amino acids 1 to 18; 19-152 amino acids; 153-179 amino acid transmembrane domain; an intracellular domain of amino acids 180-220. In some embodimentsIn embodiments, the CAR can include a hinge domain derived from CD28 (e.g., amino acids 114 to 152 of the following sequence) or a fragment thereof. In some embodiments, the CAR can include a transmembrane domain derived from CD 28. In some embodiments, the CAR transmembrane domain comprises the transmembrane region of CD28 (e.g., amino acids 153 to 179 of the following sequence), or a fragment thereof. In some embodiments, the CAR cytoplasmic domain can include a co-stimulatory domain derived from CD 28. In some embodiments, the co-stimulatory domain comprises the intracellular domain of CD28 (e.g., amino acids 180 to 220 of the following sequence) or a fragment thereof. In some embodiments, the CAR may include two domains derived from CD28, a costimulatory signaling domain, and a transmembrane domain. In some embodiments, the CAR has an amino acid sequence that includes the transmembrane domain and intracellular domain of CD28, and the CAR includes amino acids 153 to 220 of CD 28. In some embodiments, the CAR can include three domains derived from CD28, a transmembrane domain, a hinge domain, and a costimulatory signaling domain. In another embodiment, the CAR comprises amino acids 114 to 220 of CD 28. It will be appreciated that CD28 sequences shorter or longer than the particular description domain may be included in the CAR, if desired.

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4-1BB，4-1BB is also known as a member 9 of the tumor necrosis factor receptor superfamily, and can be used as a ligand of Tumor Necrosis Factor (TNF) and has stimulatory activity. The 4-1BB polypeptide may have an amino acid sequence corresponding to a sequence having GenBank No. P41273 (P41273.1, GI: 728739) or NP-001552 (NP-001552.2, GI: 5730095), or a fragment thereof. See GenBank np_001552 for reference to domains within 4-1BB, e.g., signal peptides of amino acids 1-17; an extracellular domain of amino acids 18-186; a transmembrane domain of amino acids 187-213; 214-255 amino acids. In some embodiments, the CAR can include a transmembrane domain derived from 4-1 BB. In some embodiments, the CAR transmembrane domain comprises a transmembrane of 4-1BBA region (e.g., amino acids 187 to 213 of the following sequence) or a fragment thereof. In some embodiments, the CAR cytoplasmic domain can comprise a costimulatory domain derived from 4-1 BB. In some embodiments, the costimulatory domain comprises the intracellular domain of 4-1BB (e.g., amino acids 214 to 255 of the following sequence), or a fragment thereof. In some embodiments, the CAR may include two domains derived from 4-1BB, a costimulatory signaling domain, and a transmembrane domain. In some embodiments, the CAR has an amino acid sequence comprising a transmembrane domain and an intracellular domain of 4-1BB, and the CAR comprises amino acids 187 to 255 of 4-1 BB. It will be appreciated that 4-1BB sequences shorter or longer than the particular description domain may be included in the CAR, if desired.

OX40，OX40, also known as a tumor necrosis factor receptor superfamily member 4 precursor or CD134, is a member of the TNFR-receptor superfamily. OX40 polypeptides may have an amino acid sequence corresponding to the sequence provided below with GenBank No. P43489 (P43489.1, GI: 1171933) or np_003318 (np_003318.1, GI: 4507579) or fragments thereof. See GenBank np_003318 for reference to domains in OX40, e.g., signal peptides of amino acids 1-28; an extracellular domain of amino acids 29-214; a transmembrane domain of amino acids 215-235; 236-277 amino acids. It is understood that OX40 sequences shorter or longer than the particular description domain may be included in the CAR, if desired. In some embodiments, the CAR can include a transmembrane domain derived from OX 40. In some embodiments, the CAR transmembrane domain comprises the transmembrane region of OX40 (e.g., amino acids 215 to 235 of the following sequence) or a fragment thereof. In some embodiments, the CAR cytoplasmic domain can include a co-stimulatory domain derived from OX 40. In some embodiments, the co-stimulatory domain comprises an intracellular domain of OX40 (e.g., amino acids 236 to 277 of the sequence below) or a fragment thereof. In some embodiments, the CAR may include two species derived from OX40 A domain, a costimulatory signaling domain, and a transmembrane domain. In some embodiments, the CAR has an amino acid sequence that includes a transmembrane domain and an intracellular domain of OX40, and the CAR includes amino acids 215 to 277 of OX 40.

ICOS，An inducible T cell costimulatory precursor (ICOS), also known as CD278, is a CD28 superfamily costimulatory receptor expressed on activated T cells. ICOS polypeptides may have an amino acid sequence corresponding to the sequence provided below with GenBank No. np_036224 (np_036224.1, gi: 15029518) or fragments thereof. See GenBank np_036224 for reference to domains within ICOS, such as signal peptides of amino acids 1-20; an extracellular domain of amino acids 21-140; 141-161 amino acids; 162-199 amino acids. In some embodiments, the CAR may include a transmembrane domain derived from ICOS. In some embodiments, the CAR transmembrane domain comprises the transmembrane region of ICOS (e.g., amino acids 141 to 161 of the following sequence) or a fragment thereof. In some embodiments, the CAR cytoplasmic domain can include a costimulatory domain derived from ICOS. In some embodiments, the co-stimulatory domain comprises the intracellular domain of ICOS (e.g., amino acids 162 to 199 of the following sequence) or a fragment thereof. In some embodiments, the CAR may include two domains derived from ICOS, a costimulatory signaling domain and a transmembrane domain. In some embodiments, the CAR has an amino acid sequence that includes a transmembrane domain and an intracellular domain of ICOS, and the CAR includes amino acids 141 to 199 of ICOS. It will be appreciated that ICOS sequences shorter or longer than the particular description domain may be included in the CAR, if desired.

2B42B4 (CD 244) is a co-stimulatory receptor expressed on both NK cells and CD8+ T cells. The target is hematopoietic cells (including B cells and T cells) and activates non-MHC-like molecules (CD 48) expressed on monocytes and granulocytes. 2B4 is activated by binding of its ligand to the target cell, resulting in NK (or T cell) activation and killing of the target cell. The 2B4 polypeptide may have an amino acid sequence corresponding to a sequence having accession numbers Q9BZW8.2 (NP-001160135.1; GI: 47605541) or a fragment thereof as provided below. See GenBank np_001160135.1 for reference to domains within 2B4, e.g., signal peptides of amino acids 1-21; an extracellular domain of amino acids 22-229; a transmembrane domain of amino acids 230-250; the intracellular domain of amino acids 251-370. In some embodiments, the CAR can include a transmembrane domain derived from 2B 4. In some embodiments, the CAR transmembrane domain comprises a transmembrane region of 2B4 (e.g., amino acids 230 to 250 of the following sequence) or fragment thereof. In some embodiments, the CAR cytoplasmic domain can include a costimulatory domain derived from 2B 4. In some embodiments, the co-stimulatory domain comprises the intracellular domain of 2B4 (e.g., amino acids 251 to 370 of the following sequence) or a fragment thereof. In some embodiments, the CAR may include two domains derived from 2B4, a costimulatory signaling domain and a transmembrane domain. In some embodiments, the CAR has an amino acid sequence comprising a transmembrane domain and an intracellular domain of 2B4, and the CAR comprises amino acids 230 to 370 of 2B 4. It will be appreciated that 2B4 sequences shorter or longer than the particular description domain may be included in the CAR, if desired.

MLGQVVTLILLLLLKVYQGKGCQGSADHVVSISGVPLQLQPNSIQTKVDSIAWKKLLPSQNGFHHILKWENGSLPSNTSNDRFSFIVKNLSLLIKAAQQQDSGLYCLEVTSISGKVQTATFQVFVFESLLPDKVEKPRLQGQGKILDRGRCQVALSCLVSRDGNVSYAWYRGSKLIQTAGNLTYLDEEVDINGTHTYTCNVSNPVSWESHTLNLTQDCQNAHQEFRFWPFLVIIVILSALFLGTLACFCVWRRKRKEKQSETSPKEFLTIYEDVKDLKTRRNHEQEQTFPGGGSTIYSMIQSQSSAPTSQEPAYTLYSLIQPSRKSGSRKRNHSPSFNSTIYEVIGKSQPKAQNPARLSRKELENFDVYS(SEQ ID NO:174)

CD27: CD27 (TNFRSF 7) is a transmembrane receptor expressed in human cd8+, cd4+ T cell subsets, NKT cells, NK cell subsets and hematopoietic progenitor cells, and induced expression in foxp3+ CD4T cells and B cell subsets. Previous studies have found that CD27 can actively provide co-stimulatory signals in vivo, increasing human T cell survival and antitumor activity. (see Song and Powell; oncominium 1, no.4 (2012): 547-549). The CD27 polypeptide may have an amino acid sequence corresponding to the sequence provided below with UniProtKB/Swiss-Prot No. P26842.2 (GenBank NP-001233.1; GI: 269849646) or a fragment thereof. See GenBank np_001233 for reference to domains within CD27, e.g., signal peptides of amino acids 1-19; an extracellular domain of amino acids 20-191; 192-212 amino acids; 213-260 amino acids. In some embodiments, the CAR can include a transmembrane domain derived from CD 27. In some embodiments, the CAR transmembrane domain comprises the transmembrane region of CD27 (e.g., amino acids 192 to 212 of the following sequence) or a fragment thereof. In some embodiments, the CAR cytoplasmic domain can include a co-stimulatory domain derived from CD 27. In some embodiments, the co-stimulatory domain comprises the intracellular domain of CD27 (e.g., amino acids 213 to 260 of the following sequence) or a fragment thereof. In some embodiments, the CAR may include two domains derived from CD27, a costimulatory signaling domain, and a transmembrane domain. In some embodiments, the CAR has an amino acid sequence that includes a transmembrane domain and an intracellular domain of CD27, and the CAR includes amino acids 192 to 260 of CD 27. It will be appreciated that CD27 sequences shorter or longer than the particular description domain may be included in the CAR, if desired.

CD30: CD30 and its ligand (CD 30L) belong to the Tumor Necrosis Factor Receptor (TNFR) and members of the Tumor Necrosis Factor (TNF) superfamily, respectively. CD30 behaves in many ways like Ox40 and can be enhanced byTCR-stimulated proliferation and cytokine production (gornzy and Weyand, arthritis research&treatment 10, no. S1 (2008): S3). The CD30 polypeptide may have an amino acid sequence corresponding to a sequence having GenBank No. AAA51947.1 (GenBank NP-001234.3; GI: 180096) or a fragment thereof provided below. See GenBank np_001234.3 for reference to domains within CD30, e.g., signal peptides of amino acids 1-18; 19-385 amino acid; a transmembrane domain of amino acids 386-406; 407-595. In some embodiments, the CAR can include a transmembrane domain derived from CD 30. In some embodiments, the CAR transmembrane domain comprises the transmembrane region of CD30 (e.g., amino acids 386 to 406 of the sequence below) or a fragment thereof. In some embodiments, the CAR cytoplasmic domain can include a co-stimulatory domain derived from CD 30. In some embodiments, the co-stimulatory domain comprises an intracellular domain of CD30 (e.g., amino acids 407 to 595 of the following sequence) or a fragment thereof. In some embodiments, the CAR may include two domains derived from CD30, a costimulatory signaling domain, and a transmembrane domain. In some embodiments, the CAR has an amino acid sequence that includes the transmembrane domain and intracellular domain of CD30, and the CAR includes amino acids 386 to 595 of CD 30. It will be appreciated that CD30 sequences shorter or longer than the particular description domain may be included in the CAR, if desired.

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CD40: CD40 is a 48kD transmembrane glycoprotein surface receptor, one of the members of the Tumor Necrosis Factor Receptor Superfamily (TNFRSF). Exemplary amino acid sequences of human CD40 are described below (see, e.g., accession numbers: ALQ33424.1, genBank NP-001241.1, GI: 957949089), CD40 was originally thought to be a co-stimulatory receptor expressed on APC, at B-finesCells and T cells play a central role in activation. CD40 ligand CD154 (also known as TRAP, T-BAM, CD40 ligand or CD 40L) is a type II integral membrane protein. See GenBank np_001241.1 for reference to domains within CD40, e.g., signal peptides of amino acids 1-20; an extracellular domain of amino acids 21-193; a transmembrane domain of amino acids 194-215; an intracellular domain of amino acids 216-277. In some embodiments, the CAR can include a transmembrane domain derived from CD 40. In some embodiments, the CAR transmembrane domain comprises the transmembrane region of CD40 (e.g., amino acids 194 to 215 of the following sequence) or a fragment thereof. In some embodiments, the CAR cytoplasmic domain can comprise a co-stimulatory domain derived from CD 40. In some embodiments, the co-stimulatory domain comprises the intracellular domain of CD40 (e.g., amino acids 216 to 277 of the sequence below) or a fragment thereof. In some embodiments, the CAR may include two domains derived from CD40, a costimulatory signaling domain, and a transmembrane domain. In some embodiments, the CAR has an amino acid sequence that includes the transmembrane domain and intracellular domain of CD40, and the CAR includes amino acids 194 to 277 of CD 40. It will be appreciated that CD40 sequences shorter or longer than the particular description domain may be included in the CAR, if desired.

MVRLPLQCVLWGCLLTAVHPEPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFTETECLPCGESEFLDTWNRETHCHQHKYCDPNLGLRVQQKGTSETDTICTCEEGWHCTSEACESCVLHRSCSPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCETKDLVVQQAGTNKTDVVCGPQDRLRALVVIPIIFGILFAILLVLVFIKKVAKKPTNKAPHPKQEPQEINFPDDLPGSNTAAPVQETLHGCQPVTQEDGKESRISVQERQ(SEQ ID NO:177)

CD2Binding of the CD2 molecule to its ligand CD58 co-stimulates proliferation, cytokine production and effector function of the T cells, especially of a CD 28-deficient T cell subset. CD58 is widely expressed on APCs including dendritic cells. Binding of CD2 to CD28 ^- CD8 ⁺ TCR signals were amplified in T cells, indicating that CD2-CD58 interactions have a true costimulatory effect. CD2 signal promotes CD28 ^- CD8 ⁺ Control of viral infection by T cells, but also promotes CD28 ^- CD8 ⁺ T cells under sustained chronic stimulation of AgContinuous amplification (Judith Leitner Jet al., immunol,2015, 195 (2) 477-487). The CD2 polypeptide may have an amino acid sequence corresponding to the sequence number provided below: np_001758.2gi:156071472 sequence or fragment thereof. See GenBank np_001758.2 for reference to domains within CD2, e.g., signal peptides of amino acids 1-24; an extracellular domain of amino acids 25-209; a transmembrane domain of amino acids 210-235; 236-351 amino acid. In some embodiments, the CAR can include a transmembrane domain derived from CD 2. In some embodiments, the CAR transmembrane domain comprises the transmembrane region of CD2 (e.g., amino acids 210 to 235 of the following sequence) or a fragment thereof. In some embodiments, the CAR cytoplasmic domain can include a co-stimulatory domain derived from CD 2. In some embodiments, the co-stimulatory domain comprises the intracellular domain of CD2 (e.g., amino acids 236 to 351 of the following sequence) or a fragment thereof. In some embodiments, the CAR may include two domains derived from CD2, a co-stimulatory conduction domain and a transmembrane domain. In some embodiments, the CAR has an amino acid sequence that includes a transmembrane domain and an intracellular domain of CD2, and the CAR includes amino acids 210 to 351 of CD 2. It will be appreciated that CD2 sequences shorter or longer than the particular description domain may be included in the CAR, if desired.

MSFPCKFVASFLLIFNVSSKGAVSKEITNALETWGALGQDINLDIPSFQMSDDIDDIKWEKTSDKKKIAQFRKEKETFKEKDTYKLFKNGTLKIKHLKTDDQDIYKVSIYDTKGKNVLEKIFDLKIQERVSKPKISWTCINTTLTCEVMNGTDPELNLYQDGKHLKLSQRVITHKWTTSLSAKFKCTAGNKVSKESSVEPVSCPEKGLDIYLIIGICGGGSLLMVFVALLVFYITKRKKQRSRRNDEELETRAHRVATEERGRKPHQIPASTPQNPATSQHPPPPPGHRSQAPSHRPPPPGHRVQHQPQKRPPAPSGTQVHQQKGPPLPRPRVQPKPPHGAAENSLSPSSN(SEQ ID NO:178)

LIGHTTNF superfamily member 14 (also known as LTg, CD258, HVEML, and LIGHT) is a co-stimulatory receptor involved in cellular immune responses. LIGHT can act as a co-stimulatory factor to activate lymphoid cells and as a block of herpes virus infection. LIGHT has been demonstrated to stimulate proliferation of T cells, triggering apoptosis of a variety of tumor cells. LIGHT is present in T cells and stromal cells. LIGHT production in human PBMCExpression on immature Dendritic Cells (DCs) that are generated. LIGHT is involved in co-stimulating human T cell proliferation, amplifying NF- κb signaling pathways, and preferentially inducing IFN- γ (rather than IL-4) production in the presence of antigen signaling. (Tamada Ket al., J Immunol,2000,164 (8) 4105-4110). The LIGHT polypeptide may have an amino acid sequence corresponding to the sequence provided below (accession number: np_001363816.1gi: 1777376047) or a fragment thereof. See GenBank np_001363816.1 for reference to domains within LIGHT, such as the intracellular domains of amino acids 1-37; a transmembrane domain of amino acids 38-58; an extracellular domain of amino acids 59-240. In some embodiments, the CAR cytoplasmic domain can include a costimulatory domain derived from LIGHT. In some embodiments, the costimulatory domain comprises the intracellular domain of LIGHT (e.g., amino acids 1 to 37 of the following sequence), or a fragment thereof. It is understood that LIGHT sequences shorter or longer than the particular description domain may be included in the CAR, if desired.

MEESVVRPSVFVVDGQTDIPFTRLGRSHRRQSCSVARVGLGLLLLLMGAGLAVQGWFLLQLHWRLGEMVTRLPDGPAGSWEQLIQERRSHEVNPAAHLTGANSSLTGSGGPLLWETQLGLAFLRGLSYHDGALVVTKAGYYYIYSKVQLGGVGCPLGLASTITHGLYKRTPRYPEELELLVSQQSPCGRATSSSRVWWDSSFLGGVVHLEAGEKVVVRVLDERLVRLRDGTRSYFGAFMV(SEQ ID NO:179)

GITR，TNF receptor superfamily member 18 (also known as TNFRSF18, AITR, GITR; CD357; GITR-D; ENERGEN) is expressed in increased expression upon T cell activation. Stimulation of T cells by GITR can enhance immunity to tumor and viral pathogens and exacerbate autoimmune diseases. The effect of stimulation by GITR is generally thought to be due to reduced effector activity of immunosuppressive cd4+cd25+ regulatory T (TReg) cells. (Shevach, E. And Stephens, G.Nat Rev Immunol6,613-618 (2006)). The LIGHT polypeptide may have an amino acid sequence corresponding to the sequence provided below (accession number: AAI52382.1, genBank NP-004186.1, GI: 158931986) or a fragment thereof. See GenBank np_004186.1 for reference to domains within GITR, e.g., signal peptides of amino acids 1-25; an extracellular domain of amino acids 26-162; 163-183 th amino acid transmembrane domain; an intracellular domain of amino acids 184-241. In some embodiments of the present invention, in some embodiments,the CAR may include a transmembrane domain derived from GITR. In some embodiments, the CAR transmembrane domain comprises the transmembrane region of GITR (e.g., amino acids 163 to 183 of the sequence below) or a fragment thereof. In some embodiments, the CAR cytoplasmic domain can include a costimulatory domain derived from GITR. In some embodiments, the co-stimulatory domain includes the intracellular domain of GITR (e.g., amino acids 184 to 241 of the sequence below) or a fragment thereof. In some embodiments, the CAR can include two domains derived from GITR, a costimulatory signaling domain and a transmembrane domain. In some embodiments, the CAR has an amino acid sequence that includes a transmembrane domain and an intracellular domain of GITR, and the CAR includes amino acids 163 to 241 of GITR. It is understood that GITR sequences shorter or longer than the particular description domain may be included in the CAR, if desired.

MAQHGAMGAFRALCGLALLCALSLGQRPTGGPGCGPGRLLLGTGTDARCCRVHTTRCCRDYPGEECCSEWDCMCVQPEFHCGDPCCTTCRHHPCPPGQGVQSQGKFSFGFQCIDCASGTFSGGHEGHCKPWTDCTQFGFLTVFPGNKTHNAVCVPGSPPAEPLGWLTVVLLAVAACVLLLTSAQLGLHIWQLRSQCMWPRETQLLLEVPPSTEDARSCQFPEEERGERSAEEKGRLGDLWV(SEQ ID NO:180)

DR3TNF receptor superfamily member 25 (also known as DR3, TR3, DDR3, LARD, APO-3, TRAMP, WSL-1, GEF720, WSL-LR, PLEKHG5, or TNFRSF 12) is preferentially expressed in lymphocyte-enriched tissues and plays a role in regulating lymphocyte homeostasis. This receptor stimulates NF- κB activation and regulates apoptosis. The signal transduction of this receptor is mediated by various death domains containing adaptor proteins. This gene has been reported to encode multiple alternative splice transcriptional variants of different subtypes, most of which are potential secretory molecules. Selective cleavage of this gene in B cells and T cells, which predominantly produces full-length membrane-bound subtypes and is involved in controlling T cell activation-induced lymphocyte proliferation, encounters procedural changes upon T cell activation. The DR3 polypeptide may have an amino acid sequence corresponding to the sequence provided below (accession numbers: AAI17190.1, genBank NP-003781.1GI: 109658976), or a fragment thereof. See GenBank NP-003781.1 for reference to domains within DR3, e.g., amino acid positions 1-24A number peptide; an extracellular domain of amino acids 25-199; a transmembrane domain of amino acids 200-220; 221-417 amino acids. In some embodiments, the CAR can include a transmembrane domain derived from DR 3. In some embodiments, the CAR transmembrane domain comprises a transmembrane region of DR3 (e.g., amino acids 200 to 220 of the sequence below) or a fragment thereof. In some embodiments, the CAR cytoplasmic domain can include a co-stimulatory domain derived from DR 3. In some embodiments, the co-stimulatory domain includes the intracellular domain of DR3 (e.g., amino acids 221 to 417 of the sequence below) or a fragment thereof. In some embodiments, the CAR may include two domains derived from DR3, a costimulatory signaling domain and a transmembrane domain. In one embodiment, the CAR has an amino acid sequence comprising a transmembrane domain and an intracellular domain of DR3, and the CAR comprises amino acids 200 to 417 of DR 3. It will be appreciated that DR3 sequences shorter or longer than the particular description domain can be included in the CAR, if desired.

MEQRPRGCAAVAAALLLVLLGARAQGGTRSPRCDCAGDFHKKIGLFCCRGCPAGHYLKAPCTEPCGNSTCLVCPQDTFLAWENHHNSECARCQACDEQASQVALENCSAVADTRCGCKPGWFVECQVSQCVSSSPFYCQPCLDCGALHRHTRLLCSRRDTDCGTCLPGFYEHGDGCVSCPTSTLGSCPERCAAVCGWRQMFWVQVLLAGLVVPLLLGATLTYTYRHCWPHKPLVTADEAGMEALTPPPATHLSPLDSAHTLLAPPDSSEKICTVQLVGNSWTPGYPETQEALCPQVTWSWDQLPSRALGPAAAPTLSPESPAGSPAMMLQPGPQLYDVMDAVPARRWKEFVRTLGLREAEIEAVEVEIGRFRDQQYEMLKRWRQQQPAGLGAVYAALERMGLDGCVEDLRSRLQRGP(SEQ ID NO:181)

CD43，CD43 (also known as SPN-carried sialic acid protein, LSN, GALGP, GPL) is a highly sialylated glycoprotein with the function of antigen-specifically activating T cells, present on the surface of thymocytes, T lymphocytes, monocytes, granulocytes and certain B lymphocytes. Comprising a mucin-like extracellular domain, a transmembrane region and a carboxy-terminal intracellular region. In stimulated immune effector cells, proteolytic cleavage of the extracellular domain of certain cell types occurs, releasing soluble extracellular fragments. The CD43 polypeptide may have an amino acid sequence corresponding to the sequence provided below (GenBank NP-003114.1, accession number: EAW80016.1 GI: 119600422)A base acid sequence or a fragment thereof. See GenBank np_003114.1 for reference to domains within CD43, such as the signal peptide of amino acids 1-19; an extracellular domain of amino acids 20-253; 254-276 amino acid transmembrane domain; 277-400 amino acids. In some embodiments, the CAR can include a transmembrane domain derived from CD 43. In some embodiments, the CAR transmembrane domain comprises the transmembrane region of CD43 (e.g., amino acids 254 to 276 of the sequence below) or a fragment thereof. In some embodiments, the CAR cytoplasmic domain can include a co-stimulatory domain derived from CD 43. In some embodiments, the co-stimulatory domain comprises the intracellular domain of CD43 (e.g., amino acids 277 to 400 of the following sequence) or a fragment thereof. In some embodiments, the CAR may include two domains derived from CD43, a costimulatory signaling domain and a transmembrane domain. In some embodiments, the CAR has an amino acid sequence that includes a transmembrane domain and an intracellular domain of CD43, and the CAR includes amino acids 254 to 400 of CD 43. It will be appreciated that CD43 sequences shorter or longer than the particular description domain may be included in the CAR, if desired.

MATLLLLLGVLVVSPDALGSTTAVQTPTSGEPLVSTSEPLSSKMYTTSITSDPKADSTGDQTSALPPSTSINEGSPLWTSIGASTGSPLPEPTTYQEVSIKMSSVPQETPHATSHPAVPITANSLGSHTVTGGTITTNSPETSSRTSGAPVTTAASSLETSRGTSGPPLTMATVSLETSKGTSGPPVTMATDSLETSTGTTGPPVTMTTGSLEPSSGASGPQVSSVKLSTMMSPTTSTNASTVPFRNPDENSRGMLPVAVLVALLAVIVLVALLLLWRRRQKRRTGALVLSRGGKRNGVVDAWAGPAQVPEEGAVTVTVGGSGGDKGSGFPDGEGSSRRPTLTTFFGRRKSRQGSLAMEELKSGSGPSLKGEEEPLVASEDGAVDAPAPDEPEGGDGAAP(SEQ ID NO:182)

CD4，Cluster of differentiation 4 (CD 4), also known as the T cell surface glycoprotein CD4, is a glycoprotein that is present on the surface of immune cells such as helper T cells, monocytes, macrophages and dendritic cells. In some embodiments, the CAR can include a transmembrane domain derived from CD 4. CD4 exists in a variety of isomers. It will be appreciated that any isomer may be selected to achieve the desired function. Exemplary isomers include isomer 1 (NP-000607.1, GI: 10835167), isomer 2 (NP-001181943.1, GI: 303522479), isomer 3 (NP-001181944.1, GI: 303522485)The method comprises the steps of carrying out a first treatment on the surface of the Or NP-001181945.1, GI:303522491; or NP-001181946.1, GI:303522569) and the like. The sequence of an exemplary isomer, isomer 1, is provided below. See GenBank np_000607.1 for reference to domains within CD4, e.g., signal peptides such as amino acids 1-25; an extracellular domain of amino acids 26-396; a transmembrane domain of amino acids 397-418; 419-458 amino acid. In some embodiments, the CAR can include a transmembrane domain derived from CD 4. In some embodiments, the CAR transmembrane domain comprises the transmembrane region of CD4 (e.g., amino acids 397 to 418 of the following sequence) or a fragment thereof. It will be appreciated that additional sequences of CD4 outside the transmembrane domain of amino acids 397 to 418 may be included in the CAR if desired. It is further understood that CD4 sequences shorter or longer than the particular description domain may be included in the CAR, if desired.

CD8，Cluster 8 (CD 8) is a transmembrane glycoprotein that acts as a co-receptor for the T Cell Receptor (TCR). CD8 binds to Major Histocompatibility Complex (MHC) molecules and is specific for MHC class I proteins. In some embodiments, the CAR can include a transmembrane domain derived from CD 8. The CD8 polypeptide may have an amino acid sequence corresponding to the sequence provided below with GenBank No. NP-001139345.1 (GI: 225007536) or a fragment thereof. See GenBank np_001139345.1 for reference to domains within CD8, e.g., signal peptides such as amino acids 1-21; an extracellular domain of amino acids 22-182; 183-203 amino acid transmembrane domain; an intracellular domain of amino acids 204-235. In some embodiments, the CAR can include a hinge domain derived from CD 8. In some embodiments, the hinge domain may include amino acids 137-182 of a CD8 polypeptide provided below. In some embodiments, the CAR can include a transmembrane domain derived from CD 8. In some embodiments, the CAR transmembrane domain comprises the transmembrane region of CD8 (e.g., amino acids 183 to 203 of the following sequence) or a fragment thereof. In another embodimentIn a variant, the CAR may comprise amino acids 137-203 of a CD8 polypeptide provided below. In yet another embodiment, the CAR may comprise amino acids 137-209 of the CD8 polypeptide provided below. It will be appreciated that additional CD8 sequences, in addition to the hinge domain of amino acids 137 to 182 and the transmembrane domain of amino acids 183 to 203, can be included in the CAR, if desired. It is further understood that CD8 sequences shorter or longer than the particular description domain may be included in the CAR, if desired.

Thus, for exemplary purposes, a CAR of the present disclosure can include, from N-terminus to C-terminus, an anti-BCMA antibody or antigen binding fragment (e.g., an scFv of the present disclosure), a hinge (e.g., a CD8 hinge or a CD28 hinge), a transmembrane region (e.g., a CD8 transmembrane region or a CD28 transmembrane region), a costimulatory domain (e.g., the intracellular region of 4-1BB, CD28, or both), and a signaling domain (e.g., the T cell signaling domain of cd3ζ).

5.4 Polynucleotide and vector

The invention also provides polynucleotides encoding polypeptides described herein (e.g., anti-BCMA antibodies or antigen binding fragments or CARs that specifically bind BCMA). The term "polynucleotide encoding a polypeptide" encompasses: a polynucleotide comprising only the coding sequence of said polypeptide; and polynucleotides comprising additional coding and/or non-coding sequences. The polynucleotides of the invention may be in the form of RNA or in the form of DNA. The DNA may be cDNA, genomic DNA, or synthetic DNA, and may be double-stranded or single-stranded. The single-stranded DNA may be the coding strand or the non-coding (antisense) strand. The polynucleotides disclosed in the present invention may be mRNA.

The present invention expressly contemplates polynucleotides encoding any of the anti-BCMA antibodies or antigen binding fragments disclosed herein. For illustrative purposes, in some embodiments, the polynucleotides provided herein encode an anti-BCMA antibody or antigen binding fragment comprising (a) VL comprising (1) VL CDR1 having an amino acid sequence selected from the group consisting of the sequences shown in SEQ ID NOs 1-10; (2) VL CDR2 having an amino acid sequence selected from the group consisting of the sequences shown in SEQ ID NOS.11-21; and (3) a VL CDR3 having an amino acid sequence selected from the group consisting of the sequences shown in SEQ ID NOS.22-32; or a variant thereof having up to about 5 amino acid substitutions, additions and/or deletions in the VL CDRs; and/or, (b) a VH comprising (1) a VH CDR1 having an amino acid sequence selected from the group consisting of the sequences set forth in SEQ ID NOs 33-43; (2) VH CDR2 having an amino acid sequence selected from the group consisting of the sequences set forth in SEQ ID NOs 44-55; and (3) a VH CDR3 having an amino acid sequence selected from the group consisting of the sequences shown in SEQ ID NOS: 56-67; or a variant thereof having up to about 5 amino acid substitutions, additions and/or deletions in the VH CDRs. In some embodiments, the polynucleotides provided herein encode an anti-BCMA antibody or antigen binding fragment comprising (a) VL having at least 85%, at least 90%, at least 95%, at least 98%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs 68-79; and/or, (b) a VH having at least 85%, at least 90%, at least 95%, at least 98% or 100% sequence identity to an amino acid sequence selected from the group consisting of the sequences set forth in SEQ ID NOs 80-91. The polynucleotide may be in the form of DNA. The polynucleotide may be in the form of an mRNA.

In some embodiments, the polynucleotides provided herein encode an anti-BCMA antibody or antigen binding fragment disclosed herein comprising VL and VH, wherein the VL comprises VL CDR1, CDR2, and CDR3, the VH comprises VH CDR1, CDR2, and CDR3, and wherein the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 have the amino acid sequences shown in (1) SEQ ID NOs 1, 11, 22, 33, 44, and 56, respectively; (2) Amino acid sequences shown in SEQ ID NOs 2, 12, 23, 34, 45 and 57; (3) Amino acid sequences shown in SEQ ID NOs 3, 13, 24, 35, 46 and 58; (4) Amino acid sequences shown in SEQ ID NOs 4, 14, 24, 36, 47 and 59; (5) Amino acid sequences shown in SEQ ID NOs 5, 15, 25, 37, 48 and 60; (6) Amino acid sequences shown in SEQ ID NOS.6, 16, 26, 38, 49 and 61; (7) Amino acid sequences shown in SEQ ID NOs 7, 17, 27, 35, 50 and 62; (8) Amino acid sequences shown in SEQ ID NOS 8, 18, 28, 39, 51 and 63; (9) Amino acid sequences shown in SEQ ID NOs 2, 19, 29, 40, 52 and 64; (10) Amino acid sequences shown in SEQ ID NOs 2, 20, 30, 41, 53 and 65; (11) Amino acid sequences shown in SEQ ID NOs 9, 21, 31, 42, 54 and 66; or (12) the amino acid sequences shown in SEQ ID NOs 10, 14, 32, 43, 55 and 67; or a variant thereof having up to about 5 amino acid substitutions, additions and/or deletions in the VL CDRs. The polynucleotide may be in the form of DNA. The polynucleotide may be in the form of an mRNA.

In some embodiments, the polynucleotides provided herein encode an anti-BCMA antibody or antigen binding fragment disclosed herein comprising VL and VH, wherein the VL and VH have (1) the amino acid sequences shown in SEQ ID NOs 68 and 80, respectively; (2) the amino acid sequences shown in SEQ ID NOS 69 and 81; (3) the amino acid sequences shown in SEQ ID NOS.70 and 82; (4) the amino acid sequences shown in SEQ ID NOS: 71 and 83; (5) the amino acid sequences shown in SEQ ID NOS: 72 and 84; (6) the amino acid sequences shown in SEQ ID NOS: 73 and 85; (7) the amino acid sequences shown in SEQ ID NOS.74 and 86; (8) the amino acid sequences shown in SEQ ID NOS 75 and 87; (9) the amino acid sequences shown in SEQ ID NOS.76 and 88; (10) the amino acid sequences shown in SEQ ID NOS 77 and 89; (11) the amino acid sequences shown in SEQ ID NOS.78 and 90; (12) the amino acid sequences shown in SEQ ID NOS: 79 and 91. The polynucleotide may be in the form of DNA. The polynucleotide may be in the form of an mRNA.

In some embodiments, the VL and VH are linked by a linker. The connector may be a flexible connector or a rigid connector. In some embodiments, the linker has an amino acid sequence of (GGGGS) n, n=1, 2, 3, 4, or 5 (SEQ ID NO: 155). In some embodiments, the linker has an amino acid sequence of (EAAAK) n, n=1, 2, 3, 4, or 5 (SEQ ID NO: 156). In some embodiments, the linker has an amino acid sequence of (PA) nP, n=1, 2, 3, 4, or 5 (SEQ ID NO: 157). In some embodiments, the linker has the amino acid sequence of GGGGSGGGGSGGGGS (SEQ ID NO: 158).

In some embodiments, the polynucleotides provided herein encode an anti-BCMA antibody or antigen binding fragment disclosed herein comprising VL having at least 85%, at least 90%, at least 95%, at least 98%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs 68-79. In some embodiments, the polynucleotides provided herein encode an anti-BCMA antibody or antigen binding fragment disclosed herein comprising a VL having an amino acid sequence selected from the group consisting of SEQ ID NOs 68-79. In some embodiments, the polynucleotide encodes an anti-BCMA antibody or antigen binding fragment comprising a VL having the amino acid sequence shown in SEQ ID No. 68. In some embodiments, the polynucleotide encodes an anti-BCMA antibody or antigen binding fragment comprising a VL having the amino acid sequence shown in SEQ ID No. 69. In some embodiments, the polynucleotide encodes an anti-BCMA antibody or antigen binding fragment comprising a VL having the amino acid sequence shown in SEQ ID No. 70. In some embodiments, the polynucleotide encodes an anti-BCMA antibody or antigen binding fragment comprising a VL having the amino acid sequence shown in SEQ ID No. 71. In some embodiments, the polynucleotide encodes an anti-BCMA antibody or antigen binding fragment comprising a VL having the amino acid sequence shown in SEQ ID No. 72. In some embodiments, the polynucleotide encodes an anti-BCMA antibody or antigen binding fragment comprising a VL having the amino acid sequence shown in SEQ ID No. 73. In some embodiments, the polynucleotide encodes an anti-BCMA antibody or antigen binding fragment comprising a VL having the amino acid sequence shown in SEQ ID No. 74. In some embodiments, the polynucleotide encodes an anti-BCMA antibody or antigen binding fragment comprising a VL having the amino acid sequence shown in SEQ ID No. 75. In some embodiments, the polynucleotide encodes an anti-BCMA antibody or antigen binding fragment comprising a VL having the amino acid sequence shown in SEQ ID No. 76. In some embodiments, the polynucleotide encodes an anti-BCMA antibody or antigen binding fragment comprising a VL having the amino acid sequence shown in SEQ ID No. 77. In some embodiments, the polynucleotide encodes an anti-BCMA antibody or antigen binding fragment comprising a VL having the amino acid sequence shown in SEQ ID No. 78. In some embodiments, the polynucleotide encodes an anti-BCMA antibody or antigen binding fragment comprising a VL having the amino acid sequence shown in SEQ ID No. 79.

In some embodiments, polynucleotides provided herein have a nucleotide sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to a sequence selected from the group consisting of SEQ ID NOS: 92-103. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequence set forth in SEQ ID NO. 92. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequence set forth in SEQ ID NO. 93. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequence set forth in SEQ ID NO. 94. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequence set forth in SEQ ID NO. 95. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequence set forth in SEQ ID NO. 96. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequence set forth in SEQ ID NO. 97. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequence set forth in SEQ ID NO. 98. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequence set forth in SEQ ID NO 99. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequence set forth in SEQ ID NO. 100. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequence set forth in SEQ ID NO 101. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequence set forth in SEQ ID NO. 102. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequence set forth in SEQ ID NO. 103. The present invention also provides a polynucleotide which hybridizes to a polynucleotide having a nucleotide sequence selected from the group consisting of the sequences set forth in SEQ ID NOS 92-103. In some embodiments, hybridization is performed under high stringency conditions known to those of skill in the art. The polynucleotide may be in the form of DNA. The polynucleotide may be in the form of an mRNA.

In some embodiments, the polynucleotides provided herein encode an anti-BCMA antibody or antigen binding fragment disclosed herein comprising a VH having at least 85%, at least 90%, at least 95%, at least 98%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs 80-91. In some embodiments, the polynucleotides provided herein encode an anti-BCMA antibody or antigen binding fragment disclosed herein comprising a VH having an amino acid sequence selected from the group consisting of SEQ ID NOs 80-91. In some embodiments, the polynucleotide encodes an anti-BCMA antibody or antigen binding fragment comprising a VH having the amino acid sequence shown in SEQ ID No. 80. In some embodiments, the polynucleotide encodes an anti-BCMA antibody or antigen binding fragment comprising a VH having the amino acid sequence shown in SEQ ID No. 81. In some embodiments, the polynucleotide encodes an anti-BCMA antibody or antigen binding fragment comprising a VH having the amino acid sequence shown in SEQ ID No. 82. In some embodiments, the polynucleotide encodes an anti-BCMA antibody or antigen binding fragment comprising a VH having the amino acid sequence shown in SEQ ID No. 83. In some embodiments, the polynucleotide encodes an anti-BCMA antibody or antigen binding fragment comprising a VH having the amino acid sequence shown in SEQ ID No. 84. In some embodiments, the polynucleotide encodes an anti-BCMA antibody or antigen binding fragment comprising a VH having the amino acid sequence shown in SEQ ID No. 85. In some embodiments, the polynucleotide encodes an anti-BCMA antibody or antigen binding fragment comprising a VH having the amino acid sequence shown in SEQ ID No. 86. In some embodiments, the polynucleotide encodes an anti-BCMA antibody or antigen binding fragment comprising a VH having the amino acid sequence shown in SEQ ID No. 87. In some embodiments, the polynucleotide encodes an anti-BCMA antibody or antigen binding fragment comprising a VH having the amino acid sequence shown in SEQ ID No. 88. In some embodiments, the polynucleotide encodes an anti-BCMA antibody or antigen binding fragment comprising a VH having the amino acid sequence shown in SEQ ID No. 89. In some embodiments, the polynucleotide encodes an anti-BCMA antibody or antigen binding fragment comprising a VH having the amino acid sequence shown in SEQ ID No. 90. In some embodiments, the polynucleotide encodes an anti-BCMA antibody or antigen binding fragment comprising a VH having the amino acid sequence shown in SEQ ID No. 91.

