WO2024061297A1 - Anticorps anti-b7h3, anticorps multispécifiques et procédés d'utilisation - Google Patents
Anticorps anti-b7h3, anticorps multispécifiques et procédés d'utilisation Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
Definitions
- the present disclosure relates to antibodies and antibody derivatives that bind to B7H3 (also known as CD276) and methods of using the same.
- the antibody derivative is a multispecific antibody that binds to B7H3 and an additional antigen, e.g., EGFR.
- B7H3 (also known as CD276) is an immune checkpoint molecule of the B7 and CD28 families, which is involved in the regulation of T cell immune response. B7H3 is overexpressed in many types of tumor tissues and often correlates with negative prognosis in human patients. Although the receptor of B7H3 has not been characterized, inhibition of the B7H3 signal pathway can mediate potent antitumor activity of immune cells. Recent studies also showed that B7-H3 can influence cancer progression beyond the immune regulatory roles. Given the significant role for B7H3 in immune checkpoint regulation, there is a need in the art for the development of therapeutic molecules and methods to modulate B7H3-mediated immune cell regulation for immune therapy and cancer treatment.
- Epidermal growth factor receptor also known as EGFR, ErbB-1 and HER1 is a cell surface receptor of the ErbB receptor family, which family includes four closely related receptor tyrosine kinases, including EGFR (ErbB-1) , HER2/c-neu (ErbB-2) , Her 3 (ErbB-3) and Her 4 (ErbB-4) .
- EGFR epidermal growth factor
- TGF-alpha transforming growth factor alpha
- HB-EGF transforming growth factor alpha
- amphiregulin betacellulin/BTC and/or epigen/EPGN
- MAPK MAPK
- Akt transforming growth factor alpha
- JNK betacellulin/BTC
- MAPK MAPK
- Akt transforming growth factor alpha
- JNK betacellulin/BTC
- Mutations, amplifications or misregulations of EGFR or it family members are implicated in about 30%of all epithelial cancers. Given the importance of EGFR as an oncogene, there is a need for the development of anticancer therapeutics directed against EGFR.
- the present disclosure provides isolated monoclonal antibodies and antibody derivatives that bind specifically to B7H3 with high affinity, including monospecific anti-B7H3 antibodies and multispecific antibodies that binds to B7H3 and one or more additional target.
- the one or more additional target is EGFR.
- an antibody or antibody derivative disclosed herein comprises a single domain antibody that binds to B7H3.
- This disclosure further provides methods of making and using antibodies and antibody derivatives disclosed herein and pharmaceutical compositions comprising the same, e.g., for treating diseases and disorders, e.g., cancer.
- the invention is based, in part, on the discovery of novel single domain antibodies that bind to B7H3, and on the discovery of novel multispecific antibodies that bind to B7H3 and EGFR, each of which can target a tumor cell and/or increase an immune response against a tumor cell and thereby provide improved anti-tumor efficacy.
- the present disclosure provides a multispecific antibody that binds to B7H3 and EGFR, comprising: i) a first antigen-binding moiety comprising an anti-B7H3 antibody comprising a single domain antibody that binds to B7H3; and ii) a second antigen-binding moiety comprising an anti-EGFR antibody that binds to EGFR.
- the single domain antibody comprises a VHH.
- the single domain antibody or the VHH comprises a heavy chain variable region (VH) .
- the single domain antibody binds to B7H3 with a KD of 1x10 - 7 M or less. In certain embodiments, the single domain antibody binds to B7H3 with a KD of 5x10 -8 M or less. In certain embodiments, the single domain antibody binds to B7H3 with a KD of 1x10 -8 M or less. In certain embodiments, the single domain antibody binds to B7H3 with a KD of between about 1x10 -10 M and about 5x10 -8 M.
- the single domain antibody cross-competes for binding to B7H3 with a reference anti-B7H3 single domain antibody comprising a heavy chain variable region comprising: a) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 1, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 2, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 3, b) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 5, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 6, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 7, c) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 9, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 10,
- the single domain antibody comprises a heavy chain variable region comprising: a) a heavy chain variable region CDR1 comprising an amino acid sequence of any one of SEQ ID NOs: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41 and 56, or a variant thereof comprising up to about 3 amino acid substitutions; b) a heavy chain variable region CDR2 comprising an amino acid sequence of any one of SEQ ID NOs: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42 and 57, or a variant thereof comprising up to about 3 amino acid substitutions; and c) a heavy chain variable region CDR3 comprising an amino acid sequence of any one of SEQ ID NOs: 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43 and 58, or a variant thereof comprising up to about 3 amino acid substitutions.
- the single domain antibody comprises a heavy chain variable region that comprises a CDR1 domain, a CDR2 domain and a CDR3 domain, wherein the CDR1 domain, the CDR2 domain and the CDR3 domain respectively comprise a CDR1 domain, a CDR2 domain and a CDR3 domain comprised in a reference heavy chain variable region comprising the amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and 59.
- the single domain antibody comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 1, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 2, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 3.
- the single domain antibody comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 5, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 6, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 7.
- the single domain antibody comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 9, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 10, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 11.
- the single domain antibody comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 13, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 14, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 15.
- the single domain antibody comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 17, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 18, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 19.
- the single domain antibody comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 21, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 22, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 23.
- the single domain antibody comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 25, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 26, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 27.
- the single domain antibody comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 29, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 30, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 31.
- the single domain antibody comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 33, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 34, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 35.
- the single domain antibody comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 37, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 38, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 39.
- the single domain antibody comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 41, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 42, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 43.
- the single domain antibody comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 56, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 57, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 58.
- the single domain antibody comprises a heavy chain variable region comprising an amino acid sequence having at least about 90%sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and 59.
- the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 4.
- the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 8.
- the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 12.
- the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 16. In certain embodiments, the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 20. In certain embodiments, the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 24. In certain embodiments, the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 28. In certain embodiments, the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 32. In certain embodiments, the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 36.
- the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 40. In certain embodiments, the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 44. In certain embodiments, the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 48. In certain embodiments, the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 52. In certain embodiments, the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 59.
- the single domain antibody comprises a humanized framework.
- the second antigen-binding moiety comprises an anti-EGFR antibody that cross-competes with a reference anti-EGFR antibody comprising: a) a heavy chain variable domain (VH) sequence comprising (1) a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 85, (2) a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 86, and (3) a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 87; and a light chain variable domain (VL) sequence comprising (1) a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 88, (2) a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 89, and (3) a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 90; b) a heavy chain variable domain (VH) sequence comprising (1) a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 85, (2)
- the second antigen-binding moiety comprises a heavy chain variable domain (VH) sequence comprising (1) a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 85, (2) a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 86, and (3) a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 87; and a light chain variable domain (VL) sequence comprising (1) a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 88, (2) a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 89, and (3) a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 90.
- VH heavy chain variable domain
- VL light chain variable domain
- the second antigen-binding moiety comprises a heavy chain variable domain (VH) sequence comprising (1) a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 93, (2) a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 94, and (3) a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 95; and a light chain variable domain (VL) sequence comprising (1) a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 96, (2) a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 97, and (3) a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 98.
- VH heavy chain variable domain
- VL light chain variable domain
- the second antigen-binding moiety comprises a heavy chain variable domain (VH) sequence comprising (1) a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 101, (2) a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 102, and (3) a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 103; and a light chain variable domain (VL) sequence comprising (1) a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 104, (2) a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 105, and (3) a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 106.
- VH heavy chain variable domain
- VL light chain variable domain
- the second antigen-binding moiety comprises a heavy chain variable domain (VH) sequence comprising (1) a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 109, (2) a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 110, and (3) a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 111; and a light chain variable domain (VL) sequence comprising (1) a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 112, (2) a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 113, and (3) a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 114.
- VH heavy chain variable domain
- VL light chain variable domain
- the second antigen-binding moiety comprises a heavy chain variable domain (VH) sequence comprising (1) a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 117, (2) a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 118, and (3) a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 119; and a light chain variable domain (VL) sequence comprising (1) a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 120, (2) a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 121, and (3) a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 122.
- VH heavy chain variable domain
- VL light chain variable domain
- the second antigen-binding moiety comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 91, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 92. In certain embodiments, the second antigen-binding moiety comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 99, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 100. In certain embodiments, the second antigen-binding moiety comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 107, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 108.
- the second antigen-binding moiety comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 115, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 116. In certain embodiments, the second antigen-binding moiety comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 123, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 124.
- the anti-EGFR antibody comprises a humanized antibody.
- the second antigen binding moiety comprises an anti-EGFR antibody comprising two antibody heavy chains and two antibody light chains.
- the first antigen-binding moiety comprises one or more anti-B7H3 antibodies.
- the first antigen-binding moiety comprises two anti-B7H3 antibodies.
- the C-terminus of at least one of the two anti-EGFR light chains is linked to an anti-B7H3 antibody of the first antigen binding moiety.
- the C-terminus of each of the two anti-EGFR light chains is linked to an anti-B7H3 antibody of the first antigen binding moiety.
- the N-terminus of at least one of the two anti-EGFR light chains is linked to an anti-B7H3 antibody of the first antigen binding moiety. In certain embodiments, the N-terminus of each of the two anti-EGFR light chains is linked to an anti-B7H3 antibody of the first antigen binding moiety. In certain embodiments, the C-terminus of at least one of the two anti-EGFR heavy chains is linked to an anti-B7H3 antibody of the first antigen binding moiety. In certain embodiments, the C-terminus of each of the two anti-EGFR heavy chains is linked to an anti-B7H3 antibody of the first antigen binding moiety.
- the N-terminus of at least one of the two anti-EGFR heavy chains is linked to an anti-B7H3 antibody of the first antigen binding moiety. In certain embodiments, the N-terminus of each of the two anti-EGFR heavy chains is linked to an anti-B7H3 antibody of the first antigen binding moiety.
- the first antigen binding moiety is linked to the second antigen binding moiety via a linker.
- the linker is a peptide linker.
- the peptide linker comprises about four to about thirty amino acids.
- the peptide linker comprises about four to about fifteen amino acids.
- the peptide linker comprise an amino acid sequence selected from the group consisting of SEQ ID NOs: 61-82.
- the anti-EGFR antibody of the second antigen-binding moiety comprises a Fc region.
- the Fc region comprises a human Fc region.
- the anti-EGFR antibody of the second antigen-binding moiety comprises a Fc region selected from the group consisting of the Fc regions of IgG, IgA, IgD, IgE and IgM.
- the anti-EGFR antibody of the second antigen-binding moiety comprises a Fc region selected from the group consisting of the Fc regions of IgG1, IgG2, IgG3 and IgG4.
- the Fc region comprises an IgG1 Fc region.
- the IgG1 Fc region comprising one or more mutation or modification that enhances an antibody-dependent cell-mediated cytotoxicity (ADCC) .
- the IgG1 Fc region comprises an afucosylated sugar chain.
- the multispecific antibody is a bispecific antibody.
- the multispecific antibody comprises: i) a first antigen-binding moiety comprising a single domain anti-B7H3 antibody that comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 41, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 42, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 43; and ii) a second antigen-binding moiety comprising an anti-EGFR antibody comprising a heavy chain variable domain (VH) sequence that comprises (1) a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 101, (2) a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 102, and (3) a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 103; and a light chain variable domain (VL) sequence comprising (1) a CDR-L1 comprising
- the multispecific antibody comprises: i) a first antigen-binding moiety comprising a single domain anti-B7H3 antibody that comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 49, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 50, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 51; and ii) a second antigen-binding moiety comprising an anti-EGFR antibody comprising a heavy chain variable domain (VH) sequence that comprises (1) a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 101, (2) a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 102, and (3) a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 103; and a light chain variable domain (VL) sequence comprising (1) a CDR-L1 comprising
- the multispecific antibody comprises: i) a first antigen-binding moiety comprising a single domain anti-B7H3 antibody that comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 56, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 57, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 58; and ii) a second antigen-binding moiety comprising an anti-EGFR antibody comprising a heavy chain variable domain (VH) sequence that comprises (1) a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 101, (2) a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 102, and (3) a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 103; and a light chain variable domain (VL) sequence comprising (1) a CDR-L1
- the multispecific antibody comprises an anti-EGFR antibody heavy chain linked to an anti-B7H3 antibody comprising the amino acid sequence set forth in SEQ ID NO: 125, and an anti-EGFR antibody light chain comprising the amino acid sequence set forth in SEQ ID NO: 128.
- the multispecific antibody comprises an anti-EGFR antibody heavy chain linked to an anti-B7H3 antibody comprising the amino acid sequence set forth in SEQ ID NO: 126, and an anti-EGFR antibody light chain comprising the amino acid sequence set forth in SEQ ID NO: 128.
- the multispecific antibody comprises an anti-EGFR antibody heavy chain linked to an anti-B7H3 antibody comprising the amino acid sequence set forth in SEQ ID NO: 127, and an anti-EGFR antibody light chain comprising the amino acid sequence set forth in SEQ ID NO: 128.
- the multispecific antibody is conjugated to a therapeutic agent or a label.
- the label is selected from the group consisting of a radioisotope, a fluorescent dye and an enzyme.
- the present disclosure further provides immunoconjugates comprising any multispecific antibodies disclosed herein, linked to a therapeutic agent.
- the therapeutic agent is a cytotoxin.
- the therapeutic agent is a radioactive isotope.
- the present disclosure further provides pharmaceutical compositions.
- the pharmaceutical composition comprises a) a multispecific antibody or a immunoconjugate disclosed herein, and b) a pharmaceutically acceptable carrier.
- the present disclosure further provides nucleic acids encoding any multispecific antibody disclosed herein.
- the present disclosure further provides vectors comprising any nucleic acid disclosed herein.
- the present disclosure further provides host cells comprising a nucleic acid or a vector disclosed herein.
- the present disclosure further provides methods for preparing any multispecific antibody disclosed herein.
- the method comprises expressing a multispecific antibody in a host cell disclosed herein and isolating the antibody from the host cell.
- the present disclosure further provides methods of reducing tumor burden in a subject.
- the method comprises administering to the subject an effective amount of a multispecific antibody, an immunoconjugate, or a pharmaceutical composition disclosed herein.
- the method reduces the number of tumor cells. In certain embodiments, the method reduces tumor size. In certain embodiments, the method eradicates the tumor in the subject.
- the tumor is selected from the group consisting of mesothelioma, lung cancer, pancreatic cancer, ovarian cancer, breast cancer, colon cancer, pleural tumor, glioblastoma, esophageal cancer, gastric cancer, synovial sarcoma, thymic carcinoma, endometrial carcinoma, stomach cancer, cholangiocarcinoma, head and neck cancer, blood cancer and a combination thereof.
- the present disclosure further provides methods of treating and/or preventing a neoplasm in a subject.
- the method comprises administering to the subject an effective amount of a multispecific antibody, an immunoconjugate, or a pharmaceutical composition disclosed herein.
- the present disclosure further provides methods of lengthening survival of a subject having a neoplasm.
- the method comprises administering to the subject an effective amount of a multispecific antibody, an immunoconjugate, or a pharmaceutical composition disclosed herein.
- the neoplasm is selected from the group consisting of mesothelioma, lung cancer, pancreatic cancer, ovarian cancer, breast cancer, colon cancer, pleural tumor, glioblastoma, esophageal cancer, gastric cancer, synovial sarcoma, thymic carcinoma, endometrial carcinoma, stomach cancer, cholangiocarcinoma, head and neck cancer, blood cancer and a combination thereof.
- the present disclosure further provides any multispecific antibody disclosed herein for use as a medicament.
- the present disclosure further provides any multispecific antibody disclosed herein for use in treating cancer.
- the present disclosure further provides pharmaceutical compositions disclosed herein for use as a medicament.
- the present disclosure further provides pharmaceutical compositions disclosed herein for use in treating cancer.
- the cancer is selected from the group consisting of mesothelioma, lung cancer, pancreatic cancer, ovarian cancer, breast cancer, colon cancer, pleural tumor, glioblastoma, esophageal cancer, gastric cancer, synovial sarcoma, thymic carcinoma, endometrial carcinoma, stomach cancer, cholangiocarcinoma, head and neck cancer, blood cancer and a combination thereof.
- kits comprising a multispecific antibody, an immunoconjugate, a pharmaceutical composition, a nucleic acid, a vector or a host cell disclosed herein.
- the kit comprises a written instruction for treating and/or preventing a neoplasm.
- Figures 1A-1B depict ELISA binding of anti-B7H3 VHH antibodies to human or cynomolgus B7H3.
- Figure 1A depicts ELISA binding of anti-B7H3 VHH antibodies to human B7H3.
- Figure 1B depicts ELISA binding of anti-B7H3 VHH antibodies to cynomolgus B7H3.
- Figures 2A-2F depict whole cell binding of anti-B7H3 VHH antibodies to human B7H3+cells assessed by flow cytometry.
- Figure 2A depicts whole cell binding of anti-B7H3 VHH antibodies to human B7H3+A498 cells.
- Figure 2B depicts whole cell binding of 19c10 variants to human B7H3+A498 cells.
- Figure 2C depicts the comparison of the whole cell binding of 19c10-V3 and 19c10-V4 to human B7H3+A498 cells.
- Figure 2D depicts the comparison of the whole cell binding of 19c10-V4 and reference anti-B7H3 antibodies to human B7H3+A498 cells.