In some embodiments, polynucleotides provided herein have a nucleotide sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to a sequence selected from the group consisting of SEQ ID NOS: 104-115. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequence set forth in SEQ ID NO 104. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequence set forth in SEQ ID NO. 105. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequence set forth in SEQ ID NO. 106. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequence set forth in SEQ ID NO. 107. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequence set forth in SEQ ID NO. 108. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequence set forth in SEQ ID NO. 109. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequence set forth in SEQ ID NO. 110. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequence set forth in SEQ ID NO. 111. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequence set forth in SEQ ID NO. 112. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequence set forth in SEQ ID NO 113. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequence set forth in SEQ ID NO. 114. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequence set forth in SEQ ID NO. 115. The present invention also provides a polynucleotide which hybridizes to a polynucleotide having a nucleotide sequence selected from the group consisting of the sequences set forth in SEQ ID NOS: 104-115. In some embodiments, the hybridization is performed under highly stringent conditions known to those skilled in the art. The polynucleotide may be in the form of DNA. The polynucleotide may be in the form of an mRNA.

The invention also provides variants of the polynucleotides of the invention, wherein the variants encode, for example, fragments, analogs and/or derivatives of the anti-BCMA antibodies or antigen binding fragments of the invention. In some embodiments, the invention provides a polynucleotide having at least about 80% identity, at least about 85% identity, at least about 90% identity, at least about 95% identity, at least about 96% identity, at least about 97% identity, at least about 98% identity, or at least about 99% identity to a polynucleotide sequence encoding an anti-BCMA antibody or antigen binding fragment of the invention.

In some embodiments, the polynucleotides provided herein encode an anti-BCMA antibody or antigen binding fragment that is an scFv labeled as BCMA21, BCMA22, BCMA23, BCMA24, BCMA27, BCMA28, BCMA30, BCMA31, BCMA32, BCMA33, BCMA34, or BCMA 35. In some embodiments, the polynucleotides provided herein encode an anti-BCMA antibody or antigen binding fragment having an amino acid sequence selected from the group consisting of SEQ ID NOs 116-127.

The invention also provides polynucleotides encoding the disclosed TCRs. In some embodiments, the invention provides polynucleotides encoding TCR a chains comprising an anti-BCMA antibody or antigen binding fragment of the invention. In some embodiments, the invention provides polynucleotides encoding TCR β chains comprising an anti-BCMA antibody or antigen binding fragment of the invention. In some embodiments, the invention provides polynucleotides encoding TCR gamma chains comprising an anti-BCMA antibody or antigen binding fragment of the invention. In some embodiments, the invention provides polynucleotides encoding TCR delta chains comprising an anti-BCMA antibody or antigen binding fragment of the invention. The polynucleotide may be in the form of DNA. The polynucleotide may be in the form of an mRNA.

The invention also provides polynucleotides encoding the disclosed CARs of the invention. In some embodiments, the invention provides a polynucleotide encoding a CAR that specifically binds BCMA, the CAR comprising, from N-terminus to C-terminus: (a) a BCMA binding domain comprising an anti-BCMA antibody or antigen binding fragment provided by the invention, (b) a transmembrane domain, and (c) a cytoplasmic domain. The transmembrane and cytoplasmic domains can be any transmembrane and cytoplasmic domain disclosed herein. For illustrative purposes, provided herein is, for example, a polynucleotide encoding a CAR that specifically binds BCMA, the CAR comprising, from N-terminus to C-terminus: (a) a BCMA binding domain comprising an scFv against BCMA provided by the invention, (b) a transmembrane domain comprising a CD28 transmembrane region, and (c) a cytoplasmic domain comprising a CD3 signaling domain and a 4-1BB co-stimulatory domain. The polynucleotide may be in the form of DNA. The polynucleotide may be in the form of an mRNA.

In some embodiments, the polynucleotides provided herein encode an anti-BCMACAR having at least 85%, at least 90%, at least 95%, at least 98%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs 131-142. In some embodiments, the polynucleotides provided herein encode an anti-BCMACR having an amino acid sequence selected from the group consisting of SEQ ID NOs 131-142. In some embodiments, the polynucleotides provided herein encode an anti-BCMAAR having the amino acid sequence set forth in SEQ ID NO. 131. In some embodiments, the polynucleotides provided herein encode an anti-BCMAAR having the amino acid sequence set forth in SEQ ID NO. 132. In some embodiments, the polynucleotides provided herein encode an anti-BCMACR having the amino acid sequence shown in SEQ ID NO. 133. In some embodiments, the polynucleotides provided herein encode an anti-BCMACAR having the amino acid sequence shown in SEQ ID No. 134. In some embodiments, the polynucleotides provided herein encode an anti-BCMAAR having the amino acid sequence shown in SEQ ID NO. 135. In some embodiments, the polynucleotides provided herein encode an anti-BCMAAR having the amino acid sequence shown in SEQ ID NO. 136. In some embodiments, the polynucleotides provided herein encode an anti-BCMACAR having the amino acid sequence shown in SEQ ID No. 137. In some embodiments, the polynucleotides provided herein encode an anti-BCMAAR having the amino acid sequence shown in SEQ ID NO. 138. In some embodiments, the polynucleotides provided herein encode an anti-BCMACR having the amino acid sequence shown in SEQ ID NO. 139. In some embodiments, the polynucleotides provided herein encode an anti-BCMACAR having the amino acid sequence shown in SEQ ID No. 140. In some embodiments, the polynucleotides provided herein encode an anti-BCMACR having the amino acid sequence shown in SEQ ID NO. 141. In some embodiments, the polynucleotides provided herein encode an anti-BCMACR having the amino acid sequence shown in SEQ ID NO. 142.

In some embodiments, polynucleotides provided herein have a nucleotide sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to a sequence selected from the group consisting of SEQ ID NOS: 143-154. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence set forth in SEQ ID NO 143. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence set forth in SEQ ID NO. 144. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence set forth in SEQ ID NO. 145. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence set forth in SEQ ID NO 146. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence set forth in SEQ ID NO 147. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence set forth in SEQ ID NO. 148. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence set forth in SEQ ID NO. 149. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence set forth in SEQ ID NO. 150. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence set forth in SEQ ID NO. 151. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence set forth in SEQ ID NO 152. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence set forth in SEQ ID NO 153. In some embodiments, polynucleotides provided herein have an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence set forth in SEQ ID NO 154. The invention also provides polynucleotides which hybridize to polynucleotides encoding amino acid sequences selected from the group consisting of SEQ ID NOS: 143-154. In some embodiments, the hybridization is performed under highly stringent conditions known to those skilled in the art.

As used herein, the phrase "a polynucleotide having a nucleotide sequence at least about 95% identical to a polynucleotide sequence" refers to a polynucleotide whose nucleotide sequence is identical to a reference sequence except that a maximum of 5 point mutations can be included in every 100 nucleotides of the reference sequence. In other words, to obtain a polynucleotide having a sequence at least 95% identical to a reference nucleotide sequence, up to 5% of the nucleotides in the reference sequence may be deleted or replaced with other nucleotides, or up to 5% of the nucleotides in the reference sequence may be inserted into the reference sequence. These mutations of the reference sequence may occur at the 5 'or 3' end positions of the reference nucleotide sequence or anywhere in between these end positions, interspersed individually between nucleotides in the reference sequence or in one or more consecutive groups in the reference sequence.

The polynucleotide variants may comprise alterations at the coding region, the non-coding region, or both. In some embodiments, the polynucleotide variant comprises an alteration that produces a silent substitution, addition, or deletion, but does not alter the nature or activity of the encoded polypeptide. In some embodiments, the polynucleotide variant comprises silent substitutions (due to degeneracy of the genetic code) that result in no change in the amino acid sequence of the polypeptide. The generation of polynucleotide variants may be for a variety of reasons, such as optimizing the codon expression of a particular host (e.g., to change codons in human mRNA to codons preferred by bacteria such as E.coli). In some embodiments, the polynucleotide variant comprises at least one silent mutation in a non-coding region or coding region of the sequence.

In some embodiments, polynucleotide variants are prepared to modulate or alter expression (or expression levels) of the encoded polypeptide. In some embodiments, polynucleotide variants are prepared to increase expression of the encoded polypeptide. In some embodiments, polynucleotide variants are prepared to reduce expression of the encoded polypeptide. In some embodiments, the polynucleotide variant increases expression of the encoded polypeptide as compared to the parent polynucleotide sequence. In some embodiments, the polynucleotide variant reduces expression of the encoded polypeptide as compared to the parent polynucleotide sequence.

In some embodiments, the polynucleotide comprises a coding sequence for a polypeptide (e.g., CAR or antibody) fused in the same reading frame to a polynucleotide that facilitates expression and secretion of the polypeptide from the host cell (e.g., as a leader sequence for a secretion sequence that controls transport of the polypeptide). The polypeptide may have a leader sequence that is cleaved by the host cell to form the "mature" polypeptide form.

In some embodiments, the polynucleotide comprises a coding sequence for a polypeptide (e.g., CAR or antibody) fused in the same reading frame to a tag or label sequence. For example, in some embodiments, the tag sequence is a hexa-histidine tag (HIS-tag), which allows efficient purification of the polypeptide fused to the tag. In some embodiments, when a mammalian host (e.g., COS-7 cells) is used, the tag sequence is a Hemagglutinin (HA) tag derived from influenza hemagglutinin protein. In some embodiments, the tag sequence is FLAG ^TM And (5) a label. In some embodiments, the label may be used in combination with other labels or tags.

In some embodiments, the polynucleotide is isolated. In some embodiments, the polynucleotide is substantially purified.

The invention also provides vectors and cells comprising the polynucleotides of the invention. In some embodiments, vectors comprising the polynucleotides provided herein are provided. The vector may be an expression vector. In some embodiments, the invention provides vectors comprising polynucleotides encoding the anti-BCMA antibodies or antigen binding fragments of the invention. In some embodiments, the invention provides vectors comprising polynucleotides encoding a polypeptide that is part of an anti-BCMA antibody or antigen binding fragment of the invention. In some embodiments, the invention provides a vector comprising a polynucleotide encoding a CAR or TCR of the invention. In some embodiments, the invention provides a vector comprising a polynucleotide encoding a polypeptide that is part of a CAR or TCR of the invention.

In some embodiments, the invention provides recombinant expression vectors useful for amplifying and expressing polynucleotides encoding the CARs/TCRs of the invention or the anti-BCMA antibodies or antigen binding fragments that specifically bind BCMA. For example, the recombinant expression vector may be a replicable DNA construct comprising a synthetic or cDNA-derived DNA fragment encoding the polypeptide chain of a CAR/TCR or anti-BCMA antibody operably linked to appropriate transcriptional and/or translational regulatory elements derived from mammalian, microbial, viral or insect genes. In some embodiments, viral vectors are used. DNA regions are "operably linked" when they are functionally related to each other. For example, if the promoter controls transcription of a sequence, it is operably linked to a coding sequence; or operably linked to a coding sequence if the ribosome binding site is positioned so as to permit translation. In some embodiments, structural elements intended for use in certain expression systems include a leader sequence that may enable the host cell to extracellularly secrete the translated protein. In some embodiments, the polypeptide may include an N-terminal methionine residue in the absence of leader or transport sequences for expression of the recombinant protein.

A variety of expression host/vector combinations may be used. Expression vectors useful for eukaryotic hosts include, for example, vectors comprising expression control sequences from SV40, bovine papilloma virus, adenovirus and cytomegalovirus. Expression vectors useful for bacterial hosts include known bacterial plasmids, such as those from E.coli, including pCR1, pBR322, pMB9 and derivatives thereof, as well as plasmids of a broader host range, such as M13 and other filamentous single-stranded DNA phages.

In some embodiments, the CAR/TCR of the invention or the anti-BCMA antibody or antigen binding fragment is expressed in one or more vectors. Host cells suitable for expression include prokaryotes, yeast cells, insect cells, or higher eukaryotic cells under the control of appropriate promoters. Suitable cloning and expression vectors for bacterial, fungal, yeast and mammalian cell hosts, as well as protein production methods, including antibody production methods, are well known in the art.

Examples of suitable mammalian host cell lines include, but are not limited to, COS-7 (derived from monkey kidney), L-929 (derived from murine fibroblasts), C127 (derived from murine mammary tumors), 3T3 (derived from murine fibroblasts), CHO (derived from Chinese hamster ovary), heLa (derived from human cervical cancer), BHK (derived from hamster kidney fibroblasts), HEK-293 (derived from human embryonic kidney) cell lines, and variants thereof. Mammalian expression vectors may include non-transcriptional elements (e.g., origins of replication), suitable promoters and enhancers linked to the gene to be expressed, and other 5 'or 3' flanking non-transcribed and 5 'or 3' untranslated sequences (e.g., the necessary ribosome binding sites, polyadenylation sites, splice donor and acceptor sites, and transcription termination sequences). Expression of recombinant proteins in insect cell culture systems (e.g., baculoviruses) also provides a powerful method for producing correctly folded and biologically functional proteins. Baculovirus systems for producing heterologous proteins in insect cells are well known to those skilled in the art.

The invention also provides host cells comprising the polypeptides of the invention, polynucleotides encoding the polypeptides of the invention, or vectors comprising such polynucleotides. In some embodiments, the invention also provides a host cell comprising a vector comprising a polynucleotide disclosed herein. In some embodiments, the invention provides a host cell comprising a vector comprising a polynucleotide encoding an anti-BCMA antibody or antigen binding fragment of the invention. In some embodiments, the invention provides a host cell comprising a vector comprising a polynucleotide encoding a polypeptide that is part of an anti-BCMA antibody or antigen binding fragment of the invention. In some embodiments, the invention provides host cells comprising polynucleotides encoding the anti-BCMA antibodies or antigen binding fragments of the invention. In some embodiments, the cell produces an anti-BCMA antibody or antigen binding fragment of the invention. In some embodiments, the invention provides a host cell comprising a vector comprising a polynucleotide encoding a CAR or TCR of the invention. In some embodiments, the invention provides a host cell comprising a vector comprising a polynucleotide molecule encoding a polypeptide that is part of a CAR or TCR described herein. In some embodiments, the invention provides a host cell comprising a polynucleotide encoding a CAR or TCR of the invention. In some embodiments, the host cell produces BCMACAR or TCR described herein.

5.5 cells

The present invention provides cells comprising the polynucleotides disclosed herein. In some embodiments, the invention provides cells comprising polynucleotides encoding the polypeptides disclosed herein. In some embodiments, the invention provides a cell comprising a vector comprising a polynucleotide disclosed herein. In some embodiments, the invention provides cells capable of recombinant expression of the disclosed polypeptides of the invention. The polypeptide may be an anti-BCMA antibody or antigen binding fragment. The polypeptide may be BCMACAR. The polypeptide may be a BCMA TCR.

In some embodiments, the cells provided herein are immune effector cells. In some embodiments, the immune effector cell is selected from the group consisting of a T cell, a B cell, a Natural Killer (NK) cell, a NKT cell, a macrophage, a granulocyte, a neutrophil, an eosinophil, a mast cell, and a basophil. In some embodiments, the immune effector cells provided herein are selected from the group consisting of T cells, NK cells, NKT cells, macrophages, neutrophils, and granulocytes. In some embodiments, the immune effector cells provided herein are T cells. In some embodiments, the immune effector cells provided herein are NK cells. In some embodiments, the immune effector cells provided herein are NKT cells. In some embodiments, the immune effector cells provided herein are macrophages. In some embodiments, the immune effector cells provided herein are neutrophils. In some embodiments, the immune effector cells provided herein are granulocytes.

In some embodiments, the immune effector cells provided herein may be genetically engineered. In some embodiments, the genetically engineered immune effector cells provided herein are isolated. In some embodiments, the genetically engineered immune effector cells provided herein are substantially purified.

Thus, in some embodiments, the invention provides immune effector cells capable of recombinantly expressing a polypeptide (e.g., an antibody or CAR) disclosed herein. The invention also provides an immune effector cell (e.g., a T cell) comprising a polynucleotide encoding a polypeptide (e.g., an antibody or CAR) disclosed herein or a vector comprising a polynucleotide disclosed herein. In some embodiments, the invention provides an immune effector cell (e.g., T cell) comprising a polynucleotide encoding an anti-BCMA antibody or antigen binding fragment disclosed herein. In some embodiments, the invention provides immune effector cells (e.g., T cells) capable of recombinantly expressing an anti-BCMA antibody or antigen binding fragment of the invention. In some embodiments, the invention provides an immune effector cell comprising a polynucleotide encoding a BCMACAR as disclosed herein. In some embodiments, the present invention provides an immune effector cell (e.g., T cell; e.g., BCMAART cell) capable of recombinantly expressing the disclosed BCMAARs. In some embodiments, the invention provides an immune effector cell comprising a polynucleotide encoding a BCMA TCR disclosed herein. In some embodiments, the invention provides an immune effector cell (e.g., T cell; e.g., BCMA TCRT cell) capable of recombinantly expressing a BCMA TCR disclosed herein.

In some embodiments, the immune effector cells provided herein are T cells. The T cell may be a cytotoxic T cell, helper T cell, or γδ T, cd4+/cd8+ double positive T cell, cd4+ T cell, cd8+ T cell, CD4/CD8 double negative T cell, cd3+ T cell, naive T cell, effector T cell, cytotoxic T cell, helper T cell, memory T cell, regulatory T cell, th0 cell, th1 cell, th2 cell, th3 (Treg) cell, th9 cell, th17 cell, thαβ helper cell, tfh cell, stem cell-like central memory TSCM cell, central memory TCM cell, effector memory TEM cell, effector memory TEMRA cell, or γδ T cell. In some embodiments, the T cell is a cytotoxic T cell. In some embodiments, the T cells are genetically engineered. In some embodiments, the T cells provided herein are isolated. In some embodiments, the T cells provided herein are substantially purified.

In some embodiments, the genetically engineered cells provided herein are derived from cells isolated from a subject. As used herein, a genetically engineered cell "derived from" a source cell refers to a genetically engineered cell obtained by obtaining a source cell and performing genetic manipulation on the source cell. The source cells may be from natural sources. For example, the source cell may be a primary cell isolated from a subject. The subject may be an animal or a human. The source cell may also be a cell that has been passaged or genetically manipulated in vitro.

In some embodiments, the genetically engineered cells provided herein are derived from cells isolated from a human body. Immune effector cells (e.g., T cells) may be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue at the site of infection, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments, T cell lines available in the art may be used. In some embodiments, the genetically engineered cells provided herein are derived from cells isolated from peripheral blood. In some embodiments, the genetically engineered cells provided herein are derived from cells isolated from bone marrow. In some embodiments, the genetically engineered cells provided herein are derived from cells isolated from Peripheral Blood Mononuclear Cells (PBMCs).

In some embodiments, the genetically engineered cells provided herein are derived from cells differentiated in vitro from stem cells or progenitor cells. In some embodiments, the stem or progenitor cells are selected from the group consisting of T cell progenitor cells, hematopoietic stem/progenitor cells, hematopoietic multipotent progenitor cells, embryonic stem cells, and induced multipotent cells. In some embodiments, the genetically engineered cells provided herein are derived from cells differentiated in vitro from T cell progenitors. In some embodiments, the genetically engineered cells provided herein are derived from cells differentiated in vitro from hematopoietic stem/progenitor cells. In some embodiments, the genetically engineered cells provided herein are derived from cells differentiated in vitro from hematopoietic multipotent progenitor cells. In some embodiments, the genetically engineered cells provided herein are derived from cells differentiated in vitro from embryonic stem cells. In some embodiments, the genetically engineered cells provided herein are derived from cells that induce differentiation of pluripotent cells in vitro.

In some embodiments, the invention provides a population of cells comprising the disclosed cells. The cells disclosed herein may comprise a polynucleotide encoding a polypeptide disclosed herein, or recombinantly express a polypeptide disclosed herein. The polypeptide may be an anti-BCMA antibody or antigen binding fragment, BCMACAR or BCMA TCR. The cell population may be a homogenous cell population. The cell population may be a heterogeneous cell population. In some embodiments, the cell population can be a heterogeneous cell population comprising any combination of the cells disclosed herein. In some embodiments, the population of cells is derived from Peripheral Blood Mononuclear Cells (PBMCs), peripheral Blood Lymphocytes (PBLs), tumor-infiltrating lymphocytes (TILs), cytokine-induced killer Cells (CIKs), lymphokine-activated killer cells (LAKs), or bone marrow-infiltrating lymphocytes (MILs). In some embodiments, the cell populations provided herein are derived from PBMCs. In some embodiments, the cell populations provided herein are derived from PBLs. In some embodiments, the cell populations provided herein are derived from TIL. In some embodiments, the cell populations provided herein are derived from CIK. In some embodiments, the cell populations provided herein are derived from LAK. In some embodiments, the cell populations provided herein are derived from MILs. The cell population can be genetically engineered to recombinantly express a polypeptide (e.g., an antibody or CAR) disclosed herein. In some embodiments, the invention provides a population of cells comprising a polynucleotide encoding a polypeptide (e.g., an antibody or CAR) disclosed herein or a vector having a polynucleotide disclosed herein. In some embodiments, the invention provides a population of cells comprising a polynucleotide encoding an anti-BCMA antibody or antigen binding fragment disclosed herein. In some embodiments, the invention provides a population of cells recombinantly expressing an anti-BCMA antibody or antigen binding fragment disclosed herein. In some embodiments, the invention provides a population of cells comprising a polynucleotide encoding a BCMACAR as disclosed herein. In some embodiments, the invention provides a population of cells (e.g., BCMACART cells) capable of recombinantly expressing the BCMACARs disclosed herein. In some embodiments, the invention provides a population of cells comprising a polynucleotide encoding a BCMA TCR disclosed herein. In some embodiments, the invention provides a population of cells (e.g., BCMA TCRT cells) capable of recombinantly expressing a BCMA TCR disclosed herein.

5.6 pharmaceutical compositions

The invention also provides pharmaceutical compositions comprising the anti-BCMA antibodies or antigen binding fragments disclosed herein. The invention also provides a pharmaceutical composition comprising the genetically engineered immune effector cells disclosed by the invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an anti-BCMA antibody or antigen binding fragment thereof disclosed herein, further comprising a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a pharmaceutically effective amount of the genetically engineered cells disclosed herein and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is useful in immunotherapy. In some embodiments, the pharmaceutical composition is useful in immunooncology (immunology). In some embodiments, the pharmaceutical composition is useful in inhibiting tumor growth in a subject (e.g., a human patient). In some embodiments, the pharmaceutical compositions are useful in treating cancer in a subject (e.g., a human patient).

In some embodiments, the invention provides a pharmaceutical composition comprising an anti-BCMA antibody or antigen binding fragment provided herein. The anti-BCMA antibody or antigen binding fragment may be present at different concentrations. In some embodiments, the invention provides a pharmaceutical composition comprising 1-1000mg/ml of a soluble anti-BCMA antibody or antigen binding fragment provided herein. In some embodiments, the pharmaceutical composition comprises the soluble anti-BCMA antibody or antigen binding fragment provided herein in an amount of 10-500mg/ml, 10-400mg/ml, 10-300mg/ml, 10-200mg/ml, 10-100mg/ml, 20-100mg/ml, or 50-100mg/ml. In some embodiments, the invention provides pharmaceutical compositions comprising an anti-BCMA antibody or antigen binding fragment provided herein in an amount of about 10mg/ml, about 20mg/ml, about 30mg/ml, about 40mg/ml, about 50mg/ml, about 60mg/ml, about 70mg/ml, about 80mg/ml, about 90mg/ml, about 100mg/ml, about 120mg/ml, about 150mg/ml, about 180mg/ml, about 200mg/ml, about 300mg/ml, about 500mg/ml, about 800mg/ml, or about 1000mg/ml.

Pharmaceutical compositions comprising genetically engineered immune effector cells (e.g., T cells) as disclosed herein may comprise purified cell populations. The percentage of cells in a population of cells, as described herein, can be readily determined by one of ordinary skill in the art using a variety of well known methods. The purity of a cell population comprising genetically engineered cells provided herein can range from about 20% to about 25%, from about 25% to about 30%, from about 30% to about 35%, from about 35% to about 40%, from about 40% to about 45%, from about 45% to about 50%, from about 55% to about 60%, from about 65% to about 70%, from about 70% to about 75%, from about 75% to about 80%, from about 80% to about 85%, from about 85% to about 90%, from about 90% to about 95%, from about 95% to about 100%. In some embodiments, the purity of a population of cells comprising immune effector cells provided herein can range from about 20% to about 30%, from about 20% to about 50%, from about 20% to about 80%, from about 20% to about 100%, from about 50% to about 80%, or from about 50% to about 100%. The dosage can be conveniently adjusted by those skilled in the art; for example, a decrease in purity may require an increase in dosage.

The present invention also provides a kit for preparing a pharmaceutical composition comprising the anti-BCMA antibody or antigen binding fragment of the present disclosure. In some embodiments, the kit comprises an anti-BCMA antibody or antigen binding fragment of the present disclosure in one or more containers, and a pharmaceutically acceptable carrier. In another embodiment, the kit may comprise an anti-BCMA antibody or antigen binding fragment disclosed herein for administration to a subject. In particular embodiments, the kit includes instructions for the preparation and/or administration of an anti-BCMA antibody or antigen binding fragment.

The invention also provides kits for preparing the immune effector cells (e.g., T cells) disclosed herein. In one embodiment, the kit comprises one or more vectors for producing genetically engineered cells (e.g., T cells) that express an anti-BCMA antibody or antigen binding fragment thereof disclosed herein. In certain embodiments, the kits comprise an immune effector cell of the present disclosure in one or more containers.

In some embodiments, the invention provides a pharmaceutical composition comprising an anti-BCMA antibody or antigen binding fragment provided herein, wherein the composition is suitable for topical administration. In some embodiments, topical administration includes intratumoral injection, peritumoral injection, paraneoplastic injection (juxtatumoral injection), intralesional injection and/or injection into a tumor draining lymph node, or essentially any tumor targeting injection wherein the antineoplastic agent is expected to leak into a primary lymph node adjacent to the targeted solid tumor.

Pharmaceutically acceptable carriers that can be used in the compositions provided herein include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, that are physiologically compatible. In some embodiments, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal, or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the active ingredient (i.e., the anti-BCMA antibody or antigen binding fragment provided by the present invention, or immune effector cells) may be coated in a material to protect the active ingredient from acids and other natural conditions that may inactivate the active ingredient.

The present invention also provides pharmaceutical compositions or formulations that improve the stability of an anti-BCMA antibody or antigen binding fragment to allow for long term storage thereof. In some embodiments, the disclosed pharmaceutical compositions or formulations comprise: (a) The invention discloses an anti-BCMA antibody or antigen binding fragment; (b) a buffer; (c) a stabilizer; (d) a salt; (e) a filler; and/or (f) a surfactant. In some embodiments, the pharmaceutical composition or formulation is capable of being stable for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 1 year, at least 2 years, at least 3 years, at least 5 years, or more. In some embodiments, the pharmaceutical composition or formulation is stable when stored at 4 ℃, 25 ℃, or 40 ℃.

Buffers useful in the pharmaceutical compositions or formulations disclosed herein may be weak acids or weak bases for maintaining the acidity (pH) of the solution near a selected value after addition of another acid or base. Suitable buffers can maximize the stability of the formulation by maintaining control over the pH of the formulation. Suitable buffers may also ensure physiological compatibility or optimize solubility. Rheology, viscosity and other properties also depend on the pH of the formulation. Common buffers include, but are not limited to, histidine, citrate, succinate, acetate and phosphate. In some embodiments, the buffer comprises histidine (e.g., L-histidine) with the isotonic agent, and may be pH adjusted with acids or bases known in the art. In certain embodiments, the buffer is L-histidine. In certain embodiments, the pH of the formulation is maintained between about 2 to about 10, or about 4 to about 8.

Stabilizers are added to pharmaceutical products to stabilize the product. Such agents may stabilize proteins in different ways. Common stabilizers include, but are not limited to, amino acids (such as glycine, alanine, lysine, arginine, or threonine), carbohydrates (such as glucose, sucrose, trehalose, raffinose, or maltose), polyols (such as glycerol, mannitol, sorbitol, cyclodextrin, or any kind and molecular weight of dealkylated species), or PEG. In some embodiments, the stabilizing agent is to maximize stability of the FIX polypeptide in the lyophilized formulation. In certain embodiments, the stabilizing agent is sucrose and/or arginine.

Fillers may be added to the pharmaceutical composition or formulation to increase the volume and mass of the product, thereby facilitating its precise metering and handling. Common fillers include, but are not limited to, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, or magnesium stearate.

The surfactant is an amphoteric substance having a hydrophilic group and a hydrophobic group. The surfactant may be anionic, cationic, zwitterionic or nonionic. Nonionic surfactants include, but are not limited to, alkyl ethoxylates, nonylphenol ethers, ethoxylates, polyethylene oxides, polypropylene oxides, fatty alcohols (such as cetyl or oleyl alcohol), cocamide MEA, cocamide DEA, polysorbate, or dodecyldimethylamine oxide. In some embodiments, the surfactant is polysorbate 20 or polysorbate 80.

The pharmaceutical compositions disclosed herein may further comprise one or more of a buffer system, a preservative, a tonicity agent, a chelating agent, a stabilizer, and/or a surfactant, as well as various combinations thereof. The use of preservatives, isotonic agents, chelating agents, stabilizers and surfactants in pharmaceutical compositions is well known to those skilled in the art. Can be referred to Remington:The Science and Practice of Pharmacy，19 ^th edition，1995。

In some embodiments, the pharmaceutical composition is an aqueous formulation. Such formulations are typically solutions or suspensions, but may also include colloids, dispersions, emulsions and multiphase materials. The term "aqueous formulation" is defined as a formulation containing at least 50% w/w water. Likewise, the term "aqueous solution" is defined as a solution comprising at least 50% w/w water and the term "aqueous suspension" is defined as a suspension comprising at least 50% w/w water.

In some embodiments, the presently disclosed pharmaceutical compositions are lyophilized, to which the physician or patient adds solvents and/or diluents prior to use.

The pharmaceutical compositions disclosed herein may also include a pharmaceutically acceptable antioxidant. Examples of pharmaceutically acceptable antioxidants include: examples of pharmaceutically acceptable antioxidants include: (1) Water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) Oil-soluble antioxidants such as ascorbyl palmitate, butyl Hydroxy Anisole (BHA), 2, 6-di-t-butyl-p-cresol (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelators such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

Examples of suitable aqueous and nonaqueous carriers that may be used in the pharmaceutical compositions or formulations of the present invention include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate). By using a coating material (e.g., lecithin), by maintaining the desired particle size in the case of dispersions, and by using surfactants, proper fluidity is maintained.

These compositions may also contain adjuvants such as preserving, wetting, emulsifying and dispersing agents. Prevention of the presence of microorganisms can be ensured by the sterilization procedure described above and the addition of various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol sorbic acid, and the like). It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the addition of agents which delay absorption such as aluminum monostearate and gelatin.

Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. Such media and medicaments for pharmaceutically active substances are known in the art. Except insofar as any conventional medium or agent is incompatible with the active compound, its use in the pharmaceutical compositions of the present invention is contemplated. The pharmaceutical composition or formulation may or may not contain a preservative. Supplementary active compounds may be incorporated into the compositions.

Pharmaceutical compositions or formulations must generally be sterile and stable under the conditions of manufacture and storage. The compositions may be formulated as solutions, microemulsions, liposomes, or other ordered structures suitable for high antibody concentrations. The carrier may be a solvent or dispersion medium comprising, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycols, and the like), and suitable mixtures thereof. Proper fluidity is maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. In many cases, the composition may include an isotonic agent, for example, sugars, polyalcohols (such as mannitol, sorbitol, or the composition) or sodium chloride in the composition. The absorption of the injectable composition may be prolonged by the addition of agents delaying absorption, such as monostearates and gelatins, to the composition.

If desired, one or more of the above ingredients may be added to the desired amount of active compound in a suitable solvent, followed by sterilization microfiltration to produce a sterile injectable solution. Typically, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated in accordance with the present invention. In the case of sterile powders for the preparation of sterile injectable solutions, some methods of preparation are vacuum drying and freeze-drying (lyophilization) which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

The amount of active ingredient that may be combined with the carrier material in the pharmaceutical compositions or formulations disclosed herein may vary. In some embodiments, the amount of active ingredient that can be combined with the carrier material is that amount that produces a therapeutic effect. Typically, the amount of active ingredient in combination with a pharmaceutically acceptable carrier will range from about 0.01% to about 99%, from about 0.1% to about 70%, or from about 1% to about 30% by percentage.

The pharmaceutical compositions disclosed herein may be prepared with carriers that protect the active ingredient from rapid release, such as controlled release formulations, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid may be used. Many methods for preparing such formulations are patented or generally known to those skilled in the art. See, for example,Sustained and Controlled Release Drug Delivery Systems,J.R.Robinson,ed.,Marcel Dekker,Inc.,New York,1978。

in some embodiments, the anti-BCMA antibodies or antigen binding fragments of the present invention, or immune effector cells (e.g., T cells), can be formulated to ensure proper distribution in vivo. For example, the Blood Brain Barrier (BBB) excludes many highly hydrophilic compounds. To ensure that the activating components of the invention cross the BBB (if desired, e.g., for brain cancer), they can be formulated in liposomes, for example. For a method of manufacturing liposomes, see U.S. Pat. nos. 4,522,811;5,374,548; and 5,399,331. Liposomes can include one or more groups that selectively transport to specific cells or organs, thereby enhancing targeted drug delivery (see, e.g., v.ranade (1989) j.clin.pharmacol.29:685). Examples of Ranade (1989) j.clin.pharmacol.29:685) targeting groups include folic acid or biotin (see, e.g., U.S. patent 5,416,016to Low et al), mannosides (Umezawa et al, (1988) biochem.biophys.res.Commun.153:1038), antibodies (p.g. bloeman et al (1995) FEBS lett.357:140; M.Owais et al (1995) Antimicrob. Agents chemther.39:180), surface active protein A receptor (Briscoe et al (1995) am. J. Physiol. 1233:134), pl20 (Schreier et al (1994) J. Biol. Chem. 269:9090), see also K.Keinanen; M.L.Laukkanen (1994) FEBS Lett.346:123; j. killion; fidler (1994) Immunomethods 4:273.

5.7 methods and uses

The invention also provides that the invention discloses: an anti-BCMA antibody or antigen binding fragment; BCMACAR; BCMA TCR; polynucleotides encoding such anti-BCMA antibodies or antigen binding fragments, and BCMACAR/TCRs; vectors comprising such polynucleotides; cells expressing the BCMACAR/TCR; and methods of using pharmaceutical compositions having such cells in the treatment of cancer. Without being bound by theory, the anti-BCMA antibodies or antigen binding fragments, and BCMACAR/TCR-expressing cells, disclosed herein are capable of specifically targeting BCMA-expressing cancer cells in vivo, thereby achieving therapeutic effects of eliminating, lysing, and/or killing the cancer cells. In some embodiments, the methods comprise administering to a subject in need thereof a therapeutically effective amount of an anti-BCMA antibody or antigen binding fragment disclosed herein. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of an immune effector cell expressing BCMACAR as disclosed herein. In one embodiment, the method may comprise administering to a subject in need thereof a therapeutically effective amount of BCMACART as disclosed herein.

In some embodiments, the invention provides a method of treating a tumor or cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-BCMA antibody or antigen binding fragment disclosed herein. In some embodiments, the invention provides the use of an anti-BCMA antibody or antigen binding fragment disclosed herein in the treatment of a tumor or cancer. In some embodiments, the invention provides the use of an anti-BCMA antibody or antigen binding fragment disclosed herein in the manufacture of a medicament for treating a tumor or cancer.

In some embodiments, the invention provides methods of treating a tumor or cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an immune effector cell (e.g., BCMACART) disclosed herein. In some embodiments, the invention provides the use of the presently disclosed immune effector cells in the treatment of tumors or cancers. In some embodiments, the invention provides the use of an immune effector cell provided by the invention in the manufacture of a medicament for treating a tumor or cancer. In some embodiments, the presently disclosed cell populations comprising immune effector cells are used in therapy. The population of cells may be homogenous. The population of cells may be heterologous.

In some embodiments, the invention provides a method of treating a tumor or cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition disclosed herein. In some embodiments, the invention provides the use of the disclosed pharmaceutical compositions in the treatment of tumors or cancers. In some embodiments, the invention provides the use of a pharmaceutical composition provided herein in the manufacture of a medicament for treating a tumor or cancer.

The actual dosage level of the active ingredient (i.e., the anti-BCMA antibody or antigen binding fragment provided herein, or immune effector cells) in the pharmaceutical compositions of the present invention can be varied to achieve levels, compositions, and modes of administration of the active ingredient that are effective to achieve the desired therapeutic response for a particular patient without toxicity to the patient. The dosage level selected will depend on a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention, the route of administration, the time of administration, the rate of excretion, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular composition being used, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

The anti-BCMA antibody or antigen binding fragment may be administered as a slow release formulation, in which case frequent administration is not required. The dosage and frequency will vary depending on the half-life of the anti-BCMA antibody or antigen binding fragment thereof in the patient. In therapeutic applications, it is sometimes desirable to administer relatively high doses over relatively short time intervals until the progression of the disease is reduced or terminated, and until the patient exhibits a partial or complete improvement in the symptoms of the disease.

In some embodiments, the immune effector cells provided herein that are capable of recombinantly expressing the BCMACARs or TCRs disclosed herein are useful in the methods of treatment disclosed herein. When using cell therapy, the cells provided by the present invention can be administered at a dose per kilogram of cells (cells/kg) based on the body weight of the subject to which the cells are administered. The cell dose may range from about 10 ⁴ To 10 ¹⁰ Individual cells/kg body weight, e.g. about 10 ⁵ To about 10 ⁹ About 10 ⁵ To about 10 ⁸ About 10 ⁵ To about 10 ⁷ Or about 10 ⁵ To about 10 ⁶ Individual cells/kg body weight, depending on the mode and location of administration. Generally, in the case of systemic administration, a higher dose is used than in regional administration (administration of the immune effector cells in the tumor region). As described above, the precise determination of what is an effective dose may be based on the personal factors of each subject, including their body type, age, sex, weight, and condition of the particular subject. Dosages can be readily determined by one of ordinary skill in the art based on the disclosure of the present invention and prior knowledge in the art.

The anti-BCMA antibodies or antigen binding fragments thereof, immune effector cells, and pharmaceutical compositions provided herein may be administered to a subject by any method known in the art, including, but not limited to, intrathoracic, intravenous, subcutaneous, intranodal (intranodal administration), intratumoral, intramuscular, intradermal, intrathecal, intrapleural, intraperitoneal, intracranial, spinal, or other parenteral routes of administration, such as by injection or infusion, or direct thymus administration. The phrase "parenteral administration" as used herein refers to modes of administration other than enteral and topical administration, typically by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intraperitoneal injection and infusion. In some embodiments, subcutaneous administration is employed. In some embodiments, intravenous administration is employed. In some embodiments, oral administration is employed. In one embodiment, the cells provided herein may be delivered locally to a tumor using well known methods, including but not limited to liver or aortic pumps; limb, lung or liver perfusion; in the portal vein; by venous shunt; in a lumen or vessel in the vicinity of a tumor, etc. In another embodiment, the cells provided herein may be administered systemically. In a preferred embodiment, the cells are administered locally at the tumor site. The cells may also be administered intratumorally, for example, by direct injection of the cells at the tumor site and/or into the tumor vasculature. For example, in the case of malignant pleural disease, mesothelioma or lung cancer, it is preferable to administer it intrapleually (see Adusumilli et al Science Translational Medicine (261): 261ra151 (2014)). One skilled in the art can select an appropriate mode of administration based on the type and/or location of the tumor to be treated. The cells may be introduced by injection or by catheter. In one embodiment, intrapleural administration is performed to a subject in need thereof, e.g., using an intrapleural catheter. Optionally, the subject may be optionally administered an expansion and/or differentiation agent prior to, during, or after administration of the cells to increase in vivo cytogenesis provided by the present invention.

Proliferation of cells provided by the present invention is typically performed in vitro, and it is also desirable to perform in vivo after administration to a subject (see Kaiser et al Cancer Gene Therapy 22:72-78 (2015)). Proliferation of cells should be accompanied by survival of the cells to allow for expansion and persistence of the cells (e.g., T cells).

Diseases treatable using the anti-BCMA antibodies or antigen binding fragments, immune effector cells, or pharmaceutical compositions provided herein include any disease or disorder associated with BCMA, as well as any disease or disorder for which BCMA specific expression and/or BCMA is a therapeutic target (collectively, "BCMA-related disease or disorder"). Cancers associated with BCMA expression include hematological malignancies such as multiple myeloma, fahrenheit macroglobulinemia, and hodgkin's lymphoma and non-hodgkin's lymphoma. See review of BCMA, coquery et al, crit Rev immunol.,2012,32 (4): 287-305.

In some embodiments, the BCMA-related disease or disorder is a B-cell related disorder. In some embodiments, the BCMA-related disease or disorder is glioblastoma, lymphomatoid granuloma, post-transplant lymphoproliferative disorder, immunomodulatory disease, heavy chain disease (havy-chain disease), primary or immune cell-related amyloidosis, or an undefined monoclonal gammaglobulosis.