- Figure 2E depicts whole cell binding of anti-B7H3 VHH antibodies to Jurkat cells which do not express B7H3.
- Figure 2F depicts whole cell binding of 19c10-V4 and reference anti-B7H3 antibodies to Raji cells which do not express B7H3.
- Figures 3A-3B depict ADCC effects of anti-B7H3 VHH antibodies.
- Figure 3A depicts ADCC effects of various anti-B7H3 VHH antibodies compared to Reference Ab 1.
- Figure 3B depicts ADCC effects of 19c10-V4 antibody compared to Reference Ab 1 and Reference Ab 2.
- Figures 4A-4B depict in vivo antitumor effects of anti-B7H3 VHH antibodies.
- Figure 4A depicts in vivo tumor growth curves in mice treated with negative control (PBS) , 19c10-V4 antibody, Reference Ab 1 (MGA-271, an enoblituzumab analog) and Reference Ab 2 (an hl702 analog) .
- Figure 4B depicts mice body weight changes during the treatment.
- Figures 5A-5D depict ADCC effects of anti-B7H3/EGFR bispecific antibody.
- Figure 5A depicts ADCC effects of 19c10-V3xanti-EGFR antibody against Detroit 526 tumor cells compared to anti-B7H3 monospecific antibody, anti-EGFR monospecific antibody and a combination of anti-B7H3 and anti-EGFR monospecific antibodies.
- Figure 5B depicts ADCC effects of 19c10-V3xanti-EGFR antibody against A498 tumor cells compared to anti-B7H3 monospecific antibody, anti-EGFR monospecific antibody and a combination of anti-B7H3 and anti-EGFR monospecific antibodies.
- Figure 5C depicts ADCC effects of 19c10-V3xanti-EGFR antibody against HCT116 cells compared to anti-B7H3 monospecific antibody, anti-EGFR monospecific antibody and a combination of anti-B7H3 and anti-EGFR monospecific antibodies.
- Figure 5D depicts ADCC effects of 19c10-V3xanti-EGFR antibody against A549 cells compared to anti-B7H3 monospecific antibody, anti-EGFR monospecific antibody and a combination of anti-B7H3 and anti-EGFR monospecific antibodies.
- Figure 6 depicts ADCC effects of 19c10-V3xanti-EGFR and 19c10-V4xanti-EGFR antibodies against A549 tumor cells compared to anti-B7H3 monospecific antibodies.
- an antibody or antibody derivative disclosed herein comprises a single domain antibody that binds to B7H3.
- This disclosure further provides methods of making and using antibodies and antibody derivatives disclosed herein and pharmaceutical compositions comprising the same, e.g., for treating diseases and disorders, e.g., cancer.
- the invention is based, in part, on the discovery of novel single domain antibodies that bind to B7H3, which can target a tumor cell and/or increase an immune response against a tumor cell and thereby provide improved anti-tumor efficacy.
- antibody as referred to herein includes full-length antibodies and any antigen-binding fragment thereof (i.e., antibody fragment) .
- An “antibody” can be a standalone molecule or a portion of an antibody derivative.
- Exemplary antibody derivatives include, but are not limited to, a multispecific antibody (e.g., a bispecific antibody) , an antigen-recognizing receptor (e.g., a chimeric antigen receptor) , an antibody conjugate comprising an additional proteinaceous or non-proteinaceous moiety (e.g., an antibody-drug conjugate or a polymer-coated antibody) , and other multifuctional molecules comprising an antibody.
- a “full-length antibody” , “intact antibody” and “whole antibody” refers to an antibody similar to a native antibody structure or having heavy chains that contain an Fc region as defined herein.
- a full-length antibody comprises two heavy chains and two light chains.
- the variable regions of the light and heavy chains are responsible for antigen binding.
- the variable regions of a heavy chain and a light chain may be referred to as “VH” and “VL” , respectively.
- variable regions in both chains generally contain three highly variable loops called the complementarity determining regions (CDRs) (light chain (LC) CDRs including LC-CDR1, LC-CDR2, and LC-CDR3, heavy chain (HC) CDRs including HC-CDR1, HC-CDR2, and HC-CDR3) .
- CDR boundaries for the antibodies and antigen-binding fragments disclosed herein may be defined or identified by well-known conventions, e.g., the conventions of Kabat, Chothia, MacCallum, IMGT and AHo as described below.
- the three CDRs of the heavy or light chains are interposed between flanking stretches known as framework regions (FRs) , which are more conserved than the CDRs and form a scaffold to support the hypervariable loops.
- the constant regions of the heavy and light chains are not involved in antigen binding but exhibit various effector functions.
- Antibodies are assigned to classes based on the amino acid sequence of the constant region of their heavy chain.
- the five major classes or isotypes of antibodies are IgA, IgD, IgE, IgG, and IgM, which are characterized by the presence of ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ heavy chains, respectively.
- a full-length antibody is glycosylated.
- a full-length antibody comprises a glycan linked to its Fc region.
- a full-length antibody comprises a branched glycan.
- antibody portion refers to one or more fragments of a full-length antibody that retain the ability to specifically bind to an antigen. It has been shown that the antigen-binding function of a full-length antibody can be performed by fragments of a full-length antibody.
- antibody fragments include but are not limited to Fv, Fab, Fab', Fab'-SH, F (ab') 2, diabodies, linear antibodies, single-chain antibody molecules (e.g., scFv and scFv-Fc) , a single domain antibody, a VHH, a VHH-Fc, a nanobody, a domain antibody, a bivalent domain antibody, or any other fragment or combination thereof of an antibody that binds to an antigen.
- a “VHH” refers to a single domain antibody isolated from a camelid animal.
- a VHH comprises a variable region of a heavy chain of a camelid heavy chain antibody.
- a VHH has a size of no more than about 25 kDa. In certain embodiments, a VHH has a size of no more than about 20 kDa. In certain embodiments, a VHH has a size of no more than about 15 kDa.
- an “antibody that cross-competes for binding” with a reference antibody refers to an antibody that blocks binding of the reference antibody to its antigen in a competition assay by 50%or more, and conversely, the reference antibody blocks binding of the antibody to its antigen in a competition assay by 50%or more.
- An exemplary competition assay is described in Antibodies, Harlow and Lane (Cold Spring Harbor Press, Cold Spring Harbor, NY) .
- “Fv” is a minimum antibody fragment which contains a complete antigen-recognition and-binding site. This fragment consists of a dimer of one heavy-and one light-chain variable region in tight, non-covalent association. From the folding of these two domains emanate six hypervariable loops (3 loops in each of the heavy and light chains) that contribute the amino acid residues to antigen binding and confer antigen binding specificity to the antibody. However, even a single variable domain (or halfof an Fv comprising only three CDRs specific for an antigen) can recognize and bind to an antigen, although sometimes at a lower affinity than the entire binding site.
- Single-chain Fv also abbreviated as “sFv” or “scFv, ” are antibody fragments that comprise the V H and V L antibody domains connected into a single polypeptide chain.
- the scFv polypeptide further comprises a polypeptide linker between the V H and V L domains which enables the scFv to form the desired structure for antigen binding.
- Plückthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994) .
- acceptor human framework or “human framework” for the purposes herein is a framework comprising the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework.
- An acceptor human framework “derived from” a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence thereof, or it may contain amino acid sequence changes. In certain embodiments, the number of amino acid changes are 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less.
- the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or human consensus framework sequence.
- Binding affinity refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen) .
- binding affinity refers to intrinsic binding affinity which reflects a 1: 1 interaction between members of a binding pair (e.g., antibody and antigen) .
- the affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (KD) . Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described in the following.
- an “affinity matured” antibody refers to an antibody with one or more alterations in one or more CDRs or hypervariable regions (HVRs) , compared to a parent antibody which does not possess such alterations, which alterations provide improved affinity of the antibody for antigen.
- HVRs hypervariable regions
- B7H3 refers to any B7H3 polypeptide from any vertebrate source, including mammals such as primates (e.g., humans and cynomolgus monkeys) , or any fragment thereof, and may optionally comprise up to one, up to two, up to three, up to four, up to five, up to six, up to seven, up to eight, up to nine or up to ten amino acid substitutions, additions and/or deletions.
- the term encompasses full-length, unprocessed B7H3 as well as any form of B7H3 that results from processing in the cell.
- a B7H3 polypeptide comprises or has an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%or at least about 100%homologous or identical to the sequence having a NCBI Reference No: NP_001316557.1, NP_001316558.1, NP_079516.1 or NP_001019907.1 (homology herein may be determined using standard software such as BLAST or FASTA) .
- the B7H3 polypeptide comprises or has an amino acid sequence that is the entirety or a consecutive portion of SEQ ID NO: 83.
- ECD of B7H3 refers to an extracellular domain of B7H3.
- the ECD of an exemplary B7H3 polypeptide can comprise the amino acid sequence set forth in SEQ ID NO: 84.
- anti-B7H3 antibody and “an antibody that binds to B7H3” refer to an antibody that is capable of binding to B7H3 with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent for targeting B7H3.
- the extent of binding of an anti-B7H3 antibody to an unrelated, non-B7H3 protein is less than about 10%of the binding of the antibody to B7H3 as measured, e.g., by a surface plasmon resonance assay.
- an antibody that binds to B7H3 has a dissociation constant (KD) of ⁇ about 1 ⁇ M, ⁇ about 100 nM, ⁇ about 10 nM, ⁇ about 1 nM, ⁇ about 0.1 nM, ⁇ about 0.01 nM, or ⁇ about 0.001 nM (e.g., 10 -8 M or less, e.g., from 10 -8 M to 10 -12 M, e.g., from 10 -9 M to 10 -10 M) .
- KD dissociation constant
- an anti-B7H3 antibody binds to an epitope of B7H3 that is conserved among B7H3 from different species.
- an anti-B7H3 antibody binds to an epitope on B7H3 that is in the ECD of the protein.
- chimeric antibody refers to an antibody in which a portion of the heavy and/or light chain is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from a different source or species.
- a chimeric antibody disclosed herein comprises a camelid heavy chain variable region and a human Fc region.
- CDR complementarity determining region
- CDR complementarity determining region
- Residue numbering follows the nomenclature of Kabat et al., supra. 2 Residue numbering follows the nomenclature of Chothia et al., supra. 3 Residue numbering follows the nomenclature of MacCallum et al., supra. 4 Residue numbering follows the nomenclature of Lefranc et al., supra. 5 Residue numbering follows the nomenclature of Honegger and Plückthun, supra.
- variable-domain residue-numbering as in Kabat or “amino-acid-position numbering as in Kabat, ” and variations thereof, refers to the numbering system used for heavy-chain variable domains or light-chain variable domains of the compilation of antibodies in Kabat et al., supra. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, a FR or CDR of the variable domain.
- a heavy-chain variable domain may include a single amino acid insert (residue 52a according to Kabat) after residue 52 of H2 and inserted residues (e.g. residues 82a, 82b, and 82c, etc. according to Kabat) after heavy-chain FR residue 82.
- the Kabat numbering of residues may be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a “standard” Kabat numbered sequence.
- the amino acid residues which encompass the CDRs of a single domain antibody is defined according to the IMGT nomenclature in Lefranc et al., supra.
- the amino acid residues which encompass the CDRs of a full-length antibody is defined according to the Kabat nomenclature in Kabat et al., supra.
- the numbering of the residues in an immunoglobulin heavy chain, e.g., in an Fc region is that of the EU index as in Kabat et al., supra.
- the “EU index as in Kabat” refers to the residue numbering of the human IgG1 EU antibody.
- Framework or “FR” refers to residues are those variable-domain residues other than the CDR residues as herein defined.
- a “humanized” antibody refers to a chimeric antibody comprising amino acid residues from non-human CDRs/HVRs and amino acid residues from human FRs.
- a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs/CDRs correspond to those of a non-human antibody, and all or substantially all of the FRs correspond to those of a human antibody.
- a humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody.
- a “humanized form” of an antibody, e.g., a non-human antibody refers to an antibody that has undergone humanization.
- a “human antibody” is an antibody that possesses an amino-acid sequence corresponding to that of an antibody produced by a human and/or has been made using any of the techniques for making human antibodies as disclosed herein. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues.
- Human antibodies can be produced using various techniques known in the art, including phage-display libraries. Hoogenboom and Winter, J. Mol. Biol., 227: 381 (1991) ; Marks et al., J. Mol. Biol., 222: 581 (1991) . Also available for the preparation of human monoclonal antibodies are methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R.
- Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled, e.g., immunized xenomice (see, e.g., U.S. Pat. Nos. 6,075,181 and 6,150,584 regarding XENOMOUSE TM technology) . See also, for example, Li et al., Proc. Natl. Acad. Sci. USA, 103: 3557-3562 (2006) regarding human antibodies generated via a human B-cell hybridoma technology.
- Percent (%) amino acid sequence identity or “homology” with respect to the polypeptide and antibody sequences identified herein is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the polypeptide being compared, after aligning the sequences considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, Megalign (DNASTAR) , or MUSCLE software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full-length of the sequences being compared.
- %amino acid sequence identity values are generated using the sequence comparison computer program MUSCLE (Edgar, R.C., Nucleic Acids Research 32 (5) : 1792-1797, 2004; Edgar, R.C., BMC Bioinformatics 5 (1) : 113, 2004) .
- “Homologous” refers to the sequence similarity or sequence identity between two polypeptides or between two nucleic acid molecules. When a position in both of the two compared sequences is occupied by the same base or amino acid monomer subunit, e.g., if a position in each of two DNA molecules is occupied by adenine, then the molecules are homologous at that position.
- the percent of homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences divided by the number of positions compared times 100. For example, if 6 of 10 of the positions in two sequences are matched or homologous then the two sequences are 60%homologous.
- the DNA sequences ATTGCC and TATGGC share 50%homology. Generally, a comparison is made when two sequences are aligned to give maximum homology.
- constant domain refers to the portion of an immunoglobulin molecule having a more conserved amino acid sequence relative to the other portion of the immunoglobulin, the variable domain, which contains the antigen-binding site.
- the constant domain contains the C H 1, C H 2 and C H 3 domains (collectively, C H ) of the heavy chain and the C L domain of the light chain.
- the “light chains” of antibodies e.g., immunoglobulins
- kappa “ ⁇ ”
- lambda “ ⁇ ”
- CH1 domain (also referred to as “C1” of “H1” domain) usually extends from about amino acid 118 to about amino acid 215 (EU numbering system) .
- Hinge region is generally defined as a region in IgG corresponding to Glu216 to Pro230 of human IgG1 (Burton, Molec. Immunol. 22: 161-206 (1985) ) . Hinge regions of other IgG isotypes may be aligned with the IgG1 sequence by placing the first and last cysteine residues forming inter-heavy chain S-S bonds in the same positions.
- the “CH2 domain” of a human IgG Fc region usually extends from about amino acid 231 to about amino acid 340.
- the CH2 domain is unique in that it is not closely paired with another domain. Rather, two N-linked branched carbohydrate chains are interposed between the two CH2 domains of an intact native IgG molecule. It has been speculated that the carbohydrate may provide a substitute for the domain-domain pairing and help stabilize the CH2 domain.
- CH3 domain (also referred to as “C2” domain) comprises the residues between a CH2 domain and the C-terminal of an Fc region (i.e. from about amino acid residue 341 to the C-terminal end of an antibody sequence, typically at amino acid residue 446 or 447 of an IgG) .
- Fc region or “fragment crystallizable region” herein is used to define a C-terminal region of an immunoglobulin heavy chain, including native-sequence Fc regions and variant Fc regions.
- the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy-chain Fc region is usually defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof.
- the C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region may be removed, for example, during production or purification of the antibody, or by recombinantly engineering the nucleic acid encoding a heavy chain of the antibody.
- composition of intact antibodies may comprise antibody populations with all K447 residues removed, antibody populations with no K447 residues removed, and antibody populations having a mixture of antibodies with and without the K447 residue.
- Suitable native-sequence Fc regions for use in the antibodies described herein include human IgG1, IgG2 (IgG2A, IgG2B) , IgG3 and IgG4.
- Fc receptor or “FcR” describes a receptor that binds the Fc region of an antibody.
- the preferred FcR is a native human FcR.
- a preferred FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII subclasses, including allelic variants and alternatively spliced forms of these receptors
- Fc ⁇ RII receptors include Fc ⁇ RIIA (an “activating receptor” ) and Fc ⁇ RIIB (an “inhibiting receptor” ) , which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof.
- Activating receptor Fc ⁇ RIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain.
- Inhibitory receptor Fc ⁇ RIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain.
- ITAM immunoreceptor tyrosine-based activation motif
- ITIM immunoreceptor tyrosine-based inhibition motif
- epitope refers to the specific group of atoms or amino acids on an antigen to which an antibody or antibody derivative binds. Two antibodies or antigen-binding moieties may bind the same epitope within an antigen if they exhibit competitive binding for the antigen.
- the terms “specifically binds, ” “specifically recognizing, ” and “is specific for” refer to measurable and reproducible interactions, such as binding between a target and an antibody or antibody moiety, which is determinative of the presence of the target in the presence of a heterogeneous population of molecules, including biological molecules.
- an antibody or antibody moiety that specifically recognizes a target is an antibody or antibody moiety that binds this target with greater affinity, greater avidity, greater readiness, and/or greater duration than its bindings to other targets.
- the extent of binding of an antibody to an unrelated target is less than about 10%of the binding of the antibody to the target as measured, e.g., by a radioimmunoassay (RIA) .
- an antibody that specifically binds a target has a dissociation constant (K D ) of ⁇ 10 -5 M, ⁇ 10 -6 M, ⁇ 10 -7 M, ⁇ 10 -8 M, ⁇ 10 -9 M, ⁇ 10 -10 M, ⁇ 10 -11 M, or ⁇ 10 -12 M.
- K D dissociation constant
- an antibody specifically binds an epitope on a protein that is conserved among the protein from different species.
- specific binding can include, but does not require exclusive binding.
- Binding specificity of the antibody or antigen-binding domain can be determined experimentally by methods known in the art. Such methods comprise, but are not limited to Western blots, ELISA-, RIA-, ECL-, IRMA-, EIA-, BIACORE TM -tests and peptide scans.
- an “isolated” antibody is one that has been identified, separated and/or recovered from a component of its production environment (e.g., natural or recombinant) .
- the isolated polypeptide is free or substantially free from association with all other components from its production environment.
- an “isolated” nucleic acid molecule encoding a construct, antibody, or antigen-binding fragment thereof described herein is a nucleic acid molecule that is identified and separated from at least one contaminant nucleic acid molecule with which it is ordinarily associated in the environment in which it was produced. In certain embodiments, the isolated nucleic acid is free or substantially free from association with all components associated with the production environment.
- the isolated nucleic acid molecules encoding the polypeptides and antibodies described herein is in a form other than in the form or setting in which it is found in nature. Isolated nucleic acid molecules therefore are distinguished from nucleic acid encoding the polypeptides and antibodies described herein existing naturally in cells.
- An isolated nucleic acid includes a nucleic acid molecule contained in cells that ordinarily contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.
- control sequences refers to DNA sequences necessary for the expression of an operably linked coding sequence in a particular host organism.
- the control sequences that are suitable for prokaryotes include a promoter, optionally an operator sequence, and a ribosome binding site.
- Eukaryotic cells are known to utilize promoters, polyadenylation signals, and enhancers.
- Nucleic acid is “operably linked” when it is placed into a functional relationship with another nucleic acid sequence.
- DNA for a presequence or secretory leader is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide;
- apromoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or
- a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation.
- “operably linked” means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading frame. However, enhancers do not have to be contiguous. Linking is accomplished by ligation at convenient restriction sites. If such sites do not exist, the synthetic oligonucleotide adaptors or linkers are used in accordance with conventional practice.
- vector refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked.
- the term includes the vector as a self- replicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced.
- Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as “expression vectors. ”
- transfected or “transformed” or “transduced” as used herein refers to a process by which exogenous nucleic acid is transferred or introduced into the host cell.
- a “transfected” or “transformed” or “transduced” cell is one which has been transfected, transformed or transduced with exogenous nucleic acid, which cell includes the primary subject cell and its progeny.
- host cell refers to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells.
- Host cells include “transformants” and “transformed cells, ” which include the primary transformed cell and progeny derived therefrom without regard to the number of passages. Progeny may not be completely identical in nucleic acid content to a parent cell and may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell are included herein.
- subject “individual, ” and “patient” are used interchangeably herein to refer to a mammal, including, but not limited to, human, bovine, horse, feline, canine, rodent, or primate. In some embodiments, the subject is a human.
- an “effective amount” of an agent refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.
- the specific dose may vary depending on one or more of the particular agent chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to be imaged, and the physical delivery system in which it is carried.
- a “therapeutically effective amount” of a substance/molecule of the application, agonist or antagonist may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the substance/molecule, agonist or antagonist to elicit a desired response in the individual.
- a therapeutically effective amount is also one in which any toxic or detrimental effects of the substance/molecule, agonist or antagonist are outweighed by the therapeutically beneficial effects.
- a therapeutically effective amount may be delivered in one or more administrations.
- prophylactically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, but not necessarily, since aprophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.
- beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease) , preventing or delaying the spread (e.g., metastasis) of the disease, preventing or delaying the recurrence of the disease, delaying or slowing the progression of the disease, ameliorating the disease state, providing a remission (partial or total) of the disease, decreasing the dose of one or more other medications required to treat the disease, delaying the progression of the disease, increasing or improving the quality of life, increasing weight gain, and/or prolonging survival.
- treatment is a reduction of pathological consequence of cancer (such as, for example, tumor volume) .
- pathological consequence of cancer such as, for example, tumor volume
- the methods of the application contemplate any one or more of these aspects of treatment.
- Treatment does not necessarily mean that the condition being treated will be cured.
- the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. In certain embodiments, “about” can mean within 3 or more than 3 standard deviations, per the practice in the art. In certain embodiments, “about” can mean a range of up to 20%, e.g., up to 10%, up to 5%, or up to 1%of a given value. In certain embodiments, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, e.g., within 5-fold or within 2-fold, of a value.
- modulate means positively or negatively alter.
- exemplary modulations include a about 1%, about 2%, about 5%, about 10%, about 25%, about 50%, about 75%, or about 100%change.
- the term “increase” means alter positively by at least about 5%.
- An alteration may be by about 5%, about 10%, about 25%, about 30%, about 50%, about 75%, about 100%or more.
- the term “reduce” means alter negatively by at least about 5%.
- An alteration may be by about 5%, about 10%, about 25%, about 30%, about 50%, about 75%, or even by about 100%.
- “Effector functions” refer to those biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: C1q binding and complement dependent cytotoxicity (CDC) , Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC) , phagocytosis, down regulation of cell surface receptors (e.g., B cell receptor) , and B cell activation.
- an “immunoconjugate” refers to an antibody conjugated to one or more heterologous molecule (s) , including but not limited to a cytotoxic agent.
- pharmaceutical formulation refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.
- a “pharmaceutically acceptable carrier, ” as used herein, refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject.
- a pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.
- variable region refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen.
- variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three CDRs.
- FRs conserved framework regions
- a single VH or VL domain may be sufficient to confer antigen-binding specificity.
- antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150: 880-887 (1993) ; Clarkson et al., Nature 352: 624-628 (1991) .
- antigen-recognizing receptor refers to a receptor that is capable of activating an immunoresponsive cell (e.g., a T-cell) in response to its binding to an antigen.
- immunoresponsive cell e.g., a T-cell
- antigen-recognizing receptors include native and modified T cell receptors ( “TCRs” ) and chimeric antigen receptors ( “CARs” ) .
- chimeric antigen receptor refers to a molecule comprising an extracellular antigen-binding domain that is fused to an intracellular signaling domain that is capable of activating or stimulating an immunoresponsive cell, and a transmembrane domain.
- the extracellular antigen-binding domain of a CAR comprises an antibody or an antibody fragment, e.g., a VHH or a scFv.
- the antibody e.g., VHH or scFv
- the CAR is selected to have high binding affinity or avidity for the antigen.
- immunoresponsive cell is meant a cell that functions in an immune response or a progenitor or progeny thereof.
- the present disclosure provides antibodies and antibody derivatives.
- the disclosure is based, in part, on the discovery of single domain antibodies that bind to B7H3, which can be used in antitumor therapeutics where the antibodies selectively target a tumor cell and/or inhibit a signal pathway mediated by B7H3 and thereby induce beneficial anti-tumor effects against a tumor cell.
- an antibody disclosed herein binds to a tumor cell and/or an immune cell expressing B7H3.
- an antibody disclosed herein is an antagonist antibody, which inhibits B7H3 functions.
- the anti-B7H3 antibody inhibit an interaction between B7H3 and its receptor.
- the anti-B7H3 antibody blocks or reduces an immune inhibitory signal caused by a B7H3 protein.
- the anti-B7H3 antibody comprises a single domain antibody, e.g., a camelid antibody or a VHH antibody.
- the anti-B7H3 antibody has an improved capability of tissue infiltration due to its smaller size compared to traditional antibodies in IgG, Fab and/or scFv forms.
- an antibody of the present disclosure can be or comprise a monoclonal antibody, including a chimeric, humanized or human antibody.
- the antibody disclosed herein comprises a humanized antibody.
- the antibody comprises an acceptor human framework, e.g., a human immunoglobulin framework or a human consensus framework.
- an antibody of the present disclosure can be an antibody fragment, e.g., a Fv, Fab, Fab', scFv, diabody, or F (ab') 2 fragment.
- the antibody is a full-length antibody, e.g., an intact IgG 1 antibody, or other antibody class or isotype as defined herein.
- an antibody or antibody derivative of the present disclosure can incorporate any of the features, singly or in combination, as described in this application, e.g., Sections 2.1-2.12 detailed herein.
- Antibodies and antibody derivatives of the present disclosure are useful, e.g., for the diagnosis or treatment of a neoplasm or a cancer.
- the neoplasia and cancers whose growth may be inhibited using the antibodies of this disclosure include neoplasia and cancers typically responsive to immunotherapy.
- the neoplasia and cancers include breast cancer (e.g., breast cell carcinoma) , ovarian cancer (e.g., ovarian cell carcinoma) and renal cell carcinoma (RCC) .
- cancers examples include melanoma (e.g., metastatic malignant melanoma) , prostate cancer, colon cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, brain tumors, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphomas (e.g., Hodgkin's and non-Hodgkin's lymphoma, lymphocytic lymphoma, primary CNS lymphoma, T-cell lymphoma) nasopharangeal carcinomas, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the
- an anti-B7H3 antibody of the present disclosure binds to the ECD of B7H3.
- the anti-B7H3 antibody binds to the ECD of B7H3 that comprises the amino acid sequence set forth in SEQ ID NO: 84.
- the anti-B7H3 antibody binds to the same epitope with an anti-B7H3 antibody described herein, e.g., 19C10, 19C10-V3 or 19C10-V4.
- the anti-B7H3 antibody disclosed herein can function as an antagonist of a B7H3-based signal pathway.
- the anti-B7H3 antibody can block or reduce the interaction between a B7H3 protein and its receptor.
- the anti-B7H3 antibody can reduce the interaction between a B7H3 protein and its receptor by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 99%or about 99.9%.
- the anti-B7H3 antibody can block the downstream immune inhibitory signaling of a B7H3 protein or its receptor.
- treatment using the anti-B7H3 antibody exhibits antitumor efficacy in a subject, whereby reduces tumor growth and/or lengthen the survival of a subject.
- the anti-B7H3 antibody increases an immune response and/or an antitumor effect of an immune cell, e.g., a T cell and/or a NK cell.
- the anti-B7H3 antibody comprising a single domain antibody has a smaller molecule size compared to a full-length antibody due to the smaller size of a single domain antibody compared to a Fab domain of a full-length antibody, which can result in superior tissue infiltration, e.g., at a tumor site, compared to a full-length antibody.
- treatment using the anti-B7H3 antibody exhibits superior antitumor efficacy compared to treatment using a full-length anti-B7H3 antibody, e.g., analogs of MGA-271 (also known as enoblituzumab) and/or h1702, which sequences are disclosed in US 8,802,091 and US 20200031934 A1, respectively.
- MGA-271 also known as enoblituzumab
- h1702 which sequences are disclosed in US 8,802,091 and US 20200031934 A1, respectively.
- the anti-B7H3 antibody comprises a single domain antibody that binds to B7H3.
- the single domain antibody comprises a VHH.
- the single domain antibody comprises a heavy chain variable region (VH) .
- VH variable region
- the single domain antibody is linked to a Fc region. In certain embodiments, the single domain antibody is not linked to a Fc region.
- the single domain antibody binds to B7H3 with a KD of about 1x10 -7 M or less. In certain embodiments, the single domain antibody binds to B7H3 with a KD of about 1x10 -8 M or less. In certain embodiments, the single domain antibody binds to B7H3 with a KD of about 5x10 -9 M or less. In certain embodiments, the single domain antibody binds to B7H3 with a KD of about 1x10 -9 M or less. In certain embodiments, the single domain antibody binds to B7H3 with a KD of about 1x10 -10 M or less.
- the single domain antibody binds to B7H3 with a KD of between about 1x10 -11 M and about 1x10 -7 M. In certain embodiments, the single domain antibody binds to B7H3 with a KD of between about 1x10 -10 M and about 1x10 -7 M. In certain embodiments, the single domain antibody binds to B7H3 with a KD of between about 1x10 -10 M and about 1x10 -8 M. In certain embodiments, the single domain antibody binds to B7H3 with a KD of between about 1x10 -11 M and about 1x10 -9 M.
- the single domain antibody binds to B7H3 with a KD of between about 2x10 -10 M and about 5x10 -9 M. In certain embodiments, the single domain antibody binds to B7H3 with a KD of between about 1x10 -9 M and about 5x10 - 8 M. In certain embodiments, the single domain antibody binds to B7H3 with a KD of between about 1x10 -10 M and about 1x10 -9 M.
- the single domain antibody cross-competes for binding to B7H3 with a reference anti-B7H3 single domain antibody comprising a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 1, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 2, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 3.
- the single domain antibody cross-competes for binding to B7H3 with a reference anti-B7H3 single domain antibody comprising a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 5, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 6, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 7.
- the single domain antibody cross-competes for binding to B7H3 with a reference anti-B7H3 single domain antibody comprising a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 9, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 10, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 11.
- the single domain antibody cross-competes for binding to B7H3 with a reference anti-B7H3 single domain antibody comprising a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 13, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 14, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 15.
- the single domain antibody cross-competes for binding to B7H3 with a reference anti-B7H3 single domain antibody comprising a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 17, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 18, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 19.
- the single domain antibody cross-competes for binding to B7H3 with a reference anti-B7H3 single domain antibody comprising a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 21, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 22, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 23.
- the single domain antibody cross-competes for binding to B7H3 with a reference anti-B7H3 single domain antibody comprising a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 25, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 26, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 27.
- the single domain antibody cross-competes for binding to B7H3 with a reference anti-B7H3 single domain antibody comprising a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 29, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 30, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 31.
- the single domain antibody cross-competes for binding to B7H3 with a reference anti-B7H3 single domain antibody comprising a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 33, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 34, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 35.
- the single domain antibody cross-competes for binding to B7H3 with a reference anti-B7H3 single domain antibody comprising a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 37, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 38, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 39.
- the single domain antibody cross-competes for binding to B7H3 with a reference anti-B7H3 single domain antibody comprising a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 41, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 42, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 43.
- the single domain antibody cross-competes for binding to B7H3 with a reference anti-B7H3 single domain antibody comprising a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 56, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 57, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 58.
- the single domain antibody comprises a heavy chain variable region comprising: a) a heavy chain variable region CDR1 comprises an amino acid sequence of any one of SEQ ID NOs: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41 and 56, or a variant thereof comprising up to about 3 amino acid substitutions; b) a heavy chain variable region CDR2 comprises an amino acid sequence of any one of SEQ ID NOs: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42 and 57, or a variant thereof comprising up to about 3 amino acid substitutions; and c) a heavy chain variable region CDR3 comprises an amino acid sequence of any one of SEQ ID NOs: 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43 and 58, or a variant thereof comprising up to about 3 amino acid substitutions.
- the single domain antibody comprises a heavy chain variable region that comprises a CDR1 domain, a CDR2 domain and a CDR3 domain, wherein the CDR1 domain, the CDR2 domain and the CDR3 domain respectively comprise a CDR1 domain, a CDR2 domain and a CDR3 domain comprised in a reference heavy chain variable region comprising the amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and 59.
- the single domain antibody comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 1, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 2, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 3.
- the single domain antibody comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 5, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 6, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 7.
- the single domain antibody comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 9, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 10, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 11.
- the single domain antibody comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 13, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 14, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 15.
- the single domain antibody comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 17, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 18, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 19.
- the single domain antibody comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 21, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 22, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 23.
- the single domain antibody comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 25, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 26, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 27.
- the single domain antibody comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 29, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 30, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 31.
- the single domain antibody comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 33, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 34, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 35.
- the single domain antibody comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 37, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 38, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 39.
- the single domain antibody comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 41, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 42, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 43.
- the single domain antibody comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 56, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 57, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 58.
- the single domain antibody comprises a heavy chain variable region comprising an amino acid sequence having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to the amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and 59.
- the single domain antibody comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and 59.
- the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 4. In certain embodiments, the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 8. In certain embodiments, the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 12. In certain embodiments, the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 16. In certain embodiments, the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 20. In certain embodiments, the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 24.
- the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 28. In certain embodiments, the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 32. In certain embodiments, the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 36. In certain embodiments, the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 40. In certain embodiments, the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 44. In certain embodiments, the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 48.
- the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 52. In certain embodiments, the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 59.
- any one of the amino acid sequences comprised in the heavy chain variable region can comprise up to about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 amino acid substitutions, deletions and/or additions.
- the amino acid substitution is a conservative substitution.
- the single domain antibody comprises a humanized framework.
- the humanized framework comprises a framework sequence of the heavy chain variable region sequences selected from the group consisting of SEQ ID NOs: 48, 52 and 59.
- the humanized framework comprises the framework sequences of SEQ ID NO: 48.
- the humanized framework comprises the framework sequences of SEQ ID NO: 52.
- the humanized framework comprises the framework sequences of SEQ ID NO: 59.