Under certain diseases and conditions BCMA is expressed on malignant cells and cancers. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematologic cancer. In some embodiments, the cancer is a B cell malignancy. In some embodiments, the cancer is a lymphoma, leukemia, or plasma cell malignancy. Lymphomas according to the present invention include, but are not limited to, burkitt's lymphoma (e.g., endemic burkitt's lymphoma or sporadic burkitt's lymphoma), non-hodgkin's lymphoma (NHL), hodgkin's lymphoma, fahrenheit macroglobulinemia, follicular lymphoma, small anaplastic lymphoma, mucosa-associated lymphoid tissue lymphoma (MALT), marginal zone lymphoma, spleen lymphoma, lymph node monocytic B cell lymphoma, immunoblastic lymphoma, large cell lymphoma, diffuse mixed cell lymphoma (diffuse mixed cell lymphoma), pulmonary B cell vascular central lymphoma (pulmonary B cell angiocentric lymphoma), small lymphocytic lymphoma, primary mediastinal B cell lymphoma, lymphoplasmacytic lymphoma (LPL), or Mantle Cell Lymphoma (MCL). The leukemias described herein include, but are not limited to, chronic Lymphocytic Leukemia (CLL), plasma cell leukemia, or Acute Lymphocytic Leukemia (ALL).

The plasma cell malignancies described herein include, but are not limited to, multiple Myeloma (MM) and plasmacytoma.

In some embodiments, the anti-BCMA antibodies or antigen binding fragments, immune effector cells, or pharmaceutical compositions provided herein are useful for treating MM. In some embodiments, the MM to be treated is a non-secretory MM. In some embodiments, the MM is a smoky (smoldering) MM. In some embodiments, the disease or disorder is relapsed and/or refractory multiple myeloma (R/R MM).

Among these diseases, BCMA-related disorders or conditions (e.g., BCMA-expressing cancers) that may be treated include, but are not limited to, neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell carcinoma, melanoma, myeloma (e.g., multiple myeloma), gastric cancer, brain cancer, lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer, and head and neck cancer.

In some embodiments, the method comprises: a subject having, suspected of having, or at risk of having a BCMA-related disease or disorder is identified. Accordingly, the present invention provides a method for identifying a subject suffering from a disease or disorder associated with increased BCMA expression and selecting it for treatment using an anti-BCMA antibody or antigen binding fragment, immune effector cell, or pharmaceutical composition provided herein.

In some embodiments, the subject may be screened for the presence of a disease or disorder associated with increased BCMA expression, e.g., a BCMA expressing cancer. In some embodiments, the method comprises: screening for or detecting the presence of BCMA related diseases (e.g., tumors). Thus, in some embodiments, a sample may be obtained from a patient suspected of having a disease or disorder associated with elevated BCMA expression, and analyzed for expression levels of BCMA. In some embodiments, a subject positive for detection of a BCMA-related disease or disorder may be selected for treatment by the methods of the invention, and a therapeutically effective amount of an anti-BCMA antibody or antigen binding fragment, immune effector cell, or pharmaceutical composition provided herein may be administered.

In cancer treatment, cancer or tumor cells of a subject may be eliminated, but any clinical improvement is beneficial. The anti-tumor effect can be manifested by a decrease in tumor volume, a decrease in the number of tumor cells, a decrease in the number of metastases, an increase in life expectancy, or an improvement in various physiological symptoms associated with the cancer condition. Antitumor effects can also be manifested by the ability of the cells or pharmaceutical compositions provided herein to prevent tumorigenesis at a first time. In some embodiments, an "anti-tumor effect" may be manifested by a reduction in cancer-induced immunosuppression. Clinical improvement includes a reduced risk or rate of progression of cancer or tumor or a reduction in pathological consequences. It is also understood that the method of treating cancer may include any effect that ameliorates a sign or symptom associated with the cancer.

Such signs or symptoms include, but are not limited to, reducing tumor burden, including inhibiting tumor growth, slowing tumor growth rate, reducing tumor size, reducing tumor number, eliminating tumors, all of which can be measured using conventional tumor imaging techniques well known in the art. Other signs or symptoms associated with cancer include, but are not limited to, fatigue, pain, weight loss, and other signs or symptoms associated with various cancers.

In some embodiments, the methods or uses provided herein can reduce tumor burden. Thus, administration of an anti-BCMA antibody or antigen binding fragment, cell, or pharmaceutical composition of the present disclosure can reduce the number of tumor cells, reduce tumor size, and/or eradicate a tumor in a subject. Methods for monitoring a patient's response to administration of the presently disclosed pharmaceutical compositions are known in the art and may be used in accordance with the presently disclosed methods. In some embodiments, methods known in the art can be used to monitor a patient's response to administration of the disclosed methods of treatment.

In the presently disclosed methods, a therapeutically effective amount of an anti-BCMA antibody or antigen binding fragment, cell, or pharmaceutical composition of the present disclosure is administered to a subject in need of cancer treatment. The subject may be a mammal. In some embodiments, the subject is a human. In some embodiments, the individuals are free of clinically measurable tumors. However, they are suspected of being at risk of disease progression, either near the original tumor site or by metastasis. This group can be further subdivided into high risk and low risk individuals. Subdivision is based on features observed before or after the initial processing. These features are known in the clinic and are appropriately defined for different types of cancer. A typical feature of the high risk subgroup is that the tumor invades adjacent tissue, or shows lymph node metastasis.

In some embodiments, the subject suffers from persistent or recurrent disease following the use of another BCMA specific antibody and/or BCMA-CART and/or other therapies, including chemotherapy, radiation therapy, and/or Hematopoietic Stem Cell Transplantation (HSCT), e.g., allogeneic HSCT or autologous HSCT. In some embodiments, the administration of the BCMA inhibitor is effective in treating a subject despite the subject having developed resistance to another BCMA targeted therapy. In some embodiments, the subject is determined to be at risk of relapse, e.g., high risk of relapse, although not relapse, and thus the compound or composition is administered prophylactically, e.g., to reduce the likelihood of relapse or prevent relapse.

In some embodiments, the subject is a subject that meets transplantation conditions, e.g., meets conditions for Hematopoietic Stem Cell Transplantation (HSCT), e.g., allogeneic HSCT or autologous HSCT. In some embodiments, the subject has not previously received a transplant, although eligible, prior to administration of the BCMA binding molecule (including an anti-BCMA antibody or antigen binding fragment, immune effector cell, or pharmaceutical composition provided herein). In some embodiments, the subject is a subject that does not meet transplantation conditions, e.g., does not meet Hematopoietic Stem Cell Transplantation (HSCT), e.g., allogeneic HSCT or autologous HSCT.

In some embodiments, the methods provided herein include adoptive cell therapies by administering to a subject genetically engineered immune effector cells expressing a provided recombinant receptor, wherein the recombinant receptor contains a BCMA-binding molecule (e.g., BCMACAR provided herein). Such administration can promote activation of cells (e.g., T cell activation) in a manner that targets BCMA, thereby enabling targeted destruction of cells of a disease or disorder. Thus, the methods and uses provided include methods and uses of adoptive cell therapy. In some embodiments, the method comprises administering the cell or a composition comprising the cell to a subject, e.g., a subject having, at risk of having, or suspected of having the disease, condition, or disorder. In some embodiments, the cells, cell populations, and compositions are administered to a subject having a particular disease or disorder to be treated by adoptive cell therapy (e.g., adoptive T cell therapy). In some embodiments, the cells or compositions are administered to the subject, e.g., a subject suffering from or at risk of likely to suffer from the disease or disorder. In some aspects, the methods thus treat, e.g., ameliorate, one or more symptoms of the disease or disorder, e.g., by reducing tumor burden in BCMA-expressing cancers.

Methods of cell administration for adoptive cell therapy are known in the art and may be used in conjunction with the provided methods and compositions. For example, adoptive T cell therapy methods have been described, for example, in U.S. patent application No.2003/0170238 to grenberg et al; U.S. Pat. No.4,690,915 to Rosenberg; rosenberg (2011) Nat Rev Clin Oncol.8 (10): 577-85). See, e.g., themeli et al (2013) Nat Biotechnol.31 (10): 928-933; tsukahara et al (2013) Biochem Biophys Res Commun 438 (1): 84-9; davila et al (2013) PLoS ONE 8 (4): e61338.

In some embodiments, the cell therapy, e.g., adoptive cell therapy (e.g., adoptive T cell therapy), is performed by autologous transplantation, wherein the cells are isolated and/or prepared by isolation from the subject that will receive the cell therapy, or from a sample from such subject. Thus, in some embodiments, the cells are derived from a subject (e.g., patient) in need of treatment, and the cells are administered to the same subject after isolation and treatment.

In some embodiments, the cell therapy, e.g., adoptive cell therapy (e.g., adoptive T cell therapy), is performed by allogeneic transplantation, wherein the cells are isolated and/or prepared from another subject, which refers to a subject other than the subject (e.g., the first subject) that will receive or ultimately receive the cell therapy. In these embodiments, the cells are then administered to a different individual of the same species, e.g., a second subject. In some embodiments, the first and second subjects are genetically identical. In some embodiments, the first and second subjects are genetically similar. In some embodiments, the second subject expresses the same HLA class or supertype as the first subject.

The anti-BCMA antibodies or antigen binding fragments, cells, or pharmaceutical compositions provided herein may be administered in combination with medical devices known in the art. For example, in some embodiments, a needleless hypodermic injection device can be used, such as that described in U.S. Pat. nos.5,399,163;5,383,851;5,312,335;5,064,413;4,941,880;4,790,824; or 4,596,556. Examples of the use of well known implants and modules described herein include: U.S. patent No.4,487,603, which discloses an implantable miniature infusion pump for dispensing a medicament at a controlled rate; U.S. patent No.4,486,194, which discloses a therapeutic device for transdermal drug delivery; U.S. Pat. No.4,447,233, which discloses a medication infusion pump for delivering medication at a precise infusion rate; U.S. Pat. No.4,447,224, which discloses a variable flow implantable infusion device for continuous administration; U.S. Pat. No.4,439,196, which discloses an osmotic drug delivery system having multiple chambers; and U.S. patent No.4,475,196 discloses an osmotic drug delivery system. These patents are incorporated by reference into the present invention. Many other such implants, delivery systems and modules are known to those skilled in the art.

Combination therapy with agents of different mechanisms of action may produce additive or synergistic effects. Combination therapy may allow for lower doses of each agent than those used in monotherapy, thereby reducing toxic side effects and/or increasing the therapeutic index of the presently disclosed agents. Combination therapy may reduce the likelihood of drug resistant cancer cell production. In some embodiments, the additional treatment results in an increase in the therapeutic index of the cells or pharmaceutical compositions described herein. In some embodiments, the additional treatment results in a reduction in toxicity and/or side effects of the cells or pharmaceutical compositions described herein. In some embodiments, an anti-BCMA antibody or antigen binding fragment, cell, or pharmaceutical composition of the invention can be administered in combination with additional therapy. In some embodiments, the additional treatment may be surgical resection, radiation therapy, or chemotherapy.

The additional treatment may be administered prior to, concurrently with, or after administration of the anti-BCMA antibodies or antigen binding fragments, cells, or pharmaceutical compositions thereof described herein. The co-administration may include co-administration, either in a single pharmaceutical formulation or using separate formulations, or sequentially in either order, but is typically performed over a period of time so that all of the active agents may exert their biological activities simultaneously. One skilled in the art can readily determine an appropriate regimen for administration of the pharmaceutical compositions of the invention and the combination additional treatment, including the timing and dosage of the additional agents used in the combination treatment, based on the needs of the subject being treated.

5.8 preparation method

5.8.1 polynucleotides, polypeptides and antibodies

Polynucleotides provided herein may be prepared, manipulated and/or expressed using any of the mature techniques known and available in the art. A number of carriers may be used. Examples of vectors are plasmids, autonomously replicating sequences and transposable elements. Typical transposon systems such as Sleeping Beauty (Sleeping beautyy) and PiggyBac may be used, which may be stably integrated into the genome (e.g., ivics et al, cell,91 (4): 501-510 (1997);et al.,(2007)Nucleic Acids Research.35(12):e87)。501–510(1997)；/>other exemplary vectors include, but are not limited to, plasmids, phages, cosmids, artificial chromosomes (e.g., yeast Artificial Chromosome (YAC), bacterial Artificial Chromosome (BAC) or P1-derived artificial chromosome (PAC)), phages (e.g., lambda phage or M13 phage), and animal viruses. Examples of animal virus species that can be used as vectors include, but are not limited to, retroviruses (including lentiviruses), adenoviruses, adeno-associated viruses, herpesviruses (e.g., herpes simplex viruses), poxviruses, baculoviruses, papillomaviruses, and papovaviruses (e.g., SV 40). Examples of expression vectors are the pClneo vector (Promega) for expression in mammalian cells; plenti4/V5-Dest for lentiviral mediated gene transduction and expression in mammalian cells ^TM 、Plenti6/V5-Dest ^TM And Plenti6.2/V5-GW/Lacz (Invitrogen).

In some embodiments, the vector is an episomal vector (episomal vector) or a vector maintained extrachromosomally. As used herein, the term "episomal" refers to a vector that is capable of replication without integration into the chromosomal DNA of the host and without gradual loss from dividing host cells, and also means that the vector replicates extrachromosomally or in episomal form. The vector is engineered to contain sequences encoding a DNA origin of replication or "ori" from lymphotrophic or gamma herpes viruses, adenoviruses, SV40, bovine papilloma viruses or yeasts, in particular an origin of replication of lymphoherpesviruses or gamma herpesviruses corresponding to oriP of EBV. In some embodiments, the lymphoherpesvirus may be Epstein Barr Virus (EBV), kaposi's Sarcoma Herpesvirus (KSHV), cynomolgus monkey Herpesvirus (HS), or Marek's Disease Virus (MDV). Epstein Barr Virus (EBV) and Kaposi's Sarcoma Herpes Virus (KSHV) are also examples of gamma herpes viruses. Typically, the host cell includes viral replication transactivators that activate replication.

"expression control sequences", "control elements" or "regulatory sequences" present in an expression vector refer to the untranslated regions of the vector (e.g., origins of replication, selection agents, promoters, enhancers, introns of the translation initiation signal (Shine Dalgarno sequence or Kozak sequence), polyadenylation sequences, 5 'and 3' untranslated regions) that interact with host cell proteins for transcription and translation. The strength and specificity of these elements vary. Any number of suitable transcription and translation elements may be used, including ubiquitous promoters and inducible promoters, depending on the vector system and host used.

Illustrative common expression control sequences useful in the present invention include, but are not limited to, the Cytomegalovirus (CMV) immediate early promoter, the viral monkey virus (SV 40) promoter (e.g., early or late), the Moloney murine leukemia virus (MoMLV) LTR promoter, the Rous Sarcoma Virus (RSV) LTR, the Herpes Simplex Virus (HSV) (thymidine kinase) promoter, the H5, P7.5 and P11 promoters from vaccinia virus, the elongation factor 1-alpha (EF 1 a) promoter, the early growth response factor 1 (EGR 1), ferritin H (FerH), ferritin L (FerL), 3-phosphoglyceraldehyde dehydrogenase (GAPDH), eukaryotic translation initiation factor 4A1 (EIF 4A 1), heat shock 70kDa protein 5 (HSPA 5), heat shock protein 90kDa beta-member 1 (HSP 90B 1), heat shock protein 70kDa (HSP-kinesin), human SA 26 gene sites (Irons et al, 3779), chicken UBC 35, and the PGK promoter (PbK) protein promoter.

Illustrative inducible promoters/systems include, but are not limited to, steroid inducible promoters (e.g., gene promoters encoding glucocorticoids or estrogen receptors (induced by treatment with the corresponding hormone), metallothionein promoters (induced by treatment with various heavy metals), MX-1 promoters (induced by interferon), "gene-switched" mifepristone-regulatory systems (Sirin et al, 2003, gene,323: 67), cumate-induced gene-switching (WO 2002/088346), tetracycline-dependent regulatory systems, and the like. The anti-BCMA antibodies or antigen binding fragments thereof of the present invention can be prepared by any method known in the art, including chemical synthesis and recombinant expression techniques. The practice of the present invention employs, unless otherwise indicated, molecular biology, microbiology, genetic analysis, recombinant DNA, organic chemistry, biochemistry, PCR, oligonucleotide synthesis and modification, nucleic acid hybridization, and related conventional techniques in the art. These techniques are described in the references cited herein and are fully explained in the literature. See, e.g., maniatis et al (1982) MOLECULAR CLONING: A LABORATORY MANUAL, cold Spring Harbor Laboratory Press; sambrook et al (1989), MOLECULAR CLONING: A LABORATORY MANUAL, second Edition, cold Spring Harbor Laboratory Press; sambrook et al (2001) MOLECULAR CLONING: A LABORATORY MANUAL, cold Spring Harbor Laboratory Press, cold Spring Harbor, NY; ausubel et al CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, john Wiley & Sons (1987 and annual updates); CURRENT PROTOCOLS IN IMMUNOLOGY, john Wiley & Sons (1987 and annual updates) Gait (ed.) (1984) OLIGONUCLEOTIDE SYNTHESIS: A PRACTICAL APPROACH, IRL Press; eckstein (ed.) (1991) OLIGONUCLEOTIDES AND ANALOGUES: A PRACTICAL APPROACH, IRL Press; birren et al (eds.) (1999) geme ANALYSIS: A LABORATORY MANUAL, cold Spring Harbor Laboratory Press; borrebaeck (ed.) (1995) ANTIBODY ENGINEERING, second Edition, oxford University Press; lo (ed.) (2006) ANTIBODY ENGINEERING: METHODS AND PROTOCOLS (METHODS IN MOLECULAR BIOLOGY); vol.248, humana Press, inc; each of which is incorporated by reference in its entirety.

The polypeptides of the invention (e.g., the anti-BCMA antibodies or antigen binding fragments) can be produced and isolated using methods well known in the art. Peptides may be synthesized in whole or in part using chemical methods (see, e.g., caruthers (1980), nucleic Acids Res. Symp. Ser.215; horn (1980); and Banga, A.K., therapeutic Peptides and Proteins, formulation, processing and Delivery Systems (1995) Technomic Publishing Co., lancaster, pa.). Peptide synthesis can be performed using a variety of solid phase techniques (see, e.g., roberge Science269:202 (1995); merrifield, methods. Enzymol.289:3 (1997)) and automated synthesis can be accomplished, e.g., using an ABI 431A peptide synthesizer (Perkin Elmer) according to manufacturer's instructions. Peptides can also be synthesized using combinatorial methods. The artificially synthesized residues and polypeptides may be synthesized using various procedures and methods known in the art (see, e.g., organic Syntheses Collective Volumes, gilman, et al (Eds) John Wiley & Sons, inc., NY). The modified polypeptides may be produced by chemical modification (see, e.g., belosus, nucleic Acids Res.25:3440 (1997); frenkel, free radio. Biol. Med.19:373 (1995); and Blommers Biochemistry 33:7886 (1994)). Peptide sequence variations, derivatives, substitutions and modifications can also be made using oligonucleotide-mediated (site-directed) mutagenesis, alanine scanning, and PCR-based mutagenesis. Site-directed mutagenesis (Carter et al, nucleic acids Res.,13:4331 (1986)), zoller et al, nucleic acids Res., 10:6487 (1987)), cassette mutagenesis (Wells et al, gene 34:315 (1985)), restriction-selective mutagenesis (Wells et al, philos. Trans. R. Soc. London serA 317:415 (1986)), and other techniques can be performed on cloned DNA to produce peptide sequences, variants, fusions and chimeras of the invention, as well as variants, derivatives, substitutions and modifications thereof.

The polypeptides of the invention may be prepared using a variety of techniques known in the art, including using hybridoma and recombinant techniques, or combinations thereof. In some embodiments, recombinant expression vectors are used to express polynucleotides encoding the polypeptides of the invention. For example, the recombinant expression vector may be a replicable DNA construct comprising a synthetic or cDNA derived DNA fragment encoding a polypeptide operably linked to appropriate transcriptional and/or translational regulatory elements derived from mammalian, microbial, viral, or insect genes. In some embodiments, the coding sequences for the polypeptides disclosed herein may be ligated into such expression vectors for expression in mammalian cells. In some embodiments, viral vectors are used. DNA regions are "operably linked" when they are functionally related to each other. For example, if the promoter controls transcription of a sequence, it is operably linked to a coding sequence; or operably linked to a coding sequence if the ribosome binding site is positioned so as to permit translation. In some embodiments, structural elements intended for use in yeast expression systems include a leader sequence that may enable the host cell to secrete the translated protein extracellularly. In some embodiments, the polypeptide may include an N-terminal methionine residue in the absence of leader or transport sequences for expression of the recombinant protein.

A variety of expression host/vector combinations may be used. Host cells suitable for expression include prokaryotes, yeast cells, insect cells, or higher eukaryotic cells under the control of appropriate promoters. Suitable cloning and expression vectors for bacterial, fungal, yeast and mammalian cell hosts, as well as protein production methods, including antibody production methods, are well known in the art. Expression vectors useful for bacterial hosts include known bacterial plasmids, such as those from E.coli, including pCR1, pBR322, pMB9 and derivatives thereof, as well as plasmids of a broader host range, such as M13 and other filamentous single-stranded DNA phages.

Expression vectors useful for eukaryotic hosts include, for example, vectors comprising expression control sequences from SV40, bovine papilloma virus, adenovirus and cytomegalovirus. Examples of suitable mammalian host cell lines include, but are not limited to, COS-7 (derived from monkey kidney), L-929 (derived from murine fibroblasts), C127 (derived from murine mammary tumors), 3T3 (derived from murine fibroblasts), CHO (derived from Chinese hamster ovary), heLa (derived from human cervical cancer), BHK (derived from hamster kidney fibroblasts), HEK-293 (derived from human embryonic kidney) cell lines, and variants thereof. Mammalian expression vectors may include non-transcriptional elements (e.g., origins of replication), suitable promoters and enhancers linked to the gene to be expressed, and other 5 'or 3' flanking non-transcribed and 5 'or 3' untranslated sequences (e.g., the necessary ribosome binding sites, polyadenylation sites, splice donor and acceptor sites, and transcription termination sequences). Expression of recombinant proteins in insect cell culture systems (e.g., baculoviruses) also provides a powerful method for producing correctly folded and biologically functional proteins. Baculovirus systems for producing heterologous proteins in insect cells are well known to those skilled in the art.

Antibodies and antigen binding fragments thereof provided herein include, but are not limited to, monoclonal antibodies, polyclonal antibodies, synthetic antibodies, human antibodies, humanized antibodies, and antigen binding fragments thereof.

Methods of antibody preparation are well known in the art. See, e.g., harlow et al, antibodies: ALaboratory Manual, (Cold Spring Harbor Laboratory Press,2nd ed.1988); hammerling et al, in Monoclonal Antibodies and T-Cell hybrid 563 681 (Elsevier, N.Y., 1981), each of which is incorporated herein by reference in its entirety. For antibodies used in the human body, it may be preferable to use human antibodies. Fully human antibodies are particularly desirable for therapeutic treatment of human subjects. Human antibodies can be prepared by a variety of methods known in the art, including phage display methods using libraries of antibodies derived from human immunoglobulin sequences, including improvements to these techniques. See also, U.S. Pat. nos. 4,444,887and 4,716,111; and PCT publications WO 98/46645, WO 98/50433, WO 98/24893, WO98/16654, WO 96/34096, WO 96/33735, and WO 91/10741; each of which is incorporated by reference in its entirety. A human antibody may also be an antibody in which the heavy and light chains are encoded by nucleotide sequences derived from one or more human DNA sources.

Human antibodies can also be produced using transgenic mice that are incapable of expressing functional endogenous immunoglobulins, but are capable of expressing human immunoglobulin genes. For example, human heavy and light chain immunoglobulin gene complexes may be introduced into mouse embryonic stem cells randomly or by homologous recombination. In addition, human variable, constant and diversity regions may be introduced into mouse embryonic stem cells in addition to human heavy and light chain genes. The mouse heavy chain and light chain immunoglobulin genes can be introduced into human immunoglobulin gene loci singly or simultaneously by homologous recombination so as to make the human immunoglobulin gene loci nonfunctional. For example, homozygous deletion of the antibody heavy chain Junction (JH) gene in chimeric and germ-line mutant mice is described as resulting in complete inhibition of endogenous antibody production. The modified embryonic stem cells are expanded and microinjected into blasts to generate chimeric mice. The chimeric mice are then incubated to produce homozygous offspring expressing the human antibodies. Transgenic mice are immunized in a normal manner with a selected antigen (e.g., all or part of a polypeptide of the invention). For example, anti-BCMA antibodies against human BCMA antigen can be obtained from immunized transgenic mice using conventional hybridoma technology. The human immunoglobulin transgenes carried by transgenic mice rearrange during B cell differentiation, followed by class switching and somatic mutation. Thus, using such techniques, therapeutically useful IgG, igA, igM and IgE antibodies, including but not limited to IgG1 (γ1) and IgG3, can be produced. For a brief description of this technology for the production of human antibodies, see Lonberg and Huszar (int. Rev. Immunol.,13:65-93 (1995)). For a detailed discussion of the techniques for producing human antibodies and human monoclonal antibodies, and protocols for producing such antibodies see, for example, PCT publication Nos. WO 98/24893, WO 96/34096, and WO 96/33735; and U.S. Pat. nos.5,413,923;5,625,126;5,633,425;5,569,825;5,661,016;5,545,806;5,814,318; and 5,939,598, each of which is incorporated by reference in its entirety. In addition, abgenix, inc (Freemont, calif.) and Genpharm (Jose, calif.) can provide human antibodies to selected antigens using techniques similar to those described above. For a specific discussion of transduction of human germline immunoglobulin gene arrays in germline mutant mice see, e.g., jakobovits et al, proc.Natl.Acad.Sci.USA,90:2551 (1993); jakobovits et al, nature,362:255-258 (1993); bruggermann et al, year in immunol.,7:33 (1993); and Duchosal et al, nature,355:258 (1992), the array of genes will result in the production of human antibodies upon antigen challenge.

Human antibodies can also be obtained from phage display libraries (Hoogenboom et al, J. Mol. Biol.,227:381 (1991); marks et al, J. Mol. Biol.,222:581-597 (1991); vaughan et al, nature Biotech.,14:309 (1996)). Phage display technology (McCafferty et al, nature,348:552-553 (1990)) can be used to produce human antibodies and antibody fragments in vitro from the immunoglobulin variable (V) region gene library of a non-immunized donor. According to this technique, the antibody V region genes are cloned into the framework of the major or minor coat protein genes of filamentous phage, such as M13 or fd, and displayed as functional antibody fragments on the phage particle surface. Since the filamentous particle contains copies of single-stranded DNA of the phage genome, selection based on antibody functionality will also result in selection of genes encoding antibodies with these properties. Thus, phages mimic certain properties of B cells. Phage display can be performed in a variety of forms; for a review, see, e.g., johnson and Chiswell, current Opinion in Structural Biology 3:564-571 (1993). Several sources of V gene fragments are available for phage display. A collection of different anti-oxazolone antibodies was isolated from a small random combinatorial library of V genes derived from the spleen of non-immunized mice, nature,352:624628 (1991). The V gene bank can be constructed from an immunized human donor and antibodies to a variety of antigens, including autoantigens, can be isolated by the methods described in Marks et al, j.mol. Biol.,222:581-597 (1991), or Griffith et al, EMBO j.,12:725-734 (1993). Reference is also made to U.S. Pat. Nos.5,565,332 and 5,573,905, each of which is incorporated herein by reference in its entirety.

Human antibodies may also be produced by in vitro activated B cells (see, U.S. Pat. nos.5,567,610 and 5,229,275, each of which is incorporated herein by reference in its entirety). Human antibodies can also be produced in vitro using hybridoma techniques, such as, but not limited to, those described by Roder et al (Methods enzymes, 121:140-167 (1986)).

Alternatively, in some embodiments, the non-human antibody is humanized wherein specific sequences or regions of the antibody are modified to increase similarity to antibodies naturally occurring in humans. In some embodiments, the antigen binding domain portion is humanized.

Humanized antibodies can be produced using a variety of techniques known in the art, including, but not limited to, CDR-grafting (see, e.g., european Patent No. EP 239,400; international publication No. WO 91/09967; and U.S. Pat. nos.5,225,539,5,530,101,and 5,585,089, each of which is incorporated herein by reference in its entirety), trim (veneering) or surface remodeling (resurfacing) (see, e.g., european Patent nos. EP 592,106and EP 519,596;Padlan,1991,Molecular Immunology,28 (4/5): 489-498;Studnicka et al, 1994,Protein Engineering,7 (6): 805-814;and Roguska et al, 1994, PNAS,91:969-973, each of which is incorporated by reference in its entirety), chain shuffling (see, e.g., U.S. Pat.No.5,565,332, each of which is incorporated by reference in its entirety), and U.S. Pat Application Publication No. US2005/0042664,U.S.Patent Application Publication No.US2005/0048617,U.S.Pat.No.6,407,213,U.S.Pat.No.5,766,886,International Publication No.WO 9317105,Tan et al, J.Immunol, 169:1119-25 (2002), caldas et al, protein en, 13 (5): 353-60 (2000), morea et al, methods,20 (3): 267-79 (2000), baca et al, J.Biol.Chem, 272 (16 10678-84 (1997), roguska et al, protein en, 9 (10): 895-904 (1996), coco et al, 55, sangusta et al, 1995-55, and 1995) and 1995 (35), and 35, 35 (35) and 35, and 55. 235 (3) the techniques disclosed in 959-73 (1994), each of which is incorporated by reference in its entirety. In general, framework residues in the framework regions can be replaced with corresponding residues from a CDR donor antibody to alter, preferably improve, antigen binding. These framework substitutions are identified by methods well known in the art, for example, by modeling the interactions of CDRs with framework residues to identify framework residues important for antigen binding, and sequence comparisons to identify aberrant framework residues at specific positions. ( See, e.g., queen et al, u.s.pat.no.5,585,089; and Riechmann et al, 1988, nature,332:323, each of which is incorporated herein by reference in its entirety. )

Humanized antibodies have one or more amino acid residues introduced from a non-humanized source. These non-human amino acid residues are often referred to as "import" residues, which are typically taken from an "import" variable region. Thus, a humanized antibody comprises one or more CDRs from a non-human immunoglobulin molecule and a framework region from a human. Humanization of antibodies is well known in the art and can be performed essentially as described by Winter and coworkers (Jones et al, nature,321:522-525 (1986); riechmann et al, nature,332:323-327 (1988); verhoeyen et al, science,239:1534-1536 (1988)), with rodent CDR or CDR sequences replacing the corresponding sequences of human antibodies, namely CDR-grafting (EP 239,400;PCT Publication No.WO 91/09967;and U.S.Pat.Nos.4,816,567;6,331,415;5,225,539;5,530,101;5,585,089;6,548,640, the contents of which are incorporated herein by reference in their entirety). In such humanized chimeric antibodies, significantly less than the entire human variable domain is replaced by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are replaced by residues at similar sites in rodent antibodies. Humanization of the antibodies may also be achieved by veneering or resurfacing (EP 592,106;EP 519,596;Padlan,1991,Molecular Immunology,28 (4/5): 489-498;Studnicka et al, protein Engineering,7 (6): 805-814 (1994) and Roguska et al, PNAS,91:969-973 (1994)) or chain shuffling (U.S. Pat. No.5,565,332), the contents of which are incorporated herein by reference in their entirety.

In the preparation of humanized antibodies, human variable domains (including light and heavy chains) are selected to reduce antigenicity. The variable domain sequences of rodent antibodies were screened against the entire library of known human variable region sequences according to the so-called "best match" method. The human sequence closest to the rodent sequence was then taken as the human Framework (FR) of the humanized antibody (Sims et al, J.Immunol.,151:2296 (1993); chothia et al, J.mol. Biol.,196:901 (1987), the contents of which are incorporated herein by reference in their entirety). Another approach uses a specific framework of all human antibody consensus sequences derived from a specific light chain or heavy chain subgroup. The same framework can be used for several different humanized antibodies (Carter et al, proc. Natl. Acad. Sci. USA,89:4285 (1992); presta et al, J. Immunol, 151:2623 (1993), the contents of which are incorporated herein by reference in their entirety).

Antibodies can be humanized and retain high affinity for the antigen of interest and other favorable biological properties. For example, humanized antibodies can be prepared by analyzing a parent sequence and various conceptual humanized products using three-dimensional models of the parent sequence and the humanized sequence. Three-dimensional immunoglobulin models are generally available and familiar to those skilled in the art. The computer program may illustrate and display the possible three-dimensional conformational structures of the selected candidate immunoglobulin sequences. Examining these displays allows for analysis of the likely role of residues in the function of the candidate immunoglobulin sequence, i.e., analysis of residues that affect the ability of the candidate immunoglobulin to bind its antigen. In this way, FR residues can be selected and combined from the receptor and input sequences such that the desired antibody characteristics, e.g., enhanced affinity for the target antigen, are achieved. Generally, CDR residues are directly and most essentially involved in the effect of antigen binding.

"humanized antibodies retain antigen specificity similar to the original antibody, e.g., the ability to bind human BCMA antigen. However, using certain humanization methods, the affinity and/or specificity of antibodies for binding to a particular antigen can be improved using a "directed evolution" method, which is described in Wu et al, j.mol.biol.,294:151 (1999), the contents of which are incorporated herein by reference in their entirety.

5.8.2 genetically engineered immune effector cells

In some embodiments, the invention provides genetically engineered immune effector cells comprising polynucleotides encoding the disclosed BCMACARs or TCRs of the invention. In some embodiments, the invention provides genetically engineered immune effector cells capable of recombinantly expressing the disclosed BCMACARs or TCRs of the invention. In some embodiments, the invention provides genetically engineered immune effector cells comprising a vector comprising a polynucleotide encoding a BCMACAR or TCR disclosed herein. In some embodiments, the immune effector cell is a T cell.

5.8.2.1 genetic engineering method

With respect to producing cells capable of recombinantly expressing the BCMACARs or TCRs disclosed herein, one or more polynucleotides encoding the BCMACARs or TCRs are introduced into a target cell using a suitable expression vector. One or more BCMACAR or TCR-encoding polynucleotides are transferred to a target immune effector cell (e.g., T cell). The genetically engineered cells may also express an anti-BCMA antibody or antigen binding fragment disclosed herein.

In some embodiments, the invention provides methods of genetically engineering immune effector cells by transferring polynucleotides provided herein to immune effector cells using a non-viral delivery system. The BCMA CAR or TCR-encoding polynucleotide may be mRNA, which allows for transient expression and self-elimination of immune effector cells expressing such BCMACAR or TCR. Physical methods for introducing polynucleotides into host cells include calcium phosphate precipitation, liposome transfection, particle bombardment, microinjection, electroporation, and the like. In some embodiments, RNA electroporation may be used (Van Driessche et al Folia histochemica et cytobiologica 43:4:213-216 (2005)). The method may further comprise preparing mRNA by in vitro transcription of the polynucleotide of the invention. In some embodiments, the invention provides methods of genetically engineering immune effector cells by transferring into the cells a polynucleotide encoding an anti-BCMA antibody or antigen binding fragment provided herein using electroporation. In some embodiments, the invention provides methods of genetically engineering immune effector cells by transferring into the cells a polynucleotide encoding a BCMACAR or TCR provided herein using electroporation.

In some embodiments, DNA transfection and transposons may be used. In some embodiments, a sleep Beauty system or a PiggyBac system is used (e.g., ivics et al, cell,91 (4): 501-510 (1997);et al (2007) Nucleic Acids research.35 (12): e 87). Chemical methods for introducing polynucleotides into host cells include colloidal dispersion systems, such as macromolecular complexes, nanocapsules, microspheres, microbeads, and lipid systems, including oil-in-water emulsions, micelles, mixed micelles, and liposomes. An exemplary colloidal system for use as an in vitro and in vivo delivery vehicle is a liposome (e.g., an artificial membrane vesicle).

For example, the disclosed BCMACAR or TCR-encoding polynucleotides can be cloned into suitable vectors and introduced into target cells using well-known molecular biology techniques (see Ausubel et al Current Protocols in Molecular Biology, john Wiley and Sons, baltimore, MD (1999)). Any vector suitable for expression in a cell, in particular in a human cell, may be used. The vector contains suitable expression elements, such as promoters that provide expression of the encoding nucleic acid in the target cell.

Expression in T cells or other immune effector cells (including engineered T cells) using retroviral vectors has been described (see Scholler et al, sci. Transl. Med.4:132-153 (2012; parente-Pereira et al, J. Biol. Methods 1 (2): e7 (1-9) (2014); blood 117 (1): 72-82 (2011); revier et al, proc.Natl. Acad.Sci.USA 92:6733-6737 (1995)). In some embodiments, the vector is a gamma retroviral vector, in one embodiment, an SGF retroviral vector, e.g., SGFgamma-retroviral vector, which is a Moloney murine leukemia-based retroviral vector.SGF vector has been described previously (see, e.g., wang et al., gene Therapy 15:1454-1459 (2008)), cells can be selectively activated to increase transduction efficiency (see ParentePereira et et al., J.biol.Methods 1 (2) e7 (doi 10.14440/jbm.2014.30) (2014); movasag et al., hum.11811:2000); rev. 1200 (1998) and/v.E.10:35; see also GeneTherO6:10-1459 (1998)), and methods such as those described previously (see, e.g., wang et al., geneTherThe et al 15:1454-1459 (2008)), and methods of improving transduction efficiency (see ParentePereira et et al, J.Biol.Biol.Meter 1 (2) e.7 (2014); hui.110:2014); hu.gene-1998, yu.Gene25: ^TM Human T cell activator product, thermo Fisher Scientific, waltham, MA). It should be understood that any suitable viral vector or non-viral delivery system may be used. Combinations of retroviral vectors and suitable packaging cell lines are also suitable, wherein the capsid proteins will act on the infected human cells. Various cell lines that produce the facultative virus (amphotropic virus) are known, including but not limited to PA12 (Miller et al, mol. Cell. Biol.5:431-437 (1985)); PA317 (Miller et al, mol.cell.biol.6:2895-2902 (1986)); and CRIP (Danos et al, proc.natl. Acad. Sci. USA 85:6460-6464 (1988)). Non-isotropic particles are also suitable, for example, enveloped with VSVG, RD114 or GALV and any other pseudotyped particles known in the art (Relander et al, mol. Therapeutic. 11:452-459 (2005)). Possible transduction methods also include direct co-culture of cells with producer cells (e.g., bregni et al, blood 80:1418-1422 (1992)) or culture alone with viral supernatants or concentrated carrier stock (with or without appropriate growth factors or polycations) (see, e.g., xu et al, exp. Hemat.22:223-230 (1994); hughes, et al J. Clin. Invest.89:1817-1824 (1992)).

Other viral vectors that may be used include, for example, adenovirus, lentiviral and adeno-associated viral vectors, vaccinia virus, bovine papilloma virus derived vectors, or herpes viruses, such as Epstein-Barr virus (see, e.g., miller, hum. Gene Ther.1 (1): 5-14 (1990), friedman, science 244:1275-1281 (1989), eglitis et al, bioTechniques6:608-614 (1988), tolstoshaev et al, current options. Biotechnol.1:55-61 (1990), sharp, lancet337:1277-1278 (1991), cornetta et al, prog. Nucleic Acid Res. Mol. 36:311-322 (1989), anderson, science 226:401-409 (1984), moen, blood 17:407-416 (1991), bioTechniques6: 608-614), tolshaev et al, current operations: 55-61 (1990), sharp, lancet337:1277-1278 (1999), prog. Nucleic Acid injection.36: 311-322 (1989), anderson, science 226:401-409 (1984), blood 17: 407-416). Retroviral vectors have evolved well and have been used clinically (Rosenberg et al, N.Engl. J. Med.323:370 (1990); anderson et al, U.S. Pat. No.5,399,346). In general, the vectors selected exhibit high infection efficiency and stable integration and expression (see, e.g., cayouete et al Human Gene Therapy8:423-430 (1997); kido et al Current Eye Research 15:833844 (1996); bloom et al J. Virol.71:6641-6649 (1997); naldini et al Science 272:263-267 (1996); and Miyoshi et al Proc. Natl. Acad. Sci. U.S.A.94:10319-10323 (1997)).

The vectors used in the present invention are expressed in a particular host cell using a suitable promoter. The promoter may be an inducible promoter or a constitutive promoter. In some embodiments, the promoter of the expression vector provides expression in a stem cell (e.g., a hematopoietic stem cell). In some embodiments, the promoter of the expression vector provides expression in immune effector cells (e.g., T cells). Non-viral vectors may also be used, provided that the vector contains expression elements suitable for expression in the target cell. Some vectors, such as retroviral vectors, may be integrated into the host genome.

In some embodiments, the invention provides methods of genetically engineering immune effector cells by transferring a polynucleotide provided by the invention into immune effector cells using gene editing. If desired, site-directed integration can be achieved using techniques such as nucleases, transcription activator-like effector nucleases (TALENs), zinc Finger Nucleases (ZFNs), regularly clustered short palindromic repeats (CRISPRs), homologous recombination, non-homologous end joining, microhomologous mediated end joining, homologous mediated end joining, and the like (Gersbach et al, nucleic acids Res.39:7868-7878 (2011); vaselivava, et al cell Death Dis.6:e1831. (Jul 23 2015); sontheimer, hum. Gene Ther.26 (7): 413-424 (2015); yao et al cell Research volume 27,801-814 (2017)). In some embodiments, the methods provided herein use ZFN systems. Zinc finger nucleases consist of a DNA recognition domain and a non-specific endonuclease. The DNA recognition domain consists of a series of tandem Cys2-His2 zinc finger proteins, each zinc finger unit containing about 30 amino acids for specifically binding DNA. The nonspecific endonuclease is a FokI endonuclease that forms dimers to cleave DNA. In some embodiments, the methods provided herein use a TALEN system. TALENs are a type of transcriptional activator-like effector nucleases. The TALE protein is a core component of the DNA binding domain, and typically consists of a plurality of basic repeat units in tandem. The series of units designed and combined can specifically recognize a DNA sequence and cleave the specific DNA sequence by coupling a fokl endonuclease.