- the anti-B7H3 antibody does not comprise a Fc region. In certain embodiments, the anti-B7H3 antibody further comprises a Fc region. In certain embodiments, the Fc region comprises a human Fc region. In certain embodiments, the Fc region comprises a Fc region selected from the group consisting of the Fc regions of IgG, IgA, IgD, IgE and IgM. In certain embodiments, the Fc region comprises a Fc region selected from the group consisting of the Fc regions of IgG1, IgG2, IgG3 and IgG4. In certain embodiments, the Fc region comprises an IgG1 Fc region.
- the IgG1 Fc region comprising one or more mutation or modification that modifies an antibody-dependent cell-mediated cytotoxicity (ADCC) . In certain embodiments, the IgG1 Fc region comprising one or more mutation or modification that reduces an antibody-dependent cell-mediated cytotoxicity (ADCC) . In certain embodiments, the IgG1 Fc region comprising one or more mutation or modification that enhances an antibody-dependent cell-mediated cytotoxicity (ADCC) . In certain embodiments, the IgG1 Fc region comprises an afucosylated sugar chain. In certain embodiments, the IgG1 Fc region comprises the mutations of L235V, F243L, R292P, Y300L and P396L.
- the IgG1 Fc region comprises the mutations of L235V, F243L, R292P and Y300L. In certain embodiments, the IgG1 Fc region comprises the mutations of S239D, A330L and I332E.
- the anti-B7H3 antibody comprises the amino acid sequence set forth in SEQ ID NO: 53. In certain embodiments, the anti-B7H3 antibody comprises the amino acid sequence set forth in SEQ ID NO: 54. In certain embodiments, the anti-B7H3 antibody comprises the amino acid sequence set forth in SEQ ID NO: 55. In certain embodiments, the anti-B7H3 antibody comprises the amino acid sequence set forth in SEQ ID NO: 60.
- the heavy chain variable region is linked to a Fc region via a linker.
- the linker is a peptide linker.
- the peptide linker comprises about four to about thirty amino acids.
- the peptide linker comprises about four to about fifteen amino acids.
- the peptide linker comprise an amino acid sequence selected from the group consisting of SEQ ID NOs: 61-82.
- the anti-B7H3 antibody comprises a full-length immunoglobulin, a single-chain Fv (scFv) fragment, a Fab fragment, a Fab’ fragment, a F (ab’) 2, an Fv fragment, a disulfide stabilized Fv fragment (dsFv) , a (dsFv) 2, a VHH, a Fv-Fc fusion, a scFv-Fc fusion, a VHH-Fv fusion, a diabody, a tribody, a tetrabody or any combination thereof.
- the antibody is comprised in a larger molecule that is an antibody derivative.
- the antibody derivative is a multispecific antibody, e.g., a bispecific antibody, wherein the multispecific antibody comprises a second antibody moiety that specificallybinds to a second antigen.
- the second antigen is a tumor associated antigen.
- the tumor associated antigen is selected from the group consisting of Her-2, EGFR, PD-L1, c-Met, B Cell Maturation Antigen (BCMA) , carbonic anhydrase IX (CA1X) , carcinoembryonic antigen (CEA) , CD5, CD7, CD10, CD19, CD20, CD22, CD30, CD33, CD34, CD38, CD41, CD44, CD49f, CD56, CD74, CD123, CD133, CD138, CD276 (B7H3) , epithelial glycoprotein (EGP2) , trophoblast cell-surface antigen 2 (TROP-2) , epithelial glycoprotein-40 (EGP-40) , epithelial cell adhesion molecule (EpCAM) , receptor tyrosine-protein kinases erb-B2, 3, 4, folate-binding protein (FBP) , fetal acetylcholine receptor (AChR) , folate receptor
- FBP
- the anti-B7H3 antibody is conjugated to a therapeutic agent or a label.
- the label is selected from the group consisting of a radioisotope, a fluorescent dye and an enzyme.
- an anti-EGFR antibody disclosed herein binds to an EGFR protein with high affinity.
- the anti-EGFR antibody blocks the interaction between EGFR and a ligand thereof, e.g., epidermal growth factor (EGF) , transforming growth factor alpha (TGF-alpha) , HB-EGF, amphiregulin, betacellulin/BTC and/or epigen/EPGN.
- the antibody is any anti-EGFR antibody disclosed in PCT/US2015/033402 (published as International Publication WO2015184403A2) , the content of which is incorporated herein by references in its entirety.
- the anti-EGFR antibody cross-competes with a reference anti-EGFR antibody that comprises: a) a heavy chain variable domain (VH) sequence comprising (1) a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 85, (2) a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 86, and (3) a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 87; and a light chain variable domain (VL) sequence comprising (1) a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 88, (2) a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 89, and (3) a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 90; b) a heavy chain variable domain (VH) sequence comprising (1) a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 93, (2) a CDR-H
- the anti-EGFR antibody comprises a heavy chain variable domain (VH) sequence comprising (1) a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 85, (2) a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 86, and (3) a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 87; and a light chain variable domain (VL) sequence comprising (1) a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 88, (2) a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 89, and (3) a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 90.
- VH heavy chain variable domain
- VL light chain variable domain
- the anti-EGFR antibody comprises a heavy chain variable domain (VH) sequence comprising (1) a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 93, (2) a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 94, and (3) a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 95; and a light chain variable domain (VL) sequence comprising (1) a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 96, (2) a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 97, and (3) a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 98.
- VH heavy chain variable domain
- VL light chain variable domain
- the anti-EGFR antibody comprises a heavy chain variable domain (VH) sequence comprising (1) a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 101, (2) a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 102, and (3) a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 103; and a light chain variable domain (VL) sequence comprising (1) a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 104, (2) a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 105, and (3) a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 106.
- VH heavy chain variable domain
- VL light chain variable domain
- the anti-EGFR antibody comprises a heavy chain variable domain (VH) sequence comprising (1) a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 109, (2) a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 110, and (3) a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 111; and a light chain variable domain (VL) sequence comprising (1) a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 112, (2) a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 113, and (3) a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 114.
- VH heavy chain variable domain
- VL light chain variable domain
- the anti-EGFR antibody comprises a heavy chain variable domain (VH) sequence comprising (1) a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 117, (2) a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 118, and (3) a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 119; and a light chain variable domain (VL) sequence comprising (1) a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 120, (2) a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 121, and (3) a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 122.
- VH heavy chain variable domain
- VL light chain variable domain
- the anti-EGFR antibody comprises a heavy chain variable region comprising an amino acid sequence having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to the amino acid sequence selected from the group consisting of SEQ ID NOs: 91, 99, 107, 115 and 123, and a light chain variable region comprising an amino acid sequence having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to the amino acid sequence selected from the group consisting of SEQ ID NOs: 92, 100, 108, 116 and 124.
- the anti-EGFR antibody comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 91, 99, 107, 115 and 123, and a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 92, 100, 108, 116 and 124.
- the anti-EGFR antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 91, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 92. In certain embodiments, the anti-EGFR antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 99, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 100. In certain embodiments, the anti-EGFR antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 107, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 108.
- the anti-EGFR antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 115, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 116. In certain embodiments, the anti-EGFR antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 123, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 124.
- any one of the amino acid sequences comprised in the heavy chain variable region and/or the light chain variable region can comprise up to about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 amino acid substitutions, deletions and/or additions.
- the amino acid substitution is a conservative substitution.
- the anti-EGFR antibody comprises a Fc region.
- the Fc region is selected from the group consisting of the Fc regions of IgG, IgA, IgD, IgE and IgM.
- the Fc region is selected from the group consisting of the Fc regions of IgG1, IgG2, IgG3 and IgG4.
- the Fc region comprises a human Fc region.
- the Fc region comprises an IgG1 Fc region.
- the IgG1 Fc region comprising one or more mutation that modifies an antibody-dependent cell-mediated cytotoxicity (ADCC) .
- ADCC antibody-dependent cell-mediated cytotoxicity
- the IgG1 Fc region comprising one or more mutation that enhances an antibody-dependent cell-mediated cytotoxicity (ADCC) . In certain embodiments, the IgG1 Fc region comprising one or more mutation that reduces an antibody-dependent cell-mediated cytotoxicity (ADCC) . In certain embodiments, the IgG1 Fc region comprising one or more mutation that enhances an antibody-dependent cell-mediated cytotoxicity (ADCC) . In certain embodiments, the IgG1 Fc region comprises an afucosylated sugar chain. In certain embodiments, the IgG1 Fc region comprises the mutations of L235V, F243L, R292P, Y300L and P396L.
- the IgG1 Fc region comprises the mutations of S239D, A330L and I332E. In certain embodiments, the IgG1 Fc region comprises the mutations of L235V, F243L, R292P and Y300L. In certain embodiments, the Fc region comprises an IgG4 Fc region. In certain embodiments, the IgG4 Fc region comprises an S228P mutation. In certain embodiments, the IgG4 Fc region comprises the mutations of F234A and L235A.
- the anti-EGFR antibody of the second antigen-binding moiety comprises a humanized framework.
- the humanized framework comprises a heavy chain framework sequence of the heavy chain variable region sequences selected from the group consisting of SEQ ID NOs: 91, 99, 107, 115 and 123.
- the humanized framework comprises a light chain framework sequence of the heavy chain variable region sequences selected from the group consisting of SEQ ID NOs: 92, 100, 108, 116 and 124.
- the present disclosure further provides multispecific antibodies, e.g., a bispecific antibody.
- Multispecific antibodies are antibody derivatives that have binding specificities for at least two different antigens or antigen epitopes.
- one of the binding specificities is for an epitope present on B7H3 and the other is for an epitope present on a different antigen.
- one of the binding specificities is for an epitope present on EGFR and the other is for an epitope present on a different antigen.
- a multispecific antibody of the present disclosure can bind to an epitope on B7H3 and an epitope on EGFR.
- a multispecific antibody of the present disclosure can comprise a full-length antibody, an antibody fragment and/or any combination thereof.
- a multispecific antibody disclosed herein binds to B7H3 and EGFR.
- the multispecific antibody is a bispecific, anti-B7H3/anti-EGFR antibody.
- the multispecific antibody has at least two different binding specificities, see, e.g., U.S. Patent Nos. 5,922,845 and 5,837,243; Zeilder (1999) J. Immunol. 163: 1246-1 252; Somasundaram (1999) Hum. Antibodies 9: 47-54; Keler (1997) Cancer Res. 57: 4008-401 4.
- the presently disclosed subject matter provides multispecific antibodies comprising one antigen-binding moiety for a first epitope present on B7H3 and a second antigen-binding moiety for a second epitope present on EGFR.
- the multispecific antibody comprises a first antigen-binding moiety comprising an anti-B7H3 antibody disclosed herein; and a second antigen-binding moiety comprising an anti-EGFR antibody disclosed herein.
- the anti-B7H3/anti-EGFR antibody disclosed herein can function as an antagonist of both B7H3 signaling and EGFR signaling.
- the anti-EGFR moiety of the anti-B7H3/anti-EGFR antibody can guide and/or concentrate the antibody at a tumor site, whereby enhances the antitumor functions of an immune cell at the vicinity of the tumor site and/or reduces the toxicity and side effects of aperipheral cells.
- treatment using the anti-B7H3/anti-EGFR antibody exhibits superior antitumor efficacy compared to treatment using a monospecific anti-B7H3 antibody or a monospecific anti-EGFR antibody.
- treatment using the anti-B7H3/anti-EGFR antibody exhibits superior antitumor efficacy compared to treatment using a combination of a monospecific anti-B7H3 antibody and a monospecific anti-EGFR antibody.
- the anti-B7H3/anti-EGFR multispecific antibody comprises a first antigen-binding moiety comprising an anti-B7H3 antibody comprising a single domain antibody that binds to B7H3, and a second antigen-binding moiety comprising an anti-EGFR antibody that binds to EGFR.
- the first antigen-binding moiety comprises an anti-B7H3 antibody disclosed herein.
- the second antigen-binding moiety comprises an anti-EGFR antibody disclosed herein.
- the second antigen-binding moiety comprises an anti-EGFR antibody disclosed in PCT/US2015/033402 (published as International Publication WO2015184403A2) , the content of which is incorporated herein by references in its entirety.
- the anti-B7H3/anti-EGFR multispecific antibody can be a multivalent antibody.
- the multispecific antibody can be bivalent, trivalent, tetravalent, pentavalent, hexavalent, heptavalent or octavalent.
- each of the first and the second antigen-binding moieties of the anti-B7H3/anti-EGFR antibody can be monovalent, bivalent, trivalent, tetravalent, pentavalent, hexavalent, heptavalent or octavalent.
- each of the first and the second antigen-binding moieties is monovalent.
- each of the first and the second antigen-binding moieties is bivalent.
- the multispecific antibody is bivalent.
- the multispecific antibody is tetravalent.
- the second antigen binding moiety comprises an anti-EGFR antibody comprising two antibody heavy chains and two antibody light chains.
- the first antigen-binding moiety comprises one or more anti-B7H3 antibodies.
- the first antigen-binding moiety comprises two anti-B7H3 antibodies.
- the C-terminus of at least one of the two anti-EGFR light chains is linked to an anti-B7H3 antibody of the first antigen binding moiety.
- the C-terminus of each of the two anti-EGFR light chains is linked to an anti-B7H3 antibody of the first antigen binding moiety.
- the N-terminus of at least one of the two anti-EGFR light chains is linked to an anti-B7H3 antibody of the first antigen binding moiety. In certain embodiments, the N-terminus of each of the two anti-EGFR light chains is linked to an anti-B7H3 antibody of the first antigen binding moiety. In certain embodiments, the C-terminus of at least one of the two anti-EGFR heavy chains is linked to an anti-B7H3 antibody of the first antigen binding moiety. In certain embodiments, the C-terminus of each of the two anti-EGFR heavy chains is linked to an anti-B7H3 antibody of the first antigen binding moiety.
- the N-terminus of at least one of the two anti-EGFR heavy chains is linked to an anti-B7H3 antibody of the first antigen binding moiety. In certain embodiments, the N-terminus of each of the two anti-EGFR heavy chains is linked to an anti-B7H3 antibody of the first antigen binding moiety.
- the multispecific antibody comprises i) a first antigen-binding moiety comprising a single domain anti-B7H3 antibody that comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 41, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 42, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 43; and ii) a second antigen-binding moiety comprising an anti-EGFR antibody comprising a heavy chain variable domain (VH) sequence that comprises (1) a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 101, (2) a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 102, and (3) a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 103; and a light chain variable domain (VL) sequence comprising (1) a CDR-L1 comprising the
- the multispecific antibody comprises i) a first antigen-binding moiety comprising a single domain anti-B7H3 antibody that comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 49, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 50, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 51; and ii) a second antigen-binding moiety comprising an anti-EGFR antibody comprising a heavy chain variable domain (VH) sequence that comprises (1) a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 101, (2) a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 102, and (3) a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 103; and a light chain variable domain (VL) sequence comprising (1) a CDR-L1 comprising the
- the multispecific antibody comprises i) a first antigen-binding moiety comprising a single domain anti-B7H3 antibody that comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 56, a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 57, and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 58; and ii) a second antigen-binding moiety comprising an anti-EGFR antibody comprising a heavy chain variable domain (VH) sequence that comprises (1) a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 101, (2) a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 102, and (3) a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 103; and a light chain variable domain (VL) sequence comprising (1) a CDR-L1 comprising amino acids having
- the first antigen binding moiety is linked to the second antigen binding moiety via a linker.
- the linker is a peptide linker.
- the peptide linker comprises about four to about thirty amino acids.
- the peptide linker comprises about four to about fifteen amino acids.
- the peptide linker comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 61-82.
- the anti-EGFR antibody of the second antigen-binding moiety comprises a Fc region.
- the Fc region is selected from the group consisting of the Fc regions of IgG, IgA, IgD, IgE and IgM.
- the Fc region is selected from the group consisting of the Fc regions of IgG1, IgG2, IgG3 and IgG4.
- the Fc region comprises a human Fc region.
- the Fc region comprises an IgG1 Fc region.
- the IgG1 Fc region comprises one or more mutation or modification that modifies an antibody-dependent cell-mediated cytotoxicity (ADCC) .
- ADCC antibody-dependent cell-mediated cytotoxicity
- the IgG1 Fc region comprises one or more mutation or modification that reduces an antibody-dependent cell-mediated cytotoxicity (ADCC) . In certain embodiments, the IgG1 Fc region comprises one or more mutation or modification that enhances an antibody-dependent cell-mediated cytotoxicity (ADCC) . In certain embodiments, the IgG1 Fc region comprises an afucosylated sugar chain. In certain embodiments, the IgG1 Fc region comprises the mutations of L235V, F243L, R292P, Y300L and P396L. In certain embodiments, the IgG1 Fc region comprises the mutations of S239D, A330L and I332E.
- the IgG1 Fc region comprises the mutations of L235V, F243L, R292P and Y300L. In certain embodiments, the Fc region comprises an IgG4 Fc region. In certain embodiments, the IgG4 Fc region comprises an S228P mutation.
- the anti-B7H3 antibody of the first antigen-binding moiety comprises a humanized framework.
- the humanized framework comprises a framework sequence of the heavy chain variable region sequences selected from the group consisting of SEQ ID NOs: 48, 52 and 59.
- the humanized framework comprises the framework sequences of SEQ ID NO: 48.
- the humanized framework comprises the framework sequences of SEQ ID NO: 52.
- the humanized framework comprises the framework sequences of SEQ ID NO: 59.
- the anti-EGFR antibody of the second antigen-binding moiety comprises a humanized framework.
- the humanized framework comprises a heavy chain framework sequence of the heavy chain variable region sequences selected from the group consisting of SEQ ID NOs: 91, 99, 107, 115 and 123.
- the humanized framework comprises a light chain framework sequence of the heavy chain variable region sequences selected from the group consisting of SEQ ID NOs: 92, 100, 108, 116 and 124.
- the multispecific antibody comprises an anti-EGFR antibody heavy chain linked to an anti-B7H3 antibody comprising the amino acid sequence set forth in SEQ ID NO: 125, and an anti-EGFR antibody light chain comprising the amino acid sequence set forth in SEQ ID NO: 128.
- the multispecific antibody comprises an anti-EGFR antibody heavy chain linked to an anti-B7H3 antibody comprising the amino acid sequence set forth in SEQ ID NO: 126, and an anti-EGFR antibody light chain comprising the amino acid sequence set forth in SEQ ID NO: 128.
- the multispecific antibody comprises an anti-EGFR antibody heavy chain linked to an anti-B7H3 antibody comprising the amino acid sequence set forth in SEQ ID NO: 127, and an anti-EGFR antibody light chain comprising the amino acid sequence set forth in SEQ ID NO: 128.
- the multispecific antibody comprises two anti-EGFR antibody heavy chains, each of which is linked to an anti-B7H3 antibody and comprises the amino acid sequence set forth in SEQ ID NO: 125, and two anti-EGFR antibody light chains comprising the amino acid sequence set forth in SEQ ID NO: 128.
- the multispecific antibody comprises two anti-EGFR antibody heavy chains, each of which is linked to an anti-B7H3 antibody and comprises the amino acid sequence set forth in SEQ ID NO: 126, and two anti-EGFR antibody light chains comprising the amino acid sequence set forth in SEQ ID NO: 128.
- the multispecific antibody comprises two anti-EGFR antibody heavy chains, each of which is linked to an anti-B7H3 antibody and comprises the amino acid sequence set forth in SEQ ID NO: 127, and two anti-EGFR antibody light chains comprising the amino acid sequence set forth in SEQ ID NO: 128.
- an antibody or antibody derivative disclosed herein has a high binding affinity to its target antigen.
- the antibody or antibody derivative binds to the target with a KD of about 1x10 -7 M or less. In certain embodiments, the antibody or antibody derivative binds to the target with a KD of about 1x10 -8 M or less. In certain embodiments, the antibody or antibody derivative binds to the target with a KD of about 5x10 -9 M or less. In certain embodiments, the antibody or antibody derivative binds to the target with a KD of about 1x10 -9 M or less. In certain embodiments, the antibody or antibody derivative binds to the target with a KD of about 1x10 -10 M or less.
- the antibody or antibody derivative binds to the target with a KD of between about 1x10 -11 M and about 1x10 -7 M. In certain embodiments, the antibody or antibody derivative binds to the target with a KD of between about 1x10 -10 M and about 1x10 - 7 M. In certain embodiments, the antibody or antibody derivative binds to the target with a KD of between about 1x10 -10 M and about 1x10 -8 M. In certain embodiments, the antibody or antibody derivative binds to the target with a KD of between about 1x10 -11 M and about 1x10 - 9 M.
- the antibody or antibody derivative binds to the target with a KD of between about 2x10 -10 M and about 5x10 -9 M. In certain embodiments, the antibody or antibody derivative binds to the target with a KD of between about 1x10 -9 M and about 5x10 -8 M. In certain embodiments, the antibody or antibody derivative binds to the target with a KD of between about 1x10 -10 M and about 1x10 -9 M.
- the KD of the antibody or antibody derivative can be determined by methods known in the art. Such methods comprise, but are not limited to Western blots, ELISA-, RIA-, ECL-, IRMA-, EIA-, Octet- -tests and peptide scans.
- KD can be measured using a surface plasmon resonance assay.
- a surface plasmon resonance assay For example, and not by way of limitation, an assay using a -2000 or a 3000 (Biacore, Inc., Piscataway, NJ) is performed at 25°C with immobilized antigen CMS chips at about 10 response units (RU) .
- CMS, Biacore, Inc. carboxymethylated dextran biosensor chips
- EDC N-ethyl-N'- (3-dimethylaminopropyl) -carbodiimide hydrochloride
- NHS N-hydroxysuccinimide
- Antigen is diluted with 10 mM sodium acetate, pH 4.8, to 5 ⁇ g/ml (about 0.2 ⁇ M) before injection at a flow rate of 5 ⁇ l/minute to achieve approximately 10 response units (RU) of coupled protein. Following the injection of antigen, 1 M ethanolamine is injected to block unreacted groups. For kinetics measurements, two-fold serial dilutions of Fab (0.78 nM to 500 nM) are injected in PBS with 0.05%polysorbate 20 (TWEEN-20TM) surfactant (PBST) at 25°C at a flow rate of approximately 25 ⁇ l/min.
- TWEEN-20TM 0.05%polysorbate 20
- association rates (k on ) and dissociation rates (k off ) are calculated using a simple one-to-one Langmuir binding model ( Evaluation Software version 3.2) by simultaneously fitting the association and dissociation sensorgrams.
- the equilibrium dissociation constant (KD) can be calculated as the ratio koff/kon. See, e.g., Chen et al., J. Mol. Biol. 293: 865-881 (1999) .
- an antibody of the present disclosure comprises an antigen-binding fragment or antibody fragment.
- Antibody fragments include, but are not limited to, Fab, Fab', Fab'-SH, F (ab') 2, VHH, Fv, and scFv fragments, and other fragments described herein.
- Fab fragment antigen-binding fragment
- Fab' fragment antigen-binding fragment antigen-binding fragment antigen-binding fragment antigen-binding fragment or antibody fragment.
- Fab' fragment antigen-binding fragment or antibody fragment.
- an antibody of the present disclosure can be a diabody.
- Diabodies are antibody fragments with two antigen-binding sites that may be bivalent or bispecific. See, for example, EP 404, 097; WO 1993/01 161; Hudson et al., Nat. Med. 9: 129-134 (2003) ; and Hollinger et al., Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993) . Triabodies and tetrabodies are also described in Hudson et al., Nat. Med. 9: 129-134 (2003) .
- an antibody of the present disclosure can comprise a single domain antibody.
- Single domain antibodies are antibody fragments that comprise all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody.
- the single domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, MA; see, e.g., U.S. Patent No. 6,248,516 Bl) .
- the single domain antibody is camelid single-domain antibody.
- the single domain antibody is a VHH.
- the single domain antibody is humanized.
- Antibody fragments can be made by various techniques including, but not limited to, proteolytic digestion of an intact antibody as well as production by recombinant host cells (e.g., E. coli or phage) , as described herein.
- recombinant host cells e.g., E. coli or phage
- an antibody of the present disclosure is a chimeric antibody.
- Certain chimeric antibodies are described, e.g., in U.S. Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81: 6851-6855 (1984) ) .
- a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from mouse) and a human constant region.
- a chimeric antibody is a “class switched” antibody in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.
- an antibody of the present disclosure can be a humanized antibody.
- a non-human antibody is humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody.
- a humanized antibody comprises one or more variable domains in which HVRs, e.g., CDRs, (or portions thereof) are derived from a non-human antibody, and one or more framework (FR) (or any portion thereof) are derived from human antibody sequences.
- HVRs e.g., CDRs
- FR framework
- a humanized antibody optionally can also comprise at least a portion of a human constant region.
- certain FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived) , e.g., to restore or improve antibody specificity or affinity.
- a non-human antibody e.g., the antibody from which the HVR residues are derived
- Human framework regions that may be used for humanization include but are not limited to: framework regions selected using the “best-fit” method (see, e.g., Sims et al. J. Immunol. 151: 2296 (1993) ) ; Framework regions derived from the consensus sequence of human antibodies of a particular subgroup of light or heavy chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Sci. USA, 89: 4285 (1992) ; and Presta et al. J. Immunol., 151: 2623 (1993) ) ; human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front.
- an antibody of the present disclosure can be a human antibody (e.g., human domain antibody, or human DAb) .
- Human antibodies can be produced using various techniques known in the art. Human antibodies are described generally in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2001) , Lonberg, Curr. Opin. Immunol. 20: 450-459 (2008) , and Chen, Mol. Immunol. 47 (4) : 912-21 (2010) . Transgenic mice or rats capable of producing fully human single-domain antibodies (or DAb) are known in the art. See, e.g., US20090307787A1, U.S. Pat. No. 8,754,287, US20150289489A1, US20100122358A1, and WO2004049794.
- Human antibodies may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge.
- Such animals typically contain all or a portion of the human immunoglobulin loci, which replace the endogenous immunoglobulin loci, or which are present extrachromosomally or integrated randomly into the animal’s chromosomes.
- the endogenous immunoglobulin loci have generally been inactivated.
- Human variable regions from intact antibodies generated by such animals may be further modified, e.g., by combining with a different human constant region.
- Human antibodies can also be made by hybridoma-based methods.
- Human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies have been described (See, e.g., Kozbor J. Immunol., 133: 3001 (1984) ; Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987) ; and Boerner et al., J. Immunol., 147: 86 (1991) ) .
- Human antibodies generated via human B-cell hybridoma technology are also described in Li et al., Proc. Natl.
- Human antibodies may also be generated by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences may then be combined with a desired human constant domain. Techniques for selecting human antibodies from antibody libraries are described below.
- An antibody of the present disclosure may be isolated by screening combinatorial libraries for antibodies with the desired activity or activities.
- a variety of methods are known in the art for generating phage display libraries and screening such libraries for antibodies possessing the desired binding characteristics. Such methods are described, e.g., in Hoogenboom et al. in Methods in Molecular Biology 178: 1-37 (O’Brien et al., ed., Human Press, Totowa, NJ, 2001) and further described, e.g., in the McCafferty et al., Nature 348: 552-554; Clackson et al., Nature 352: 624-628 (1991) ; Marks et al., J. Mol. Biol.
- repertoires of V H and V L genes are separately cloned by polymerase chain reaction (PCR) and recombined randomly in phage libraries, which can then be screened for antigen-binding phage as described in Winter et al., Ann. Rev. Immunol., 12: 433-455 (1994) .
- Phage typically displays antibody fragments, either as scFv fragments or as Fab fragments.
- Libraries from immunized sources provide high-affinity antibodies to the immunogen without the requirement of constructing hybridomas.
- naive repertoire can be cloned (e.g., from human) to provide a single source of antibodies to a wide range of non-self and also self-antigens without any immunization as described by Griffiths et al., EMBO J, 12: 725-734 (1993) .
- naive libraries can also be made synthetically by cloning unrearranged V-gene segments from stem cells, and using PCR primers containing random sequence to encode the highly variable CDR3 regions and to accomplish rearrangement in vitro, as described by Hoogenboom and Winter, J. Mol. Biol., 227: 381-388 (1992) .
- Patent publications describing human antibody phage libraries include, for example: US Patent No. 5,750,373, and US Patent Publication Nos. 2005/0079574, 2005/0119455, 2005/0266000, 2007/0117126, 2007/0160598, 2007/0237764, 2007/0292936, and 2009/0002360.
- Antibodies or antibody fragments isolated from human antibody libraries are considered human antibodies or human antibody fragments herein.
- amino acid sequence variants of the disclosed antibodies For example, it may be desirable to improve the binding affinity and/or other biological properties of the antibody.
- Amino acid sequence variants of an antibody can be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, but are not limited to, deletions from, and/or insertions into and/or substitutions of residues within the amino acid sequences of the antibody. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final antibody, i.e., modified, possesses the desired characteristics, e.g., antigen-binding.
- antibody variants having one or more amino acid substitutions are provided.
- Sites of interest for substitutional mutagenesis include the HVRs (or CDRs) and FRs.
- Conservative substitutions are shown in Table 2 under the heading of “Preferred substitutions. ” More substantial changes are provided in Table 2 under the heading of “exemplary substitutions, ” and as further described below in reference to amino acid side chain classes.
- Amino acid substitutions may be introduced into an antibody of interest and the products screened for a desired activity, e.g., retained/improved antigen binding, decreased immunogenicity, or improved ADCC or CDC.
- Amino acids may be grouped according to common side-chain properties: (1) hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile; (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) residues that influence chain orientation: Gly, Pro; and (6) aromatic: Trp, Tyr, Phe.
- non-conservative substitutions will entail exchanging a member of one of these classes for another class.
- a type of substitutional variant involves substituting one or more hypervariable region residues of aparent antibody (e.g., a humanized or human antibody) .
- aparent antibody e.g., a humanized or human antibody
- the resulting variant (s) selected for further study will have modifications (e.g., improvements) in certain biological properties (e.g., increased affinity, reduced immunogenicity) relative to the parent antibody and/or will have substantially retained certain biological properties of the parent antibody.
- An exemplary substitutional variant is an affinity matured antibody, which may be conveniently generated, e.g., using phage display-based affinity maturation techniques such as those described herein. Briefly, one or more HVR (or CDR) residues are mutated and the variant antibodies displayed on phage and screened for a particular biological activity (e.g. binding affinity) .
- Alterations may be made in HVRs (or CDRs) , e.g., to improve antibody affinity.
- Such alterations may be made in HVR (or CDRs) “hotspots, ” i.e., residues encoded by codons that undergo mutation at high frequency during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207: 179-196 (2008) ) , and/or SDRs (a-CDRs) , with the resulting variant VH or VL being tested for binding affinity.
- Affinity maturation by constructing and reselecting from secondary libraries has been described, e.g., in Hoogenboom et al.
- HVR or CDRs
- CDRs HVR residues
- substitutions, insertions, or deletions may occur within one or more HVRs (or CDRs) so long as such alterations do not substantially reduce the ability of the antibody to bind antigen.
- conservative alterations e.g., conservative substitutions as provided herein
- Such alterations may be outside of HVR (or CDR) “hotspots” or CDRs.
- each HVR (or CDR) either is unaltered, or contains no more than one, two or three amino acid substitutions.
- a useful method for identification of residues or regions of an antibody that may be targeted for mutagenesis is called “alanine scanning mutagenesis” as described by Cunningham and Wells (1989) Science, 244: 1081-1085.
- a residue or group of target residues e.g., charged residues such as Arg, Asp, His, Lys, and Glu
- a neutral or negatively charged amino acid e.g., alanine or polyalanine
- Further substitutions may be introduced at the amino acid locations demonstrating functional sensitivity to the initial substitutions.
- a crystal structure of an antigen-antibody complex to identify contact points between the antibody and antigen. Such contact residues and neighboring residues may be targeted or eliminated as candidates for substitution.
- Variants may be screened to determine whether they contain the desired properties.
- Amino acid sequence insertions include amino-and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues.
- terminal insertions include an antibody with an N-terminal methionyl residue.
- Other insertional variants of the antibody molecule include the fusion to the N-or C-terminus of the antibody to an enzyme (e.g., for ADEPT) or a polypeptide which increases the serum half-life of the antibody.
- an antibody is altered to increase or decrease the extent to which the construct is glycosylated.
- Addition or deletion of glycosylation sites to an antibody may be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites is created or removed.
- the carbohydrate attached thereto may be altered.
- Native antibodies produced by mammalian cells typically comprise a branched, biantennary oligosaccharide that is generally attached by an N-linkage to Asn297 of the C H 2 domain of the Fc region. See, e.g., Wright et al. TIBTECH 15: 26-32 (1997) .
- the oligosaccharide may include various carbohydrates, e.g., mannose, N-acetyl glucosamine (GlcNAc) , galactose, and sialic acid, as well as a fucose attached to a GlcNAc in the “stem” of the biantennary oligosaccharide structure.
- modifications of the oligosaccharide in the antibody may be made in order to create antibody variants with certain improved properties.
- the antibody has a carbohydrate structure that lacks fucose attached (directly or indirectly) to an Fc region.
- the amount of fucose in such antibody may be from 1%to 80%, from 1%to 65%, from 5%to 65%or from 20%to 40%.
- the amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn 297 (e.g., complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008/077546, for example.
- Asn297 refers to the asparagine residue located at about position 297 in the Fc region (EU numbering of Fc region residues) ; however, Asn297 may also be located about ⁇ 3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function. See, e.g., US Patent Publication Nos. US 2003/0157108 (Presta, L. ) ; US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd) .
- Examples of publications related to “afucosylated” , “defucosylated” or “fucose-deficient” antibody variants include: US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614; US 2002/0164328; US 2004/0093621; US 2004/0132140; US 2004/0110704; US 2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO 2005/035586; WO 2005/035778; WO2005/053742; WO2002/031140; Okazaki et al. J. Mol. Biol.
- Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249: 533-545 (1986) ; US Patent Application No. US 2003/0157108 A1, Presta, L; and WO 2004/056312 A1, Adams et al. ) , and knockout cell lines, such as alpha-1, 6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004) ; Kanda, Y. et al., Biotechnol. Bioeng., 94 (4) : 680-688 (2006) ; and WO2003/085107) .
- the antibody has bisected oligosaccharides, e.g., in which a biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GlcNAc.