In some embodiments, the methods provided herein use a CRISPR-Cas system. The CRISPR-Cas system may be a CRISPR-Cas9 system. The CRISPR/Cas system is a nuclease system consisting of a regularly clustered short palindromic repeat (CRISPR) and a CRISPR binding protein (i.e., cas protein) that can cleave almost all genomic sequences adjacent to the Protospacer Adjacent Motif (PAM) in eukaryotic cells (Cong et al science 2013.339:819-823). "CRISPR/Cas system" is used to refer collectively to transcripts related to CRISPR-associated ("Cas") genes, as well as to other elements whose expression or directing their activity, including sequences encoding Cas genes, tracr (transactivated CRISPR) sequences (e.g., tracrRNA or active moiety tracrRNA), tracr mate sequences (in the context of endogenous CRISPR systems, covering "direct repeats" and processed moiety direct repeats), guide sequences, or other sequences from CRISPR sites and transcripts. In general, CRISPR systems are characterized by elements (also referred to as pre-spacers in endogenous CRISPR systems) that promote the formation of CRISPR complexes at the site of the target sequence. In general, CRISPR systems are characterized by elements (also referred to as pre-spacers in endogenous CRISPR systems) that promote the formation of CRISPR complexes at the site of the target sequence. Non-limiting examples of Cas proteins include Cas1, cas1B, cas2, cas3, cas4, cas5, cas6, cas7, cas8, cas9 (also known as Csn1 and Csx 12), cas10, csy1, csy2, csy3, cse1, cse2, csc1, csc2, csa5, csn2, csm3, csm4, csm5, csm6, cmr1, cmr3, cmr4, cmr5, cmr6, csb1, csb2, csb3, csx17, csx14, csx10, csx16, csaX, csx3, csx1, csx15, csf1, csf2, csf3, csf4 homologs, or modified versions thereof. In some embodiments, the Cas protein is a Cas9 protein (gasiuas, barrenu et al 2012; jink, chldinki et al 2012; deltcheva, chldinki et al 2011; makarova, grishin et al (2006)). The amino acid sequence of Cas9 proteins is known in the art. Example sequences can be found, for example, in the SwissProt database, accession number Q99ZW2, in the UniProt database, accession number A1IQ68, Q03LF7, or J7RUA5.

The vector and construct may alternatively be designed to include a reporter. For example, the vector may be designed to express a reporter protein that can be used to recognize cells comprising the vector or a polynucleotide provided on the vector (e.g., a polynucleotide that has been integrated into a host chromosome). In one embodiment, the reporter may be expressed with an anti-BCMA antibody or antigen binding fragment, or BCMACAR or TCR as a bicistronic or polycistronic construct. Exemplary reporter proteins include, but are not limited to, fluorescent proteins such as mCherry, green Fluorescent Protein (GFP), blue fluorescent proteins (e.g., EBFP2, azurite, and mKalama 1), cyan fluorescent proteins (e.g., ECFP, cerulean and CyPet), and yellow fluorescent proteins (e.g., YFP, citrine, venus and YPet).

Transduction efficiencies can be determined by testing using conventional molecular biology techniques. If a marker (e.g., fluorescent protein) is included in the construct, gene transfer efficiency can be monitored by FACS analysis to quantify the proportion of transduced (e.g., gfp+) immune effector cells (e.g., T cells), and/or by quantitative PCR. Using a mature co-culture system (gap et al, cancer Res.65:9080-9088 (2005); gong et al, neoplasia 1:123-127 (1999); latouch et al, nat. Biotechnol.18:405-409 (2000)), it was determined whether Cancer antigen-expressing fibroblast AAPCs (compared to controls) led to release of cytokines from transduced immune effector cells such as CAR-expressing T cells (IL-2, IL-4, IL-10, IFN-gamma, TNF-alpha and GM-CSF cell supernatant LUMINEX (Austin TX) assays), T cell proliferation (labeled by carboxyfluorescein succinimidyl ester (CFSE)) and T cell survival (stained by Annexin V). The effect of CD80 and/or 4-1BBL on T cell survival, proliferation and efficacy can be assessed. T cells can be exposed to repeated stimulation of cancer antigen positive target cells and it can be determined whether T cell proliferation and cytokine response remain similar or diminish with repeated stimulation. The cancer antigen CAR constructs can be compared side-by-side under equivalent assay conditions. Various E can be performed using the chromium release test: t ratio cytotoxicity assay.

Combinations and permutations of the various methods described herein or otherwise known in the art are expressly contemplated for preparing the genetically engineered cells disclosed herein.

5.8.2.2 manipulation of immune effector cells

The immune effector cells provided by the invention can be obtained from a subject. The immune effector cell sources provided by the present invention include, but are not limited to, hematopoietic cells of peripheral blood, umbilical cord blood, bone marrow, or other sources.

cord blood, bone marrow, or other sources of hematopoietic cells immune effector cells (e.g., T cells) can be obtained from a number of sources including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue at the site of infection, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments, cell lines useful in the art may be used. Immune effector cells provided by the present invention may be isolated by methods well known in the art, including commercially available isolation methods (see, e.g., rowland Jones et al, LYMPHOCYTES: A PRACTICAL APPROACH, oxford University Press, new York (1999)). Various methods for isolating immune effector cells have been previously described and can be used including, but not limited to, the use of peripheral donor lymphocytes (Sadelain et al, nat. Rev. Cancer3:35-45 (2003); morgan et al, science 314:126-129 (2006)), and the selective use of antigen-specific peripheral Blood lymphocytes that are expanded in vitro using Artificial Antigen Presenting Cells (AAPCs) or dendritic cells (Dupont et al, cancer Res.65:5417-5427 (2005); papanicolaou et al 102, blood:2498-2505 (2003)).

In certain embodiments, the presently disclosed immune effector cells (e.g., T cells) can be obtained using any technique known to those skilled in the art (e.g., ficoll ^TM Isolation) is obtained from blood units collected from the subject. In some embodiments, cells from the circulating blood of the individual are obtained by apheresis. The apheresis product typically contains lymphocytes, including T cells, monocytes, granulocytes, B cells, other nucleated leukocytes, erythrocytes, and platelets. In some embodiments, cells collected by apheresis may be washed to remove plasma fractions and the cells placed in an appropriate buffer or medium for subsequent processing steps. In some embodiments, the cells are washed with Phosphate Buffered Saline (PBS). In another embodiment, the wash solution lacks calcium, and may lack magnesium, or may lack many, if not all, divalent cations. In the absence of calcium, the initial activation step results in amplification activation. Such asThe washing step may be accomplished by methods known to those skilled in the art, such as using a semi-automated "flow-through" centrifuge (e.g., cobe 2991 cell processor, baxter CytoMate, or autologous blood recovery machine 5) according to manufacturer's instructions, as will be readily appreciated by those of ordinary skill in the art. After washing, the cells can be resuspended in various biocompatible buffers, e.g., ca-free ²⁺ No Mg ²⁺ Is described herein as PBS, bowmember A (PlasmaLyte A), or other physiological saline solution with or without a buffer. Alternatively, the unwanted components of the apheresis sample may be removed and the cells resuspended directly in culture medium.

In another embodiment, the method is performed by lysing erythrocytes and depleting monocytes (e.g., by Percoll ^TM Gradient centrifugation or countercurrent centrifugation elution) to separate T cells from peripheral blood lymphocytes. A specific subset of T cells, such as CD3 ⁺ ,CD28 ⁺ ,CD4 ⁺ ,CD8 ⁺ ，CD45RA ⁺ And CD45RO ⁺ T cells can be further isolated by positive or negative selection techniques. For example, in one embodiment, the conjugate is formed by coupling microbeads (e.g., 3X 28)M-450CD3/CD 28T) for a sufficient period of time for positive selection of the desired T cells. In one embodiment, the period of time is about 30 minutes. In another embodiment, the period of time ranges from 30 minutes to 36 hours or more, and all integer values included therebetween. In another embodiment, the period of time is at least 1, 2, 3, 4, 5, or 6 hours. In yet another preferred embodiment, the period of time is from 10 to 24 hours. In a preferred embodiment, the incubation period is 24 hours. For T cell isolation in leukemia patients, using longer incubation times (e.g., 24 hours) can increase cell yield. In any case where there are fewer T cells than other cell types, longer incubation times may be used to isolate T cells, such as Tumor Infiltrating Lymphocytes (TILs) from tumor tissue or immunocompromised individuals. In addition, use more A long incubation time may increase the efficiency of capturing cd8+ T cells. Thus, by simply shortening or extending the time for T cells to bind to CD3/CD28 microbeads and/or by increasing or decreasing the ratio of microbeads to T cells (as further described herein), T cell subsets can be preferentially selected or eliminated at the beginning of culture or at other points in the process. In addition, by increasing or decreasing the proportion of anti-CD 3 and/or anti-CD 28 antibodies on the microbeads or other surface, T cell subsets can be preferentially selected or eliminated at the beginning of culture or at other desired points in time. Those skilled in the art will recognize that multiple rounds of selection may also be used in the context of the present invention.

Various techniques can be used to isolate cells to enrich for desired immune effector cells. For example, negative selection methods can be used to remove cells that are not desired immune effector cells. In addition, positive selection methods may be used to isolate or enrich for desired immune effector cells or their precursors, or a combination of positive and negative selection methods may be used. Monoclonal antibodies (MAbs) are particularly useful for identifying markers associated with specific cell lineages and/or differentiation stages associated with positive and negative selections. If a particular type of CELL, e.g., a particular type of T CELL, is to be isolated, various CELL surface markers or combinations of markers can be used to isolate the CELL, including but not limited to CD3, CD4, CD8, CD34 (for hematopoietic stem/progenitor CELLs), etc., as is well known in the art (see, kearse, T CELL PROTOCOLS: DEVELOPMENT AND ACTIVATION, huma Press, totowa NJ (2000); de Libero, T CELL PROTOCOLS, vol.514of Methods in Molecular Biology, huma Press, totowa NJ (2009)). In some embodiments, enrichment of T cell populations by negative selection may be accomplished with antibody binding to a surface marker specific for the negative selection cells. One approach is cell sorting and/or selection by negative magnetic immunoadhesion or flow cytometry using a mixture of monoclonal antibodies directed against cell surface markers present on negative selection cells. For example, to enrich for CD4 by negative selection ⁺ The cell, monoclonal antibody mixture typically includes CD14, CD20, CD11b, CD16, HLA-DR, and CD8 antibodies. At the position ofIn certain embodiments, it may be desirable to enrich or positively select for regulatory T cells that normally express cd4+, cd25+, cd62Lhi, gitr+ and foxp3+. Alternatively, in certain embodiments, T regulatory cells are eliminated by anti-C25 coupled microbeads or other similar selection methods.

Isolation procedures for immune effector cells include, but are not limited to, density gradient centrifugation, coupling particles that modify cell density, magnetic separation with antibody-coated magnetic beads, affinity chromatography; cytotoxic agents used in conjunction or coupling with monoclonal antibodies (mabs) include, but are not limited to, complement and cytotoxins, as well as antibody panning attached to a solid substrate, such as a plate or chip, elution, flow cytometry, or any other convenient technique (see, e.g., recktenwald et al, CELL SEPARATION METHODS AND APPLICATIONS, marcel Dekker, inc., new York (1998)).

It will be appreciated that the immune effector cells used in the methods provided herein may be substantially pure cells or may be polyclonal populations. In some embodiments, the polyclonal population can be enriched for desired immune effector cells. This enrichment can be performed before or after the cells are genetically engineered to express BCMACARs or TCRs provided by the present invention, as desired.

The immune effector cells may be autologous or non-autologous to the subject to whom they are administered according to the disclosed methods of treatment. Autologous cells are isolated from the subject to whom the engineered cells have been administered. Alternatively, cells may be obtained by apheresis, wherein leukocytes are selectively removed from the extracted blood, made into recombinants, and then reinfused into the donor. Alternatively, allogeneic cells from a non-autologous donor that is not the subject may be used. In the case of non-autologous donors, cells are typed and matched to Human Leukocyte Antigens (HLA) to determine appropriate levels of compatibility, as is well known in the art. Cells may optionally be cryopreserved after isolation and/or genetic engineering and/or cell expansion after genetic engineering (see Kaiser et al, supra, 2015)). Methods OF cryopreserving cells are well known in the art (see, e.g., freshney, CULTURE OF ANIMAL CELLS: A MANUAL OF BASIC TECHNIQUES,4th ed., wiley-Lists, new York (2000); harrison and Rae, GENERAL TECHNIQUES OF CELL CULTURE, cambridge University Press (1997)).

In some embodiments, the isolated immune effector cells are genetically engineered in vitro for recombinant expression of a polypeptide (e.g., CAR or TCR). In some embodiments, the isolated immune effector cells are genetically engineered in vitro for recombinant expression of BCMACAR or TCR. In some embodiments, the immune effector cells provided herein are obtained by in vitro sensitization (sensitization), wherein the sensitization may occur before or after the immune effector cells are genetically engineered to recombinantly express the polypeptides disclosed herein. In one embodiment, sensitized immune effector cells (e.g., T cells) are isolated from an in vivo source, and it will be self-evident that sensitized immune effector cells have been genetically engineered. [00363] It is also contemplated in the present invention to collect a blood sample or a apheresis product from a subject for a period of time prior to the time that genetically engineered cells as described herein may be required. Thus, the source of cells to be expanded can be collected at any necessary point in time and the desired cells (e.g., T cells) isolated and frozen for later use in T cell therapy for any number of diseases or conditions (e.g., those described herein) that would benefit from T cell therapy. In one embodiment, the blood sample or single is taken from a generally healthy subject. In certain embodiments, a blood sample or single sample is taken from a generally healthy subject at risk of developing but not yet developing, and the desired cells are isolated and frozen for later use. In certain embodiments, the T cells may be expanded, frozen, and used at a later time. In certain embodiments, samples are collected from the patient shortly after diagnosis of a particular disease as described herein, but prior to any treatment. In another embodiment, cells are isolated from a blood sample or single sample of a subject prior to employing any number of relevant therapeutic regimens including, but not limited to, treatment with a drug (e.g., natalizumab, efalizumab, antiviral), chemotherapy, radiation therapy, immunosuppressants (e.g., cyclosporine, azathioprine, methotrexate, mycophenolic acid, and FK 506), antibodies or other immunosuppressants (e.g., CAMPATH, anti-CD 3 antibodies, cyclophosphamide, fludarabine, cyclosporine, FK506, rapamycin, mycophenolic acid, steroids, FR 901228), and irradiation. These drugs inhibit the calcium-dependent phosphatase calcineurin (cyclosporin and FK 506) or inhibit p70S6 kinase (rapamycin) important for growth factor-induced signaling (Liu et al, cell 66:807-815,1991;Henderson et al, immun 73:316-321,1991;Bierer et al, curr. Opin. Immun.5:763-773, 1993). In further embodiments, cells are isolated and frozen for subsequent use in conjunction with bone marrow transplantation or stem cell transplantation (e.g., prior to, concurrent with, or subsequent to transplantation), T cell ablation therapy using a chemotherapeutic agent (e.g., fludarabine), external electron beam radiation therapy (XRT), cyclophosphamide, or an antibody (e.g., OKT3 or CAMPATH). In another embodiment, the cells are isolated prior to B cell ablation therapy and may be frozen for later use in a later therapy, such as a drug that reacts to CD20 (e.g., rituxan). [00364] In a further embodiment, T cells are obtained directly from the patient after treatment. In this regard, it has been observed that after certain cancer treatments, particularly treatments with drugs that damage the immune system, patients often recover from the treatment shortly after the treatment, and the quality of the T cells obtained may be optimized or improved due to their ability to expand in vitro. Likewise, after in vitro manipulations using the methods described herein, these cells may be in a preferred state for enhanced transplantation and in vivo expansion. Thus, it is contemplated that blood cells, including T cells, NK cells, or other immune effector cells of the hematopoietic lineage, are collected during this recovery phase. Furthermore, in certain embodiments, mobilization (e.g., mobilization with GM-CSF) and pretreatment protocols can be used to create conditions in a subject that favor the re-proliferation, recycling, regeneration, and/or expansion of a particular cell type, particularly during a defined time window after treatment. Exemplary cell types include T cells, B cells, dendritic cells, and other cells of the immune system.

The immune effector cells disclosed herein may be subjected to conditions well known in the art that facilitate cell maintenance or expansion. (De Liberto, T Cell Protocols, vol.514of Methods in Molecular Biology, humana Press, totowa N.J. (2009); parente-Pereira et al, J.biol.methods 1 (2) e7 (doi 10.14440/jbm.2014.30) (2014); movasmagh et al, hum.Gene Ther.11:11891200 (2000); rettig et al, mol.Ther.8:29-41 (2003); agarwal et al, J.Virol.72:3720-3728 (1998); polook et al, hum.Gene Ther.10:2221-2236 (1999); quinn et al, hum.Gene Ther.9:1457-1467 (1998)), and other commercially available methods such as Dynabeads T Cell activator products, thermo Fisher Scientific, waltham, MA). The immune effector cells (e.g., T cells) disclosed herein can optionally be expanded before or after in vitro genetic engineering. Expansion of cells is particularly useful for increasing the number of cells in a subject for administration. Such methods for cell expansion are well known in the art (see, e.g., kaiser et al, cancer Gene Therapy 22:72-78 (2015); wolfl et al, nat. Protocols 9:950-966 (2014)). In addition, the cells may optionally be cryopreserved after isolation and/or genetic engineering and/or expansion of the genetically engineered cells (see Kaiser et al, supra, 2015)). Methods for cryopreserving cells are well known in the art (see, e.g., freshney, CULTURE OF ANIMAL CELLS: A MANUAL OF BASIC TECHNIQUES,4th ed., wiley-Lists, new York (2000); harrison and Rae, GENERAL TECHNIQUES OF CELL CULTURE, cambridge University Press (1997)).

In general, T cells provided by the invention can be expanded by contact with a surface to which are attached reagents that stimulate a CD3/TCR complex-associated signal and ligands that stimulate co-stimulatory receptors on the surface of the T cells. In particular, the T cell population may be stimulated as described herein, for example by contacting with an anti-CD 3 antibody or antigen binding fragment thereof, or an anti-CD 2 antibody immobilized on a surface, or by contacting with a protein kinase C activator (e.g., bryostatin) that binds to a calcium ionophore. To co-stimulate the helper molecule on the surface of the T cell, a ligand that binds to the helper molecule is used. For example, a population of T cells may be contacted with an anti-CD 3 antibody and an anti-CD 28 antibody under conditions suitable to stimulate T cell proliferation. To stimulate proliferation of cd4+ T cells or cd8+ T cells, anti-CD 3 antibodies and anti-CD 28 antibodies. Examples of anti-CD 28 antibodies include 9.3, B-T3, XR-CD28 (diacetone, besancon, france), other methods common in the art can also be used (Berg et al, transplant Proc.30 (8): 39753977,1998;Haanen et al, J.exp. Med.190 (9): 13191328,1999;Garland et al, J.Immunol Meth.227 (1-2): 53-63,1999).

The invention is described herein in a number of embodiments using certain language. The invention also specifically includes embodiments that exclude particular subject-matter, such as matters or materials, method steps and conditions, protocols, procedures, assays or analyses, entirely or in part. Thus, even though the invention is not generally expressed in terms of what the invention does not include, aspects not explicitly included in the invention are still disclosed in the invention.

Specific embodiments of the application are described herein, including the best mode known to the inventors for carrying out the application. Variations of those disclosed embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description, and it is contemplated that such variations may be suitably employed by those of ordinary skill in the art. Accordingly, this application is intended to be practiced otherwise than as specifically described and this application includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Furthermore, any combination of the above-described elements in all possible variations thereof is encompassed by the application unless otherwise indicated herein or otherwise clearly contradicted by context.

All publications, patent applications, accession numbers, and other references cited in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Citation or identification of any reference in the description of some embodiments of the application shall not be construed as an admission that such reference is available as prior art to the present application. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed.

Various embodiments of the present invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, the description in the experiments is intended to illustrate but not limit the scope of the invention as described in the claims.

5.9 experiment

Twelve novel anti-BCMA scFv were generated and characterized as described below. T cells expressing CARs comprising these BCMA scFv were also generated and characterized. The cytotoxicity of these BCMACART against BCMA expressing tumors was demonstrated.

5.9.1 materials and methods

Primary human lymphocytes. Primary human cd4+ T cells and cd8+ T cells were isolated from healthy volunteers. T cells were stimulated with anti-CD 3/CD28 Dynabeads magnetic beads (Life Technologies, grand Island, N.Y.) and cultured in R10 medium supplemented with 100IU/mL IL-2 (10% fetal bovine serum, 1% HEPES, 1% GuthaMAX, 1% penicillin and streptomycin, 1% MEM NEAA and 1% sodium pyruvate in RPMI-1640 medium).

Cell lines. The following cell lines were cultured in R10 medium and used for the relevant experiments: nalm6 (human leukemia cells), jeko1 (human lymphoma cells), RPMI-8226 (human myeloma cells), raji (human lymphoma cells), THP1 (human leukemia cells), HCC70 (human breast cancer cells), 786-O (human renal cell carcinoma cells), SH-SY5Y (human neuroblastoma cells), A549ESO (human lung cancer cells), SKOV3 (human ovarian cancer cells), PC3 (human prostate cancer cells), H226 (human lung cancer cells), ASPC1 (human pancreatic tumor cells), caski (human cervical cancer cells) and K562 (human leukemia cells).

Lentivirus production and transduction. Lentiviral vectors were generated from HEK293T cells transfected with transfer and packaging plasmids prsv.rev, pmd2.g and pmdlg.prre. Lentiviral vectors were harvested 24 and 48 hours later and concentrated by ultracentrifugation.

T cells (CD 4: cd8=1:1) were stimulated on day 0 by CD3/CD28 Dynabead magnetic beads. Lentiviruses were added to the medium on day 1. Cells were fed daily or every two days with R10 medium containing 100IU/ml IL-2.

BCMA31.BBz and LACO mRNA production. In vitro transcription of mRNA was performed using Ambion mMessage mMACHINE T Ultra kit (Life Technologies, carlsbad, calif.).

Electroporation of BCMA31.BBz and LACO mRNA. mRNA was added to 0.1ml T cells (1X 10) ⁸ Individual cells/ml), the T cells were washed twice and resuspended with OPTI-MEM. Electroporation was performed in a 0.2cm cuvette using BTX830 (Harvard Apparatus BTX) at 500V and 0.7 ms.

Tumor killing assays using an intucyte real-time cell analyzer. Tumor cells and T cells were washed twice with R10 medium and then resuspended in R10 medium. Tumor cells and car+ T cells were both seeded in 96-well plates at a concentration of 10000 cells/well. The total cumulative intensity was recorded every 4 hours.

ELISA.10 ten thousand CAR-T cells and 10 ten thousand tumor cells were co-cultured at 37℃for 24 hours, and then the supernatant was collected and assayed according to ELISA kit (R&D Systems) to measure secretion levels of IL-2 and ifnγ.

CD107a test. CAR-T cells and tumor cells were mixed in a 1:2 ratio. CD107 antibody was added to the medium. After 1 hour of co-cultivation, golgi stop solution was added. After 3 hours, cells were stained with CD3-BV421 and CD8-APC antibodies and analyzed by flow cytometry.

Preparation of 5.9.2 anti-BCMA antibodies

An anti-BCMA antibody was prepared using a fully human antibody phage display library according to the following procedure:

(1) Expression and purification of phage display libraries: infection of log-phase TG1 library cultures with freshly thawed M13K07 helper phage at a multiple infection rate of 20:1 (phage to cell ratio) and induction with IPTG overnight; phage libraries were purified by PEG/NaCl precipitation and phage titers were determined. Phage were stored at 4℃and later subjected to scFv selection.

(2) Selection of BCMA-specific scFv-phages: in the first round of selection, 20. Mu.g/ml BCMA-6His protein dissolved in 1 XPBS was coated on Maxisorp plates and incubated overnight at 4 ℃. (in the subsequent rounds of selection, lower protein concentrations were used for more stringent selection, including 2. Mu.g/ml in the second round of biological screening, 0.5. Mu.g/ml in the third round of biological screening.) and then after washing the plates three times with PBS, blocking buffer (5% milk and 1% BSA in 1 XPBS) was added to each well. After incubation for 2 hours at room temperature, the blocking buffer was discarded, phage solution was added, the plate was sealed with preservative film and incubated for 2 hours with gentle shaking. In the first round of selection, plates were then washed 10 times with PBST. (in the next few rounds, the stringency of the wash is increased by adding more wash cycles: 20 wash cycles for the second round and 30 wash cycles for the third round). Antigen-binding scFv-phage were then eluted using 1mL of acid wash buffer (pH 2.2), neutralized, inoculated into 15mL of log-phase TG1 culture (od600=0.5), left to stand at 37 ℃ for 30min and shake for 30min, inoculated onto 2xYT-GA agar plates, and incubated overnight at 30 ℃ for subsequent selection.

(3) mpELISA screening: after three rounds of screening, 480 phage-infected colony clones were selected for monoclonal phage ELISA (mpELISA) screening. Phage supernatants were generated from individual colony clones and tested for binding to BCMA-Fc protein. The supernatant was incubated with pre-blocked Maxisorp plates coated with 2. Mu.g/ml BCMA-6His protein. After three washes, 100 μl/well of HRP conjugated anti-M13 antibody was added, which was subjected to 1: diluted 5000 and then incubated at room temperature for 60min. After washing the plates 5 times with PBST, 100. Mu.l/well TMB matrix solution was added and incubated for 10-30 minutes until blue color appeared. The reaction was stopped by adding 50. Mu.l/well of stop solution (2N H2SO 4).

In the microplate reader, the absorbance was read at 450 nm. Table 4 below provides three representative anti-human BCMA-Fc monoclonal phage ELISA 96-well plate readings. Clones with grey highlights were positive clones. In phage ELISA assays, 36 positive clones were selected in total, scFv fragments were amplified by PCR and sequenced.

Table 4: flat plate-1

Panel-2

Panel-3

(4) Cloning and sequence analysis: positive clones were selected according to ELISA results and used as templates for PCR cloning of scFv sequences (forward primer sequence: tgcagctggcacgacaggtttc, reverse primer sequence: cgtcagactgtagcacgtt). The PCR product was then sequenced by the sanger sequencing method (forward primer sequence: aacaattgaattcaggagga, reverse primer sequence: cctcctaagaagcgtagtc). CDR regions of scFv were analyzed by the abysis website (http:// abysis. Org /), see tables 1 and 2 above.

(5) Screening of functional anti-BCMA scFv in T cells: the anti-BCMA scFv was constructed into a bicistronic lentiviral CAR expression vector containing an IRES truncated EGFR (tgfr) expression cassette. Lentiviruses were produced by transient transfection of 293T cells, followed by purification and concentration by ultracentrifugation. T cells were transduced with CAR lentiviruses to generate CAR-T cells, and then cultured for an additional 10 days. 10 days after lentiviral transduction, CAR-T cells were collected and stained with 5 μg/ml CD19-Fc protein (Ctrl Fc protein) or BCMA-Fc recombinant protein at 4℃for 30 min. After washing, CAR-T cells were stained with anti-human IgG Fc and anti-EGFR mAb. The samples were analyzed using a flow cytometer. As shown, T cells expressing CAR (containing the following anti-BCMA scFv) showed binding to BCMA-Fc (fig. 1B) and were selected for further study: BCMA21, BCMA22, BCMA23, BCMA24, BCMA27, BCMA28, BCMA30, BCMA31, BCMA32, BCMA33, BCMA34, and BCMA35.

Preparation and characterization of 5.9.3BCMA-CART

We constructed 12 different anti-BCMAARs using the anti-BCMA scFv described above. Parallel tests were performed on 3 other CART products, including NBC10 (Novartis AG and University of Pennsylvania, bmca10. Bbz), FHVH33 (National Institutes of Health, US), and B38M (south genipin biotechnology). All CARs tested had 41BBz coactivator domains.

Table 5: BCMACART, CAR% and expression level

CART	scFv	CAR％	MFI
				1	NBC10	22％	1.2E+05
2	FHVH33	84％	3.2E+05
				3	BCMA21	31％	1.6E+05
4	BCMA22	12％	7.5E+04
				5	BCMA23	18％	2.2E+05
6	BCMA24	23％	9.4E+04
				7	BCMA27	27％	1.7E+05
8	BCMA28	29％	6.5E+04
				9	BCMA30	25％	4.6E+04
10	BCMA31	37％	2.5E+05
				11	BCMA32	19％	5.6E+04
12	BCMA33	27％	2.6E+05
				13	BCMA34	16％	9.5E+04
14	BCMA35	18％	1.1E+05
				15	B38M	51％	5.8E+05
16	NTD

T cells are transduced by lentiviral vectors to express different BCMAARs. Table 5 above shows the CART cells, the percentage of CAR expressing cells and their respective expression levels used in the studies disclosed herein. Figures 2A and 2B show the frequency of car+ T cells and their expression levels ("MFI" is the mean fluorescence intensity), respectively. Of the 12 scFvs produced in the present invention, BCMA31 (# 10; SEQ ID NO: 138) and BCMA33 (# 12; SEQ ID NO: 140) were expressed at higher levels than the other scFvs. Figure 3 shows comparable frequencies of car+cd8 cells in test CART (comparable frequencies). FIG. 4 shows the phenotype of CART cells. The frequency of naive T-cell populations (CD 45RO-; CCR7+) in BCMA27 (# 7), BCMA31 (# 10), and BCMA33 (# 12) T-cells was higher than in the other samples, indicating that these T-cells differentiated to a lesser extent.

Expression of 5.9.4BCMA in tumor cells

BCMA expression was detected for different tumor cell lines by FACS staining (fig. 5A) and RT-PCR (fig. 5B), as shown in fig. 5A and 5B. BCMA expression was detected in Jeko-1 (low level), raji (medium level) and RPMI-8226 cells (high level) by FACS staining. Although BCMA expression in Nalm6 was not detected by FACS, RT-PCR analysis showed BCMA expression in Nalm6, although the expression level was low.

5.9.5BCMACART cytotoxicity to tumor cells

The CART cells were co-cultured with Jeko-1 cells and RPMI-8226 tumor cells. INF-gamma and IL-2 production was detected. As shown in FIGS. 6A (INF-. Gamma.) and 6B (IL-2), of the 12 CARTs produced by the present invention, BCMA23 (# 5; SEQ ID NO: 133), BCMA24 (# 6; SEQ ID NO: 134), BCMA27 (# 7; SEQ ID NO: 135), BCMA31 (# 10; SEQ ID NO: 138) and BCMA33 (# 12; SEQ ID NO: 140) were able to produce more cytokines than other CART cells (including NBC10 and B38M CAR T cells).

We also examined the cytolytic activity of CART cells on Jeko-1 (FIGS. 7A-7D) and RPMI-8226 cells (FIGS. 8A-8E), respectively. BCMA23 (# 5), BCMA24 (# 6), BCMA31 (# 10) and BCMA33 (# 12) CART cells exhibit different degrees of cytotoxicity to Jeko-1 cells, with BCMA31 (# 10) having the highest cytotoxicity, jeko-1 being effectively eliminated. In addition, BCMA21 (# 3; SEQ ID NO: 131), BCMA22 (# 4; SEQ ID NO: 132), BCMA23 (# 5; SEQ ID NO: 133), BCMA24 (# 6; SEQ ID NO: 134), BCMA27 (# 7; SEQ ID NO: 135), BCMA31 (# 10; SEQ ID NO: 138), BCMA33 (# 12; SEQ ID NO: 140), BCMA4 (# 13; SEQ ID NO: 141) and BCMA35 (# 14; SEQ ID NO: 142) exhibited different levels of cytotoxicity to RPMI-8226 cells, with BCMA21 (# 3), BCMA23 (# 5), BCMA24 (# 6), BCMA27 (# 7), BCMA31 (# 10) and BCMA33 (# 12) effectively eliminating RPMI-8226 cells.

6. Electronically submitted sequence list references

The present application incorporates by reference the sequence listing of the ASCII text file "313 a006wo01_st25.txt" of size 224,849 bytes created by the present application at 2021, 8, 11.

SEQUENCE LISTING

<110> Shanghai Uteji biological medicine Co., ltd

<120> BCMA targeting antibodies, chimeric antigen receptors and uses thereof

<130> PWNCN210910-MO

<160> 184

<170> PatentIn version 3.5

<210> 1

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> BCMA21 LCDR1

<400> 1

Arg Ala Ser Gln Ser Val Ser Ser Asn Phe Leu Ala

1 5 10

<210> 2

<211> 14

<212> PRT

<213> artificial sequence

<220>

<223> BCMA21, BCMA32, BCMA33 LCDR1

<400> 2

Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser

1 5 10

<210> 3

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> BCMA23 LCDR1

<400> 3

Ser Gly Ser Ser Pro Asn Ile Gly Gly Asn Ser Val Asn

1 5 10

<210> 4

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> BCMA24 LCDR1

<400> 4

Ser Gly Ser Ser Ser Asn Ile Gly Ser Tyr Ser Val Asn

1 5 10

<210> 5

<211> 14

<212> PRT

<213> artificial sequence

<220>

<223> BCMA27 LCDR1

<400> 5

Thr Gly Ser Arg Ser Asn Val Gly Ser Tyr Asn Asp Val Ser

1 5 10

<210> 6

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> BCMA28 LCDR1

<400> 6

Ser Gly Ser Ser Ser Asn Ile Gly Gln Asn Ala Val Asn

1 5 10

<210> 7

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> BCMA30 LCDR1

<400> 7

Arg Ala Ser Gln Gly Ile Ser Ser Tyr Leu Ala

1 5 10

<210> 8

<211> 14

<212> PRT

<213> artificial sequence

<220>

<223> BCMA31 LCDR1

<400> 8

Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr Asn Tyr Val Ser

1 5 10

<210> 9

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> BCMA34 LCDR1

<400> 9

Thr Gly Asn Ser Asn Asn Val Gly Asn Gln Gly Ala Ala

1 5 10

<210> 10

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> BCMA35 LCDR1

<400> 10

Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Thr Val Asn

1 5 10

<210> 11

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> BCMA21 LCDR2

<400> 11

Gly Ala Ser Asn Arg Ala Thr

1 5

<210> 12

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> BCMA22 LCDR2

<400> 12

Glu Val Thr Asn Arg Pro Ser

1 5

<210> 13

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> BCMA23 LCDR2

<400> 13

Thr Asn Asn Gln Arg Pro Ser

1 5

<210> 14

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> BCMA24, BCMA35 LCDR2

<400> 14

Ser Asn Asn Gln Arg Pro Ser

1 5

<210> 15

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> BCMA27 LCDR2

<400> 15

Asp Val Asp Lys Arg Pro Ala

1 5

<210> 16

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> BCMA28 LCDR2

<400> 16

Tyr Asn Asp Leu Val Ser Ser

1 5

<210> 17

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> BCMA30 LCDR2

<400> 17

Ala Ala Ser Thr Leu Gln Ser

1 5

<210> 18

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> BCMA31 LCDR2

<400> 18

Asp Val Asn Gln Arg Pro Ser

1 5

<210> 19

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> BCMA32 LCDR2

<400> 19

Asp Val Ser Lys Arg Pro Ser

1 5

<210> 20

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> BCMA33 LCDR2

<400> 20

Glu Val Ser Lys Arg Pro Ser

1 5

<210> 21

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> BCMA34 LCDR2

<400> 21

Arg Asn Asn Asn Arg Pro Ser

1 5

<210> 22

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> BCMA21 LCDR3

<400> 22

Gln His Tyr Asp Gly Ser Pro Pro Met Tyr Thr

1 5 10

<210> 23

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> BCMA22 LCDR3

<400> 23

Ile Ser Tyr Thr Ser Ser Ser Thr Leu Asp Tyr Val

1 5 10

<210> 24

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> BCMA23, BCMA24 LCDR3

<400> 24

Ala Ala Trp Asp Asp Ser Leu Asn Gly Val Val

1 5 10

<210> 25

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> BCMA27 LCDR3

<400> 25

Ser Ser Tyr Gly Gly Thr Tyr Ser Leu Phe Val

1 5 10

<210> 26

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> BCMA28 LCDR3

<400> 26

Ala Thr Trp Asp Asp Ser Leu Asn Gly Val Val

1 5 10

<210> 27

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> BCMA30 LCDR3

<400> 27

Gln Gln Leu Asn Ser Tyr Pro Pro Trp Thr

1 5 10

<210> 28

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> BCMA31 LCDR3

<400> 28

Ser Ser Tyr Gly Gly Ser Asn Asn Leu Val

1 5 10

<210> 29

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> BCMA32 LCDR3

<400> 29

Ser Ser Tyr Thr Ser Ser Ser Thr Val Val

1 5 10

<210> 30

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> BCMA33 LCDR3

<400> 30

Ser Ser Tyr Ala Gly Ser Asn Asn Phe Val Val

1 5 10

<210> 31

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> BCMA34 LCDR3

<400> 31

Ser Ala Trp Asp Ser Ser Leu Ser Ala Arg Val

1 5 10

<210> 32

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> BCMA35 LCDR3

<400> 32

Ala Ala Trp Asp Asp Ser Leu Asn Gly Gly Val

1 5 10

<210> 33

<211> 5

<212> PRT

<213> artificial sequence

<220>

<223> BCMA21 HCDR1

<400> 33

Ser Tyr Ala Met Ser

1 5

<210> 34

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> BCMA22 HCDR1

<400> 34

Ser Ser Asn Trp Trp Ser

1 5

<210> 35

<211> 5

<212> PRT

<213> artificial sequence

<220>

<223> BCMA23, BCMA30 HCDR1

<400> 35

Ser Tyr Trp Ile Gly

1 5

<210> 36

<211> 5

<212> PRT

<213> artificial sequence

<220>

<223> BCMA24 HCDR1

<400> 36

Ser Tyr Ala Ile Ser

1 5

<210> 37

<211> 5

<212> PRT

<213> artificial sequence

<220>

<223> BCMA27 HCDR1

<400> 37

Ser Tyr Gly Met His

1 5

<210> 38

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> BCMA28 HCDR1

<400> 38

Ser Asn Ser Ala Ala Trp Asn

1 5

<210> 39

<211> 5

<212> PRT

<213> artificial sequence

<220>

<223> BCMA31 HCDR1

<400> 39

Ser Tyr Trp Met Ser

1 5

<210> 40

<211> 5

<212> PRT

<213> artificial sequence

<220>

<223> BCMA32 HCDR1

<400> 40

Arg Tyr Ala Ile Ser

1 5

<210> 41

<211> 5

<212> PRT

<213> artificial sequence

<220>

<223> BCMA33 HCDR1

<400> 41

Asp Tyr Ala Met His

1 5

<210> 42

<211> 5

<212> PRT

<213> artificial sequence

<220>

<223> BCMA34 HCDR1

<400> 42

Asn Pro Phe Val His

1 5

<210> 43

<211> 5

<212> PRT

<213> artificial sequence

<220>

<223> BCMA35 HCDR1

<400> 43

Ser Tyr Asp Ile Ser

1 5

<210> 44

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> BCMA21 HCDR2

<400> 44

Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 45

<211> 16

<212> PRT

<213> artificial sequence

<220>

<223> BCMA22 HCDR2

<400> 45

Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser

1 5 10 15

<210> 46

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> BCMA23 HCDR2

<400> 46

Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln

1 5 10 15

Gly

<210> 47

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> BCMA24 HCDR2

<400> 47

Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

<210> 48

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> BCMA27 HCDR2

<400> 48

Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 49

<211> 18

<212> PRT

<213> artificial sequence

<220>

<223> BCMA28 HCDR2

<400> 49

Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Asp Tyr Ala Val Ser Val

1 5 10 15

Lys Ser

<210> 50

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> BCMA30 HCDR2

<400> 50

Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Pro Phe Gln

1 5 10 15

Gly

<210> 51

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> BCMA31 HCDR2

<400> 51

Asn Ile Lys Pro Asp Gly Ser Asp Lys Tyr Tyr Val Asp Ser Val Lys

1 5 10 15

Gly

<210> 52

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> BCMA32 HCDR2

<400> 52

Gly Ile Ile Pro Phe Phe Gly Thr Ser Asp Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

<210> 53

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> BCMA33 HCDR2

<400> 53

Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 54

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> BCMA34 HCDR2

<400> 54

Ile Ile Asn Leu Ser Gly Gly Asp Thr Leu Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