- Such antibody variants may have reduced fucosylation and/or improved ADCC function. Examples of such antibody variants are described, e.g., in WO 2003/011878 (Jean-Mairet et al. ) ; US Patent No. 6,602,684 (Umana et al. ) ; and US 2005/0123546 (Umana et al. ) .
- Antibody variants with at least one galactose residue in the oligosaccharide attached to the Fc region are also provided.
- Such antibody variants may have improved CDC function.
- Such antibody variants are described, e.g., in WO 1997/30087 (Patel et al. ) ; WO 1998/58964 (Raju, S. ) ; and WO 1999/22764 (Raju, S. ) .
- the Fc region of a presently disclosed antibody or antibody derivative may comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3 or IgG4 Fc region) comprising an amino acid modification (e.g. a substitution) at one or more amino acid positions.
- one or more amino acid modifications may be introduced into the Fc region of the antibody moiety (e.g., scFv-Fc or VHH-Fc) , thereby generating an Fc region variant.
- the Fc region possesses some but not all effector functions, which make it a desirable candidate for applications in which the half-life of the antibody in vivo is important yet certain effector functions (such as complement and ADCC) are unnecessary or deleterious.
- In vitro and/or in vivo cytotoxicity assays can be conducted to confirm the reduction/depletion of CDC and/or ADCC activities.
- Fc receptor (FcR) binding assays can be conducted to ensure that the antibody lacks Fc ⁇ R binding (hence likely lacking ADCC activity) but retains FcRn binding ability.
- NK cells express Fc ⁇ RIII only, whereas monocytes express Fc ⁇ RI, Fc ⁇ RII and Fc ⁇ RIII.
- FcR expression on hematopoietic cells is summarized in Table 2 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9: 457-492 (1991) .
- Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest is described in U.S. Patent No. 5,500,362 (see, e.g. Hellstrom, I. et al. Proc. Nat’l Acad. Sci. USA 83: 7059-7063 (1986) ) and Hellstrom, I et al., Proc.
- non-radioactive assays methods may be employed (see, for example, ACTI TM non-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc. Mountain View, CA; and CytoTox non-radioactive cytotoxicity assay (Promega, Madison, WI) .
- Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells.
- ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. Proc. Nat’l Acad. Sci. USA 95: 652-656 (1998) .
- C1q binding assays may also be carried out to confirm that the antibody is unable to bind C1q and hence lacks CDC activity. See, e.g., C1q and C3c binding ELISA in WO 2006/029879 and WO 2005/100402.
- a CDC assay may be performed (see, for example, Gazzano-Santoro et al., J. Immunol.
- FcRn binding and in vivo clearance/half-life determinations can also be performed using methods known in the art (see, e.g., Petkova, S.B. et al., Int’l. Immunol. 18 (12) : 1759-1769 (2006) ) .
- Antibodies with reduced effector function include those with substitution of one or more of Fc region residues 238, 265, 269, 270, 297, 327 and 329 (U.S. Patent No. 6,737,056) .
- Such Fc mutants include Fc mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297 and 327, including the so-called “DANA” Fc mutant with substitution of residues 265 and 297 to alanine (US Patent No. 7,332,581) .
- the Fc region comprises one or more mutation according to EU numbering of residues.
- the Fc region is an IgG1 Fc region.
- the IgG1 Fc region comprises a L234A mutation and/or a L235A mutation.
- the Fc region is an IgG2 or IgG4 Fc region.
- the Fc region is an IgG4 Fc region comprising a F234A, and/or a L235A mutation.
- the Fc region is an IgG1 Fc region.
- the IgG1 Fc region comprising one or more mutation that modifies an antibody-dependent cell-mediated cytotoxicity (ADCC) .
- the IgG1 Fc region comprising one or more mutation that reduces an antibody-dependent cell-mediated cytotoxicity (ADCC) .
- the IgG1 Fc region comprising one or more mutation that enhances an antibody-dependent cell-mediated cytotoxicity (ADCC) .
- the IgG1 Fc region comprises the mutations of L235V, F243L, R292P, Y300L and P396L.
- the IgG1 Fc region comprises the mutations of S239D, A330L and I332E. In certain embodiments, the IgG1 Fc region comprises the mutations of L235V, F243L, R292P and Y300L. In certain embodiments, the IgG1 Fc region comprises substitutions at positions 298, 333, and/or 334 of the Fc region.
- the Fc region comprises an IgG4 Fc region.
- the IgG4 Fc region comprises an S228P mutation.
- alterations are made in the Fc region that result in altered (i.e., either improved or diminished) C1q binding and/or Complement Dependent Cytotoxicity (CDC) , e.g., as described in US Patent No. 6,194,551, WO 99/51642, and Idusogie et al. J. Immunol. 164: 4178-4184 (2000) .
- CDC Complement Dependent Cytotoxicity
- the antibody (e.g., scFv-Fc or VHH-Fc) variant comprising a variant Fc region comprising one or more amino acid substitutions which alters half-life and/or changes binding to the neonatal Fc receptor (FcRn) .
- Antibodies with increased half-lives and improved binding to the neonatal Fc receptor (FcRn) which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol. 117: 587 (1976) and Kim et al., J. Immunol. 24: 249 (1994) ) , are described in US2005/0014934A1 (Hinton et al. ) .
- Those antibodies comprise an Fc region with one or more substitutions therein which alters binding of the Fc region to FcRn.
- Fc variants include those with substitutions at one or more of Fc region residues, e.g., substitution of Fc region residue 434 (US Patent No. 7,371,826) .
- cysteine engineered antibody moieties e.g., “thioMAbs, ” in which one or more residues of an antibody are substituted with cysteine residues.
- the substituted residues occur at accessible sites of the antibody.
- reactive thiol groups are thereby positioned at accessible sites of the antibody and may be used to conjugate the antibody to other moieties, such as drug moieties or linker-drug moieties, to create an immunoconjugate, as described further herein.
- any one or more of the following residues may be substituted with cysteine: A118 (EU numbering) of the heavy chain; and S400 (EU numbering) of the heavy chain Fc region.
- Cysteine engineered antibody moieties may be generated as described, e.g., in U.S. Patent No. 7,521,541.
- an antibody described herein may be further modified to be an antibody derivative comprising additional proteinaceous or nonproteinaceous moieties that are known in the art and readily available.
- Nonproteinaceous moieties suitable for derivatization of the antibody include but are not limited to water soluble polymers.
- Non-limiting examples of water soluble polymers include, but are not limited to, polyethylene glycol (PEG) , copolymers of ethylene glycol/propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1, 3-dioxolane, poly-1, 3, 6-trioxane, ethylene/maleic anhydride copolymer, polyaminoacids (either homopolymers or random copolymers) , and dextran or poly (n-vinyl pyrrolidone) polyethylene glycol, propropylene glycol homopolymers, prolypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols (e.g., glycerol) , polyvinyl alcohol, and mixtures thereof.
- PEG polyethylene glycol
- copolymers of ethylene glycol/propylene glycol carboxymethylcellulose
- dextran polyvinyl alcohol
- Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water.
- the polymer may be of any molecular weight, and may be branched or unbranched.
- the number of polymers attached to the antibody may vary, and if more than one polymer are attached, they can be the same or different molecules. In general, the number and/or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the particular properties or functions of the antibody to be improved, whether the antibody derivative will be used in diagnosis under defined conditions, etc.
- an antibody may be further modified to be an antibody derivative comprising one or more biologically active protein, polypeptides or fragments thereof.
- Bioactive or “biologically active” , as used herein interchangeably, means showing biological activity in the body to carry out a specific function. For example, it may mean the combination with a particular biomolecule such as protein, DNA, etc., and then promotion or inhibition of the activity of such biomolecule.
- the bioactive protein or fragments thereof include proteins and polypeptides that are administered to patients as the active drug substance for prevention of or treatment of a disease or condition, as well as proteins and polypeptides that are used for diagnostic purposes, such as enzymes used in diagnostic tests or in vitro assays, as well as proteins and polypeptides that are administered to a patient to prevent a disease such as a vaccine.
- antibodies and antibody derivatives disclosed herein can be produced using any available or known technique in the art.
- antibodies and antibody derivatives can be produced using recombinant methods and compositions, e.g., as described in U.S. Patent No. 4,816,567. Detailed procedures to generate antibodies and antibody derivatives are described in the Examples below.
- the presently disclosed subject matter further provides isolated nucleic acids encoding an antibody or antibody derivative disclosed herein.
- the isolated nucleic acid can encode an amino acid sequence comprising the VL and/or an amino acid sequence comprising the VH of the antibody, e.g., the light and/or heavy chains of the antibody.
- the nucleic acid can be present in one or more vectors, e.g., expression vectors.
- vector refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked.
- plasmid a circular double stranded DNA loop into which additional DNA segments can be ligated.
- viral vector a viral vector, where additional DNA segments can be ligated into the viral genome.
- Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors) .
- vectors e.g., non-episomal mammalian vectors
- Other vectors are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome.
- certain vectors, expression vectors are capable of directing the expression of genes to which they are operably linked.
- expression vectors of utility in recombinant DNA techniques are often in the form of plasmids (vectors) .
- the disclosed subject matter is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses) that serve equivalent functions.
- an antibody or antibody derivative disclosed herein can be constructed in a single, multicistronic expression cassette, in multiple expression cassettes of a single vector, or in multiple vectors.
- elements that create polycistronic expression cassette include, but are not limited to, various viral and non-viral Internal Ribosome Entry Sites (IRES, e.g., FGF-l IRES, FGF-2 IRES, VEGF IRES, IGF-II IRES, NF-kB IRES, RUNX1 IRES, p53 IRES, hepatitis A IRES, hepatitis C IRES, pestivirus IRES, aphthovirus IRES, picornavirus IRES, poliovirus IRES and encephalomyocarditis virus IRES) and cleavable linkers (e.g., 2A peptides, e.g., P2A, T2A, E2A and F2A peptides) .
- IRES Internal Ribosome Entry Site
- Combinations of retroviral vector and an appropriate packaging line are also suitable, where the capsid proteins will be functional for infecting human cells.
- Various amphotropic virus-producing cell lines are known, including, but not limited to, PA12 (Miller, et al. (1985) Mol. Cell. Biol. 5: 431-437) ; PA317 (Miller, et al. (1986) Mol. Cell. Biol. 6: 2895-2902) ; and CRIP (Danos, et al. (1988) Proc. Natl. Acad. Sci. USA 85: 6460-6464) .
- Non-amphotropic particles are suitable too, e.g., particles pseudotyped with VSVG, RD114 or GALV envelope and any other known in the art.
- the nucleic acid encoding an antibody or antibody derivative of the present disclosure and/or the one or more vectors including the nucleic acid can be introduced into a host cell.
- the introduction of a nucleic acid into a cell can be carried out by any method known in the art including, but not limited to, transfection, electroporation, microinjection, infection with a viral or bacteriophage vector containing the nucleic acid sequences, cell fusion, chromosome-mediated gene transfer, microcell-mediated gene transfer, spheroplast fusion, etc.
- a host cell can include, e.g., has been transformed with: a vector comprising a nucleic acid that encodes an amino acid sequence comprising a single domain antibody and/or the VH of a single domain antibody.
- a host cell can include, e.g., has been transformed with: (1) a vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antibody and an amino acid sequence comprising the VH of the antibody, or (2) a first vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antibody and a second vector comprising a nucleic acid that encodes an amino acid sequence comprising the VH of the antibody.
- the host cell is eukaryotic, e.g., a Chinese Hamster Ovary (CHO) cell or lymphoid cell (e.g., YO, NSO, Sp20 cell) .
- the methods of making an antibody or antibody derivative disclosed herein can include culturing a host cell, in which a nucleic acid encoding the antibody or antibody derivative has been introduced, under conditions suitable for expression of the antibody or antibody derivative, and optionally recovering the antibody or antibody derivative from the host cell and/or host cell culture medium.
- the antibody or antibody derivative is recovered from the host cell through chromatography techniques.
- a nucleic acid encoding an antibody or antibody derivative can be isolated and inserted into one or more vectors for further cloning and/or expression in a host cell.
- Such nucleic acid may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the antibody or antibody derivative) .
- Suitable host cells for cloning or expression of antibody-encoding vectors include prokaryotic or eukaryotic cells described herein.
- an antibody or antibody derivative can be produced in bacteria, in particular when glycosylation and Fc effector function are not needed.
- expression of antibody fragments and polypeptides in bacteria see, e.g., U.S. Patent Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, NJ, 2003) , pp. 245-254, describing expression of antibody fragments in E. coli. )
- the antibody or antibody derivative may be isolated from the bacterial cell paste in a soluble fraction and can be further purified.
- eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for antibody-encoding vectors, including fungi and yeast strains whose glycosylation pathways have been “humanized, ” resulting in the production of an antibody or antibody derivative with a partially or fully human glycosylation pattern.
- fungi and yeast strains whose glycosylation pathways have been “humanized, ” resulting in the production of an antibody or antibody derivative with a partially or fully human glycosylation pattern.
- Suitable host cells for the expression of glycosylated antibody can also derived from multicellular organisms (invertebrates and vertebrates) . Examples of invertebrate cells include plant and insect cells.
- plant cell cultures can be utilized as host cells. See, e.g., US Patent Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (describing PLANTIBODIES TM technology for producing antibodies in transgenic plants) .
- vertebrate cells can also be used as hosts.
- mammalian cell lines that are adapted to grow in suspension can be useful.
- useful mammalian host cell lines are monkey kidney CV1 line transformed by SY40 (COS-7) ; human embryonic kidney line (293 or 293 cells as described, e.g., in Graham et al., J Gen Viral. 36: 59 (1977) ) ; baby hamster kidney cells (BHK) ; mouse sertoli cells (TM4 cells as described, e.g., in Mather, Biol. Reprod.
- monkey kidney cells (CV 1) ; African green monkey kidney cells (VERO-76) ; human cervical carcinoma cells (HELA) ; canine kidney cells (MDCK; buffalo rat liver cells (BRL 3A) ; human lung cells (W138) ; human liver cells (Hep 02) ; mouse mammary tumor (MMT 060562) ; TRI cells, as described, e.g., in Mather et al., Annals N. Y. Acad. Sci. 383: 44-68 (1982) ; MRC 5 cells; and FS4 cells.
- CHO Chinese hamster ovary
- DHFK CHO cells Urlaub et al., Proc. Natl. Acad. Sci. USA 77: 42 I6 (1980)
- myeloma cell lines such as YO, NSO and Sp2/0.
- Yazaki and Wu Methods in Molecular Biology, Vol. 248 (B. K. C. Lo, ed., Humana Press, Totowa, NJ) , pp. 255-268 (2003) .
- techniques for making bispecific and/or multispecific antibodies include, but are not limited to, recombinant expression of two immunoglobulin heavy chain-light chain pairs having the same specificity, where one or two of the heavy chains or the light chains are fuse to an antigen binding moiety (e.g., a single domain antibody, e.g., aVHH) having a different specificity, recombinant coexpression of two immunoglobulin heavy chain-light chain pairs having different specificities (see Milstei n and Cuello, Nature 305: 537 (1983) ) , PCT Patent Application No.
- an antigen binding moiety e.g., a single domain antibody, e.g., aVHH
- Bispecific antibodies can also be made by engineering electrostatic steering effects for making antibody Fc-heterodimeric molecules (WO 2009/089004A 1) ; cross-linking two or more antibodies or fragments (see, e.g., US Patent No.
- Bispecific and multispecific molecules of the present disclosure can also be made using chemical techniques (see, e.g., Kranz (1981) Proc. Natl. Acad. Sci. USA 78: 5807) , “polydoma” techniques (see, e.g., U.S. Patent 4,474,893) , or recombinant DNA techniques.
- Bispecific and multispecific molecules of the presently disclosed subject matter can also be prepared by conjugating the constituent binding specificities, e.g., a first epitope and a second epitope binding specificities, using methods known in the art and as described herein.
- each binding specificity of the bispecific and multispecific molecule can be generated together by recombinant fusion protein techniques, or can be generated separately and then conjugated to one another.
- the binding specificities are proteins or peptides
- a variety of coupling or cross-linking agents can be used for covalent conjugation.
- Non-limiting examples of cross-linking agents include protein A, carbodiimide, N-succinimidyl-S-acetyl-thioacetate (SATA) , N-succinimidyl-3- (2-pyridyldithio) propionate (SPDP) , and sulfosuccinimidyl 4- (N-maleimidomethyl) cyclohaxane-1-carboxylate (sulfo-SMCC) (see, e.g., Karpovsky (1984) J. Exp. Med. 160: 1686; Liu (1985) Proc. Natl. Acad. Sci. USA 82: 8648) .
- SATA N-succinimidyl-S-acetyl-thioacetate
- SPDP N-succinimidyl-3- (2-pyridyldithio) propionate
- binding specificities are antibodies (e.g., two humanized antibodies)
- they can be conjugated via sulfhydryl bonding of the C-terminus hinge regions of the two heavy chains.
- the hinge region can be modified to contain an odd number of sulfhydryl residues, e.g., one, prior to conjugation.
- both binding specificities of a bispecific antibody can be encoded in the same vector and expressed and assembled in the same host cell. This method is particularly useful where the bispecific and multispecific molecule is a MAb x MAb, MAb x Fab, Fab x F (ab’) 2 or ligand x Fab fusion protein.
- a bispecific antibody of the present disclosure can be a single chain molecule, such as a single chain bispecific antibody, a single chain bispecific molecule comprising one single chain antibody and a binding determinant, or a single chain bispecific molecule comprising two binding determinants. Bispecific and multispecific molecules can also be single chain molecules or can comprise at least two single chain molecules.
- an animal system can be used to produce an antibody or antibody derivative of the present disclosure.
- One animal system for preparing hybridomas is the murine system.
- Hybridoma production in the mouse is a very well-established procedure. Immunization protocols and techniques for isolation of immunized splenocytes for fusion are known in the art. Fusion partners (e.g., murine myeloma cells) and fusion procedures are also known (see, e.g., Harlow and Lane (1988) , Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor New York) .
- antibodies and antibody derivatives of the present disclosure provided herein can be identified, screened for, or characterized for their physical/chemical properties and/or biological activities by various assays known in the art and provided herein.
- an antibody or antibody derivative of the present disclosure can be tested for its antigen binding activity by known methods, such enzyme-linked immunosorbent assay (ELISA) , a radioimmunoassay (RIA) , or a Western Blot Assay.
- ELISA enzyme-linked immunosorbent assay
- RIA radioimmunoassay
- Western Blot Assay Each of these assays generally detects the presence of protein-antibody complexes of particular interest by employing a labeled reagent (e.g., an antibody) specific for the complex of interest.
- the antibody or antibody derivative can be detected using, e.g., an enzyme-linked antibody or antibody fragment which recognizes and specifically binds to the antibody or antibody derivative.
- the antibody or antibody derivative can be detected using any of a variety of other immunoassays.
- the antibody or antibody derivative can be radioactively labeled and used in a radioimmunoassay (RIA) (see, for example, Weintraub, B., Principles of Radioimmunoassays, Seventh Training Course on Radioligand Assay Techniques, The Endocrine Society, March 1986, which is incorporated by reference herein) .
- RIA radioimmunoassay
- the radioactive isotope can be detected by such means as the use of a Geiger counter or a scintillation counter or by autoradiography.
- competition assays can be used to identify an antibody or antibody derivative that competes with an antibody of the present disclosure for binding to B7H3.
- a competing antibody binds to the same epitope (e.g., a linear or a conformational epitope) that is bound by an antibody disclosed herein.
- epitope e.g., a linear or a conformational epitope
- Detailed exemplary methods for mapping an epitope to which an antibody binds are provided in Morris (1996) “Epitope Mapping Protocols, ” in Methods in Molecular Biology vol. 66 (Humana Press, Totowa, NJ) .
- immobilized B7H3 can be incubated in a solution comprising a first labeled antibody or antibody derivative that binds to B7H3 and a second unlabeled antibody that is being tested for its ability to compete with the first antibody for binding to B7H3.
- the second antibody may be present in a hybridoma supernatant.
- immobilized B7H3 is incubated in a solution comprising the first labeled antibody but not the second unlabeled antibody. After incubation under conditions permissive for binding of the first antibody to B7H3, excess unbound antibody is removed, and the amount of label associated with immobilized B7H3 is measured.
- the present disclosure provides assays for identifying anti-B7H3 antibodies or antibody derivatives thereof having biological activity.
- Biological activity may include, e.g., activating an immune cell or an immune activation reporter, e.g., a NFAT reporter or a NF- ⁇ B reporter.
- Antibodies having such biological activity in vivo and/or in vitro are also provided.
- the presently disclosed subject matter further provides immunoconjugates comprising an antibody or antibody derivative, disclosed herein, conjugated to one or more detection probe and/or cytotoxic agents, such as chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof) , or radioactive isotopes.
- cytotoxic agents such as chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof) , or radioactive isotopes.
- cytotoxic agents such as chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof)
- toxins e.g., protein toxins, enzy
- an immunoconjugate is an antibody drug conjugate (ADC) in which an antibody is conjugated to one or more drugs, including but not limited to a maytansinoid (see U.S. Patent Nos. 5,208,020, 5,416,064 and European Patent EP 0 425 235) ; an auristatin such as monomethylauristatin drug moieties DE and DF (MMAE and MMAF) (see U.S. Patent Nos. 5,635,483 and 5,780,588, and 7,498,298) ; a dolastatin; a calicheamicin or derivative thereof (see U.S. Patent Nos.
- ADC antibody drug conjugate
- drugs including but not limited to a maytansinoid (see U.S. Patent Nos. 5,208,020, 5,416,064 and European Patent EP 0 425 235) ; an auristatin such as monomethylauristatin drug moieties DE and DF (MMAE and MMAF) (see U.
- an immunoconjugate comprises an antibody as described herein conjugated to an enzymatically active toxin or fragment thereof, including but not limited to diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa) , ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S) , momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes.
- an enzymatically active toxin or fragment thereof including but not limited to diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxi
- an immunoconjugate comprises an antibody as described herein conjugated to a radioactive atom to form a radioconjugate.
- a variety of radioactive isotopes are available for the production of radioconjugates. Non-limiting examples include At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 and radioactive isotopes of Lu.
- the radioconjugate When used for detection, it can include a radioactive atom for scintigraphic studies, for example tc99m or 1123, or a spin label for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, MRI) , such as iodine-123, iodine-131, indium-11, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese or iron.
- NMR nuclear magnetic resonance
- Conjugates of an antibody and cytotoxic agent can be made using a variety of bi functional protein coupling agents such as N-succinimid yl-3- (2-pyridyldithio) propionate (SPDP) , succinimidyl-4- (N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) , iminothiolane (IT) , bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCl) , active esters (such as disuccinimidyl suberate) , aldehydes (such as glutaraldehyde) , bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine) , bis-diazonium derivatives (such as bis- (p-diazoniumbenzoyl) -ethylenediamine) , diisocyanates (such as toluene 2, 6-d
- a ricin immunotoxin can be prepared as described in Vitetta et al., Science 238: 1098 (1987) .
- Carbon-4-labeled l-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See WO94/11026.
- the linker can be a “cleavable linker” facilitating release of a cytotoxic drug in the cell.
- an acid-labile linker, peptidase-sensitive linker, photolabile linker, dimethyl linker or disulfide-containing linker (Chari et al., Cancer Res. 52: 127-131 (1992) ; U.S. Patent No. 5,208,020) can be used.
- the immunuoconjugates or ADCs herein expressly contemplate, but are not limited to, such conjugates prepared with cross-linker reagents including, but not limited to, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, and sulfo-SMPB, and SVSB (succinimidyl- (4-vinylsulfone) benzoate) which are commercially available (e.g., from Pierce Biotechnology, Inc., Rockford, IL., U.S.A) .
- cross-linker reagents including, but not limited to, BMPS, EMCS, GMBS, HBVS,
- antigen-recognizing receptors comprising an antibody or antibody fragment disclosed herein.
- An antigen-recognizing receptor is a receptor that is capable of activating, stimulating or inhibiting an immunoresponsive cell (e.g., a T-cell) in response to its binding to an antigen.
- antigen-recognizing receptors include native and recombinant T cell receptors ( “TCRs” ) , a chimeric co-stimulating receptor (CCR) , a chimeric antigen receptors ( “CARs” ) or an inhibitory CAR (iCAR) .
- Antigen-recognizing receptor designs and methods of use are well known in the art, and is described in the literature, e.g., International Publications WO 2018/027155, WO 2019/099483, WO 2019/157454, WO 2019/133969, WO 2019/099993, WO 2015/142314, WO 2018/027197 and WO 2014055668.
- the presently disclosed subject matter provides chimeric antigen receptors (CARs) comprising an antibody or antibody fragment disclosed herein.
- CARs are engineered receptors, which can graft or confer a specificity of interest onto an immune effector cell.
- a CAR can be used to graft the specificity of a monoclonal antibody onto a T cell; with transfer of its coding sequence facilitated by a vector.
- the CAR is a “First generation” CAR, which is typically composed of an extracellular antigen-binding domain (e.g., a scFv or a VHH) fused to a transmembrane domain, which is fused to cytoplasmic/intracellular signaling domain.
- First generation CARs can provide de novo antigen recognition and cause activation of an immunoresponsive cell, e.g., CD4+and CD8+T cells, through their CD3z chain signaling domain in a single fusion molecule, independent of HLA-mediated antigen presentation.
- an immunoresponsive cell e.g., CD4+and CD8+T cells
- the CAR is a “Second generation” CAR, which further comprises an intracellular signaling domain from various co-stimulatory molecules (e.g., CD28, 4-1BB, ICOS, 0X40, CD27, CD40/My88 and NKGD2) to the cytoplasmic tail of the CAR to provide additional signals to the immunoresponsive cell, whereby the “Second generation” CAR comprise those that provide both co-stimulation (e.g., CD28 or4-1BB) and activation (CD3z) .
- the CAR is a “Third generation” CAR, which comprises multiple co-stimulation domains (e.g., CD28 and 4-1BB) and activation (CD3z) .
- the CAR is a second- generation CAR.
- the CAR comprises an extracellular antigen-binding domain that binds to an antigen, a transmembrane domain, and an intracellular signaling domain, wherein the intracellular signaling domain comprises a co-stimulatory signaling domain.
- the CAR further comprises a hinger/spacer region between the extracellular antigen-binding domain and the transmembrane domain.
- the extracellular antigen-binding domain comprises an antibody or antibody fragment disclosed herein.
- the antibody or antibody fragment comprises a VHH or a scFv.
- the presently disclosed subject matter provides recombinant TCRs comprising an antibody or antibody fragment disclosed herein.
- a native TCR is aprotein complex comprising a disulfide-linked heterodimeric protein consisting of two variable chains expressed as part of a complex with CD3 chain molecules.
- a native TCR is found on the surface of T cells, and is responsible for recognizing antigens as peptides bound to major histocompatibility complex (MHC) molecules.
- MHC major histocompatibility complex
- a native TCR comprises an alpha chain and a beta chain (encoded by TRA and TRB genes, respectively) .
- a TCR comprises a gamma chain and a delta chain (encoded by TRG and TRD genes, respectively) .
- Each of the alpha chain, the beta chain, the gamma chain and the delta chain is comprises two extracellular domains: a Variable (V) region and a Constant (C) region.
- the Constant region is proximal to the cell membrane, followed by a transmembrane region and a short cytoplasmic tail.
- the Variable region binds to the peptide/MHC complex.
- Each variable region has three complementarity determining regions (CDRs) .
- a TCR comprises a receptor complex with CD3 ⁇ , CD3 ⁇ , CD3 ⁇ and CD3 ⁇ . When a TCR complex engages with its antigen and MHC (peptide/MHC) , the T cell expressing the TCR complex is activated.
- a recombinant TCR is a non-naturally occurring TCR.
- the recombinant TCR comprises a recombinant alpha chain and/or a recombinant b chain, wherein a part or the entire variable region of the recombinant alpha chain and/or the recombinant b chain is replaced by an antibody or an antibody fragment disclosed herein.
- the antibody or antibody fragment comprises a VHH, a VH, a VL or a scFv.
- the antibody or antibody fragment comprises a VHH.
- the recombinant TCR binds to an antigen of interest in an MHC/HLA-independent manner. In certain non-limiting embodiments, binding of the antigen is capable of activating an immunoresponsive cell comprising the recombinant TCR.
- the presently disclosed subject matter provides immunoresponsive cells comprising (a) an antigen-recognizing receptor (e.g., CAR or TCR) disclosed herein.
- the antigen-recognizing receptor is capable of activating the immunoresponsive cell.
- the immunoresponsive cells of the presently disclosed subject matter can be cells of the lymphoid lineage.
- the lymphoid lineage comprising B, T and natural killer (NK) cells, provides for the production of antibodies, regulation of the cellular immune system, detection of foreign agents in the blood, detection of cells foreign to the host, and the like.
- Non-limiting examples of immunoresponsive cells of the lymphoid lineage include T cells, Natural Killer (NK) cells, embryonic stem cells, and pluripotent stem cells (e.g., those from which lymphoid cells may be differentiated) .
- T cells can be lymphocytes that mature in the thymus and are chiefly responsible for cell-mediated immunity. T cells are involved in the adaptive immune system.
- the T cells of the presently disclosed subject matter can be any type of T cells, including, but not limited to, helper T cells, cytotoxic T cells, memory T cells (including central memory T cells, stem-cell-like memory T cells (or stem-like memory T cells) , and two types of effector memory T cells: e.g, TEM cells and TEMRA cells, Regulatory T cells (also known as suppressor T cells) , Natural killer T cells, Mucosal associated invariant T cells, and gd T cells.
- Cytotoxic T cells CTL or killer T cells are a subset of T lymphocytes capable of inducing the death of infected somatic or tumor cells.
- a patient’s own T cells may be genetically modified to target specific antigens through the introduction of an antigen recognizing receptor, e.g., a CAR or a TCR.
- the immunoresponsive cell is a T cell.
- the T cell can be a CD4+T cell or a CD8+T cell.
- the T cell is a CD4+T cell.
- the T cell is a CD8+T cell.
- Natural killer (NK) cells can be lymphocytes that are part of cell-mediated immunity and act during the innate immune response. NK cells do not require prior activation in order to perform their cytotoxic effect on target cells.
- Types of human lymphocytes of the presently disclosed subject matter include, without limitation, peripheral donor lymphocytes, e.g., those disclosed in Sadelain, M., et al. 2003 Nat Rev Cancer 3: 35-45 (disclosing peripheral donor lymphocytes genetically modified to express CARs) , in Morgan, R.A., et al. 2006 Science 314: 126-129 (disclosing peripheral donor lymphocytes genetically modified to express a full-length tumor antigen-recognizing T cell receptor complex comprising the a and b heterodimer) , in Panelli, M.C., et al. 2000 J Immunol 164: 495-504; Panelli, M.C., et al.
- the immunoresponsive cells e.g., T cells
- the presently disclosed subject matter further provides methods for using the disclosed antibodies and antibody derivatives.
- the methods are directed to therapeutic uses of a presently disclosed antibody or antibody derivative.
- the methods are directed to diagnostic use of a presently disclosed antibody or antibody derivative.
- the present disclosure provides methods and use of an antibody or antibody derivative disclosed herein for treatment of diseases and disorders or for increasing an immune response.
- the antibody, antibody derivative or pharmaceutical compositions comprising the same disclosed herein can be administered to subjects (e.g., mammals such as humans) to treat diseases and disorders or to increases an immune response.
- the diseases and disorders involve immune checkpoint inhibitions and/or abnormal B7H3 activity.
- the diseases and disorders that can be treated by an antibody or antibody derivative disclosed herein include, but are not limited to, neoplasia, e.g., cancer.
- the present disclosure provides an antibody or antibody derivative described herein (or fragments thereof) for use in the manufacture of a medicament. In certain embodiments, the present disclosure provides antibody or antibody derivative described herein (or fragments thereof) for use in the manufacture of a medicament for treating of cancer. In certain embodiments, the present disclosure provides an antibody or antibody derivative described herein (or fragments thereof) for use in treating cancer in a subject. In certain embodiments, the present disclosure provides pharmaceutical compositions comprising an antibody or antibody derivative provided herein (or fragments thereof) for use in treating cancer in a subject. In certain embodiments, the cancer can be blood cancers (e.g.
- leukemias, lymphomas, and myelomas ovarian cancer, breast cancer, bladder cancer, brain cancer, colon cancer, intestinal cancer, liver cancer, lung cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, glioblastoma, throat cancer, melanoma, neuroblastoma, adenocarcinoma, glioma, soft tissue sarcoma, and various carcinomas (including prostate and small cell lung cancer) .
- Suitable carcinomas further include any known carcinoma in the field of oncology, including, but not limited to, astrocytoma, fibrosarcoma, myxosarcoma, liposarcoma, oligodendroglioma, ependymoma, medulloblastoma, primitive neural ectodermal tumor (PNET) , chondrosarcoma, osteogenic sarcoma, pancreatic ductal adenocarcinoma, small and large cell lung adenocarcinomas, chordoma, angiosarcoma, endotheliosarcoma, squamous cell carcinoma, bronchoalveolarcarcinoma, epithelial adenocarcinoma, and liver metastases thereof, lymphangiosarcoma, lymphangioendotheliosarcoma, hepatoma, cholangiocarcinoma, synovioma, mesothelioma, E
- the cancer can be melanoma, NSCLC, head and neck cancer, urothelial cancer, breast cancer (e.g., triple-negative breast cancer, TNBC) , gastric cancer, cholangiocarcinoma, classical Hodgkin's lymphoma (cHL) , Non-Hodgkin lymphoma primary mediastinal B-Cell lymphoma (NHL PMBCL) , mesothelioma, ovarian cancer, lung cancer (e.g., small-cell lung cancer) , esophageal cancer, nasopharyngeal carcinoma (NPC) , biliary tract cancer, colorectal cancer, cervical cancer or thyroid cancer.
- breast cancer e.g., triple-negative breast cancer, TNBC
- gastric cancer e.g., gastric cancer, cholangiocarcinoma, classical Hodgkin's lymphoma (cHL) , Non-Hodgkin lymphoma primary mediastinal
- the subject to be treated is a mammal (e.g., human, non-human primate, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, etc. ) .
- the subject is a human.