<210> 55

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> BCMA35 HCDR2

<400> 55

Trp Ile Asn Ala Tyr Asn Gly Asn Ala Asn Tyr Ala Gln Lys Leu Gln

1 5 10 15

Gly

<210> 56

<211> 14

<212> PRT

<213> artificial sequence

<220>

<223> BCMA21 HCDR3

<400> 56

Ile Thr Ala Met Val Thr His Asn Phe Tyr Gly Met Asp Val

1 5 10

<210> 57

<211> 16

<212> PRT

<213> artificial sequence

<220>

<223> BCMA22 HCDR3

<400> 57

Val Gly Ser Gly Tyr Ser Tyr Gly Tyr Gly Asp Arg Val Leu Asp Tyr

1 5 10 15

<210> 58

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> BCMA23 HCDR3

<400> 58

Arg Gly Gly Ala Leu Asp Tyr

1 5

<210> 59

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> BCMA24 HCDR3

<400> 59

Gly Ser Phe Tyr Ser Ser Val Asn Val

1 5

<210> 60

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> BCMA27 HCDR3

<400> 60

Glu Glu Phe Tyr Gly Asp Ser Ser Tyr Gly Met Asp Val

1 5 10

<210> 61

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> BCMA28 HCDR3

<400> 61

Asp Tyr Tyr Tyr Gly Met Asp Val

1 5

<210> 62

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> BCMA30 HCDR3

<400> 62

Leu Asp Ala Ser Gly Ser Gln Arg Gly Gly Met Asp Val

1 5 10

<210> 63

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> BCMA31 HCDR3

<400> 63

Gly Ala Thr Thr Tyr Gly Ser

1 5

<210> 64

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> BCMA32 HCDR3

<400> 64

Arg Val Ala Thr Thr Gly Thr Gly Phe Tyr Tyr Ala Met Asp Val

1 5 10 15

<210> 65

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> BCMA33 HCDR3

<400> 65

Val Gly Ala Ser Ala Ala Leu Gly Ala Phe Asp Ile

1 5 10

<210> 66

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> BCMA34 HCDR3

<400> 66

Asp Gln Ala Gly Phe Gly Asp Ser Ala Tyr

1 5 10

<210> 67

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> BCMA35 HCDR3

<400> 67

Glu Tyr Tyr Tyr Phe Trp Ser Asn Arg Ala Phe Tyr Tyr Gly Met Asp

1 5 10 15

Val

<210> 68

<211> 110

<212> PRT

<213> artificial sequence

<220>

<223> BCMA21 VL AA

<400> 68

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn

20 25 30

Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Arg Leu Leu

35 40 45

Ile Phe Gly Ala Ser Asn Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Gly Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Asp Gly Ser Pro

85 90 95

Pro Met Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 69

<211> 112

<212> PRT

<213> artificial sequence

<220>

<223> BCMA22 VL AA

<400> 69

Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr

20 25 30

Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Glu Val Thr Asn Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala His Tyr Tyr Cys Ile Ser Tyr Thr Ser Ser

85 90 95

Ser Thr Leu Asp Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu

100 105 110

<210> 70

<211> 110

<212> PRT

<213> artificial sequence

<220>

<223> BCMA23 VL AA

<400> 70

Gln Ser Ala Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln

1 5 10 15

Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Pro Asn Ile Gly Gly Asn

20 25 30

Ser Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu

35 40 45

Met Tyr Thr Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln

65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu

85 90 95

Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 71

<211> 110

<212> PRT

<213> artificial sequence

<220>

<223> BCMA24 VL AA

<400> 71

Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln

1 5 10 15

Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Tyr

20 25 30

Ser Val Asn Trp Tyr Gln Gln Ile Pro Gly Thr Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Ser Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln

65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Ser Cys Ala Ala Trp Asp Asp Ser Leu

85 90 95

Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 72

<211> 111

<212> PRT

<213> artificial sequence

<220>

<223> BCMA27 VL AA

<400> 72

Gln Ser Ala Leu Thr Gln Pro Pro Ser Ala Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Val Thr Ile Ser Cys Thr Gly Ser Arg Ser Asn Val Gly Ser Tyr

20 25 30

Asn Asp Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Ile Ile Tyr Asp Val Asp Lys Arg Pro Ala Gly Val Pro Asp Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Val Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Asp Ala Asp Tyr Tyr Cys Ser Ser Tyr Gly Gly Thr

85 90 95

Tyr Ser Leu Phe Val Phe Gly Thr Gly Thr Glu Leu Thr Val Leu

100 105 110

<210> 73

<211> 110

<212> PRT

<213> artificial sequence

<220>

<223> BCMA28 VL AA

<400> 73

Gln Ser Ala Leu Thr Gln Pro Pro Ser Val Ser Glu Ala Pro Arg Gln

1 5 10 15

Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Gln Asn

20 25 30

Ala Val Asn Trp Tyr Gln Lys Leu Pro Gly Lys Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Tyr Asn Asp Leu Val Ser Ser Gly Val Ser Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln

65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Asp Ser Leu

85 90 95

Asn Gly Val Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu

100 105 110

<210> 74

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> BCMA30 VL AA

<400> 74

Asp Ile Gln Met Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Pro

85 90 95

Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 75

<211> 110

<212> PRT

<213> artificial sequence

<220>

<223> BCMA31 VL AA

<400> 75

Gln Ser Ala Leu Thr Gln Pro Pro Ser Ala Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr

20 25 30

Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Asp Val Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Val Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Gly Gly Ser

85 90 95

Asn Asn Leu Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu

100 105 110

<210> 76

<211> 110

<212> PRT

<213> artificial sequence

<220>

<223> BCMA32 VL AA

<400> 76

Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr

20 25 30

Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser

85 90 95

Ser Thr Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 77

<211> 111

<212> PRT

<213> artificial sequence

<220>

<223> BCMA33 VL AA

<400> 77

Gln Ser Ala Leu Thr Gln Pro Pro Ser Ala Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr

20 25 30

Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Glu Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Val Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Phe Cys Ser Ser Tyr Ala Gly Ser

85 90 95

Asn Asn Phe Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 78

<211> 110

<212> PRT

<213> artificial sequence

<220>

<223> BCMA34 VL AA

<400> 78

Gln Pro Gly Leu Thr Gln Pro Pro Ser Val Ser Lys Gly Leu Arg Gln

1 5 10 15

Thr Ala Thr Leu Thr Cys Thr Gly Asn Ser Asn Asn Val Gly Asn Gln

20 25 30

Gly Ala Ala Trp Leu Gln Gln His Gln Gly His Pro Pro Lys Leu Leu

35 40 45

Ser Tyr Arg Asn Asn Asn Arg Pro Ser Gly Ile Ser Glu Arg Phe Ser

50 55 60

Ala Ser Arg Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Leu Gln

65 70 75 80

Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Ser Ser Leu

85 90 95

Ser Ala Arg Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 79

<211> 110

<212> PRT

<213> artificial sequence

<220>

<223> BCMA35 VL AA

<400> 79

Gln Ala Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln

1 5 10 15

Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn

20 25 30

Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Ser Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln

65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu

85 90 95

Asn Gly Gly Val Phe Gly Gly Gly Thr Glu Leu Thr Val Leu

100 105 110

<210> 80

<211> 123

<212> PRT

<213> artificial sequence

<220>

<223> BCMA21 VH AA

<400> 80

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Ile Thr Ala Met Val Thr His Asn Phe Tyr Gly Met Asp Val

100 105 110

Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 81

<211> 125

<212> PRT

<213> artificial sequence

<220>

<223> BCMA22 VH AA

<400> 81

Glu Val Gln Leu Val Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Val Gly Ser Gly Tyr Ser Tyr Gly Tyr Gly Asp Arg Val Leu

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 82

<211> 116

<212> PRT

<213> artificial sequence

<220>

<223> BCMA23 VH AA

<400> 82

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg Arg Gly Gly Ala Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 83

<211> 118

<212> PRT

<213> artificial sequence

<220>

<223> BCMA24 VH AA

<400> 83

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Ser Phe Tyr Ser Ser Val Asn Val Trp Gly Gln Gly Thr

100 105 110

Thr Val Thr Val Ser Ser

115

<210> 84

<211> 122

<212> PRT

<213> artificial sequence

<220>

<223> BCMA27 VH AA

<400> 84

Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Glu Glu Phe Tyr Gly Asp Ser Ser Tyr Gly Met Asp Val Trp

100 105 110

Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 85

<211> 120

<212> PRT

<213> artificial sequence

<220>

<223> BCMA28 VH AA

<400> 85

Gln Val Gln Leu Val Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Asn

20 25 30

Ser Ala Ala Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu

35 40 45

Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Asp Tyr Ala

50 55 60

Val Ser Val Lys Ser Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn

65 70 75 80

Gln Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val

85 90 95

Tyr Tyr Cys Ala Arg Asp Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 86

<211> 122

<212> PRT

<213> artificial sequence

<220>

<223> BCMA30 VH AA

<400> 86

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Ser Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Pro Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Asp Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg Leu Asp Ala Ser Gly Ser Gln Arg Gly Gly Met Asp Val Trp

100 105 110

Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 87

<211> 116

<212> PRT

<213> artificial sequence

<220>

<223> BCMA31 VH AA

<400> 87

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Trp Met Ser Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Asn Ile Lys Pro Asp Gly Ser Asp Lys Tyr Tyr Val Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Asp

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Gly Glu Asp Thr Ala Ile Tyr Tyr Cys

85 90 95

Ala Arg Gly Ala Thr Thr Tyr Gly Ser Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 88

<211> 124

<212> PRT

<213> artificial sequence

<220>

<223> BCMA32 VH AA

<400> 88

Gln Val Gln Leu Gln Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Phe Phe Gly Thr Ser Asp Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Asp Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Val Arg Val Ala Thr Thr Gly Thr Gly Phe Tyr Tyr Ala Met Asp

100 105 110

Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 89

<211> 121

<212> PRT

<213> artificial sequence

<220>

<223> BCMA33 VH AA

<400> 89

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr

20 25 30

Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Lys Val Gly Ala Ser Ala Ala Leu Gly Ala Phe Asp Ile Trp Gly

100 105 110

Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 90

<211> 119

<212> PRT

<213> artificial sequence

<220>

<223> BCMA34 VH AA

<400> 90

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Thr Ser Gly Tyr Thr Phe Ser Asn Pro

20 25 30

Phe Val His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val

35 40 45

Gly Ile Ile Asn Leu Ser Gly Gly Asp Thr Leu Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Gly Val Thr Met Thr Arg Asp Thr Ser Thr Asn Thr Ala Tyr

65 70 75 80

Met Glu Leu Thr Ser Leu Thr Phe Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Gln Ala Gly Phe Gly Asp Ser Ala Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 91

<211> 126

<212> PRT

<213> artificial sequence

<220>

<223> BCMA35 VH AA

<400> 91

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Ala Tyr Asn Gly Asn Ala Asn Tyr Ala Gln Lys Leu

50 55 60

Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Met Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Glu Tyr Tyr Tyr Phe Trp Ser Asn Arg Ala Phe Tyr Tyr Gly

100 105 110

Met Asp Val Trp Gly Gln Gly Thr Thr Val Ser Val Ser Ser

115 120 125

<210> 92

<211> 330

<212> DNA

<213> artificial sequence

<220>

<223> BCMA21 VL NT

<400> 92

gaaatagtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60

ctctcctgca gggccagtca gagtgttagc agcaacttct tagcctggta ccagcagaaa 120

cctggccagt ctcccagact cctcatcttc ggtgcatcca acagggccac tggcatccca 180

gacaggttca gtggcggtgg gtctgggaca gacttcactc tcaccatcag ccgcctggaa 240

cctgaagact ttgcagttta ctactgtcag cactatgacg gctcacctcc gatgtacact 300

tttggccagg ggaccaagct ggagatcaaa 330

<210> 93

<211> 336

<212> DNA

<213> artificial sequence

<220>

<223> BCMA22 VL NT

<400> 93

caatctgccc tgactcagcc tgcctccgtg tctgggtctc ctggacagtc gatcaccatc 60

tcctgcactg gaaccagcag tgacgttggt ggttataact atgtctcctg gtaccaacag 120

cacccaggca aagcccccaa actcatgatt tatgaggtca ctaatcggcc ctcaggggtt 180

tctaatcgct tctctggctc caagtctggc aacacggcct ccctgaccat ctctgggctc 240

caggctgaag acgaggctca ttattactgc atctcatata caagcagcag cactctcgat 300

tatgtcttcg gaactggcac caaggtgacc gtcctc 336

<210> 94

<211> 330

<212> DNA

<213> artificial sequence

<220>

<223> BCMA23 VL NT

<400> 94

cagtctgccc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60

tcttgttctg gcagcagccc gaacatcgga ggtaattctg tcaactggta ccagcaactc 120

ccaggaacgg cccccaaact cctcatgtac actaataatc agcggccctc aggggtccct 180

gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tgggctccag 240

tctgaggatg aggctgatta ctactgtgca gcatgggatg acagcctgaa tggtgtggta 300

ttcggcggag ggaccaagct gaccgtccta 330

<210> 95

<211> 330

<212> DNA

<213> artificial sequence

<220>

<223> BCMA24 VL NT

<400> 95

cagtctgtgt tgacgcagcc gccctcagcg tctgggaccc ccgggcagag ggtcaccatc 60

tcttgttctg gaagcagctc caacatcgga agttacagtg tgaactggta ccagcagatc 120

ccaggaacgg cccccaaact cctcatctat agtaataatc agcggccctc aggggtccct 180

gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tgggctccag 240

tctgaggatg aggctgatta ttcctgtgca gcatgggatg acagcctgaa tggtgtggta 300

ttcggcggag ggaccaagct gaccgtccta 330

<210> 96

<211> 333

<212> DNA

<213> artificial sequence

<220>

<223> BCMA27 VL NT

<400> 96

cagtctgccc tgactcagcc tccctccgcg tccggatctc ctggacagtc agtcaccatc 60

tcctgcactg gaagtcgcag taacgttggg tcttataacg atgtctcttg gtaccaacaa 120

cacccaggca aagcccccaa actcataatt tatgacgtcg ataagaggcc cgcaggggtc 180

cctgatcgct tctctggctc caagtctggc aacacggcct ccctgaccgt ctctgggctc 240

caggctgaag atgacgctga ctattattgc agttcatatg gaggcaccta cagccttttc 300

gtcttcggaa ctgggaccga gctgaccgtc cta 333

<210> 97

<211> 330

<212> DNA

<213> artificial sequence

<220>

<223> BCMA28 VL NT

<400> 97

cagtctgccc tgactcagcc accctcggtg tctgaagccc ccaggcagag ggtcaccatc 60

tcctgttctg gaagcagctc caacatcgga cagaatgctg tcaactggta tcagaagctc 120

ccaggaaagg ctcccaaact cctcatctat tataatgatc tggtgtcctc aggggtctct 180

gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tgggctccag 240

tctgaggatg aggctgatta ttactgtgca acatgggatg acagcctgaa tggtgtggta 300

ttcggcggag ggaccaaggt caccgtccta 330

<210> 98

<211> 324

<212> DNA

<213> artificial sequence

<220>

<223> BCMA30 VL NT

<400> 98

gacatccaga tgacccagtc tccatccttc ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgcc gggccagtca gggcattagc agttatttag cctggtatca gcaaaaacca 120

gggaaagccc ctaagctcct gatctatgct gcatccactt tgcaaagtgg ggtcccatca 180

aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240

gaagattttg caacttatta ctgtcaacag cttaatagtt accctccgtg gacgttcggc 300

caagggacca aggtggagat caaa 324

<210> 99

<211> 330

<212> DNA

<213> artificial sequence

<220>

<223> BCMA31 VL NT

<400> 99

caatctgccc tgactcagcc tccctccgcg tccgggtctc ctggacagtc agtcaccatc 60

tcctgcactg gaaccagcag tgacgttggt acttataatt atgtctcctg gtaccaacaa 120

cacccaggca aagcccccaa gctcatgatt tatgacgtca atcagcggcc ctcaggggtc 180

cctgatcgct tctctggctc caagtctggc aacacggcct ccctgaccgt ctctgggctc 240

caggctgagg atgaggctga ttattactgc agctcatatg gaggcagcaa caatttggta 300

ttcggcggag ggaccaaggt caccgtccta 330

<210> 100

<211> 330

<212> DNA

<213> artificial sequence

<220>

<223> BCMA32 VL NT

<400> 100

caatctgccc tgactcagcc tgcctccgtg tctgggtctc ctggacagtc gatcaccatc 60

tcctgcactg gaaccagcag tgacgttggt ggttataact atgtctcctg gtaccaacaa 120

cacccaggca aagcccccaa actcatgatt tatgatgtca gtaagcggcc ctcaggggtt 180

tctaatcgct tctctggctc caagtctggc aacacggcct ccctgaccat ctctgggctc 240

caggctgagg acgaggctga ttattactgc agctcatata caagcagcag cactgtggta 300

ttcggcggag ggaccaagct gaccgtccta 330

<210> 101

<211> 333

<212> DNA

<213> artificial sequence

<220>

<223> BCMA33 VL NT

<400> 101

caatctgccc tgactcagcc tccctccgcg tccgggtctc ctggacagtc agtcaccatc 60

tcctgcactg gaaccagcag tgacgttggt ggttataact atgtctcctg gtaccaacag 120

cacccaggca aagcccccaa actcatgatt tatgaggtca gtaagcggcc ctcaggggtc 180

cctgatcgct tctctggctc caagtctggc aacacggcct ccctgaccgt ctctgggctc 240

caggctgagg atgaggctga ttatttctgc agctcatatg caggcagcaa caatttcgtg 300

gtattcggcg gagggaccaa gctgaccgtc cta 333

<210> 102

<211> 330

<212> DNA

<213> artificial sequence

<220>

<223> BCMA34 VL NT

<400> 102

cagccagggc tgactcagcc accctcggtg tccaagggct tgagacagac cgccacactc 60

acctgcactg ggaacagcaa caatgttggc aaccaaggag cagcttggct gcagcagcac 120

cagggccacc ctcccaaact cctatcctac aggaataaca accggccctc agggatctca 180

gagagattct ctgcatccag gtcaggaaac acagcctccc tgaccattac tggactccag 240

cctgaggacg aggctgacta ttactgctca gcatgggaca gcagcctcag tgctcgggtg 300

ttcggcggag ggaccaagct gaccgtccta 330

<210> 103

<211> 330

<212> DNA

<213> artificial sequence

<220>

<223> BCMA35 VL NT

<400> 103

caggctgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60

tcttgttctg gaagcagctc caacatcgga agtaatactg taaactggta ccagcagctc 120

ccaggaacgg cccccaaact cctcatctat agtaataatc agcggccctc aggggtccct 180

gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tgggctccag 240

tctgaggatg aggctgatta ttactgtgca gcatgggatg acagcctgaa tggcggggtg 300

ttcggcggag ggaccgagct gaccgtccta 330

<210> 104

<211> 369

<212> DNA

<213> artificial sequence

<220>

<223> BCMA21 VH NT

<400> 104

gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgaag cctctggatt cacctttagc agctatgcca tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagct attagtggta gtggtggtag cacatactac 180

gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaagatcaca 300

gctatggtta ctcataactt ctacggtatg gacgtctggg gccaagggac cacggtcacc 360

gtctcctca 369

<210> 105

<211> 375

<212> DNA

<213> artificial sequence

<220>

<223> BCMA22 VH NT

<400> 105

gaggtgcaac tggtggagtc gggcccagga ctggtgaagc cttcggggac cctgtccctc 60

acctgcgctg tctctggtgg ctccatcagc agtagtaact ggtggagttg ggtccgccag 120

cccccaggga aggggctgga gtggattggg gaaatctatc atagtgggag caccaactac 180

aacccgtccc tcaagagtcg agtcaccata tcagtagaca agtccaagaa ccagttctcc 240

ctgaagctga gctctgtgac cgccgcggac acggccgtgt attactgtgc gagagtgggg 300

agtggataca gctatggtta cggcgatcgg gttcttgact actggggcca gggaaccctg 360

gtcaccgtct cctca 375

<210> 106

<211> 348

<212> DNA

<213> artificial sequence

<220>

<223> BCMA23 VH NT

<400> 106

caggtccagc tggtgcagtc tggagcagag gtgaaaaagc cgggggagtc tctgaagatc 60

tcctgtaagg gttctggata cagctttacc agctactgga tcggctgggt gcgccagatg 120

cccgggaaag gcctggagtg gatggggatc atctatcctg gtgactctga taccagatac 180

agcccgtcct tccaaggcca ggtcaccatc tcagccgaca agtccatcag caccgcctac 240

ctgcagtgga gcagcctgaa ggcctcggac accgccatgt attactgtgc gagacggggt 300

ggagcccttg actactgggg ccagggaacc ctggtcactg tctcctca 348

<210> 107

<211> 354

<212> DNA

<213> artificial sequence

<220>

<223> BCMA24 VH NT

<400> 107

caggtccagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60

tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggaggg atcatcccta tctttggtac agcaaactac 180

gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240

atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagagggagt 300

ttctattcta gtgtgaacgt ctggggccaa gggaccacgg tcaccgtctc ctca 354

<210> 108

<211> 366

<212> DNA

<213> artificial sequence

<220>

<223> BCMA27 VH NT

<400> 108

gaagtgcagc tggtggagtc tgggggagac ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120

ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180

gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaagaagaa 300

ttttacggtg actcctccta cggtatggac gtctggggcc aagggaccac ggtcactgtc 360

tcctca 366

<210> 109

<211> 360

<212> DNA

<213> artificial sequence

<220>

<223> BCMA28 VH NT

<400> 109

caggtccagc tggtgcagtc tggtccagga ctggtgaagc cctcgcagac cctctcactc 60

acctgtgcca tctccgggga cagtgtctct agcaacagtg ctgcttggaa ctggatcagg 120

cagtccccat cgagaggcct tgagtggctg ggaaggacat actacaggtc caagtggtat 180

aatgattatg cagtatctgt gaaaagtcga ataaccatca acccagacac atccaagaac 240

cagttctccc tgcagctgaa ctctgtgact cccgaggaca cggctgtgta ttactgtgca 300

agggactact actacggtat ggacgtctgg ggccaaggga ccacggtcac cgtctcctca 360

<210> 110

<211> 366

<212> DNA

<213> artificial sequence

<220>

<223> BCMA30 VH NT

<400> 110

caggtgcagc tggtacagtc tggagcagag gtgaaaaagc ccggggagtc tctgaagata 60

tcctgtaagg gttctggata caggtttacc agttactgga tcggctgggt gcgccagatg 120

cccgggaaag gcctggagtg gatgggaatc atctatcctg gtgactctga taccagatac 180

agcccgccct tccaaggcca ggtcaccatc tcagccgaca agtccatcga caccgcctac 240

ctgcagtgga gcagcctgaa ggcctcggac accgccatgt attactgtgc gagactggac 300

gcttcgggga gtcaaagggg gggtatggac gtctggggcc aagggaccac ggtcaccgtc 360

tcctca 366

<210> 111

<211> 348

<212> DNA

<213> artificial sequence

<220>

<223> BCMA31 VH NT

<400> 111

gaagtgcaac tggtggagtc tgggggaggc ttgatccagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagt agctattgga tgagctgggt ccgccaaagt 120

ccagggaagg ggctggagtg ggtggccaac ataaagccag atggaagtga caaatactat 180

gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactggat 240

ctgcaaatga acagcctgag aggcgaagac acggctattt attactgcgc gagaggtgcc 300

accacctatg gctcctgggg ccagggaacc ctggtcactg tctcctca 348

<210> 112

<211> 372

<212> DNA

<213> artificial sequence

<220>

<223> BCMA32 VH NT

<400> 112

caggtgcagc tgcaggagtc gggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60

tcctgcaagg cttctggagg caccttcagc aggtatgcta tcagctgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggaggg atcatccctt tctttggtac atcagactac 180

gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240

atggacctga gtagactgag atctgaggac acggccgtgt attactgtgc ggtccgtgtg 300

gcaaccactg gaaccgggtt ctactacgct atggacgtct ggggccaggg gaccacggtc 360

accgtctcct ca 372

<210> 113

<211> 363

<212> DNA

<213> artificial sequence

<220>

<223> BCMA33 VH NT

<400> 113

gaggtgcaac tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120

ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag cataggctat 180

gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240

ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagtcggc 300

gcttcggcag ccctgggtgc ttttgatatc tggggccaag ggacaatggt caccgtctcc 360

tca 363

<210> 114

<211> 357

<212> DNA

<213> artificial sequence

<220>

<223> BCMA34 VH NT

<400> 114

caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtt 60

tcctgcaaga catctggata caccttcagc aaccccttcg tgcactgggt gcgacaggcc 120

cctggacaag ggcttgagtg ggtgggcata attaacctta gtggaggtga cacactctac 180

gcacagaagt tccagggcgg agtcaccatg accagggaca cgtctacgaa cacagcctac 240

atggagctga ccagcctgac atttgaagac acggccgtgt attactgtgc gagagatcaa 300

gcgggcttcg gtgactctgc ctactggggc cagggaaccc tggtcaccgt ctcctca 357

<210> 115

<211> 378

<212> DNA

<213> artificial sequence

<220>

<223> BCMA35 VH NT

<400> 115

caggtccagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60

tcctgcaagg cttctggata cacctttacc agctatgata tcagctgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggatgg atcaacgctt acaatggtaa cgcaaactat 180

gcacagaagc tccagggcag agtcaccatg accacagaca catccatgag cacagcctac 240

atggagctga ggagcctgag atctgacgac tcggccgtct attactgtgc gagggagtat 300

tactatttct ggagtaatcg agccttctac tacggtatgg acgtctgggg ccaggggacc 360

acggtcagcg tctcctca 378

<210> 116

<211> 248

<212> PRT

<213> artificial sequence

<220>

<223> BCMA21 scFv

<400> 116

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn

20 25 30

Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Arg Leu Leu

35 40 45

Ile Phe Gly Ala Ser Asn Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Gly Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Asp Gly Ser Pro

85 90 95

Pro Met Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly

100 105 110

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln

115 120 125

Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg

130 135 140

Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Ser

145 150 155 160

Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile

165 170 175

Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg

180 185 190

Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met

195 200 205

Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile

210 215 220

Thr Ala Met Val Thr His Asn Phe Tyr Gly Met Asp Val Trp Gly Gln

225 230 235 240

Gly Thr Thr Val Thr Val Ser Ser

245

<210> 117

<211> 252

<212> PRT

<213> artificial sequence

<220>

<223> BCMA22 scFv

<400> 117

Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr

20 25 30

Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Glu Val Thr Asn Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala His Tyr Tyr Cys Ile Ser Tyr Thr Ser Ser

85 90 95

Ser Thr Leu Asp Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu

100 105 110

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly Thr

130 135 140

Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser Asn

145 150 155 160

Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

165 170 175

Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys

180 185 190

Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser Leu

195 200 205

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

210 215 220

Arg Val Gly Ser Gly Tyr Ser Tyr Gly Tyr Gly Asp Arg Val Leu Asp

225 230 235 240

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

245 250

<210> 118

<211> 241

<212> PRT

<213> artificial sequence

<220>

<223> BCMA23 scFv

<400> 118

Gln Ser Ala Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln

1 5 10 15

Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Pro Asn Ile Gly Gly Asn

20 25 30

Ser Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu

35 40 45

Met Tyr Thr Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln

65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu

85 90 95

Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly

100 105 110

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln

115 120 125

Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser Leu Lys

130 135 140

Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr Trp Ile Gly

145 150 155 160

Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met Gly Ile Ile

165 170 175

Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln Gly Gln

180 185 190

Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu Gln Trp

195 200 205

Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Arg

210 215 220

Gly Gly Ala Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

225 230 235 240

Ser

<210> 119

<211> 243

<212> PRT

<213> artificial sequence

<220>

<223> BCMA24 scFv

<400> 119

Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln

1 5 10 15

Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Tyr

20 25 30

Ser Val Asn Trp Tyr Gln Gln Ile Pro Gly Thr Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Ser Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln

65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Ser Cys Ala Ala Trp Asp Asp Ser Leu

85 90 95

Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly

100 105 110

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln

115 120 125

Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys

130 135 140

Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser

145 150 155 160

Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Gly Ile

165 170 175

Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg

180 185 190

Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr Met Glu Leu

195 200 205

Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly

210 215 220

Ser Phe Tyr Ser Ser Val Asn Val Trp Gly Gln Gly Thr Thr Val Thr

225 230 235 240

Val Ser Ser

<210> 120

<211> 248

<212> PRT

<213> artificial sequence

<220>

<223> BCMA27 scFv

<400> 120

Gln Ser Ala Leu Thr Gln Pro Pro Ser Ala Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Val Thr Ile Ser Cys Thr Gly Ser Arg Ser Asn Val Gly Ser Tyr

20 25 30

Asn Asp Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Ile Ile Tyr Asp Val Asp Lys Arg Pro Ala Gly Val Pro Asp Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Val Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Asp Ala Asp Tyr Tyr Cys Ser Ser Tyr Gly Gly Thr

85 90 95

Tyr Ser Leu Phe Val Phe Gly Thr Gly Thr Glu Leu Thr Val Leu Gly

100 105 110

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Gly Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Gly Met

145 150 155 160

His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Val

165 170 175

Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys

210 215 220

Glu Glu Phe Tyr Gly Asp Ser Ser Tyr Gly Met Asp Val Trp Gly Gln

225 230 235 240

Gly Thr Thr Val Thr Val Ser Ser

245

<210> 121

<211> 245

<212> PRT

<213> artificial sequence

<220>

<223> BCMA28 scFv

<400> 121

Gln Ser Ala Leu Thr Gln Pro Pro Ser Val Ser Glu Ala Pro Arg Gln

1 5 10 15

Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Gln Asn

20 25 30

Ala Val Asn Trp Tyr Gln Lys Leu Pro Gly Lys Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Tyr Asn Asp Leu Val Ser Ser Gly Val Ser Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln

65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Asp Ser Leu

85 90 95

Asn Gly Val Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu Gly Gly

100 105 110

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln

115 120 125

Leu Val Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Thr Leu Ser

130 135 140

Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Asn Ser Ala Ala

145 150 155 160

Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu Trp Leu Gly

165 170 175

Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Asp Tyr Ala Val Ser Val

180 185 190

Lys Ser Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn Gln Phe Ser

195 200 205

Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val Tyr Tyr Cys

210 215 220

Ala Arg Asp Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr

225 230 235 240

Val Thr Val Ser Ser

245

<210> 122

<211> 245

<212> PRT

<213> artificial sequence

<220>

<223> BCMA30 scFv

<400> 122

Asp Ile Gln Met Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Pro

85 90 95

Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly

100 105 110

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val

115 120 125

Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser

130 135 140

Cys Lys Gly Ser Gly Tyr Arg Phe Thr Ser Tyr Trp Ile Gly Trp Val

145 150 155 160

Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met Gly Ile Ile Tyr Pro

165 170 175

Gly Asp Ser Asp Thr Arg Tyr Ser Pro Pro Phe Gln Gly Gln Val Thr

180 185 190

Ile Ser Ala Asp Lys Ser Ile Asp Thr Ala Tyr Leu Gln Trp Ser Ser

195 200 205

Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Leu Asp Ala

210 215 220

Ser Gly Ser Gln Arg Gly Gly Met Asp Val Trp Gly Gln Gly Thr Thr

225 230 235 240

Val Thr Val Ser Ser

245

<210> 123

<211> 241

<212> PRT

<213> artificial sequence

<220>

<223> BCMA31 scFv

<400> 123

Gln Ser Ala Leu Thr Gln Pro Pro Ser Ala Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr

20 25 30

Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Asp Val Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Val Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Gly Gly Ser

85 90 95

Asn Asn Leu Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu Gly Gly

100 105 110

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln

115 120 125

Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly Ser Leu Arg

130 135 140

Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Trp Met Ser

145 150 155 160

Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Val Ala Asn Ile

165 170 175

Lys Pro Asp Gly Ser Asp Lys Tyr Tyr Val Asp Ser Val Lys Gly Arg

180 185 190

Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Asp Leu Gln Met

195 200 205

Asn Ser Leu Arg Gly Glu Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Gly

210 215 220

Ala Thr Thr Tyr Gly Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser

225 230 235 240

Ser

<210> 124

<211> 249

<212> PRT

<213> artificial sequence

<220>

<223> BCMA32 scFv

<400> 124

Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr

20 25 30

Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser

85 90 95

Ser Thr Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly

100 105 110

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln

115 120 125

Leu Gln Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys

130 135 140

Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg Tyr Ala Ile Ser

145 150 155 160

Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Gly Ile

165 170 175

Ile Pro Phe Phe Gly Thr Ser Asp Tyr Ala Gln Lys Phe Gln Gly Arg

180 185 190

Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr Met Asp Leu

195 200 205

Ser Arg Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Val Arg

210 215 220

Val Ala Thr Thr Gly Thr Gly Phe Tyr Tyr Ala Met Asp Val Trp Gly

225 230 235 240

Gln Gly Thr Thr Val Thr Val Ser Ser

245

<210> 125

<211> 247

<212> PRT

<213> artificial sequence

<220>

<223> BCMA33 scFv

<400> 125

Gln Ser Ala Leu Thr Gln Pro Pro Ser Ala Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr

20 25 30

Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Glu Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Val Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Phe Cys Ser Ser Tyr Ala Gly Ser

85 90 95

Asn Asn Phe Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly

100 105 110

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Ala Met

145 150 155 160

His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly

165 170 175

Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Lys

210 215 220

Val Gly Ala Ser Ala Ala Leu Gly Ala Phe Asp Ile Trp Gly Gln Gly

225 230 235 240

Thr Met Val Thr Val Ser Ser

245

<210> 126

<211> 244

<212> PRT

<213> artificial sequence

<220>

<223> BCMA34 scFv

<400> 126

Gln Pro Gly Leu Thr Gln Pro Pro Ser Val Ser Lys Gly Leu Arg Gln

1 5 10 15

Thr Ala Thr Leu Thr Cys Thr Gly Asn Ser Asn Asn Val Gly Asn Gln

20 25 30

Gly Ala Ala Trp Leu Gln Gln His Gln Gly His Pro Pro Lys Leu Leu

35 40 45

Ser Tyr Arg Asn Asn Asn Arg Pro Ser Gly Ile Ser Glu Arg Phe Ser

50 55 60

Ala Ser Arg Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Leu Gln

65 70 75 80

Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Ser Ser Leu

85 90 95

Ser Ala Arg Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly

100 105 110

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln

115 120 125

Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys

130 135 140

Val Ser Cys Lys Thr Ser Gly Tyr Thr Phe Ser Asn Pro Phe Val His

145 150 155 160

Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val Gly Ile Ile

165 170 175

Asn Leu Ser Gly Gly Asp Thr Leu Tyr Ala Gln Lys Phe Gln Gly Gly

180 185 190

Val Thr Met Thr Arg Asp Thr Ser Thr Asn Thr Ala Tyr Met Glu Leu

195 200 205

Thr Ser Leu Thr Phe Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp

210 215 220

Gln Ala Gly Phe Gly Asp Ser Ala Tyr Trp Gly Gln Gly Thr Leu Val

225 230 235 240

Thr Val Ser Ser

<210> 127

<211> 251

<212> PRT

<213> artificial sequence

<220>

<223> BCMA35 scFv

<400> 127

Gln Ala Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln

1 5 10 15

Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn

20 25 30

Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Ser Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln

65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu

85 90 95

Asn Gly Gly Val Phe Gly Gly Gly Thr Glu Leu Thr Val Leu Gly Gly

100 105 110

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln

115 120 125

Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys

130 135 140

Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Asp Ile Ser

145 150 155 160

Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Trp Ile

165 170 175

Asn Ala Tyr Asn Gly Asn Ala Asn Tyr Ala Gln Lys Leu Gln Gly Arg

180 185 190

Val Thr Met Thr Thr Asp Thr Ser Met Ser Thr Ala Tyr Met Glu Leu

195 200 205

Arg Ser Leu Arg Ser Asp Asp Ser Ala Val Tyr Tyr Cys Ala Arg Glu

210 215 220

Tyr Tyr Tyr Phe Trp Ser Asn Arg Ala Phe Tyr Tyr Gly Met Asp Val

225 230 235 240

Trp Gly Gln Gly Thr Thr Val Ser Val Ser Ser

245 250

<210> 128

<211> 142

<212> PRT

<213> artificial sequence

<220>

<223> FHVH33

<400> 128

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Thr Phe Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Asp Tyr Ile Tyr

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Ile Ser

85 90 95

Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Lys Glu Gly Thr Gly Ala Asn Ser Ser Leu

115 120 125

Ala Asp Tyr Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser

130 135 140

<210> 129

<211> 260

<212> PRT

<213> artificial sequence

<220>

<223> NBC10 scFv

<400> 129

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe

35 40 45

Ala Leu Ser Asn His Gly Met Ser Trp Val Arg Arg Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ser Gly Ile Val Tyr Ser Gly Ser Thr Tyr Tyr

65 70 75 80

Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Arg

85 90 95

Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala

100 105 110

Ile Tyr Tyr Cys Ser Ala His Gly Gly Glu Ser Asp Val Trp Gly Gln

115 120 125

Gly Thr Thr Val Thr Val Ser Ser Ala Ser Gly Gly Gly Gly Ser Gly

130 135 140

Gly Arg Ala Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser

145 150 155 160

Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys

165 170 175

Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys

180 185 190

Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln

195 200 205

Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe

210 215 220

Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr

225 230 235 240

Cys Gln Gln Ser Tyr Ser Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys

245 250 255

Val Glu Ile Lys

260

<210> 130

<211> 244

<212> PRT

<213> artificial sequence

<220>

<223> B38M scFv

<400> 130

Gln Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Glu His Thr Phe Ser Ser His

20 25 30

Val Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Ser Val

35 40 45

Ala Val Ile Gly Trp Arg Asp Ile Ser Thr Ser Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Arg Arg Ile Asp Ala Ala Asp Phe Asp Ser Trp Gly Gln Gly

100 105 110

Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Met Gly Trp Phe Arg Gln

145 150 155 160

Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Leu Ser Pro

165 170 175

Thr Leu Ala Tyr Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser

180 185 190

Arg Asp Asn Ala Lys Asn Thr Val Val Leu Gln Met Asn Ser Leu Lys

195 200 205

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Arg Lys Ser Val

210 215 220

Met Ser Ile Arg Pro Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val

225 230 235 240

Ser Ser Thr Ser

<210> 131

<211> 493

<212> PRT

<213> artificial sequence

<220>

<223> BCMA21.BBZ

<400> 131

Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro

1 5 10 15

Ala Phe Leu Leu Ile Pro Glu Ile Val Leu Thr Gln Ser Pro Gly Thr

20 25 30

Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser

35 40 45

Gln Ser Val Ser Ser Asn Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly

50 55 60

Gln Ser Pro Arg Leu Leu Ile Phe Gly Ala Ser Asn Arg Ala Thr Gly

65 70 75 80

Ile Pro Asp Arg Phe Ser Gly Gly Gly Ser Gly Thr Asp Phe Thr Leu

85 90 95

Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln

100 105 110

His Tyr Asp Gly Ser Pro Pro Met Tyr Thr Phe Gly Gln Gly Thr Lys

115 120 125

Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

130 135 140

Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln

145 150 155 160

Pro Gly Gly Ser Leu Arg Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe

165 170 175

Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

180 185 190

Glu Trp Val Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala

195 200 205

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn

210 215 220

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val

225 230 235 240

Tyr Tyr Cys Ala Lys Ile Thr Ala Met Val Thr His Asn Phe Tyr Gly

245 250 255

Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Thr Thr

260 265 270

Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln

275 280 285

Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala

290 295 300

Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala

305 310 315 320

Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr

325 330 335

Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln

340 345 350

Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser

355 360 365

Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys

370 375 380

Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln

385 390 395 400

Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu

405 410 415

Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg

420 425 430

Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met

435 440 445

Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly

450 455 460

Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp

465 470 475 480

Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 132

<211> 497

<212> PRT

<213> artificial sequence

<220>

<223> BCMA22.BBZ

<400> 132

Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro

1 5 10 15

Ala Phe Leu Leu Ile Pro Gln Ser Ala Leu Thr Gln Pro Ala Ser Val

20 25 30

Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser

35 40 45

Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln His Pro

50 55 60

Gly Lys Ala Pro Lys Leu Met Ile Tyr Glu Val Thr Asn Arg Pro Ser

65 70 75 80

Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser

85 90 95

Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala His Tyr Tyr Cys

100 105 110

Ile Ser Tyr Thr Ser Ser Ser Thr Leu Asp Tyr Val Phe Gly Thr Gly

115 120 125

Thr Lys Val Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Pro Gly Leu

145 150 155 160

Val Lys Pro Ser Gly Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly

165 170 175

Ser Ile Ser Ser Ser Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly

180 185 190

Lys Gly Leu Glu Trp Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn

195 200 205

Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser

210 215 220

Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr

225 230 235 240

Ala Val Tyr Tyr Cys Ala Arg Val Gly Ser Gly Tyr Ser Tyr Gly Tyr

245 250 255

Gly Asp Arg Val Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val

260 265 270

Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr

275 280 285

Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala

290 295 300

Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile

305 310 315 320

Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser

325 330 335

Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr

340 345 350

Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu

355 360 365

Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu

370 375 380

Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln

385 390 395 400

Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu

405 410 415

Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly

420 425 430

Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln

435 440 445

Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu

450 455 460

Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr

465 470 475 480

Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro

485 490 495

Arg

<210> 133

<211> 486

<212> PRT

<213> artificial sequence

<220>

<223> BCMA23.BBZ

<400> 133

Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro

1 5 10 15

Ala Phe Leu Leu Ile Pro Gln Ser Ala Leu Thr Gln Pro Pro Ser Ala

20 25 30

Ser Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser

35 40 45

Pro Asn Ile Gly Gly Asn Ser Val Asn Trp Tyr Gln Gln Leu Pro Gly

50 55 60

Thr Ala Pro Lys Leu Leu Met Tyr Thr Asn Asn Gln Arg Pro Ser Gly

65 70 75 80

Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu

85 90 95

Ala Ile Ser Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala

100 105 110

Ala Trp Asp Asp Ser Leu Asn Gly Val Val Phe Gly Gly Gly Thr Lys

115 120 125

Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

130 135 140

Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys

145 150 155 160

Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe

165 170 175

Thr Ser Tyr Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu

180 185 190

Glu Trp Met Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser

195 200 205

Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser

210 215 220

Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met

225 230 235 240

Tyr Tyr Cys Ala Arg Arg Gly Gly Ala Leu Asp Tyr Trp Gly Gln Gly

245 250 255

Thr Leu Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro

260 265 270

Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu

275 280 285

Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp

290 295 300

Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly

305 310 315 320

Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg

325 330 335

Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln

340 345 350

Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu

355 360 365

Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala

370 375 380

Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu

385 390 395 400

Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp

405 410 415

Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu

420 425 430

Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile

435 440 445

Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr

450 455 460

Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met

465 470 475 480

Gln Ala Leu Pro Pro Arg

485

<210> 134

<211> 488

<212> PRT

<213> artificial sequence

<220>

<223> BCMA24.BBZ

<400> 134

Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro

1 5 10 15

Ala Phe Leu Leu Ile Pro Gln Ser Val Leu Thr Gln Pro Pro Ser Ala

20 25 30

Ser Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser

35 40 45

Ser Asn Ile Gly Ser Tyr Ser Val Asn Trp Tyr Gln Gln Ile Pro Gly

50 55 60

Thr Ala Pro Lys Leu Leu Ile Tyr Ser Asn Asn Gln Arg Pro Ser Gly

65 70 75 80

Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu

85 90 95

Ala Ile Ser Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Ser Cys Ala

100 105 110

Ala Trp Asp Asp Ser Leu Asn Gly Val Val Phe Gly Gly Gly Thr Lys

115 120 125

Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

130 135 140

Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys

145 150 155 160

Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe

165 170 175

Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu

180 185 190

Glu Trp Met Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala

195 200 205

Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser

210 215 220

Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val

225 230 235 240

Tyr Tyr Cys Ala Arg Gly Ser Phe Tyr Ser Ser Val Asn Val Trp Gly

245 250 255

Gln Gly Thr Thr Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg

260 265 270

Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg

275 280 285

Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly

290 295 300

Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr

305 310 315 320

Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg

325 330 335

Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro

340 345 350

Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu

355 360 365

Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala

370 375 380

Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu

385 390 395 400

Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly

405 410 415

Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu

420 425 430

Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser

435 440 445

Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly

450 455 460

Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu

465 470 475 480

His Met Gln Ala Leu Pro Pro Arg

485

<210> 135

<211> 493

<212> PRT

<213> artificial sequence

<220>

<223> BCMA27.BBZ

<400> 135

Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro

1 5 10 15

Ala Phe Leu Leu Ile Pro Gln Ser Ala Leu Thr Gln Pro Pro Ser Ala

20 25 30

Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly Ser Arg

35 40 45

Ser Asn Val Gly Ser Tyr Asn Asp Val Ser Trp Tyr Gln Gln His Pro

50 55 60

Gly Lys Ala Pro Lys Leu Ile Ile Tyr Asp Val Asp Lys Arg Pro Ala

65 70 75 80

Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser

85 90 95

Leu Thr Val Ser Gly Leu Gln Ala Glu Asp Asp Ala Asp Tyr Tyr Cys

100 105 110

Ser Ser Tyr Gly Gly Thr Tyr Ser Leu Phe Val Phe Gly Thr Gly Thr

115 120 125

Glu Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

130 135 140

Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val

145 150 155 160

Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr

165 170 175

Phe Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly

180 185 190

Leu Glu Trp Val Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr

195 200 205

Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys

210 215 220

Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala

225 230 235 240

Val Tyr Tyr Cys Ala Lys Glu Glu Phe Tyr Gly Asp Ser Ser Tyr Gly

245 250 255

Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Thr Thr

260 265 270

Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln

275 280 285

Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala

290 295 300

Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala

305 310 315 320

Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr

325 330 335

Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln

340 345 350

Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser

355 360 365

Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys

370 375 380

Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln

385 390 395 400

Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu

405 410 415

Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg

420 425 430

Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met

435 440 445

Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly

450 455 460

Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp

465 470 475 480

Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 136

<211> 490

<212> PRT

<213> artificial sequence

<220>

<223> BCMA28.BBZ

<400> 136

Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro

1 5 10 15

Ala Phe Leu Leu Ile Pro Gln Ser Ala Leu Thr Gln Pro Pro Ser Val

20 25 30

Ser Glu Ala Pro Arg Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser

35 40 45

Ser Asn Ile Gly Gln Asn Ala Val Asn Trp Tyr Gln Lys Leu Pro Gly

50 55 60

Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Asn Asp Leu Val Ser Ser Gly

65 70 75 80

Val Ser Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu

85 90 95

Ala Ile Ser Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala

100 105 110

Thr Trp Asp Asp Ser Leu Asn Gly Val Val Phe Gly Gly Gly Thr Lys

115 120 125

Val Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

130 135 140

Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Pro Gly Leu Val Lys

145 150 155 160

Pro Ser Gln Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val

165 170 175

Ser Ser Asn Ser Ala Ala Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg

180 185 190

Gly Leu Glu Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn

195 200 205

Asp Tyr Ala Val Ser Val Lys Ser Arg Ile Thr Ile Asn Pro Asp Thr

210 215 220

Ser Lys Asn Gln Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp

225 230 235 240

Thr Ala Val Tyr Tyr Cys Ala Arg Asp Tyr Tyr Tyr Gly Met Asp Val

245 250 255

Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Thr Thr Thr Pro Ala

260 265 270

Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser

275 280 285

Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr

290 295 300

Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala

305 310 315 320

Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys

325 330 335

Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

340 345 350

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

355 360 365

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg

370 375 380

Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn

385 390 395 400

Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg

405 410 415

Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro

420 425 430

Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala

435 440 445

Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His

450 455 460

Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp

465 470 475 480

Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 137

<211> 490

<212> PRT

<213> artificial sequence

<220>

<223> BCMA30.BBZ

<400> 137

Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro

1 5 10 15

Ala Phe Leu Leu Ile Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Phe

20 25 30

Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser

35 40 45

Gln Gly Ile Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys

50 55 60

Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val

65 70 75 80

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr

85 90 95

Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln

100 105 110

Leu Asn Ser Tyr Pro Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu

115 120 125

Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

130 135 140

Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly

145 150 155 160

Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Ser

165 170 175

Tyr Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp

180 185 190

Met Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Pro

195 200 205

Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Asp Thr Ala

210 215 220

Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr

225 230 235 240

Cys Ala Arg Leu Asp Ala Ser Gly Ser Gln Arg Gly Gly Met Asp Val

245 250 255

Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Thr Thr Thr Pro Ala

260 265 270

Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser

275 280 285

Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr

290 295 300

Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala

305 310 315 320

Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys

325 330 335

Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

340 345 350

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

355 360 365

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg

370 375 380

Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn

385 390 395 400

Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg

405 410 415

Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro

420 425 430

Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala

435 440 445

Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His

450 455 460

Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp

465 470 475 480

Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 138

<211> 486

<212> PRT

<213> artificial sequence

<220>

<223> BCMA31.BBZ

<400> 138

Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro

1 5 10 15

Ala Phe Leu Leu Ile Pro Gln Ser Ala Leu Thr Gln Pro Pro Ser Ala

20 25 30

Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly Thr Ser

35 40 45

Ser Asp Val Gly Thr Tyr Asn Tyr Val Ser Trp Tyr Gln Gln His Pro

50 55 60

Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Asn Gln Arg Pro Ser

65 70 75 80

Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser

85 90 95

Leu Thr Val Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys

100 105 110

Ser Ser Tyr Gly Gly Ser Asn Asn Leu Val Phe Gly Gly Gly Thr Lys

115 120 125

Val Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

130 135 140

Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln

145 150 155 160

Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

165 170 175

Ser Ser Tyr Trp Met Ser Trp Val Arg Gln Ser Pro Gly Lys Gly Leu

180 185 190

Glu Trp Val Ala Asn Ile Lys Pro Asp Gly Ser Asp Lys Tyr Tyr Val

195 200 205

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn

210 215 220

Ser Leu Asp Leu Gln Met Asn Ser Leu Arg Gly Glu Asp Thr Ala Ile

225 230 235 240

Tyr Tyr Cys Ala Arg Gly Ala Thr Thr Tyr Gly Ser Trp Gly Gln Gly

245 250 255

Thr Leu Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro

260 265 270

Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu

275 280 285

Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp

290 295 300

Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly

305 310 315 320

Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg

325 330 335

Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln

340 345 350

Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu

355 360 365

Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala

370 375 380

Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu

385 390 395 400

Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp

405 410 415

Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu

420 425 430

Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile

435 440 445

Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr

450 455 460

Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met

465 470 475 480

Gln Ala Leu Pro Pro Arg

485

<210> 139

<211> 494

<212> PRT

<213> artificial sequence

<220>

<223> BCMA32.BBZ

<400> 139

Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro

1 5 10 15

Ala Phe Leu Leu Ile Pro Gln Ser Ala Leu Thr Gln Pro Ala Ser Val

20 25 30

Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser

35 40 45

Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln His Pro

50 55 60

Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Lys Arg Pro Ser

65 70 75 80

Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser

85 90 95

Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys

100 105 110

Ser Ser Tyr Thr Ser Ser Ser Thr Val Val Phe Gly Gly Gly Thr Lys

115 120 125

Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

130 135 140

Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Ala Glu Val Lys Lys

145 150 155 160

Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe

165 170 175

Ser Arg Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu

180 185 190

Glu Trp Met Gly Gly Ile Ile Pro Phe Phe Gly Thr Ser Asp Tyr Ala

195 200 205

Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser

210 215 220

Thr Ala Tyr Met Asp Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala Val

225 230 235 240

Tyr Tyr Cys Ala Val Arg Val Ala Thr Thr Gly Thr Gly Phe Tyr Tyr

245 250 255

Ala Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Thr

260 265 270

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

275 280 285

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

290 295 300

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

305 310 315 320

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

325 330 335

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

340 345 350

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

355 360 365

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

370 375 380

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn

385 390 395 400

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

405 410 415

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

420 425 430

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

435 440 445

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

450 455 460

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

465 470 475 480

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 140

<211> 492

<212> PRT

<213> artificial sequence

<220>

<223> BCMA33.BBZ

<400> 140

Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro

1 5 10 15

Ala Phe Leu Leu Ile Pro Gln Ser Ala Leu Thr Gln Pro Pro Ser Ala

20 25 30

Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly Thr Ser

35 40 45

Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln His Pro

50 55 60

Gly Lys Ala Pro Lys Leu Met Ile Tyr Glu Val Ser Lys Arg Pro Ser

65 70 75 80

Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser

85 90 95

Leu Thr Val Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Phe Cys

100 105 110

Ser Ser Tyr Ala Gly Ser Asn Asn Phe Val Val Phe Gly Gly Gly Thr

115 120 125

Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

130 135 140

Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val

145 150 155 160

Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr

165 170 175

Phe Asp Asp Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly

180 185 190

Leu Glu Trp Val Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr

195 200 205

Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys

210 215 220

Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala

225 230 235 240

Leu Tyr Tyr Cys Ala Lys Val Gly Ala Ser Ala Ala Leu Gly Ala Phe

245 250 255

Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Thr Thr Thr

260 265 270

Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro

275 280 285

Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val

290 295 300

His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro

305 310 315 320

Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu

325 330 335

Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro

340 345 350

Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys

355 360 365

Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe

370 375 380

Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu

385 390 395 400

Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp

405 410 415

Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys

420 425 430

Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala

435 440 445

Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys

450 455 460

Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr

465 470 475 480

Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 141

<211> 489

<212> PRT

<213> artificial sequence

<220>

<223> BCMA34.BBZ

<400> 141

Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro

1 5 10 15

Ala Phe Leu Leu Ile Pro Gln Pro Gly Leu Thr Gln Pro Pro Ser Val

20 25 30

Ser Lys Gly Leu Arg Gln Thr Ala Thr Leu Thr Cys Thr Gly Asn Ser

35 40 45

Asn Asn Val Gly Asn Gln Gly Ala Ala Trp Leu Gln Gln His Gln Gly

50 55 60

His Pro Pro Lys Leu Leu Ser Tyr Arg Asn Asn Asn Arg Pro Ser Gly

65 70 75 80

Ile Ser Glu Arg Phe Ser Ala Ser Arg Ser Gly Asn Thr Ala Ser Leu

85 90 95

Thr Ile Thr Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ser

100 105 110

Ala Trp Asp Ser Ser Leu Ser Ala Arg Val Phe Gly Gly Gly Thr Lys

115 120 125

Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

130 135 140

Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys

145 150 155 160

Pro Gly Ala Ser Val Lys Val Ser Cys Lys Thr Ser Gly Tyr Thr Phe

165 170 175

Ser Asn Pro Phe Val His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu

180 185 190

Glu Trp Val Gly Ile Ile Asn Leu Ser Gly Gly Asp Thr Leu Tyr Ala

195 200 205

Gln Lys Phe Gln Gly Gly Val Thr Met Thr Arg Asp Thr Ser Thr Asn

210 215 220

Thr Ala Tyr Met Glu Leu Thr Ser Leu Thr Phe Glu Asp Thr Ala Val

225 230 235 240

Tyr Tyr Cys Ala Arg Asp Gln Ala Gly Phe Gly Asp Ser Ala Tyr Trp

245 250 255

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro

260 265 270

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

275 280 285

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

290 295 300

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

305 310 315 320

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys

325 330 335

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

340 345 350

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

355 360 365

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

370 375 380

Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu

385 390 395 400

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

405 410 415

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

420 425 430

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

435 440 445

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

450 455 460

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

465 470 475 480

Leu His Met Gln Ala Leu Pro Pro Arg

485

<210> 142

<211> 496

<212> PRT

<213> artificial sequence

<220>

<223> BCMA35.BBZ

<400> 142

Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro

1 5 10 15

Ala Phe Leu Leu Ile Pro Gln Ala Val Leu Thr Gln Pro Pro Ser Ala

20 25 30

Ser Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser

35 40 45

Ser Asn Ile Gly Ser Asn Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly

50 55 60

Thr Ala Pro Lys Leu Leu Ile Tyr Ser Asn Asn Gln Arg Pro Ser Gly

65 70 75 80

Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu

85 90 95

Ala Ile Ser Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala

100 105 110

Ala Trp Asp Asp Ser Leu Asn Gly Gly Val Phe Gly Gly Gly Thr Glu

115 120 125

Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

130 135 140

Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys

145 150 155 160

Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe

165 170 175

Thr Ser Tyr Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu

180 185 190

Glu Trp Met Gly Trp Ile Asn Ala Tyr Asn Gly Asn Ala Asn Tyr Ala

195 200 205

Gln Lys Leu Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Met Ser

210 215 220

Thr Ala Tyr Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Ser Ala Val

225 230 235 240

Tyr Tyr Cys Ala Arg Glu Tyr Tyr Tyr Phe Trp Ser Asn Arg Ala Phe

245 250 255

Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Ser Val Ser

260 265 270

Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile

275 280 285

Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala

290 295 300

Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr

305 310 315 320

Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu

325 330 335

Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile

340 345 350

Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp

355 360 365

Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu

370 375 380

Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly

385 390 395 400

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

405 410 415

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

420 425 430

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

435 440 445

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

450 455 460

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

465 470 475 480

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490 495

<210> 143

<211> 1479

<212> DNA

<213> artificial sequence

<220>

<223> BCMA21.BBZ NT

<400> 143

atgctgctgc tggtgaccag cctgctgctg tgcgagctgc cccaccccgc ctttctgctg 60

atccccgaaa tagtgttgac gcagtctcca ggcaccctgt ctttgtctcc aggggaaaga 120

gccaccctct cctgcagggc cagtcagagt gttagcagca acttcttagc ctggtaccag 180

cagaaacctg gccagtctcc cagactcctc atcttcggtg catccaacag ggccactggc 240

atcccagaca ggttcagtgg cggtgggtct gggacagact tcactctcac catcagccgc 300

ctggaacctg aagactttgc agtttactac tgtcagcact atgacggctc acctccgatg 360

tacacttttg gccaggggac caagctggag atcaaaggtg gtggtggttc tggcggcggc 420

ggctccggag gtggtggatc cgaagtgcag ctggtggagt ctgggggagg cttggtacag 480

cctggggggt ccctgagact ctcctgtgaa gcctctggat tcacctttag cagctatgcc 540

atgagctggg tccgccaggc tccagggaag gggctggagt gggtctcagc tattagtggt 600

agtggtggta gcacatacta cgcagactcc gtgaagggcc ggttcaccat ctccagagac 660

aattccaaga acacgctgta tctgcaaatg aacagcctga gagccgagga cacggccgta 720

tattactgtg cgaagatcac agctatggtt actcataact tctacggtat ggacgtctgg 780

ggccaaggga ccacggtcac cgtctcctca accactaccc cagcaccgcg gccacccacc 840

ccggctccta ccatcgcctc ccagcctctg tccctgcgtc cggaggcatg tagacccgca 900

gctggtgggg ccgtgcatac ccggggtctt gacttcgcct gcgatatcta catttgggcc 960

cctctggctg gtacttgcgg ggtcctgctg ctttcactcg tgatcactct ttactgtaaa 1020

cggggcagaa agaaactcct gtatatattc aaacaaccat ttatgagacc agtacaaact 1080

actcaagagg aagatggctg tagctgccga tttccagaag aagaagaagg aggatgtgaa 1140

ctgagagtga agttcagcag gagcgcagac gcccccgcgt accagcaggg ccagaaccag 1200

ctctataacg agctcaatct aggacgaaga gaggagtacg atgttttgga caagagacgt 1260

ggccgggacc ctgagatggg gggaaagccg agaaggaaga accctcagga aggcctgtac 1320

aatgaactgc agaaagataa gatggcggag gcctacagtg agattgggat gaaaggcgag 1380

cgccggaggg gcaaggggca cgatggcctt taccagggtc tcagtacagc caccaaggac 1440

acctacgacg cccttcacat gcaggccctg ccccctcgc 1479

<210> 144

<211> 1491

<212> DNA

<213> artificial sequence

<220>

<223> BCMA22.BBZ NT

<400> 144

atgctgctgc tggtgaccag cctgctgctg tgcgagctgc cccaccccgc ctttctgctg 60

atcccccaat ctgccctgac tcagcctgcc tccgtgtctg ggtctcctgg acagtcgatc 120

accatctcct gcactggaac cagcagtgac gttggtggtt ataactatgt ctcctggtac 180

caacagcacc caggcaaagc ccccaaactc atgatttatg aggtcactaa tcggccctca 240

ggggtttcta atcgcttctc tggctccaag tctggcaaca cggcctccct gaccatctct 300

gggctccagg ctgaagacga ggctcattat tactgcatct catatacaag cagcagcact 360

ctcgattatg tcttcggaac tggcaccaag gtgaccgtcc tcggtggtgg tggttctggc 420

ggcggcggct ccggaggtgg tggatccgag gtgcaactgg tggagtcggg cccaggactg 480

gtgaagcctt cggggaccct gtccctcacc tgcgctgtct ctggtggctc catcagcagt 540

agtaactggt ggagttgggt ccgccagccc ccagggaagg ggctggagtg gattggggaa 600

atctatcata gtgggagcac caactacaac ccgtccctca agagtcgagt caccatatca 660

gtagacaagt ccaagaacca gttctccctg aagctgagct ctgtgaccgc cgcggacacg 720

gccgtgtatt actgtgcgag agtggggagt ggatacagct atggttacgg cgatcgggtt 780

cttgactact ggggccaggg aaccctggtc accgtctcct caaccactac cccagcaccg 840

cggccaccca ccccggctcc taccatcgcc tcccagcctc tgtccctgcg tccggaggca 900

tgtagacccg cagctggtgg ggccgtgcat acccggggtc ttgacttcgc ctgcgatatc 960

tacatttggg cccctctggc tggtacttgc ggggtcctgc tgctttcact cgtgatcact 1020

ctttactgta aacggggcag aaagaaactc ctgtatatat tcaaacaacc atttatgaga 1080

ccagtacaaa ctactcaaga ggaagatggc tgtagctgcc gatttccaga agaagaagaa 1140

ggaggatgtg aactgagagt gaagttcagc aggagcgcag acgcccccgc gtaccagcag 1200

ggccagaacc agctctataa cgagctcaat ctaggacgaa gagaggagta cgatgttttg 1260

gacaagagac gtggccggga ccctgagatg gggggaaagc cgagaaggaa gaaccctcag 1320

gaaggcctgt acaatgaact gcagaaagat aagatggcgg aggcctacag tgagattggg 1380

atgaaaggcg agcgccggag gggcaagggg cacgatggcc tttaccaggg tctcagtaca 1440

gccaccaagg acacctacga cgcccttcac atgcaggccc tgccccctcg c 1491

<210> 145

<211> 1458

<212> DNA

<213> artificial sequence

<220>

<223> BCMA23.BBZ NT

<400> 145

atgctgctgc tggtgaccag cctgctgctg tgcgagctgc cccaccccgc ctttctgctg 60

atcccccagt ctgccctgac tcagccaccc tcagcgtctg ggacccccgg gcagagggtc 120

accatctctt gttctggcag cagcccgaac atcggaggta attctgtcaa ctggtaccag 180

caactcccag gaacggcccc caaactcctc atgtacacta ataatcagcg gccctcaggg 240

gtccctgacc gattctctgg ctccaagtct ggcacctcag cctccctggc catcagtggg 300

ctccagtctg aggatgaggc tgattactac tgtgcagcat gggatgacag cctgaatggt 360

gtggtattcg gcggagggac caagctgacc gtcctaggtg gtggtggttc tggcggcggc 420

ggctccggag gtggtggatc ccaggtccag ctggtgcagt ctggagcaga ggtgaaaaag 480

ccgggggagt ctctgaagat ctcctgtaag ggttctggat acagctttac cagctactgg 540

atcggctggg tgcgccagat gcccgggaaa ggcctggagt ggatggggat catctatcct 600

ggtgactctg ataccagata cagcccgtcc ttccaaggcc aggtcaccat ctcagccgac 660

aagtccatca gcaccgccta cctgcagtgg agcagcctga aggcctcgga caccgccatg 720

tattactgtg cgagacgggg tggagccctt gactactggg gccagggaac cctggtcact 780

gtctcctcaa ccactacccc agcaccgcgg ccacccaccc cggctcctac catcgcctcc 840

cagcctctgt ccctgcgtcc ggaggcatgt agacccgcag ctggtggggc cgtgcatacc 900

cggggtcttg acttcgcctg cgatatctac atttgggccc ctctggctgg tacttgcggg 960

gtcctgctgc tttcactcgt gatcactctt tactgtaaac ggggcagaaa gaaactcctg 1020

tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 1080

agctgccgat ttccagaaga agaagaagga ggatgtgaac tgagagtgaa gttcagcagg 1140

agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 1200

ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1260

ggaaagccga gaaggaagaa ccctcaggaa ggcctgtaca atgaactgca gaaagataag 1320

atggcggagg cctacagtga gattgggatg aaaggcgagc gccggagggg caaggggcac 1380

gatggccttt accagggtct cagtacagcc accaaggaca cctacgacgc ccttcacatg 1440

caggccctgc cccctcgc 1458

<210> 146

<211> 1464

<212> DNA

<213> artificial sequence

<220>

<223> BCMA24.BBZ NT

<400> 146

atgctgctgc tggtgaccag cctgctgctg tgcgagctgc cccaccccgc ctttctgctg 60

atcccccagt ctgtgttgac gcagccgccc tcagcgtctg ggacccccgg gcagagggtc 120

accatctctt gttctggaag cagctccaac atcggaagtt acagtgtgaa ctggtaccag 180

cagatcccag gaacggcccc caaactcctc atctatagta ataatcagcg gccctcaggg 240

gtccctgacc gattctctgg ctccaagtct ggcacctcag cctccctggc catcagtggg 300

ctccagtctg aggatgaggc tgattattcc tgtgcagcat gggatgacag cctgaatggt 360

gtggtattcg gcggagggac caagctgacc gtcctaggtg gtggtggttc tggcggcggc 420

ggctccggag gtggtggatc ccaggtccag ctggtgcagt ctggggctga ggtgaagaag 480

cctgggtcct cggtgaaggt ctcctgcaag gcttctggag gcaccttcag cagctatgct 540

atcagctggg tgcgacaggc ccctggacaa gggcttgagt ggatgggagg gatcatccct 600

atctttggta cagcaaacta cgcacagaag ttccagggca gagtcacgat taccgcggac 660

gaatccacga gcacagccta catggagctg agcagcctga gatctgagga cacggccgtg 720

tattactgtg cgagagggag tttctattct agtgtgaacg tctggggcca agggaccacg 780

gtcaccgtct cctcaaccac taccccagca ccgcggccac ccaccccggc tcctaccatc 840

gcctcccagc ctctgtccct gcgtccggag gcatgtagac ccgcagctgg tggggccgtg 900

catacccggg gtcttgactt cgcctgcgat atctacattt gggcccctct ggctggtact 960

tgcggggtcc tgctgctttc actcgtgatc actctttact gtaaacgggg cagaaagaaa 1020

ctcctgtata tattcaaaca accatttatg agaccagtac aaactactca agaggaagat 1080

ggctgtagct gccgatttcc agaagaagaa gaaggaggat gtgaactgag agtgaagttc 1140

agcaggagcg cagacgcccc cgcgtaccag cagggccaga accagctcta taacgagctc 1200

aatctaggac gaagagagga gtacgatgtt ttggacaaga gacgtggccg ggaccctgag 1260

atggggggaa agccgagaag gaagaaccct caggaaggcc tgtacaatga actgcagaaa 1320

gataagatgg cggaggccta cagtgagatt gggatgaaag gcgagcgccg gaggggcaag 1380

gggcacgatg gcctttacca gggtctcagt acagccacca aggacaccta cgacgccctt 1440

cacatgcagg ccctgccccc tcgc 1464

<210> 147

<211> 1479

<212> DNA

<213> artificial sequence

<220>

<223> BCMA27.BBZ NT

<400> 147

atgctgctgc tggtgaccag cctgctgctg tgcgagctgc cccaccccgc ctttctgctg 60

atcccccagt ctgccctgac tcagcctccc tccgcgtccg gatctcctgg acagtcagtc 120

accatctcct gcactggaag tcgcagtaac gttgggtctt ataacgatgt ctcttggtac 180

caacaacacc caggcaaagc ccccaaactc ataatttatg acgtcgataa gaggcccgca 240

ggggtccctg atcgcttctc tggctccaag tctggcaaca cggcctccct gaccgtctct 300

gggctccagg ctgaagatga cgctgactat tattgcagtt catatggagg cacctacagc 360

cttttcgtct tcggaactgg gaccgagctg accgtcctag gtggtggtgg ttctggcggc 420

ggcggctccg gaggtggtgg atccgaagtg cagctggtgg agtctggggg agacttggta 480

cagcctgggg ggtccctgag actctcctgt gcagcctctg gattcacctt cagtagctat 540

ggcatgcact gggtccgcca ggctccaggc aaggggctgg agtgggtggc agttatatca 600

tatgatggaa gtaataaata ctatgcagac tccgtgaagg gccgattcac catctccaga 660

gacaattcca agaacacgct gtatctgcaa atgaacagcc tgagagctga ggacacggct 720

gtgtattact gtgcgaaaga agaattttac ggtgactcct cctacggtat ggacgtctgg 780

ggccaaggga ccacggtcac tgtctcctca accactaccc cagcaccgcg gccacccacc 840

ccggctccta ccatcgcctc ccagcctctg tccctgcgtc cggaggcatg tagacccgca 900

gctggtgggg ccgtgcatac ccggggtctt gacttcgcct gcgatatcta catttgggcc 960

cctctggctg gtacttgcgg ggtcctgctg ctttcactcg tgatcactct ttactgtaaa 1020

cggggcagaa agaaactcct gtatatattc aaacaaccat ttatgagacc agtacaaact 1080

actcaagagg aagatggctg tagctgccga tttccagaag aagaagaagg aggatgtgaa 1140

ctgagagtga agttcagcag gagcgcagac gcccccgcgt accagcaggg ccagaaccag 1200

ctctataacg agctcaatct aggacgaaga gaggagtacg atgttttgga caagagacgt 1260

ggccgggacc ctgagatggg gggaaagccg agaaggaaga accctcagga aggcctgtac 1320

aatgaactgc agaaagataa gatggcggag gcctacagtg agattgggat gaaaggcgag 1380

cgccggaggg gcaaggggca cgatggcctt taccagggtc tcagtacagc caccaaggac 1440

acctacgacg cccttcacat gcaggccctg ccccctcgc 1479

<210> 148

<211> 1470

<212> DNA

<213> artificial sequence

<220>

<223> BCMA28.BBZ NT

<400> 148

atgctgctgc tggtgaccag cctgctgctg tgcgagctgc cccaccccgc ctttctgctg 60

atcccccagt ctgccctgac tcagccaccc tcggtgtctg aagcccccag gcagagggtc 120

accatctcct gttctggaag cagctccaac atcggacaga atgctgtcaa ctggtatcag 180

aagctcccag gaaaggctcc caaactcctc atctattata atgatctggt gtcctcaggg 240

gtctctgacc gattctctgg ctccaagtct ggcacctcag cctccctggc catcagtggg 300

ctccagtctg aggatgaggc tgattattac tgtgcaacat gggatgacag cctgaatggt 360

gtggtattcg gcggagggac caaggtcacc gtcctaggtg gtggtggttc tggcggcggc 420

ggctccggag gtggtggatc ccaggtccag ctggtgcagt ctggtccagg actggtgaag 480

ccctcgcaga ccctctcact cacctgtgcc atctccgggg acagtgtctc tagcaacagt 540

gctgcttgga actggatcag gcagtcccca tcgagaggcc ttgagtggct gggaaggaca 600

tactacaggt ccaagtggta taatgattat gcagtatctg tgaaaagtcg aataaccatc 660

aacccagaca catccaagaa ccagttctcc ctgcagctga actctgtgac tcccgaggac 720

acggctgtgt attactgtgc aagggactac tactacggta tggacgtctg gggccaaggg 780

accacggtca ccgtctcctc aaccactacc ccagcaccgc ggccacccac cccggctcct 840

accatcgcct cccagcctct gtccctgcgt ccggaggcat gtagacccgc agctggtggg 900

gccgtgcata cccggggtct tgacttcgcc tgcgatatct acatttgggc ccctctggct 960

ggtacttgcg gggtcctgct gctttcactc gtgatcactc tttactgtaa acggggcaga 1020

aagaaactcc tgtatatatt caaacaacca tttatgagac cagtacaaac tactcaagag 1080

gaagatggct gtagctgccg atttccagaa gaagaagaag gaggatgtga actgagagtg 1140

aagttcagca ggagcgcaga cgcccccgcg taccagcagg gccagaacca gctctataac 1200

gagctcaatc taggacgaag agaggagtac gatgttttgg acaagagacg tggccgggac 1260

cctgagatgg ggggaaagcc gagaaggaag aaccctcagg aaggcctgta caatgaactg 1320

cagaaagata agatggcgga ggcctacagt gagattggga tgaaaggcga gcgccggagg 1380

ggcaaggggc acgatggcct ttaccagggt ctcagtacag ccaccaagga cacctacgac 1440

gcccttcaca tgcaggccct gccccctcgc 1470

<210> 149

<211> 1470

<212> DNA

<213> artificial sequence

<220>

<223> BCMA30.BBZ NT

<400> 149

atgctgctgc tggtgaccag cctgctgctg tgcgagctgc cccaccccgc ctttctgctg 60

atccccgaca tccagatgac ccagtctcca tccttcctgt ctgcatctgt aggagacaga 120

gtcaccatca cttgccgggc cagtcagggc attagcagtt atttagcctg gtatcagcaa 180

aaaccaggga aagcccctaa gctcctgatc tatgctgcat ccactttgca aagtggggtc 240

ccatcaaggt tcagcggcag tggatctggg acagaattca ctctcacaat cagcagcctg 300

cagcctgaag attttgcaac ttattactgt caacagctta atagttaccc tccgtggacg 360

ttcggccaag ggaccaaggt ggagatcaaa ggtggtggtg gttctggcgg cggcggctcc 420

ggaggtggtg gatcccaggt gcagctggta cagtctggag cagaggtgaa aaagcccggg 480

gagtctctga agatatcctg taagggttct ggatacaggt ttaccagtta ctggatcggc 540

tgggtgcgcc agatgcccgg gaaaggcctg gagtggatgg gaatcatcta tcctggtgac 600

tctgatacca gatacagccc gcccttccaa ggccaggtca ccatctcagc cgacaagtcc 660

atcgacaccg cctacctgca gtggagcagc ctgaaggcct cggacaccgc catgtattac 720

tgtgcgagac tggacgcttc ggggagtcaa agggggggta tggacgtctg gggccaaggg 780

accacggtca ccgtctcctc aaccactacc ccagcaccgc ggccacccac cccggctcct 840

accatcgcct cccagcctct gtccctgcgt ccggaggcat gtagacccgc agctggtggg 900

gccgtgcata cccggggtct tgacttcgcc tgcgatatct acatttgggc ccctctggct 960

ggtacttgcg gggtcctgct gctttcactc gtgatcactc tttactgtaa acggggcaga 1020

aagaaactcc tgtatatatt caaacaacca tttatgagac cagtacaaac tactcaagag 1080

gaagatggct gtagctgccg atttccagaa gaagaagaag gaggatgtga actgagagtg 1140

aagttcagca ggagcgcaga cgcccccgcg taccagcagg gccagaacca gctctataac 1200

gagctcaatc taggacgaag agaggagtac gatgttttgg acaagagacg tggccgggac 1260

cctgagatgg ggggaaagcc gagaaggaag aaccctcagg aaggcctgta caatgaactg 1320

cagaaagata agatggcgga ggcctacagt gagattggga tgaaaggcga gcgccggagg 1380

ggcaaggggc acgatggcct ttaccagggt ctcagtacag ccaccaagga cacctacgac 1440

gcccttcaca tgcaggccct gccccctcgc 1470

<210> 150

<211> 1461

<212> DNA

<213> artificial sequence

<220>

<223> BCMA31.BBZ NT

<400> 150

atgctgctgc tggtgaccag cctgctgctg tgcgagctgc cccaccccgc ctttctgctg 60

atcccccaat ctgccctgac tcagcctccc tccgcgtccg ggtctcctgg acagtcagtc 120

accatctcct gcactggaac cagcagtgac gttggtactt ataattatgt ctcctggtac 180

caacaacacc caggcaaagc ccccaagctc atgatttatg acgtcaatca gcggccctca 240

ggggtccctg atcgcttctc tggctccaag tctggcaaca cggcctccct gaccgtctct 300

gggctccagg ctgaggatga ggctgattat tactgcagct catatggagg cagcaacaat 360

ttggtattcg gcggagggac caaggtcacc gtcctaggtg gtggtggttc tggcggcggc 420

ggctccggag gtggtggatc cgaagtgcaa ctggtggagt ctgggggagg cttgatccag 480

cctggggggt ccctgagact ctcctgtgca gcctctggat tcacctttag tagctattgg 540

atgagctggg tccgccaaag tccagggaag gggctggagt gggtggccaa cataaagcca 600

gatggaagtg acaaatacta tgtggactct gtgaagggcc gattcaccat ctccagagac 660

aacgccaaga actcactgga tctgcaaatg aacagcctga gaggcgaaga cacggctatt 720

tattactgcg cgagaggtgc caccacctat ggctcctggg gccagggaac cctggtcact 780

gtctcctcaa ccactacccc agcaccgcgg ccacccaccc cggctcctac catcgcctcc 840

cagcctctgt ccctgcgtcc ggaggcatgt agacccgcag ctggtggggc cgtgcatacc 900

cggggtcttg acttcgcctg cgatatctac atttgggccc ctctggctgg tacttgcggg 960

gtcctgctgc tttcactcgt gatcactctt tactgtaaac ggggcagaaa gaaactcctg 1020

tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 1080

agctgccgat ttccagaaga agaagaagga ggatgtgaac tgagagtgaa gttcagcagg 1140

agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 1200

ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1260

ggaaagccga gaaggaagaa ccctcaggaa ggcctgtaca atgaactgca gaaagataag 1320

atggcggagg cctacagtga gattgggatg aaaggcgagc gccggagggg caaggggcac 1380

gatggccttt accagggtct cagtacagcc accaaggaca cctacgacgc ccttcacatg 1440

caggccctgc cccctcgcta a 1461

<210> 151

<211> 1482

<212> DNA

<213> artificial sequence

<220>

<223> BCMA32.BBZ NT

<400> 151

atgctgctgc tggtgaccag cctgctgctg tgcgagctgc cccaccccgc ctttctgctg 60

atcccccaat ctgccctgac tcagcctgcc tccgtgtctg ggtctcctgg acagtcgatc 120

accatctcct gcactggaac cagcagtgac gttggtggtt ataactatgt ctcctggtac 180

caacaacacc caggcaaagc ccccaaactc atgatttatg atgtcagtaa gcggccctca 240

ggggtttcta atcgcttctc tggctccaag tctggcaaca cggcctccct gaccatctct 300

gggctccagg ctgaggacga ggctgattat tactgcagct catatacaag cagcagcact 360

gtggtattcg gcggagggac caagctgacc gtcctaggtg gtggtggttc tggcggcggc 420

ggctccggag gtggtggatc ccaggtgcag ctgcaggagt cgggggctga ggtgaagaag 480

cctgggtcct cggtgaaggt ctcctgcaag gcttctggag gcaccttcag caggtatgct 540

atcagctggg tgcgacaggc ccctggacaa gggcttgagt ggatgggagg gatcatccct 600

ttctttggta catcagacta cgcacagaag ttccagggca gagtcacgat taccgcggac 660

gaatccacga gcacagccta catggacctg agtagactga gatctgagga cacggccgtg 720

tattactgtg cggtccgtgt ggcaaccact ggaaccgggt tctactacgc tatggacgtc 780

tggggccagg ggaccacggt caccgtctcc tcaaccacta ccccagcacc gcggccaccc 840

accccggctc ctaccatcgc ctcccagcct ctgtccctgc gtccggaggc atgtagaccc 900

gcagctggtg gggccgtgca tacccggggt cttgacttcg cctgcgatat ctacatttgg 960

gcccctctgg ctggtacttg cggggtcctg ctgctttcac tcgtgatcac tctttactgt 1020

aaacggggca gaaagaaact cctgtatata ttcaaacaac catttatgag accagtacaa 1080

actactcaag aggaagatgg ctgtagctgc cgatttccag aagaagaaga aggaggatgt 1140

gaactgagag tgaagttcag caggagcgca gacgcccccg cgtaccagca gggccagaac 1200

cagctctata acgagctcaa tctaggacga agagaggagt acgatgtttt ggacaagaga 1260

cgtggccggg accctgagat ggggggaaag ccgagaagga agaaccctca ggaaggcctg 1320

tacaatgaac tgcagaaaga taagatggcg gaggcctaca gtgagattgg gatgaaaggc 1380

gagcgccgga ggggcaaggg gcacgatggc ctttaccagg gtctcagtac agccaccaag 1440

gacacctacg acgcccttca catgcaggcc ctgccccctc gc 1482

<210> 152

<211> 1476

<212> DNA

<213> artificial sequence

<220>

<223> BCMA33.BBZ NT

<400> 152

atgctgctgc tggtgaccag cctgctgctg tgcgagctgc cccaccccgc ctttctgctg 60

atcccccaat ctgccctgac tcagcctccc tccgcgtccg ggtctcctgg acagtcagtc 120

accatctcct gcactggaac cagcagtgac gttggtggtt ataactatgt ctcctggtac 180

caacagcacc caggcaaagc ccccaaactc atgatttatg aggtcagtaa gcggccctca 240

ggggtccctg atcgcttctc tggctccaag tctggcaaca cggcctccct gaccgtctct 300

gggctccagg ctgaggatga ggctgattat ttctgcagct catatgcagg cagcaacaat 360

ttcgtggtat tcggcggagg gaccaagctg accgtcctag gtggtggtgg ttctggcggc 420

ggcggctccg gaggtggtgg atccgaggtg caactggtgg agtctggggg aggcttggta 480

cagcctggca ggtccctgag actctcctgt gcagcctctg gattcacctt tgatgattat 540

gccatgcact gggtccggca agctccaggg aagggcctgg agtgggtctc aggtattagt 600

tggaatagtg gtagcatagg ctatgcggac tctgtgaagg gccgattcac catctccaga 660

gacaacgcca agaactccct gtatctgcaa atgaacagtc tgagagctga ggacacggcc 720

ttgtattact gtgcaaaagt cggcgcttcg gcagccctgg gtgcttttga tatctggggc 780

caagggacaa tggtcaccgt ctcctcaacc actaccccag caccgcggcc acccaccccg 840

gctcctacca tcgcctccca gcctctgtcc ctgcgtccgg aggcatgtag acccgcagct 900

ggtggggccg tgcatacccg gggtcttgac ttcgcctgcg atatctacat ttgggcccct 960

ctggctggta cttgcggggt cctgctgctt tcactcgtga tcactcttta ctgtaaacgg 1020

ggcagaaaga aactcctgta tatattcaaa caaccattta tgagaccagt acaaactact 1080

caagaggaag atggctgtag ctgccgattt ccagaagaag aagaaggagg atgtgaactg 1140

agagtgaagt tcagcaggag cgcagacgcc cccgcgtacc agcagggcca gaaccagctc 1200

tataacgagc tcaatctagg acgaagagag gagtacgatg ttttggacaa gagacgtggc 1260

cgggaccctg agatgggggg aaagccgaga aggaagaacc ctcaggaagg cctgtacaat 1320

gaactgcaga aagataagat ggcggaggcc tacagtgaga ttgggatgaa aggcgagcgc 1380

cggaggggca aggggcacga tggcctttac cagggtctca gtacagccac caaggacacc 1440

tacgacgccc ttcacatgca ggccctgccc cctcgc 1476

<210> 153

<211> 1467

<212> DNA

<213> artificial sequence

<220>

<223> BCMA34.BBZ NT

<400> 153

atgctgctgc tggtgaccag cctgctgctg tgcgagctgc cccaccccgc ctttctgctg 60

atcccccagc cagggctgac tcagccaccc tcggtgtcca agggcttgag acagaccgcc 120

acactcacct gcactgggaa cagcaacaat gttggcaacc aaggagcagc ttggctgcag 180

cagcaccagg gccaccctcc caaactccta tcctacagga ataacaaccg gccctcaggg 240

atctcagaga gattctctgc atccaggtca ggaaacacag cctccctgac cattactgga 300

ctccagcctg aggacgaggc tgactattac tgctcagcat gggacagcag cctcagtgct 360

cgggtgttcg gcggagggac caagctgacc gtcctaggtg gtggtggttc tggcggcggc 420

ggctccggag gtggtggatc ccaggtgcag ctggtgcagt ctggggctga ggtgaagaag 480

cctggggcct cagtgaaggt ttcctgcaag acatctggat acaccttcag caaccccttc 540

gtgcactggg tgcgacaggc ccctggacaa gggcttgagt gggtgggcat aattaacctt 600

agtggaggtg acacactcta cgcacagaag ttccagggcg gagtcaccat gaccagggac 660

acgtctacga acacagccta catggagctg accagcctga catttgaaga cacggccgtg 720

tattactgtg cgagagatca agcgggcttc ggtgactctg cctactgggg ccagggaacc 780

ctggtcaccg tctcctcaac cactacccca gcaccgcggc cacccacccc ggctcctacc 840

atcgcctccc agcctctgtc cctgcgtccg gaggcatgta gacccgcagc tggtggggcc 900

gtgcataccc ggggtcttga cttcgcctgc gatatctaca tttgggcccc tctggctggt 960

acttgcgggg tcctgctgct ttcactcgtg atcactcttt actgtaaacg gggcagaaag 1020

aaactcctgt atatattcaa acaaccattt atgagaccag tacaaactac tcaagaggaa 1080

gatggctgta gctgccgatt tccagaagaa gaagaaggag gatgtgaact gagagtgaag 1140

ttcagcagga gcgcagacgc ccccgcgtac cagcagggcc agaaccagct ctataacgag 1200

ctcaatctag gacgaagaga ggagtacgat gttttggaca agagacgtgg ccgggaccct 1260

gagatggggg gaaagccgag aaggaagaac cctcaggaag gcctgtacaa tgaactgcag 1320

aaagataaga tggcggaggc ctacagtgag attgggatga aaggcgagcg ccggaggggc 1380

aaggggcacg atggccttta ccagggtctc agtacagcca ccaaggacac ctacgacgcc 1440

cttcacatgc aggccctgcc ccctcgc 1467

<210> 154

<211> 1488

<212> DNA

<213> artificial sequence

<220>

<223> BCMA35.BBZ NT

<400> 154

atgctgctgc tggtgaccag cctgctgctg tgcgagctgc cccaccccgc ctttctgctg 60

atcccccagg ctgtgctgac tcagccaccc tcagcgtctg ggacccccgg gcagagggtc 120

accatctctt gttctggaag cagctccaac atcggaagta atactgtaaa ctggtaccag 180

cagctcccag gaacggcccc caaactcctc atctatagta ataatcagcg gccctcaggg 240

gtccctgacc gattctctgg ctccaagtct ggcacctcag cctccctggc catcagtggg 300

ctccagtctg aggatgaggc tgattattac tgtgcagcat gggatgacag cctgaatggc 360

ggggtgttcg gcggagggac cgagctgacc gtcctaggtg gtggtggttc tggcggcggc 420

ggctccggag gtggtggatc ccaggtccag ctggtgcagt ctggagctga ggtgaagaag 480

cctggggcct cagtgaaggt ctcctgcaag gcttctggat acacctttac cagctatgat 540

atcagctggg tgcgacaggc ccctggacaa gggcttgagt ggatgggatg gatcaacgct 600

tacaatggta acgcaaacta tgcacagaag ctccagggca gagtcaccat gaccacagac 660

acatccatga gcacagccta catggagctg aggagcctga gatctgacga ctcggccgtc 720

tattactgtg cgagggagta ttactatttc tggagtaatc gagccttcta ctacggtatg 780

gacgtctggg gccaggggac cacggtcagc gtctcctcaa ccactacccc agcaccgcgg 840

ccacccaccc cggctcctac catcgcctcc cagcctctgt ccctgcgtcc ggaggcatgt 900

agacccgcag ctggtggggc cgtgcatacc cggggtcttg acttcgcctg cgatatctac 960

atttgggccc ctctggctgg tacttgcggg gtcctgctgc tttcactcgt gatcactctt 1020

tactgtaaac ggggcagaaa gaaactcctg tatatattca aacaaccatt tatgagacca 1080

gtacaaacta ctcaagagga agatggctgt agctgccgat ttccagaaga agaagaagga 1140

ggatgtgaac tgagagtgaa gttcagcagg agcgcagacg cccccgcgta ccagcagggc 1200

cagaaccagc tctataacga gctcaatcta ggacgaagag aggagtacga tgttttggac 1260

aagagacgtg gccgggaccc tgagatgggg ggaaagccga gaaggaagaa ccctcaggaa 1320

ggcctgtaca atgaactgca gaaagataag atggcggagg cctacagtga gattgggatg 1380

aaaggcgagc gccggagggg caaggggcac gatggccttt accagggtct cagtacagcc 1440

accaaggaca cctacgacgc ccttcacatg caggccctgc cccctcgc 1488

<210> 155

<211> 5

<212> PRT

<213> artificial sequence

<220>

<223> connector

<220>

<221> REPEAT

<222> (1)..(5)

<223> (GGGGS)n, n=1,2, 3, 4, or 5

<400> 155

Gly Gly Gly Gly Ser

1 5

<210> 156

<211> 5

<212> PRT

<213> artificial sequence

<220>

<223> connector

<220>

<221> REPEAT

<222> (1)..(5)

<223> (EAAAK)n, n=1,2, 3, 4, or 5

<400> 156

Glu Ala Ala Ala Lys

1 5

<210> 157

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> connector

<220>

<221> REPEAT

<222> (1)..(2)

<223> (PA)nP, n=1, 2, 3, 4,or 5

<400> 157

Pro Ala Pro

1

<210> 158

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> connector

<400> 158

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

1 5 10 15

<210> 159

<211> 164

<212> PRT

<213> artificial sequence

<220>

<223> human CD3 zeta

<400> 159

Met Lys Trp Lys Ala Leu Phe Thr Ala Ala Ile Leu Gln Ala Gln Leu

1 5 10 15

Pro Ile Thr Glu Ala Gln Ser Phe Gly Leu Leu Asp Pro Lys Leu Cys

20 25 30

Tyr Leu Leu Asp Gly Ile Leu Phe Ile Tyr Gly Val Ile Leu Thr Ala

35 40 45

Leu Phe Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr

50 55 60

Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg

65 70 75 80

Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met

85 90 95

Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn

100 105 110

Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met

115 120 125

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

130 135 140

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

145 150 155 160

Leu Pro Pro Arg

<210> 160

<211> 86

<212> PRT

<213> artificial sequence

<220>

<223> human FcR gamma

<400> 160

Met Ile Pro Ala Val Val Leu Leu Leu Leu Leu Leu Val Glu Gln Ala

1 5 10 15

Ala Ala Leu Gly Glu Pro Gln Leu Cys Tyr Ile Leu Asp Ala Ile Leu

20 25 30

Phe Leu Tyr Gly Ile Val Leu Thr Leu Leu Tyr Cys Arg Leu Lys Ile

35 40 45

Gln Val Arg Lys Ala Ala Ile Thr Ser Tyr Glu Lys Ser Asp Gly Val

50 55 60

Tyr Thr Gly Leu Ser Thr Arg Asn Gln Glu Thr Tyr Glu Thr Leu Lys

65 70 75 80

His Glu Lys Pro Pro Gln

85

<210> 161

<211> 317

<212> PRT

<213> artificial sequence

<220>

<223> human FcgammaRIIa

<400> 161

Met Thr Met Glu Thr Gln Met Ser Gln Asn Val Cys Pro Arg Asn Leu

1 5 10 15

Trp Leu Leu Gln Pro Leu Thr Val Leu Leu Leu Leu Ala Ser Ala Asp

20 25 30

Ser Gln Ala Ala Ala Pro Pro Lys Ala Val Leu Lys Leu Glu Pro Pro

35 40 45

Trp Ile Asn Val Leu Gln Glu Asp Ser Val Thr Leu Thr Cys Gln Gly

50 55 60

Ala Arg Ser Pro Glu Ser Asp Ser Ile Gln Trp Phe His Asn Gly Asn

65 70 75 80

Leu Ile Pro Thr His Thr Gln Pro Ser Tyr Arg Phe Lys Ala Asn Asn

85 90 95

Asn Asp Ser Gly Glu Tyr Thr Cys Gln Thr Gly Gln Thr Ser Leu Ser

100 105 110

Asp Pro Val His Leu Thr Val Leu Ser Glu Trp Leu Val Leu Gln Thr

115 120 125

Pro His Leu Glu Phe Gln Glu Gly Glu Thr Ile Met Leu Arg Cys His

130 135 140

Ser Trp Lys Asp Lys Pro Leu Val Lys Val Thr Phe Phe Gln Asn Gly

145 150 155 160

Lys Ser Gln Lys Phe Ser His Leu Asp Pro Thr Phe Ser Ile Pro Gln

165 170 175

Ala Asn His Ser His Ser Gly Asp Tyr His Cys Thr Gly Asn Ile Gly

180 185 190

Tyr Thr Leu Phe Ser Ser Lys Pro Val Thr Ile Thr Val Gln Val Pro

195 200 205

Ser Met Gly Ser Ser Ser Pro Met Gly Ile Ile Val Ala Val Val Ile

210 215 220

Ala Thr Ala Val Ala Ala Ile Val Ala Ala Val Val Ala Leu Ile Tyr

225 230 235 240

Cys Arg Lys Lys Arg Ile Ser Ala Asn Ser Thr Asp Pro Val Lys Ala

245 250 255

Ala Gln Phe Glu Pro Pro Gly Arg Gln Met Ile Ala Ile Arg Lys Arg

260 265 270

Gln Leu Glu Glu Thr Asn Asn Asp Tyr Glu Thr Ala Asp Gly Gly Tyr

275 280 285

Met Thr Leu Asn Pro Arg Ala Pro Thr Asp Asp Asp Lys Asn Ile Tyr

290 295 300

Leu Thr Leu Pro Pro Asn Asp His Val Asn Ser Asn Asn

305 310 315

<210> 162

<211> 244

<212> PRT

<213> artificial sequence

<220>

<223> human FcR beta

<400> 162

Met Asp Thr Glu Ser Asn Arg Arg Ala Asn Leu Ala Leu Pro Gln Glu

1 5 10 15

Pro Ser Ser Val Pro Ala Phe Glu Val Leu Glu Ile Ser Pro Gln Glu

20 25 30

Val Ser Ser Gly Arg Leu Leu Lys Ser Ala Ser Ser Pro Pro Leu His

35 40 45

Thr Trp Leu Thr Val Leu Lys Lys Glu Gln Glu Phe Leu Gly Val Thr

50 55 60

Gln Ile Leu Thr Ala Met Ile Cys Leu Cys Phe Gly Thr Val Val Cys

65 70 75 80

Ser Val Leu Asp Ile Ser His Ile Glu Gly Asp Ile Phe Ser Ser Phe

85 90 95

Lys Ala Gly Tyr Pro Phe Trp Gly Ala Ile Phe Phe Ser Ile Ser Gly

100 105 110

Met Leu Ser Ile Ile Ser Glu Arg Arg Asn Ala Thr Tyr Leu Val Arg

115 120 125

Gly Ser Leu Gly Ala Asn Thr Ala Ser Ser Ile Ala Gly Gly Thr Gly

130 135 140

Ile Thr Ile Leu Ile Ile Asn Leu Lys Lys Ser Leu Ala Tyr Ile His

145 150 155 160

Ile His Ser Cys Gln Lys Phe Phe Glu Thr Lys Cys Phe Met Ala Ser

165 170 175

Phe Ser Thr Glu Ile Val Val Met Met Leu Phe Leu Thr Ile Leu Gly

180 185 190

Leu Gly Ser Ala Val Ser Leu Thr Ile Cys Gly Ala Gly Glu Glu Leu

195 200 205

Lys Gly Asn Lys Val Pro Glu Asp Arg Val Tyr Glu Glu Leu Asn Ile

210 215 220

Tyr Ser Ala Thr Tyr Ser Glu Leu Glu Asp Pro Gly Glu Met Ser Pro

225 230 235 240

Pro Ile Asp Leu

<210> 163

<211> 182

<212> PRT

<213> artificial sequence

<220>

<223> human CD3 gamma

<400> 163

Met Glu Gln Gly Lys Gly Leu Ala Val Leu Ile Leu Ala Ile Ile Leu

1 5 10 15

Leu Gln Gly Thr Leu Ala Gln Ser Ile Lys Gly Asn His Leu Val Lys

20 25 30

Val Tyr Asp Tyr Gln Glu Asp Gly Ser Val Leu Leu Thr Cys Asp Ala

35 40 45

Glu Ala Lys Asn Ile Thr Trp Phe Lys Asp Gly Lys Met Ile Gly Phe

50 55 60

Leu Thr Glu Asp Lys Lys Lys Trp Asn Leu Gly Ser Asn Ala Lys Asp

65 70 75 80

Pro Arg Gly Met Tyr Gln Cys Lys Gly Ser Gln Asn Lys Ser Lys Pro

85 90 95

Leu Gln Val Tyr Tyr Arg Met Cys Gln Asn Cys Ile Glu Leu Asn Ala

100 105 110

Ala Thr Ile Ser Gly Phe Leu Phe Ala Glu Ile Val Ser Ile Phe Val

115 120 125

Leu Ala Val Gly Val Tyr Phe Ile Ala Gly Gln Asp Gly Val Arg Gln

130 135 140

Ser Arg Ala Ser Asp Lys Gln Thr Leu Leu Pro Asn Asp Gln Leu Tyr

145 150 155 160

Gln Pro Leu Lys Asp Arg Glu Asp Asp Gln Tyr Ser His Leu Gln Gly

165 170 175

Asn Gln Leu Arg Arg Asn

180

<210> 164

<211> 171

<212> PRT

<213> artificial sequence

<220>

<223> human CD3 delta

<400> 164

Met Glu His Ser Thr Phe Leu Ser Gly Leu Val Leu Ala Thr Leu Leu

1 5 10 15

Ser Gln Val Ser Pro Phe Lys Ile Pro Ile Glu Glu Leu Glu Asp Arg

20 25 30

Val Phe Val Asn Cys Asn Thr Ser Ile Thr Trp Val Glu Gly Thr Val

35 40 45

Gly Thr Leu Leu Ser Asp Ile Thr Arg Leu Asp Leu Gly Lys Arg Ile

50 55 60

Leu Asp Pro Arg Gly Ile Tyr Arg Cys Asn Gly Thr Asp Ile Tyr Lys

65 70 75 80

Asp Lys Glu Ser Thr Val Gln Val His Tyr Arg Met Cys Gln Ser Cys

85 90 95

Val Glu Leu Asp Pro Ala Thr Val Ala Gly Ile Ile Val Thr Asp Val

100 105 110

Ile Ala Thr Leu Leu Leu Ala Leu Gly Val Phe Cys Phe Ala Gly His

115 120 125

Glu Thr Gly Arg Leu Ser Gly Ala Ala Asp Thr Gln Ala Leu Leu Arg

130 135 140

Asn Asp Gln Val Tyr Gln Pro Leu Arg Asp Arg Asp Asp Ala Gln Tyr

145 150 155 160

Ser His Leu Gly Gly Asn Trp Ala Arg Asn Lys

165 170

<210> 165

<211> 207

<212> PRT

<213> artificial sequence

<220>

<223> human CD3 epsilon

<400> 165

Met Gln Ser Gly Thr His Trp Arg Val Leu Gly Leu Cys Leu Leu Ser

1 5 10 15

Val Gly Val Trp Gly Gln Asp Gly Asn Glu Glu Met Gly Gly Ile Thr

20 25 30

Gln Thr Pro Tyr Lys Val Ser Ile Ser Gly Thr Thr Val Ile Leu Thr

35 40 45

Cys Pro Gln Tyr Pro Gly Ser Glu Ile Leu Trp Gln His Asn Asp Lys

50 55 60

Asn Ile Gly Gly Asp Glu Asp Asp Lys Asn Ile Gly Ser Asp Glu Asp

65 70 75 80

His Leu Ser Leu Lys Glu Phe Ser Glu Leu Glu Gln Ser Gly Tyr Tyr

85 90 95

Val Cys Tyr Pro Arg Gly Ser Lys Pro Glu Asp Ala Asn Phe Tyr Leu

100 105 110

Tyr Leu Arg Ala Arg Val Cys Glu Asn Cys Met Glu Met Asp Val Met

115 120 125

Ser Val Ala Thr Ile Val Ile Val Asp Ile Cys Ile Thr Gly Gly Leu

130 135 140

Leu Leu Leu Val Tyr Tyr Trp Ser Lys Asn Arg Lys Ala Lys Ala Lys

145 150 155 160

Pro Val Thr Arg Gly Ala Gly Ala Gly Gly Arg Gln Arg Gly Gln Asn

165 170 175

Lys Glu Arg Pro Pro Pro Val Pro Asn Pro Asp Tyr Glu Pro Ile Arg

180 185 190

Lys Gly Gln Arg Asp Leu Tyr Ser Gly Leu Asn Gln Arg Arg Ile

195 200 205

<210> 166

<211> 226

<212> PRT

<213> artificial sequence

<220>

<223> human CD79a

<400> 166

Met Pro Gly Gly Pro Gly Val Leu Gln Ala Leu Pro Ala Thr Ile Phe

1 5 10 15

Leu Leu Phe Leu Leu Ser Ala Val Tyr Leu Gly Pro Gly Cys Gln Ala

20 25 30

Leu Trp Met His Lys Val Pro Ala Ser Leu Met Val Ser Leu Gly Glu

35 40 45

Asp Ala His Phe Gln Cys Pro His Asn Ser Ser Asn Asn Ala Asn Val

50 55 60

Thr Trp Trp Arg Val Leu His Gly Asn Tyr Thr Trp Pro Pro Glu Phe

65 70 75 80

Leu Gly Pro Gly Glu Asp Pro Asn Gly Thr Leu Ile Ile Gln Asn Val

85 90 95

Asn Lys Ser His Gly Gly Ile Tyr Val Cys Arg Val Gln Glu Gly Asn

100 105 110

Glu Ser Tyr Gln Gln Ser Cys Gly Thr Tyr Leu Arg Val Arg Gln Pro

115 120 125

Pro Pro Arg Pro Phe Leu Asp Met Gly Glu Gly Thr Lys Asn Arg Ile

130 135 140

Ile Thr Ala Glu Gly Ile Ile Leu Leu Phe Cys Ala Val Val Pro Gly

145 150 155 160

Thr Leu Leu Leu Phe Arg Lys Arg Trp Gln Asn Glu Lys Leu Gly Leu

165 170 175

Asp Ala Gly Asp Glu Tyr Glu Asp Glu Asn Leu Tyr Glu Gly Leu Asn

180 185 190

Leu Asp Asp Cys Ser Met Tyr Glu Asp Ile Ser Arg Gly Leu Gln Gly

195 200 205

Thr Tyr Gln Asp Val Gly Ser Leu Asn Ile Gly Asp Val Gln Leu Glu

210 215 220

Lys Pro

225

<210> 167

<211> 229

<212> PRT

<213> artificial sequence

<220>

<223> human CD79b

<400> 167

Met Ala Arg Leu Ala Leu Ser Pro Val Pro Ser His Trp Met Val Ala

1 5 10 15

Leu Leu Leu Leu Leu Ser Ala Glu Pro Val Pro Ala Ala Arg Ser Glu

20 25 30

Asp Arg Tyr Arg Asn Pro Lys Gly Ser Ala Cys Ser Arg Ile Trp Gln

35 40 45

Ser Pro Arg Phe Ile Ala Arg Lys Arg Gly Phe Thr Val Lys Met His

50 55 60

Cys Tyr Met Asn Ser Ala Ser Gly Asn Val Ser Trp Leu Trp Lys Gln

65 70 75 80

Glu Met Asp Glu Asn Pro Gln Gln Leu Lys Leu Glu Lys Gly Arg Met

85 90 95

Glu Glu Ser Gln Asn Glu Ser Leu Ala Thr Leu Thr Ile Gln Gly Ile

100 105 110

Arg Phe Glu Asp Asn Gly Ile Tyr Phe Cys Gln Gln Lys Cys Asn Asn

115 120 125

Thr Ser Glu Val Tyr Gln Gly Cys Gly Thr Glu Leu Arg Val Met Gly

130 135 140

Phe Ser Thr Leu Ala Gln Leu Lys Gln Arg Asn Thr Leu Lys Asp Gly

145 150 155 160

Ile Ile Met Ile Gln Thr Leu Leu Ile Ile Leu Phe Ile Ile Val Pro

165 170 175

Ile Phe Leu Leu Leu Asp Lys Asp Asp Ser Lys Ala Gly Met Glu Glu

180 185 190

Asp His Thr Tyr Glu Gly Leu Asp Ile Asp Gln Thr Ala Thr Tyr Glu

195 200 205

Asp Ile Val Thr Leu Arg Thr Gly Glu Val Lys Trp Ser Val Gly Glu

210 215 220

His Pro Gly Gln Glu

225

<210> 168

<211> 93

<212> PRT

<213> artificial sequence

<220>

<223> human DAP10

<400> 168

Met Ile His Leu Gly His Ile Leu Phe Leu Leu Leu Leu Pro Val Ala

1 5 10 15

Ala Ala Gln Thr Thr Pro Gly Glu Arg Ser Ser Leu Pro Ala Phe Tyr

20 25 30

Pro Gly Thr Ser Gly Ser Cys Ser Gly Cys Gly Ser Leu Ser Leu Pro

35 40 45

Leu Leu Ala Gly Leu Val Ala Ala Asp Ala Val Ala Ser Leu Leu Ile

50 55 60

Val Gly Ala Val Phe Leu Cys Ala Arg Pro Arg Arg Ser Pro Ala Gln

65 70 75 80

Glu Asp Gly Lys Val Tyr Ile Asn Met Pro Gly Arg Gly

85 90

<210> 169

<211> 113

<212> PRT

<213> artificial sequence

<220>

<223> human DAP12

<400> 169

Met Gly Gly Leu Glu Pro Cys Ser Arg Leu Leu Leu Leu Pro Leu Leu

1 5 10 15

Leu Ala Val Ser Gly Leu Arg Pro Val Gln Ala Gln Ala Gln Ser Asp

20 25 30

Cys Ser Cys Ser Thr Val Ser Pro Gly Val Leu Ala Gly Ile Val Met

35 40 45

Gly Asp Leu Val Leu Thr Val Leu Ile Ala Leu Ala Val Tyr Phe Leu

50 55 60

Gly Arg Leu Val Pro Arg Gly Arg Gly Ala Ala Glu Ala Ala Thr Arg

65 70 75 80

Lys Gln Arg Ile Thr Glu Thr Glu Ser Pro Tyr Gln Glu Leu Gln Gly

85 90 95

Gln Arg Ser Asp Val Tyr Ser Asp Leu Asn Thr Gln Arg Pro Tyr Tyr

100 105 110

Lys

<210> 170

<211> 220

<212> PRT

<213> artificial sequence

<220>

<223> human CD28

<400> 170

Met Leu Arg Leu Leu Leu Ala Leu Asn Leu Phe Pro Ser Ile Gln Val

1 5 10 15

Thr Gly Asn Lys Ile Leu Val Lys Gln Ser Pro Met Leu Val Ala Tyr

20 25 30

Asp Asn Ala Val Asn Leu Ser Cys Lys Tyr Ser Tyr Asn Leu Phe Ser

35 40 45

Arg Glu Phe Arg Ala Ser Leu His Lys Gly Leu Asp Ser Ala Val Glu

50 55 60

Val Cys Val Val Tyr Gly Asn Tyr Ser Gln Gln Leu Gln Val Tyr Ser

65 70 75 80

Lys Thr Gly Phe Asn Cys Asp Gly Lys Leu Gly Asn Glu Ser Val Thr

85 90 95

Phe Tyr Leu Gln Asn Leu Tyr Val Asn Gln Thr Asp Ile Tyr Phe Cys

100 105 110

Lys Ile Glu Val Met Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Lys Ser

115 120 125

Asn Gly Thr Ile Ile His Val Lys Gly Lys His Leu Cys Pro Ser Pro

130 135 140

Leu Phe Pro Gly Pro Ser Lys Pro Phe Trp Val Leu Val Val Val Gly

145 150 155 160

Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile

165 170 175

Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met

180 185 190

Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro

195 200 205

Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser

210 215 220

<210> 171

<211> 255

<212> PRT

<213> artificial sequence

<220>

<223> person 4-1BB

<400> 171

Met Gly Asn Ser Cys Tyr Asn Ile Val Ala Thr Leu Leu Leu Val Leu

1 5 10 15

Asn Phe Glu Arg Thr Arg Ser Leu Gln Asp Pro Cys Ser Asn Cys Pro

20 25 30

Ala Gly Thr Phe Cys Asp Asn Asn Arg Asn Gln Ile Cys Ser Pro Cys

35 40 45

Pro Pro Asn Ser Phe Ser Ser Ala Gly Gly Gln Arg Thr Cys Asp Ile

50 55 60

Cys Arg Gln Cys Lys Gly Val Phe Arg Thr Arg Lys Glu Cys Ser Ser

65 70 75 80

Thr Ser Asn Ala Glu Cys Asp Cys Thr Pro Gly Phe His Cys Leu Gly

85 90 95

Ala Gly Cys Ser Met Cys Glu Gln Asp Cys Lys Gln Gly Gln Glu Leu

100 105 110

Thr Lys Lys Gly Cys Lys Asp Cys Cys Phe Gly Thr Phe Asn Asp Gln

115 120 125

Lys Arg Gly Ile Cys Arg Pro Trp Thr Asn Cys Ser Leu Asp Gly Lys

130 135 140

Ser Val Leu Val Asn Gly Thr Lys Glu Arg Asp Val Val Cys Gly Pro

145 150 155 160

Ser Pro Ala Asp Leu Ser Pro Gly Ala Ser Ser Val Thr Pro Pro Ala

165 170 175

Pro Ala Arg Glu Pro Gly His Ser Pro Gln Ile Ile Ser Phe Phe Leu

180 185 190

Ala Leu Thr Ser Thr Ala Leu Leu Phe Leu Leu Phe Phe Leu Thr Leu

195 200 205

Arg Phe Ser Val Val Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe

210 215 220

Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly

225 230 235 240

Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu

245 250 255

<210> 172

<211> 277

<212> PRT

<213> artificial sequence

<220>

<223> human OX40

<400> 172

Met Cys Val Gly Ala Arg Arg Leu Gly Arg Gly Pro Cys Ala Ala Leu

1 5 10 15

Leu Leu Leu Gly Leu Gly Leu Ser Thr Val Thr Gly Leu His Cys Val

20 25 30

Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys Cys His Glu Cys Arg Pro

35 40 45

Gly Asn Gly Met Val Ser Arg Cys Ser Arg Ser Gln Asn Thr Val Cys

50 55 60

Arg Pro Cys Gly Pro Gly Phe Tyr Asn Asp Val Val Ser Ser Lys Pro

65 70 75 80

Cys Lys Pro Cys Thr Trp Cys Asn Leu Arg Ser Gly Ser Glu Arg Lys

85 90 95

Gln Leu Cys Thr Ala Thr Gln Asp Thr Val Cys Arg Cys Arg Ala Gly

100 105 110

Thr Gln Pro Leu Asp Ser Tyr Lys Pro Gly Val Asp Cys Ala Pro Cys

115 120 125

Pro Pro Gly His Phe Ser Pro Gly Asp Asn Gln Ala Cys Lys Pro Trp

130 135 140

Thr Asn Cys Thr Leu Ala Gly Lys His Thr Leu Gln Pro Ala Ser Asn

145 150 155 160

Ser Ser Asp Ala Ile Cys Glu Asp Arg Asp Pro Pro Ala Thr Gln Pro

165 170 175

Gln Glu Thr Gln Gly Pro Pro Ala Arg Pro Ile Thr Val Gln Pro Thr

180 185 190

Glu Ala Trp Pro Arg Thr Ser Gln Gly Pro Ser Thr Arg Pro Val Glu

195 200 205

Val Pro Gly Gly Arg Ala Val Ala Ala Ile Leu Gly Leu Gly Leu Val

210 215 220

Leu Gly Leu Leu Gly Pro Leu Ala Ile Leu Leu Ala Leu Tyr Leu Leu

225 230 235 240

Arg Arg Asp Gln Arg Leu Pro Pro Asp Ala His Lys Pro Pro Gly Gly

245 250 255

Gly Ser Phe Arg Thr Pro Ile Gln Glu Glu Gln Ala Asp Ala His Ser

260 265 270

Thr Leu Ala Lys Ile

275

<210> 173

<211> 199

<212> PRT

<213> artificial sequence

<220>

<223> human ICOS

<400> 173

Met Lys Ser Gly Leu Trp Tyr Phe Phe Leu Phe Cys Leu Arg Ile Lys

1 5 10 15

Val Leu Thr Gly Glu Ile Asn Gly Ser Ala Asn Tyr Glu Met Phe Ile

20 25 30

Phe His Asn Gly Gly Val Gln Ile Leu Cys Lys Tyr Pro Asp Ile Val

35 40 45

Gln Gln Phe Lys Met Gln Leu Leu Lys Gly Gly Gln Ile Leu Cys Asp

50 55 60

Leu Thr Lys Thr Lys Gly Ser Gly Asn Thr Val Ser Ile Lys Ser Leu

65 70 75 80

Lys Phe Cys His Ser Gln Leu Ser Asn Asn Ser Val Ser Phe Phe Leu

85 90 95

Tyr Asn Leu Asp His Ser His Ala Asn Tyr Tyr Phe Cys Asn Leu Ser

100 105 110

Ile Phe Asp Pro Pro Pro Phe Lys Val Thr Leu Thr Gly Gly Tyr Leu

115 120 125

His Ile Tyr Glu Ser Gln Leu Cys Cys Gln Leu Lys Phe Trp Leu Pro

130 135 140

Ile Gly Cys Ala Ala Phe Val Val Val Cys Ile Leu Gly Cys Ile Leu

145 150 155 160

Ile Cys Trp Leu Thr Lys Lys Lys Tyr Ser Ser Ser Val His Asp Pro

165 170 175

Asn Gly Glu Tyr Met Phe Met Arg Ala Val Asn Thr Ala Lys Lys Ser

180 185 190

Arg Leu Thr Asp Val Thr Leu

195

<210> 174

<211> 370

<212> PRT

<213> artificial sequence

<220>

<223> person 2B4

<400> 174

Met Leu Gly Gln Val Val Thr Leu Ile Leu Leu Leu Leu Leu Lys Val

1 5 10 15

Tyr Gln Gly Lys Gly Cys Gln Gly Ser Ala Asp His Val Val Ser Ile

20 25 30

Ser Gly Val Pro Leu Gln Leu Gln Pro Asn Ser Ile Gln Thr Lys Val

35 40 45

Asp Ser Ile Ala Trp Lys Lys Leu Leu Pro Ser Gln Asn Gly Phe His

50 55 60

His Ile Leu Lys Trp Glu Asn Gly Ser Leu Pro Ser Asn Thr Ser Asn

65 70 75 80

Asp Arg Phe Ser Phe Ile Val Lys Asn Leu Ser Leu Leu Ile Lys Ala

85 90 95

Ala Gln Gln Gln Asp Ser Gly Leu Tyr Cys Leu Glu Val Thr Ser Ile

100 105 110

Ser Gly Lys Val Gln Thr Ala Thr Phe Gln Val Phe Val Phe Glu Ser

115 120 125

Leu Leu Pro Asp Lys Val Glu Lys Pro Arg Leu Gln Gly Gln Gly Lys

130 135 140

Ile Leu Asp Arg Gly Arg Cys Gln Val Ala Leu Ser Cys Leu Val Ser

145 150 155 160

Arg Asp Gly Asn Val Ser Tyr Ala Trp Tyr Arg Gly Ser Lys Leu Ile

165 170 175

Gln Thr Ala Gly Asn Leu Thr Tyr Leu Asp Glu Glu Val Asp Ile Asn

180 185 190

Gly Thr His Thr Tyr Thr Cys Asn Val Ser Asn Pro Val Ser Trp Glu

195 200 205

Ser His Thr Leu Asn Leu Thr Gln Asp Cys Gln Asn Ala His Gln Glu

210 215 220

Phe Arg Phe Trp Pro Phe Leu Val Ile Ile Val Ile Leu Ser Ala Leu

225 230 235 240

Phe Leu Gly Thr Leu Ala Cys Phe Cys Val Trp Arg Arg Lys Arg Lys

245 250 255

Glu Lys Gln Ser Glu Thr Ser Pro Lys Glu Phe Leu Thr Ile Tyr Glu

260 265 270

Asp Val Lys Asp Leu Lys Thr Arg Arg Asn His Glu Gln Glu Gln Thr

275 280 285

Phe Pro Gly Gly Gly Ser Thr Ile Tyr Ser Met Ile Gln Ser Gln Ser

290 295 300

Ser Ala Pro Thr Ser Gln Glu Pro Ala Tyr Thr Leu Tyr Ser Leu Ile

305 310 315 320

Gln Pro Ser Arg Lys Ser Gly Ser Arg Lys Arg Asn His Ser Pro Ser

325 330 335

Phe Asn Ser Thr Ile Tyr Glu Val Ile Gly Lys Ser Gln Pro Lys Ala

340 345 350

Gln Asn Pro Ala Arg Leu Ser Arg Lys Glu Leu Glu Asn Phe Asp Val

355 360 365

Tyr Ser

370

<210> 175

<211> 260

<212> PRT

<213> artificial sequence

<220>

<223> human CD27

<400> 175

Met Ala Arg Pro His Pro Trp Trp Leu Cys Val Leu Gly Thr Leu Val

1 5 10 15

Gly Leu Ser Ala Thr Pro Ala Pro Lys Ser Cys Pro Glu Arg His Tyr

20 25 30

Trp Ala Gln Gly Lys Leu Cys Cys Gln Met Cys Glu Pro Gly Thr Phe

35 40 45

Leu Val Lys Asp Cys Asp Gln His Arg Lys Ala Ala Gln Cys Asp Pro

50 55 60

Cys Ile Pro Gly Val Ser Phe Ser Pro Asp His His Thr Arg Pro His

65 70 75 80

Cys Glu Ser Cys Arg His Cys Asn Ser Gly Leu Leu Val Arg Asn Cys

85 90 95

Thr Ile Thr Ala Asn Ala Glu Cys Ala Cys Arg Asn Gly Trp Gln Cys

100 105 110

Arg Asp Lys Glu Cys Thr Glu Cys Asp Pro Leu Pro Asn Pro Ser Leu

115 120 125

Thr Ala Arg Ser Ser Gln Ala Leu Ser Pro His Pro Gln Pro Thr His

130 135 140

Leu Pro Tyr Val Ser Glu Met Leu Glu Ala Arg Thr Ala Gly His Met

145 150 155 160

Gln Thr Leu Ala Asp Phe Arg Gln Leu Pro Ala Arg Thr Leu Ser Thr

165 170 175

His Trp Pro Pro Gln Arg Ser Leu Cys Ser Ser Asp Phe Ile Arg Ile

180 185 190

Leu Val Ile Phe Ser Gly Met Phe Leu Val Phe Thr Leu Ala Gly Ala

195 200 205

Leu Phe Leu His Gln Arg Arg Lys Tyr Arg Ser Asn Lys Gly Glu Ser

210 215 220

Pro Val Glu Pro Ala Glu Pro Cys His Tyr Ser Cys Pro Arg Glu Glu

225 230 235 240

Glu Gly Ser Thr Ile Pro Ile Gln Glu Asp Tyr Arg Lys Pro Glu Pro

245 250 255

Ala Cys Ser Pro

260

<210> 176

<211> 595

<212> PRT

<213> artificial sequence

<220>

<223> human CD30

<400> 176

Met Arg Val Leu Leu Ala Ala Leu Gly Leu Leu Phe Leu Gly Ala Leu

1 5 10 15

Arg Ala Phe Pro Gln Asp Arg Pro Phe Glu Asp Thr Cys His Gly Asn

20 25 30

Pro Ser His Tyr Tyr Asp Lys Ala Val Arg Arg Cys Cys Tyr Arg Cys

35 40 45

Pro Met Gly Leu Phe Pro Thr Gln Gln Cys Pro Gln Arg Pro Thr Asp

50 55 60

Cys Arg Lys Gln Cys Glu Pro Asp Tyr Tyr Leu Asp Glu Ala Asp Arg

65 70 75 80

Cys Thr Ala Cys Val Thr Cys Ser Arg Asp Asp Leu Val Glu Lys Thr

85 90 95

Pro Cys Ala Trp Asn Ser Ser Arg Val Cys Glu Cys Arg Pro Gly Met

100 105 110

Phe Cys Ser Thr Ser Ala Val Asn Ser Cys Ala Arg Cys Phe Phe His

115 120 125

Ser Val Cys Pro Ala Gly Met Ile Val Lys Phe Pro Gly Thr Ala Gln

130 135 140

Lys Asn Thr Val Cys Glu Pro Ala Ser Pro Gly Val Ser Pro Ala Cys

145 150 155 160

Ala Ser Pro Glu Asn Cys Lys Glu Pro Ser Ser Gly Thr Ile Pro Gln

165 170 175

Ala Lys Pro Thr Pro Val Ser Pro Ala Thr Ser Ser Ala Ser Thr Met

180 185 190

Pro Val Arg Gly Gly Thr Arg Leu Ala Gln Glu Ala Ala Ser Lys Leu

195 200 205

Thr Arg Ala Pro Asp Ser Pro Ser Ser Val Gly Arg Pro Ser Ser Asp

210 215 220

Pro Gly Leu Ser Pro Thr Gln Pro Cys Pro Glu Gly Ser Gly Asp Cys

225 230 235 240

Arg Lys Gln Cys Glu Pro Asp Tyr Tyr Leu Asp Glu Ala Gly Arg Cys

245 250 255

Thr Ala Cys Val Ser Cys Ser Arg Asp Asp Leu Val Glu Lys Thr Pro

260 265 270

Cys Ala Trp Asn Ser Ser Arg Thr Cys Glu Cys Arg Pro Gly Met Ile

275 280 285

Cys Ala Thr Ser Ala Thr Asn Ser Cys Ala Arg Cys Val Pro Tyr Pro

290 295 300

Ile Cys Ala Ala Glu Thr Val Thr Lys Pro Gln Asp Met Ala Glu Lys

305 310 315 320

Asp Thr Thr Phe Glu Ala Pro Pro Leu Gly Thr Gln Pro Asp Cys Asn

325 330 335

Pro Thr Pro Glu Asn Gly Glu Ala Pro Ala Ser Thr Ser Pro Thr Gln

340 345 350

Ser Leu Leu Val Asp Ser Gln Ala Ser Lys Thr Leu Pro Ile Pro Thr

355 360 365

Ser Ala Pro Val Ala Leu Ser Ser Thr Gly Lys Pro Val Leu Asp Ala

370 375 380

Gly Pro Val Leu Phe Trp Val Ile Leu Val Leu Val Val Val Val Gly

385 390 395 400

Ser Ser Ala Phe Leu Leu Cys His Arg Arg Ala Cys Arg Lys Arg Ile

405 410 415

Arg Gln Lys Leu His Leu Cys Tyr Pro Val Gln Thr Ser Gln Pro Lys

420 425 430

Leu Glu Leu Val Asp Ser Arg Pro Arg Arg Ser Ser Thr Gln Leu Arg

435 440 445

Ser Gly Ala Ser Val Thr Glu Pro Val Ala Glu Glu Arg Gly Leu Met

450 455 460

Ser Gln Pro Leu Met Glu Thr Cys His Ser Val Gly Ala Ala Tyr Leu

465 470 475 480

Glu Ser Leu Pro Leu Gln Asp Ala Ser Pro Ala Gly Gly Pro Ser Ser

485 490 495

Pro Arg Asp Leu Pro Glu Pro Arg Val Ser Thr Glu His Thr Asn Asn

500 505 510

Lys Ile Glu Lys Ile Tyr Ile Met Lys Ala Asp Thr Val Ile Val Gly

515 520 525

Thr Val Lys Ala Glu Leu Pro Glu Gly Arg Gly Leu Ala Gly Pro Ala

530 535 540

Glu Pro Glu Leu Glu Glu Glu Leu Glu Ala Asp His Thr Pro His Tyr

545 550 555 560

Pro Glu Gln Glu Thr Glu Pro Pro Leu Gly Ser Cys Ser Asp Val Met

565 570 575

Leu Ser Val Glu Glu Glu Gly Lys Glu Asp Pro Leu Pro Thr Ala Ala

580 585 590

Ser Gly Lys

595

<210> 177

<211> 277

<212> PRT

<213> artificial sequence

<220>

<223> human CD40

<400> 177

Met Val Arg Leu Pro Leu Gln Cys Val Leu Trp Gly Cys Leu Leu Thr

1 5 10 15

Ala Val His Pro Glu Pro Pro Thr Ala Cys Arg Glu Lys Gln Tyr Leu

20 25 30

Ile Asn Ser Gln Cys Cys Ser Leu Cys Gln Pro Gly Gln Lys Leu Val

35 40 45

Ser Asp Cys Thr Glu Phe Thr Glu Thr Glu Cys Leu Pro Cys Gly Glu

50 55 60

Ser Glu Phe Leu Asp Thr Trp Asn Arg Glu Thr His Cys His Gln His

65 70 75 80

Lys Tyr Cys Asp Pro Asn Leu Gly Leu Arg Val Gln Gln Lys Gly Thr

85 90 95

Ser Glu Thr Asp Thr Ile Cys Thr Cys Glu Glu Gly Trp His Cys Thr

100 105 110

Ser Glu Ala Cys Glu Ser Cys Val Leu His Arg Ser Cys Ser Pro Gly

115 120 125

Phe Gly Val Lys Gln Ile Ala Thr Gly Val Ser Asp Thr Ile Cys Glu

130 135 140

Pro Cys Pro Val Gly Phe Phe Ser Asn Val Ser Ser Ala Phe Glu Lys

145 150 155 160

Cys His Pro Trp Thr Ser Cys Glu Thr Lys Asp Leu Val Val Gln Gln

165 170 175

Ala Gly Thr Asn Lys Thr Asp Val Val Cys Gly Pro Gln Asp Arg Leu

180 185 190

Arg Ala Leu Val Val Ile Pro Ile Ile Phe Gly Ile Leu Phe Ala Ile

195 200 205

Leu Leu Val Leu Val Phe Ile Lys Lys Val Ala Lys Lys Pro Thr Asn

210 215 220

Lys Ala Pro His Pro Lys Gln Glu Pro Gln Glu Ile Asn Phe Pro Asp

225 230 235 240

Asp Leu Pro Gly Ser Asn Thr Ala Ala Pro Val Gln Glu Thr Leu His

245 250 255

Gly Cys Gln Pro Val Thr Gln Glu Asp Gly Lys Glu Ser Arg Ile Ser

260 265 270

Val Gln Glu Arg Gln

275

<210> 178

<211> 351

<212> PRT

<213> artificial sequence

<220>

<223> human CD2

<400> 178

Met Ser Phe Pro Cys Lys Phe Val Ala Ser Phe Leu Leu Ile Phe Asn

1 5 10 15

Val Ser Ser Lys Gly Ala Val Ser Lys Glu Ile Thr Asn Ala Leu Glu

20 25 30

Thr Trp Gly Ala Leu Gly Gln Asp Ile Asn Leu Asp Ile Pro Ser Phe

35 40 45

Gln Met Ser Asp Asp Ile Asp Asp Ile Lys Trp Glu Lys Thr Ser Asp

50 55 60

Lys Lys Lys Ile Ala Gln Phe Arg Lys Glu Lys Glu Thr Phe Lys Glu

65 70 75 80

Lys Asp Thr Tyr Lys Leu Phe Lys Asn Gly Thr Leu Lys Ile Lys His

85 90 95

Leu Lys Thr Asp Asp Gln Asp Ile Tyr Lys Val Ser Ile Tyr Asp Thr

100 105 110

Lys Gly Lys Asn Val Leu Glu Lys Ile Phe Asp Leu Lys Ile Gln Glu

115 120 125

Arg Val Ser Lys Pro Lys Ile Ser Trp Thr Cys Ile Asn Thr Thr Leu

130 135 140

Thr Cys Glu Val Met Asn Gly Thr Asp Pro Glu Leu Asn Leu Tyr Gln

145 150 155 160

Asp Gly Lys His Leu Lys Leu Ser Gln Arg Val Ile Thr His Lys Trp

165 170 175

Thr Thr Ser Leu Ser Ala Lys Phe Lys Cys Thr Ala Gly Asn Lys Val

180 185 190

Ser Lys Glu Ser Ser Val Glu Pro Val Ser Cys Pro Glu Lys Gly Leu

195 200 205

Asp Ile Tyr Leu Ile Ile Gly Ile Cys Gly Gly Gly Ser Leu Leu Met

210 215 220

Val Phe Val Ala Leu Leu Val Phe Tyr Ile Thr Lys Arg Lys Lys Gln

225 230 235 240

Arg Ser Arg Arg Asn Asp Glu Glu Leu Glu Thr Arg Ala His Arg Val

245 250 255

Ala Thr Glu Glu Arg Gly Arg Lys Pro His Gln Ile Pro Ala Ser Thr

260 265 270

Pro Gln Asn Pro Ala Thr Ser Gln His Pro Pro Pro Pro Pro Gly His

275 280 285

Arg Ser Gln Ala Pro Ser His Arg Pro Pro Pro Pro Gly His Arg Val

290 295 300

Gln His Gln Pro Gln Lys Arg Pro Pro Ala Pro Ser Gly Thr Gln Val

305 310 315 320

His Gln Gln Lys Gly Pro Pro Leu Pro Arg Pro Arg Val Gln Pro Lys

325 330 335

Pro Pro His Gly Ala Ala Glu Asn Ser Leu Ser Pro Ser Ser Asn

340 345 350

<210> 179

<211> 240

<212> PRT

<213> artificial sequence

<220>

<223> human LIGHT

<400> 179

Met Glu Glu Ser Val Val Arg Pro Ser Val Phe Val Val Asp Gly Gln

1 5 10 15

Thr Asp Ile Pro Phe Thr Arg Leu Gly Arg Ser His Arg Arg Gln Ser

20 25 30

Cys Ser Val Ala Arg Val Gly Leu Gly Leu Leu Leu Leu Leu Met Gly

35 40 45

Ala Gly Leu Ala Val Gln Gly Trp Phe Leu Leu Gln Leu His Trp Arg

50 55 60

Leu Gly Glu Met Val Thr Arg Leu Pro Asp Gly Pro Ala Gly Ser Trp

65 70 75 80

Glu Gln Leu Ile Gln Glu Arg Arg Ser His Glu Val Asn Pro Ala Ala

85 90 95

His Leu Thr Gly Ala Asn Ser Ser Leu Thr Gly Ser Gly Gly Pro Leu

100 105 110

Leu Trp Glu Thr Gln Leu Gly Leu Ala Phe Leu Arg Gly Leu Ser Tyr

115 120 125

His Asp Gly Ala Leu Val Val Thr Lys Ala Gly Tyr Tyr Tyr Ile Tyr

130 135 140

Ser Lys Val Gln Leu Gly Gly Val Gly Cys Pro Leu Gly Leu Ala Ser

145 150 155 160

Thr Ile Thr His Gly Leu Tyr Lys Arg Thr Pro Arg Tyr Pro Glu Glu

165 170 175

Leu Glu Leu Leu Val Ser Gln Gln Ser Pro Cys Gly Arg Ala Thr Ser

180 185 190

Ser Ser Arg Val Trp Trp Asp Ser Ser Phe Leu Gly Gly Val Val His

195 200 205

Leu Glu Ala Gly Glu Lys Val Val Val Arg Val Leu Asp Glu Arg Leu

210 215 220

Val Arg Leu Arg Asp Gly Thr Arg Ser Tyr Phe Gly Ala Phe Met Val

225 230 235 240

<210> 180

<211> 241

<212> PRT

<213> artificial sequence

<220>

<223> human GITR

<400> 180

Met Ala Gln His Gly Ala Met Gly Ala Phe Arg Ala Leu Cys Gly Leu

1 5 10 15

Ala Leu Leu Cys Ala Leu Ser Leu Gly Gln Arg Pro Thr Gly Gly Pro

20 25 30

Gly Cys Gly Pro Gly Arg Leu Leu Leu Gly Thr Gly Thr Asp Ala Arg

35 40 45

Cys Cys Arg Val His Thr Thr Arg Cys Cys Arg Asp Tyr Pro Gly Glu

50 55 60

Glu Cys Cys Ser Glu Trp Asp Cys Met Cys Val Gln Pro Glu Phe His

65 70 75 80

Cys Gly Asp Pro Cys Cys Thr Thr Cys Arg His His Pro Cys Pro Pro

85 90 95

Gly Gln Gly Val Gln Ser Gln Gly Lys Phe Ser Phe Gly Phe Gln Cys

100 105 110

Ile Asp Cys Ala Ser Gly Thr Phe Ser Gly Gly His Glu Gly His Cys

115 120 125

Lys Pro Trp Thr Asp Cys Thr Gln Phe Gly Phe Leu Thr Val Phe Pro

130 135 140

Gly Asn Lys Thr His Asn Ala Val Cys Val Pro Gly Ser Pro Pro Ala

145 150 155 160

Glu Pro Leu Gly Trp Leu Thr Val Val Leu Leu Ala Val Ala Ala Cys

165 170 175

Val Leu Leu Leu Thr Ser Ala Gln Leu Gly Leu His Ile Trp Gln Leu

180 185 190

Arg Ser Gln Cys Met Trp Pro Arg Glu Thr Gln Leu Leu Leu Glu Val

195 200 205

Pro Pro Ser Thr Glu Asp Ala Arg Ser Cys Gln Phe Pro Glu Glu Glu

210 215 220

Arg Gly Glu Arg Ser Ala Glu Glu Lys Gly Arg Leu Gly Asp Leu Trp

225 230 235 240

Val

<210> 181

<211> 417

<212> PRT

<213> artificial sequence

<220>

<223> human DR3

<400> 181

Met Glu Gln Arg Pro Arg Gly Cys Ala Ala Val Ala Ala Ala Leu Leu

1 5 10 15

Leu Val Leu Leu Gly Ala Arg Ala Gln Gly Gly Thr Arg Ser Pro Arg

20 25 30

Cys Asp Cys Ala Gly Asp Phe His Lys Lys Ile Gly Leu Phe Cys Cys

35 40 45

Arg Gly Cys Pro Ala Gly His Tyr Leu Lys Ala Pro Cys Thr Glu Pro

50 55 60

Cys Gly Asn Ser Thr Cys Leu Val Cys Pro Gln Asp Thr Phe Leu Ala

65 70 75 80

Trp Glu Asn His His Asn Ser Glu Cys Ala Arg Cys Gln Ala Cys Asp

85 90 95

Glu Gln Ala Ser Gln Val Ala Leu Glu Asn Cys Ser Ala Val Ala Asp

100 105 110

Thr Arg Cys Gly Cys Lys Pro Gly Trp Phe Val Glu Cys Gln Val Ser

115 120 125

Gln Cys Val Ser Ser Ser Pro Phe Tyr Cys Gln Pro Cys Leu Asp Cys

130 135 140

Gly Ala Leu His Arg His Thr Arg Leu Leu Cys Ser Arg Arg Asp Thr

145 150 155 160

Asp Cys Gly Thr Cys Leu Pro Gly Phe Tyr Glu His Gly Asp Gly Cys

165 170 175

Val Ser Cys Pro Thr Ser Thr Leu Gly Ser Cys Pro Glu Arg Cys Ala

180 185 190

Ala Val Cys Gly Trp Arg Gln Met Phe Trp Val Gln Val Leu Leu Ala

195 200 205

Gly Leu Val Val Pro Leu Leu Leu Gly Ala Thr Leu Thr Tyr Thr Tyr

210 215 220

Arg His Cys Trp Pro His Lys Pro Leu Val Thr Ala Asp Glu Ala Gly

225 230 235 240

Met Glu Ala Leu Thr Pro Pro Pro Ala Thr His Leu Ser Pro Leu Asp

245 250 255

Ser Ala His Thr Leu Leu Ala Pro Pro Asp Ser Ser Glu Lys Ile Cys

260 265 270

Thr Val Gln Leu Val Gly Asn Ser Trp Thr Pro Gly Tyr Pro Glu Thr

275 280 285

Gln Glu Ala Leu Cys Pro Gln Val Thr Trp Ser Trp Asp Gln Leu Pro

290 295 300

Ser Arg Ala Leu Gly Pro Ala Ala Ala Pro Thr Leu Ser Pro Glu Ser

305 310 315 320

Pro Ala Gly Ser Pro Ala Met Met Leu Gln Pro Gly Pro Gln Leu Tyr

325 330 335

Asp Val Met Asp Ala Val Pro Ala Arg Arg Trp Lys Glu Phe Val Arg

340 345 350

Thr Leu Gly Leu Arg Glu Ala Glu Ile Glu Ala Val Glu Val Glu Ile

355 360 365

Gly Arg Phe Arg Asp Gln Gln Tyr Glu Met Leu Lys Arg Trp Arg Gln

370 375 380

Gln Gln Pro Ala Gly Leu Gly Ala Val Tyr Ala Ala Leu Glu Arg Met

385 390 395 400

Gly Leu Asp Gly Cys Val Glu Asp Leu Arg Ser Arg Leu Gln Arg Gly

405 410 415

Pro

<210> 182

<211> 400

<212> PRT

<213> artificial sequence

<220>

<223> human CD43

<400> 182

Met Ala Thr Leu Leu Leu Leu Leu Gly Val Leu Val Val Ser Pro Asp

1 5 10 15

Ala Leu Gly Ser Thr Thr Ala Val Gln Thr Pro Thr Ser Gly Glu Pro

20 25 30

Leu Val Ser Thr Ser Glu Pro Leu Ser Ser Lys Met Tyr Thr Thr Ser

35 40 45

Ile Thr Ser Asp Pro Lys Ala Asp Ser Thr Gly Asp Gln Thr Ser Ala

50 55 60

Leu Pro Pro Ser Thr Ser Ile Asn Glu Gly Ser Pro Leu Trp Thr Ser

65 70 75 80

Ile Gly Ala Ser Thr Gly Ser Pro Leu Pro Glu Pro Thr Thr Tyr Gln

85 90 95

Glu Val Ser Ile Lys Met Ser Ser Val Pro Gln Glu Thr Pro His Ala

100 105 110

Thr Ser His Pro Ala Val Pro Ile Thr Ala Asn Ser Leu Gly Ser His

115 120 125

Thr Val Thr Gly Gly Thr Ile Thr Thr Asn Ser Pro Glu Thr Ser Ser

130 135 140

Arg Thr Ser Gly Ala Pro Val Thr Thr Ala Ala Ser Ser Leu Glu Thr

145 150 155 160

Ser Arg Gly Thr Ser Gly Pro Pro Leu Thr Met Ala Thr Val Ser Leu

165 170 175

Glu Thr Ser Lys Gly Thr Ser Gly Pro Pro Val Thr Met Ala Thr Asp

180 185 190

Ser Leu Glu Thr Ser Thr Gly Thr Thr Gly Pro Pro Val Thr Met Thr

195 200 205

Thr Gly Ser Leu Glu Pro Ser Ser Gly Ala Ser Gly Pro Gln Val Ser

210 215 220

Ser Val Lys Leu Ser Thr Met Met Ser Pro Thr Thr Ser Thr Asn Ala

225 230 235 240

Ser Thr Val Pro Phe Arg Asn Pro Asp Glu Asn Ser Arg Gly Met Leu

245 250 255

Pro Val Ala Val Leu Val Ala Leu Leu Ala Val Ile Val Leu Val Ala

260 265 270

Leu Leu Leu Leu Trp Arg Arg Arg Gln Lys Arg Arg Thr Gly Ala Leu

275 280 285

Val Leu Ser Arg Gly Gly Lys Arg Asn Gly Val Val Asp Ala Trp Ala

290 295 300

Gly Pro Ala Gln Val Pro Glu Glu Gly Ala Val Thr Val Thr Val Gly

305 310 315 320

Gly Ser Gly Gly Asp Lys Gly Ser Gly Phe Pro Asp Gly Glu Gly Ser

325 330 335

Ser Arg Arg Pro Thr Leu Thr Thr Phe Phe Gly Arg Arg Lys Ser Arg

340 345 350

Gln Gly Ser Leu Ala Met Glu Glu Leu Lys Ser Gly Ser Gly Pro Ser

355 360 365

Leu Lys Gly Glu Glu Glu Pro Leu Val Ala Ser Glu Asp Gly Ala Val

370 375 380

Asp Ala Pro Ala Pro Asp Glu Pro Glu Gly Gly Asp Gly Ala Ala Pro

385 390 395 400

<210> 183

<211> 458

<212> PRT

<213> artificial sequence

<220>

<223> human CD4

<400> 183

Met Asn Arg Gly Val Pro Phe Arg His Leu Leu Leu Val Leu Gln Leu

1 5 10 15

Ala Leu Leu Pro Ala Ala Thr Gln Gly Lys Lys Val Val Leu Gly Lys

20 25 30

Lys Gly Asp Thr Val Glu Leu Thr Cys Thr Ala Ser Gln Lys Lys Ser

35 40 45

Ile Gln Phe His Trp Lys Asn Ser Asn Gln Ile Lys Ile Leu Gly Asn

50 55 60

Gln Gly Ser Phe Leu Thr Lys Gly Pro Ser Lys Leu Asn Asp Arg Ala

65 70 75 80

Asp Ser Arg Arg Ser Leu Trp Asp Gln Gly Asn Phe Pro Leu Ile Ile

85 90 95

Lys Asn Leu Lys Ile Glu Asp Ser Asp Thr Tyr Ile Cys Glu Val Glu

100 105 110

Asp Gln Lys Glu Glu Val Gln Leu Leu Val Phe Gly Leu Thr Ala Asn

115 120 125

Ser Asp Thr His Leu Leu Gln Gly Gln Ser Leu Thr Leu Thr Leu Glu

130 135 140

Ser Pro Pro Gly Ser Ser Pro Ser Val Gln Cys Arg Ser Pro Arg Gly

145 150 155 160

Lys Asn Ile Gln Gly Gly Lys Thr Leu Ser Val Ser Gln Leu Glu Leu

165 170 175

Gln Asp Ser Gly Thr Trp Thr Cys Thr Val Leu Gln Asn Gln Lys Lys

180 185 190

Val Glu Phe Lys Ile Asp Ile Val Val Leu Ala Phe Gln Lys Ala Ser

195 200 205

Ser Ile Val Tyr Lys Lys Glu Gly Glu Gln Val Glu Phe Ser Phe Pro

210 215 220

Leu Ala Phe Thr Val Glu Lys Leu Thr Gly Ser Gly Glu Leu Trp Trp

225 230 235 240

Gln Ala Glu Arg Ala Ser Ser Ser Lys Ser Trp Ile Thr Phe Asp Leu

245 250 255

Lys Asn Lys Glu Val Ser Val Lys Arg Val Thr Gln Asp Pro Lys Leu

260 265 270

Gln Met Gly Lys Lys Leu Pro Leu His Leu Thr Leu Pro Gln Ala Leu

275 280 285

Pro Gln Tyr Ala Gly Ser Gly Asn Leu Thr Leu Ala Leu Glu Ala Lys

290 295 300

Thr Gly Lys Leu His Gln Glu Val Asn Leu Val Val Met Arg Ala Thr

305 310 315 320

Gln Leu Gln Lys Asn Leu Thr Cys Glu Val Trp Gly Pro Thr Ser Pro

325 330 335

Lys Leu Met Leu Ser Leu Lys Leu Glu Asn Lys Glu Ala Lys Val Ser

340 345 350

Lys Arg Glu Lys Ala Val Trp Val Leu Asn Pro Glu Ala Gly Met Trp

355 360 365

Gln Cys Leu Leu Ser Asp Ser Gly Gln Val Leu Leu Glu Ser Asn Ile

370 375 380

Lys Val Leu Pro Thr Trp Ser Thr Pro Val Gln Pro Met Ala Leu Ile

385 390 395 400

Val Leu Gly Gly Val Ala Gly Leu Leu Leu Phe Ile Gly Leu Gly Ile

405 410 415

Phe Phe Cys Val Arg Cys Arg His Arg Arg Arg Gln Ala Glu Arg Met

420 425 430

Ser Gln Ile Lys Arg Leu Leu Ser Glu Lys Lys Thr Cys Gln Cys Pro

435 440 445

His Arg Phe Gln Lys Thr Cys Ser Pro Ile

450 455

<210> 184

<211> 235

<212> PRT

<213> artificial sequence

<220>

<223> human CD8

<400> 184

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Ser Gln Phe Arg Val Ser Pro Leu Asp Arg Thr

20 25 30

Trp Asn Leu Gly Glu Thr Val Glu Leu Lys Cys Gln Val Leu Leu Ser

35 40 45

Asn Pro Thr Ser Gly Cys Ser Trp Leu Phe Gln Pro Arg Gly Ala Ala

50 55 60

Ala Ser Pro Thr Phe Leu Leu Tyr Leu Ser Gln Asn Lys Pro Lys Ala

65 70 75 80

Ala Glu Gly Leu Asp Thr Gln Arg Phe Ser Gly Lys Arg Leu Gly Asp

85 90 95

Thr Phe Val Leu Thr Leu Ser Asp Phe Arg Arg Glu Asn Glu Gly Tyr

100 105 110

Tyr Phe Cys Ser Ala Leu Ser Asn Ser Ile Met Tyr Phe Ser His Phe

115 120 125

Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg

130 135 140

Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg

145 150 155 160

Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly

165 170 175

Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr

180 185 190

Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Asn His

195 200 205

Arg Asn Arg Arg Arg Val Cys Lys Cys Pro Arg Pro Val Val Lys Ser

210 215 220

Gly Asp Lys Pro Ser Leu Ser Ala Arg Tyr Val

225 230 235

Claims

1. An antibody or antigen-binding fragment thereof that specifically binds BCMA, comprising:

(a) A light chain variable region (VL) comprising

(1) Light chain CDR1 (VL CDR 1) having an amino acid sequence selected from the group consisting of SEQ ID NOS 1-10;

(2) Light chain CDR2 (VL CDR 2) having an amino acid sequence selected from the group consisting of SEQ ID NOS 11-21;

(3) Light chain CDR3 (VL CDR 3) having an amino acid sequence selected from the group consisting of SEQ ID NOS 22-32;

or a variant thereof having up to about 5 amino acid substitutions, additions and/or deletions in the VL CDRs; and/or

(b) A heavy chain variable region (VH) comprising

(1) Heavy chain CDR1 (VH CDR 1) having an amino acid sequence selected from the group consisting of SEQ ID NOS 33-43;

(2) Heavy chain CDR2 (VH CDR 2) having an amino acid sequence selected from the group consisting of SEQ ID NOS 44-55;

(3) Heavy chain CDR3 (VH CDR 3) having an amino acid sequence selected from the group consisting of SEQ ID NOS: 56-67;

or a variant thereof having up to about 5 amino acid substitutions, additions and/or deletions in the VH CDRs.

2. The antibody or antigen-binding fragment of claim 1, wherein:

(a) The VL CDR1, CDR2 and CDR3 have, respectively

(1) Amino acid sequences shown in SEQ ID NOs 1, 11 and 22;

(2) Amino acid sequences shown in SEQ ID NOs 2, 12 and 23;

(3) Amino acid sequences shown in SEQ ID NOs 3, 13 and 24;

(4) Amino acid sequences shown in SEQ ID NOs 4, 14 and 24;

(5) Amino acid sequences shown in SEQ ID NOs 5, 15 and 25;

(6) Amino acid sequences shown in SEQ ID NOS.6, 16 and 26;

(7) Amino acid sequences shown in SEQ ID NOs 7, 17 and 27;

(8) Amino acid sequences shown in SEQ ID NOS.8, 18 and 28;

(9) Amino acid sequences shown in SEQ ID NOs 2, 19 and 29;

(10) Amino acid sequences shown in SEQ ID NOs 2, 20 and 30;

(11) Amino acid sequences shown in SEQ ID NOs 9, 21 and 31; or (b)

(12) Amino acid sequences shown in SEQ ID NOs 10, 14 and 32;

(b) The VH CDR1, CDR2 and CDR3 have respectively

(1) 33, 44 and 56;

(2) The amino acid sequences shown in SEQ ID NOS.34, 45 and 57;

(3) Amino acid sequences shown in SEQ ID NOs 35, 46 and 58;

(4) The amino acid sequences shown in SEQ ID NOS.36, 47 and 59;

(5) 37, 48 and 60;

(6) The amino acid sequences shown in SEQ ID NOS.38, 49 and 61;

(7) Amino acid sequences shown in SEQ ID NOs 35, 50 and 62;

(8) The amino acid sequences shown in SEQ ID NOS 39, 51 and 63;

(9) The amino acid sequences shown in SEQ ID NOS.40, 52 and 64;

(10) Amino acid sequences shown in SEQ ID NOS.41, 53 and 65;

(11) Amino acid sequences shown in SEQ ID NOS.42, 54 and 66; or (b)

(12) Amino acid sequences shown in SEQ ID NOs 43, 55 and 67;

3. The antibody or antigen-binding fragment of claim 1, wherein

(1) The VL CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NO 1, 11 and 22 respectively; and/or, the VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOs 33, 44 and 56, respectively;

(2) The VL CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NO 2, 12 and 23 respectively; and/or, the VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOs 34, 45 and 57, respectively;

(3) The VL CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NO 3, 13 and 24 respectively; and/or, the VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOs 35, 46 and 58, respectively;

(4) The VL CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOS 4, 14 and 24, respectively; and/or, the VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOs 36, 47 and 59, respectively;

(5) The VL CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOS 5, 15 and 25, respectively; and/or, the VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOs 37, 48 and 60, respectively;

(6) The VL CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOS 6, 16 and 26, respectively; and/or, the VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOs 38, 49 and 61, respectively;

(7) The VL CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOS 7, 17 and 27, respectively; and/or, the VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOs 35, 50 and 62, respectively;

(8) The VL CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOS 8, 18 and 28, respectively; and/or, the VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOs 39, 51 and 63, respectively;

(9) The VL CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NO 2, 19 and 29 respectively; and/or, the VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOs 40, 52 and 64, respectively;

(10) The VL CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NO 2, 20 and 30 respectively; and/or, the VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOs 41, 53 and 65, respectively;

(11) The VL CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NO 9, 21 and 31 respectively; and/or, the VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOs 42, 54 and 66, respectively;

Or (12) the VL CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOS 10, 14 and 32, respectively; and/or, the VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOS 43, 55 and 67, respectively.

4. The antibody or antigen-binding fragment of claim 1, comprising VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3, wherein

(a) The VL CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOS 4, 14 and 24, respectively; and

(b) The VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOS 36, 47 and 59, respectively.

5. The antibody or antigen-binding fragment of claim 1, comprising VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3, wherein

(a) The VL CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOS 8, 18 and 28, respectively; and

(b) The VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOS 39, 51 and 63, respectively.

6. The antibody or antigen-binding fragment of claim 1, comprising VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3, wherein

(a) The VL CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NO 2, 20 and 30 respectively; and

(b) The VH CDR1, CDR2 and CDR3 have the amino acid sequences shown in SEQ ID NOS 41, 53 and 65, respectively.

7. An antibody or antigen-binding fragment thereof that specifically binds BCMA, comprising:

(a) VL having at least 85%, at least 90%, at least 95%, at least 98% or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs 68-79; and/or

(b) VH having at least 85%, at least 90%, at least 95%, at least 98% or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs 80-91.

8. The antibody or antigen-binding fragment of claim 7, comprising VL and VH, wherein the VL and VH have, respectively

(1) The amino acid sequences shown in SEQ ID NOS.68 and 80;

(2) The amino acid sequences shown in SEQ ID NOS 69 and 81;

(3) Amino acid sequences shown in SEQ ID NOs 70 and 82;

(4) Amino acid sequences shown in SEQ ID NOS.71 and 83;

(5) Amino acid sequences shown in SEQ ID NOS.72 and 84;

(6) Amino acid sequences shown in SEQ ID NOS.73 and 85;

(7) Amino acid sequences shown in SEQ ID NOS.74 and 86;

(8) Amino acid sequences shown in SEQ ID NOS 75 and 87;

(9) Amino acid sequences shown in SEQ ID NOS.76 and 88;

(10) Amino acid sequences shown in SEQ ID NOS.77 and 89;

(11) Amino acid sequences shown in SEQ ID NOS.78 and 90; or (b)

(12) The amino acid sequences shown in SEQ ID NOS 79 and 91.

9. The antibody or antigen-binding fragment of claim 7, comprising VL and VH, wherein the VL and VH have the amino acid sequences shown in SEQ ID NOs 71 and 83, respectively.

10. The antibody or antigen-binding fragment of claim 7, comprising a VL and a VH, wherein the VL and VH have the amino acid sequences set forth in SEQ ID NOs 75 and 87, respectively.

11. The antibody or antigen-binding fragment of claim 7, comprising VL and VH, wherein the VL and VH have the amino acid sequences set forth in SEQ ID NOs 77 and 89, respectively.

12. An antibody or antigen-binding fragment thereof that specifically binds BCMA comprising

(a) A VL comprising VL CDR1, CDR2, and CDR3, said VL CDR1, CDR2, and CDR3 derived from a VL having an amino acid sequence selected from the group consisting of SEQ ID NOs 68-79; and/or

(b) A VH comprising VH CDR1, CDR2 and CDR3, said VH CDR1, CDR2 and CDR3 being derived from a VH having an amino acid sequence selected from the group consisting of SEQ ID NOs 80-91.

13. The antibody or antigen-binding fragment of claim 12, comprising

(1) A VL comprising VL CDR1, CDR2 and CDR3, said VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence shown in SEQ ID No. 68; and/or, a VH comprising a VH CDR1, CDR2 and CDR3, said VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID No. 80;

(2) A VL comprising VL CDR1, CDR2 and CDR3, said VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence shown in SEQ ID No. 69, and/or a VH comprising VH CDR1, CDR2 and CDR3, said VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID No. 81;

(3) A VL comprising VL CDR1, CDR2 and CDR3, said VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence shown in SEQ ID No. 70, and/or a VH comprising VH CDR1, CDR2 and CDR3, said VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID No. 82;

(4) A VL comprising VL CDR1, CDR2 and CDR3, said VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence shown in SEQ ID NO:71 and/or a VH comprising VH CDR1, CDR2 and CDR3, said VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID NO: 83;

(5) VL comprising VL CDR1, CDR2 and CDR3, said VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence shown in SEQ ID No. 72 and/or VH comprising VH CDR1, CDR2 and CDR3, said VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID No. 84;

(6) A VL comprising VL CDR1, CDR2 and CDR3, said VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence shown in SEQ ID No. 73, and/or a VH comprising VH CDR1, CDR2 and CDR3, said VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID No. 85;

(7) A VL comprising VL CDR1, CDR2 and CDR3, said VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence shown in SEQ ID No. 74 and/or a VH comprising VH CDR1, CDR2 and CDR3, said VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID No. 86;

(8) A VL comprising VL CDR1, CDR2 and CDR3, said VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence shown in SEQ ID No. 75, and/or a VH comprising VH CDR1, CDR2 and CDR3, said VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID No. 87;

(9) A VL comprising VL CDR1, CDR2 and CDR3, said VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence shown in SEQ ID No. 76, and/or a VH comprising VH CDR1, CDR2 and CDR3, said VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID No. 88;

(10) A VL comprising VL CDR1, CDR2 and CDR3, said VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence shown in SEQ ID NO:77, and/or a VH comprising VH CDR1, CDR2 and CDR3, said VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID NO: 89;

(11) A VL comprising VL CDR1, CDR2 and CDR3, said VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence shown in SEQ ID No. 78, and/or a VH comprising VH CDR1, CDR2 and CDR3, said VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID No. 90; or (b)

(12) VL comprising VL CDR1, CDR2 and CDR3, said VL CDR1, CDR2 and CDR3 being derived from a VL having the amino acid sequence shown in SEQ ID No. 79 and/or VH comprising VH CDR1, CDR2 and CDR3, said VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID No. 91.

14. The antibody or antigen-binding fragment of claim 12, comprising a VL and a VH, wherein the VL comprises VL CDR1, CDR2, and CDR3, the VL CDR1, CDR2, and CDR3 being derived from a VL having the amino acid sequence shown in SEQ ID No. 71; and, the VH includes a VH CDR1, a CDR2 and a CDR3, the VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID NO 83.

15. The antibody or antigen-binding fragment of claim 12, comprising a VL and a VH, wherein the VL comprises VL CDR1, CDR2, and CDR3, the VL CDR1, CDR2, and CDR3 being derived from a VL having the amino acid sequence shown in SEQ ID No. 75; and, the VH includes a VH CDR1, a CDR2 and a CDR3, the VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID NO 87.

16. The antibody or antigen-binding fragment of claim 12, comprising a VL and a VH, wherein the VL comprises VL CDR1, CDR2, and CDR3, the VL CDR1, CDR2, and CDR3 being derived from a VL having the amino acid sequence shown in SEQ ID No. 77; and, the VH includes a VH CDR1, a CDR2 and a CDR3, the VH CDR1, CDR2 and CDR3 being derived from a VH having the amino acid sequence shown in SEQ ID NO 89.

17. An antibody or antigen-binding fragment thereof that competes for binding to BCMA with the antibody or antigen-binding fragment of any one of claims 1-16.

18. The antibody or antigen-binding fragment of any one of claims 1 to 17, which is a monoclonal antibody or antigen-binding fragment.

19. The antibody or antigen-binding fragment of any one of claims 1 to 18, which is a bispecific antibody or a multispecific antibody.

20. The antibody or antigen binding fragment of claim 19, which is a bispecific T cell engager (BiTE).

21. The antibody or antigen-binding fragment of any one of claims 1-20, selected from the group consisting of an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, and an IgG4 antibody.

22. The antibody or antigen-binding fragment of any one of claims 1 to 20, which is selected from the group consisting of Fab, fab ', F (ab') ₂ 、Fv、scFv、(scFv) ₂ A single domain antibody (sdAb) and a heavy chain antibody (HCAb).

23. The antibody of claim 22, which is an scFv.

24. The antibody or antigen-binding fragment of any one of claims 1 to 23, which is a chimeric antibody or antigen-binding fragment, a humanized antibody or antigen-binding fragment, or a human antibody or antigen-binding fragment.

25. The antibody or antigen-binding fragment of claim 24, which is a human antibody or antigen-binding fragment.

26. A polynucleotide encoding the antibody or antigen-binding fragment of any one of claims 1-25.

27. The polynucleotide of claim 26, which is a messenger RNA (mRNA).

28. A vector comprising the polynucleotide of claim 26.

29. A host cell comprising the polynucleotide of claim 26 or 27 or the vector of claim 28.

30. A Chimeric Antigen Receptor (CAR) that specifically binds BCMA comprising, from N-terminus to C-terminus:

(a) A BCMA binding domain comprising the antibody or antigen binding fragment of any one of claims 1 to 25;

(b) A transmembrane domain; and

(c) Cytoplasmic domains.

31. The CAR of claim 30, wherein the transmembrane domain is derived from CD8, CD28, CD3 ζ, CD4, 4-1BB, OX40, ICOS, CTLA-4, PD-1, LAG-3, 2B4, BTLA, TCR a chain, TCR β chain, or TCR ζ chain, CD3 epsilon, CD45, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, or CD154.

32. The CAR of claim 30, wherein the transmembrane domain comprises a CD8 transmembrane region or a CD28 transmembrane region.

33. The CAR of any one of claims 30-32, wherein the cytoplasmic domain comprises a signaling domain derived from cd3ζ, fcrγ, fcγriia, fcrβ, cd3γ, cd3δ, cd3ε, CD5, CD22, CD79a, CD79b, DAP10, DAP12, or any combination thereof.

34. The CAR of claim 33, wherein the cytoplasmic domain further comprises a co-stimulatory domain derived from CD28, 4-1BB (CD 137), OX40, ICOS, DAP10, 2B4, CD27, CD30, CD40, CD2, CD7, LIGHT, GITR, TLR, DR3, CD43, or any combination thereof.

35. The CAR of any one of claims 30-34, wherein the cytoplasmic domain comprises a CD3 zeta signaling domain and a 4-1BB co-stimulatory domain.

36. The CAR of any one of claims 30-34, wherein the cytoplasmic domain comprises a CD3 zeta signaling domain and a CD28 co-stimulatory domain.

37. The CAR of any one of claims 30-36, further comprising a CD8 hinge, the CD8 hinge being located between the antibody or antigen binding fragment and the transmembrane domain.

38. A CAR that specifically binds BCMA comprising an amino acid sequence selected from the group consisting of SEQ ID NOs 131-142.

39. A polynucleotide encoding the CAR of any one of claims 30-38.

40. The polynucleotide according to claim 39 which is mRNA.

41. A vector comprising the polynucleotide of claim 39.

42. A cell comprising the polynucleotide of claim 39 or 40 or the vector of claim 41.

43. The cell of claim 42, which is an immune effector cell.

44. The cell according to claim 43, which is derived from a cell isolated from peripheral blood or bone marrow.

45. The cell of claim 43, which is derived from a cell differentiated in vitro from a stem cell or progenitor cell selected from the group consisting of a T cell progenitor cell, a hematopoietic stem/progenitor cell, a hematopoietic multipotent progenitor cell, an embryonic stem cell, and an induced multipotent cell.

46. The cell of any one of claims 42-45, which is a T cell or an NK cell.

47. The cell of claim 46 which is a cytotoxic T cell, helper T cell, γδ T cell, cd4+/cd8+ double positive T cell, cd4+ T cell, cd8+ T cell, CD4/CD8 double negative T cell, cd3+ T cell, naive T cell, effector T cell, helper T cell, memory T cell, regulatory T cell, th0 cell, th1 cell, th2 cell, th3 (Treg) cell, th9 cell, th17 cell, thαβ helper cell, tfh cell, stem cell memory TSCM cell, central memory TCM cell, effector memory TEM cell or effector memory TEMRA cell.

48. The cell of claim 46, which is a cytotoxic T cell.

49. A cell population comprising the cells of claim 42, wherein the cell population is derived from Peripheral Blood Mononuclear Cells (PBMC), peripheral Blood Lymphocytes (PBL), tumor-infiltrating lymphocytes (TIL), cytokine-induced killer Cells (CIK), lymphokine-activated killer cells (LAK), or bone marrow-infiltrating lymphocytes (MILs).

50. A pharmaceutical composition comprising a therapeutically effective amount of the antibody or antigen-binding fragment of any one of claims 1-25, and a pharmaceutically acceptable carrier.

51. A pharmaceutical composition comprising a therapeutically effective amount of the cell or cell population of any one of claims 42-49, and a pharmaceutically acceptable carrier.

52. The antibody or antigen-binding fragment of any one of claims 1 to 25, the cell or cell population of any one of claims 43 to 49, or the pharmaceutical composition of claim 50 or 51 for use in the treatment of cancer.

53. Use of an antibody or antigen-binding fragment according to any one of claims 1 to 25, a cell or cell population according to any one of claims 43 to 49, or a pharmaceutical composition according to claim 50 or 51 in the manufacture of a medicament for the treatment of cancer.

54. The use of claim 52 or 53, wherein the cell, cell population or pharmaceutical composition is used in combination with an additional therapy.

55. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody or antigen-binding fragment of any one of claims 1-25, the pharmaceutical composition of claim 50 or 51.

56. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the cell or cell population of any one of claims 43-49.

57. The method of claim 56, wherein said population of cells is a population of cells autologous to said subject.

58. The method of claim 57, further comprising: obtaining T cells from the subject.

59. The method of any one of claims 55-58, further comprising: administering an additional therapy to the subject.

60. The method of any one of claims 55-59, wherein the subject is a human.

61. The use of any one of claims 52-60, wherein the cancer is BCMA-expressing cancer.

62. The use of any one of claims 52-61, wherein the cancer is a solid tumor or a hematological cancer.

63. The use of any one of claims 52-62, wherein the cancer is a B cell malignancy.

64. The use of any one of claims 52-63, wherein the cancer is a lymphoma, leukemia, or plasma cell malignancy.

65. The use of claim 64, wherein the cancer is Multiple Myeloma (MM), megaloblastic, hodgkin's lymphoma, or non-hodgkin's lymphoma.

66. The use of claim 65, wherein the cancer is MM.

67. The use of claim 65, wherein the MM is non-secretory multiple myeloma or smoldering multiple myeloma.

68. A method of making a cell capable of expressing a CAR that specifically binds BCMA, comprising transferring the polynucleotide of claim 39 or 40 to the cell.

69. The method of claim 68, wherein the polynucleotide is transferred by electroporation.

70. The method of claim 68, wherein the polynucleotide is transferred by viral transduction.

71. The method of claim 70, comprising viral transduction using lentiviruses, retroviruses, adenoviruses or adeno-associated viruses.

72. The method of claim 68, wherein the polynucleotide is transferred using a transposon system.

73. The method of claim 72, wherein the transposon system is sleeping beauty or PiggyBac.

74. The method of claim 68, wherein the polynucleotide is transferred by gene editing.

75. The method of claim 74, wherein the polynucleotide is transferred by a CRISPR-Cas system, a ZFN system, or a TALEN system.

76. The method of any one of claims 68-75, wherein the cell is selected from the group consisting of a T cell, NK cell, NKT cell, macrophage, neutrophil, and granulocyte.