- the subject is suspected of having or at risk of having a cancer or be diagnosed with a cancer or any other disease having abnormal B7H3 expression or activity.
- diagnostic methods for cancer or any other disease exhibiting abnormal B7H3 activity and the clinical delineation of those diseases include, but are not limited to, e.g., immunohistochemistry, PCR, fluorescent in situ hybridization (FISH) . Additional details regarding diagnostic methods for abnormal B7H3 activity or expression are described in, e.g., Gupta et al. (2009) Mod Pathol. 22 (1) : 128-133; Lopez-Rios et al. (2013) J Clin Pathol. 66 (5) : 381-385; Ellison et al. (2013) J Clin Pathol 66 (2) : 79-89; and Guha et al. (2013) PLoS ONE 8 (6) : e67782.
- Administration can be by any suitable route including, e.g., intravenous, intramuscular, or subcutaneous.
- the antibody or antibody derivative (or fragments thereof) and/or compositions provided herein are administered in combination with a second, third, or fourth agent (including, e.g., an antineoplastic agent, a growth inhibitory agent, a cytotoxic agent, or a chemotherapeutic agent) to treat the diseases or disorders involving abnormal B7H3 activity.
- a second, third, or fourth agent including, e.g., an antineoplastic agent, a growth inhibitory agent, a cytotoxic agent, or a chemotherapeutic agent
- Such agents include, e.g., docetaxel, gefitinib, FOLFIRI (irinotecan, 5-fluorouracil, and leucovorin) , irinotecan, cisplatin, carboplatin, paclitaxel, bevacizumab (anti-VEGF antibody) , FOLFOX-4, infusional fluorouracil, leucovorin, and oxaliplatin, afatinib, gemcitabine, capecitabine, pemetrexed, tivantinib, everolimus, CpG-ODN, rapamycin, lenalidomide, vemurafenib, endostatin, lapatinib, PX-866, Imprime PGG, and irlotinibm.
- the antibody or antibody derivative (or fragments thereof) is conjugated to the additional agent.
- the antibody or antibody derivative (or fragments thereof) and/or compositions provided herein are administered in combination with one or more additional therapies, such as radiation therapy, surgery, chemotherapy, and/or targeted therapy.
- additional therapies such as radiation therapy, surgery, chemotherapy, and/or targeted therapy.
- the antibody, antibody derivative (or fragments thereof) and/or compositions provided herein are administered in combination with radiation therapy.
- the combination of an antibody, antibody derivative (or fragment thereof) and/or composition provided herein and radiation therapy is used for treating a neoplasm or cancer disclosed herein.
- the antibody or antibody derivative provided herein will be administered at a dosage that is efficacious for the treatment of that indication while minimizing toxicity and side effects.
- a typical dose can be, for example, in the rage of 0.001 to 1000 ⁇ g; however, doses below or above this exemplary range are within the scope of the invention.
- the daily dose can be about 0.1 ⁇ g/kg to about 100 mg/kg of total body weight, about 0.1 ⁇ g/kg to about 100 ⁇ g/kg of total body weight or about 1 ⁇ g/kg to about 100 ⁇ g/kg of total body weight.
- therapeutic or prophylactic efficacy can be monitored by periodic assessment of treated patients. For repeated administrations over several days or longer, depending on the condition, the treatment is repeated until a desired suppression of disease symptoms occurs.
- other dosage regimens may be useful and are within the scope of the invention.
- the desired dosage can be delivered by a single bolus administration of the composition, by multiple bolus administrations of the composition, or by continuous infusion administration of the composition.
- a pharmaceutical composition comprising an antibody or antibody derivative disclosed herein can be administered one, two, three, or four times daily.
- the compositions can also be administered less frequently than daily, for example, six times a week, five times a week, four times a week, three times a week, twice a week, once a week, once every two weeks, once every three weeks, once a month, once every two months, once every three months, or once every six months.
- the compositions may also be administered in a sustained release formulation, such as in an implant which gradually releases the composition for use over a period of time, and which allows for the composition to be administered less frequently, such as once a month, once every 2-6 months, once every year, or even a single administration.
- the sustained release devices (such as pellets, nanoparticles, microparticles, nanospheres, microspheres, and the like) may be administered by injection or surgically implanted in various locations.
- Cancer treatments can be evaluated by, e.g., but not limited to, tumor regression, tumor weight or size shrinkage, time to progression, duration of survival, progression free survival, overall response rate, duration of response, quality of life, protein expression and/or activity.
- Approaches to determining efficacy of the therapy can be employed, including for example, measurement of response through radiological imaging.
- the efficacy of treatment is measured by the percentage tumor growth inhibition (%TGI) , calculated using the equation 100- (T/C x 100) , where T is the mean relative tumor volume of the treated tumor, and C is the mean relative tumor volume of a non-treated tumor.
- the%TGI is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 91%, about 92%, about 93%) , about 94%) , about 95%, or more than 95%.
- Labeled antibody or antibody derivative can be used for diagnostic purposes to detect, diagnose, or monitor diseases and/or disorders associated with the expression, aberrant expression and/or activity of B7H3.
- the antibodies and antibody derivatives provided herein can be used in in situ, in vivo, ex vivo, and in vitro diagnostic assays or imaging assays.
- Methods for detecting expression of a B7H3 polypeptide comprising (a) assaying the expression of the polypeptide in cells (e.g., tissue) or body fluid of an individual using one or more antibody or antibody derivative and (b) comparing the level of gene expression with a standard gene expression level, whereby an increase or decrease in the assayed gene expression level compared to the standard expression level is indicative of aberrant expression.
- Additional embodiments provided herein include methods of diagnosing a disease or disorder associated with expression or aberrant expression of B7H3 in an animal (e.g., a mammal such as a human) .
- the methods comprise detecting B7H3 molecules in the mammal.
- diagnosis comprises: (a) administering an effective amount of a labeled antibody or antibody derivative to a mammal (b) waiting for a time interval following the administering for permitting the labeled antibody or antibody derivative to preferentially concentrate at sites in the subject where the B7H3 molecule is expressed (and for unbound labeled molecule to be cleared to background level) ; (c) determining background level; and (d) detecting the labeled molecule in the subject, such that detection of labeled molecule above the background level indicates that the subject has a particular disease or disorder associated with expression or aberrant expression of B7H3. Background level can be determined by various methods including, comparing the amount of labeled molecule detected to a standard value previously determined for a particular system.
- Antibodies and antibody derivatives provided herein can be used to assay protein levels in a biological sample using classical immunohistological methods known to those of skill in the art (e.g., see Jalkanen, et al., J. Cell. Biol. 101: 976-985 (1985) ; Jalkanen, et al., J. Cell. Biol. 105: 3087-3096 (1987) ) .
- Other antibody-based methods useful for detecting protein gene expression include immunoassays, such as the enzyme linked immunosorbent assay (ELISA) and the radioimmunoassay (RIA) .
- ELISA enzyme linked immunosorbent assay
- RIA radioimmunoassay
- Suitable antibody assay labels include enzyme labels, such as, glucose oxidase; radioisotopes, such as iodine ( 131 I, 125 I, 123 I, 121 I) , carbon ( 14 C) , sulfur ( 35 S) , tritium ( 3 H) , indium ( 115m In, 113m In, 112 In, 111 In) , and technetium ( 99 Tc, 99m Tc) , thallium ( 201 Ti) , gallium ( 68 Ga, 67 Ga) , palladium ( 103 Pd) , molybdenum ( 99 Mo) , xenon ( 133 Xe) , fluorine ( 18 F) , 153 Sm, 177 Lu, 159 Gd, 149 Pm, 140 La, 175 Yb, 166 Ho, 90 Y, 47 Sc, 186 Re, 188 Re, 142 Pr, 105 Rh, 97 Ru; luminol; and fluorescent
- Such techniques include, but are not limited to, the use of bifunctional conjugating agents (see e.g., U.S. Pat. Nos. 5,756,065; 5,714,631; 5,696,239; 5,652,361; 5,505,931; 5,489,425; 5,435,990; 5,428,139; 5,342,604; 5,274,119; 4,994,560; and 5,808,003) .
- FISH fluorescent in situ hybridization using a nucleic acid based probe corresponding to an EGFR-encoding nucleic acid or the complement thereof
- FISH fluorescent in situ hybridization using a nucleic acid based probe corresponding to an EGFR-encoding nucleic acid or the complement thereof
- PCR polymerase chain reaction
- RT-PCR real time quantitative PCR
- a detectable label e.g., a radioactive isotope
- the presently disclosed subject matter further provides pharmaceutical formulations containing an antibody or antibody derivative disclosed herein, with a pharmaceutically acceptable carrier.
- the pharmaceutical compositions can include a combination of multiple (e.g., two or more) antibodies and/or antibody derivatives of the presently disclosed subject matter.
- the disclosed pharmaceutical formulations can be prepared by combining an antibody or antibody derivative having the desired degree of purity with one or more optional pharmaceutically acceptable carriers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980) ) , in the form of lyophilized formulations or aqueous solutions.
- lyophilized antibody formulations are described in US Patent No. 6,267,958.
- aqueous antibody formulations can include those described in US Patent No. 6,171,586 and WO2006/044908, the latter formulations including a histidine-acetate buffer.
- the antibody or antibody derivative can be of a purity greater than about 80%, greater than about 90%, greater than about 91%, greater than about 92%, greater than about 93%, greater than about 94%, greater than about 95%, greater than about 96%, greater than about 97%, greater than about 98%, greater than about 99%, greater than about 99.1%, greater than about 99.2%, greater than about 99.3%, greater than about 99.4%, greater than about 99.5%, greater than about 99.6%, greater than about 99.7%, greater than about 99.8%or greater than about 99.9%.
- Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphate, citrate, and other organic acids, antioxidants including ascorbic acid and methionine, preservatives (such as octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol) , low molecular weight (less than about 10 residues) polypeptides, proteins, such as serum albumin, gelatin, or immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidone, amino acids such as glycine, glutamine, asparagine, histidine,
- Exemplary pharmaceutically acceptable carriers herein further include interstitial drug dispersion agents such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP) , for example, human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 ( Baxter International, Inc. ) .
- soluble neutral-active hyaluronidase glycoproteins such as rHuPH20 ( Baxter International, Inc. )
- rHuPH20 Baxter International, Inc.
- Certain exemplary sHASEGPs and methods of use, including rHuPH20 are described in US Patent Publication Nos. 2005/0260186 and 2006/0104968.
- a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases.
- the carrier can be suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion) .
- the active compound e.g., an anti-B7H3 antibody
- the active compound can be coated in a material to protect the compound from the action of acids and other natural conditions that may inactivate the compound.
- compositions of the present disclosure also can be administered in combination therapy, i.e., combined with other agents.
- pharmaceutical compositions disclosed herein can also contain more than one active ingredients as necessary for the particular indication being treated, for example, those with complementary activities that do not adversely affect each other.
- the pharmaceutical formulation can include a second active ingredient for treating the same disease treated by the first therapeutic.
- Such active ingredients are suitably present in combination in amounts that are effective for the purpose intended.
- the formulation of the present disclosure can also contain more than one active ingredients as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other.
- Such active ingredients are suitably present in combination in amounts that are effective for the purpose intended.
- a composition of the present disclosure can be administered by a variety of methods known in the art.
- the route and/or mode of administration vary depending upon the desired results.
- the active compounds can be prepared with carriers that protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
- Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are described by e.g., Sustained and Controlled Release Drug Delivery Systems, J.R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.
- the pharmaceutical compositions are manufactured under Good Manufacturing Practice (GMP) conditions of the U.S. Food and Drug Administration.
- GMP Good Manufacturing Practice
- sustained-release preparations containing an antibody or antibody derivative disclosed herein can also be prepared.
- suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody or antibody derivative, which matrices are in the form of shaped articles, e.g. films, or microcapsules.
- active ingredients can be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
- colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
- the compound may be administered to a subject in an appropriate carrier, for example, liposomes, or a diluent.
- suitable diluents include saline and aqueous buffer solutions.
- Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes (Strejan et al. (1984) J Neuroimmunol. 7: 27) .
- Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
- sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
- the use of such media and agents for pharmaceutically active substances is known in the art.
- compositions of the present disclosure use thereof in the pharmaceutical compositions of the present disclosure is contemplated.
- Supplementary active compounds can also be incorporated into the compositions.
- compositions typically must be sterile, substantially isotonic, and stable under the conditions of manufacture and storage.
- the composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration.
- the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like) , and suitable mixtures thereof.
- the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
- isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
- Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.
- Sterile injectable solutions can be prepared by incorporating one or more antibody or antibody derivative disclosed herein in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization microfiltration, e.g., by filtration through sterile filtration membranes.
- dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
- the preferred methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- compositions can also be administered with medical devices known in the art.
- a therapeutic composition of the present disclosure can be administered with a needleless hypodermic injection device, such as the devices disclosed in, e.g., U.S. Patent Nos. 5,399,163, 5,383,851, 5,312,335, 5,064,413, 4,941,880, 4,790,824 or 4,596,556.
- implants and modules useful in the present disclosure include: U.S. Patent No. 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S. Patent No. 4,486,194, which discloses a therapeutic device for administering medicants through the skin; U.S. Patent No.
- formulations of the present disclosure include those suitable for oral, nasal, topical (including buccal and sublingual) , rectal, vaginal and/or parenteral administration.
- the formulations can conveniently be presented in unit dosage form and may be prepared by any methods known in the art of pharmacy.
- the amount of antibody or antibody derivative, which can be combined with a carrier material to produce a single dosage form vary depending upon the subject being treated, and the particular mode of administration.
- the amount of the antibody or antibody derivative which can be combined with a carrier material to produce a single dosage form generally be that amount of the composition which produces a therapeutic effect. Generally, out of one hundred percent, this amount range from about 0.01 percent to about ninety-nine percent of active ingredient, from about 0.1 percent to about 70 percent, or from about 1 percent to about 30 per cent.
- compositions of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
- the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
- parenteral administration and “administered parenterally” mean modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.
- compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of presence of microorganisms may be ensured both by sterilization procedures, supra, and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
- an antibody or antibody derivative of the present disclosure when administered as pharmaceuticals, to humans and animals, they can be given alone or as a pharmaceutical composition containing, for example, from about 0.01%to about 99.5% (or about 0.1%to about 90%) of the antibody or antibody derivative in combination with a pharmaceutically acceptable carrier.
- the presently disclosed subject matter further provides articles of manufacture containing materials useful for the treatment, prevention and/or diagnosis of the disorders described above.
- the article of manufacture includes a container and a label or package insert on or associated with the container.
- suitable containers include bottles, vials, syringes, IV solution bags, etc.
- the containers can be formed from a variety of materials such as glass or plastic.
- the container can hold a composition which is by itself or combined with another composition effective for treating, preventing and/or diagnosing the condition and may have a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle) .
- At least one active agent in the composition is an antibody or antibody derivative of the present disclosure.
- the label or package insert can indicate that the composition is used for treating the condition of choice.
- the article of manufacture can comprise (a) a first container with a composition contained therein, wherein the composition comprises an antibody or antibody derivative of the present disclosure; and (b) a second container with a composition contained therein, wherein the composition comprises a further cytotoxic or otherwise therapeutic agent.
- the article of manufacture can further comprise a package insert indicating that the compositions can be used to treat a particular condition.
- the article of manufacture can further an additional container, e.g., a second or third container, including a pharmaceutically acceptable buffer, such as, but not limited to, bacteriostatic water for injection (BWFI) , phosphate-buffered saline, Ringer's solution and dextrose solution.
- a pharmaceutically acceptable buffer such as, but not limited to, bacteriostatic water for injection (BWFI) , phosphate-buffered saline, Ringer's solution and dextrose solution.
- BWFI bacteriostatic water for injection
- the article of manufacture can include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
- Antigen of recombinant human B7H3 extra cellular domain (ECD) protein was constructed with C-terminal poly-histidine tag or Fc tag and purified in house. Immunization of llama using B7H3 ECD-Fc was performed using standard protocols. The titer of serum antibodies was measured by ELISA assays. After 3 rounds of immunization, a high titer (1: 30,000) was observed. Whole blood was then collected, and PBMCs were isolated. RNA was then isolated from the PBMCs.
- VHH antibody genes were amplified by PCR using standard protocols, purified by DNA agarose gel, constructed into a phagemid vector pADL-23c (Antibody Design Labs) and transformed to TG1 electrocompetent cells (from Lucigen) .
- the transformed TG1 cells were cultured in Y2T medium.
- Phages with target VHH displayed were produced by adding helper phage and co-culturing overnight.
- the phages in supernatants of cell culture were harvested by centrifugation, and panning of binders to human-B7H3 (h-B7H3) antigen was performed using streptavidin-coupled Dynabeads coated with biotinylated h-B7H3.
- binders of h-B7H3 were eluted, which were used to infect SS320 cells. Colonies of the SS320 cells were picked and cultured in Y2T medium, and IPTG was added for secretion of VHH antibodies. Supernatants with VHH antibodies were screened by ELISA assays using h-B7H3 ECD coated plates. Positive h-B7H3 binders were picked for sequencing. 44 clones with different sequences were selected. Binding ability of VHH antibodies on cynomolgus B7H3 was also examined by ELISA. Reference Ab1, an enoblituzumab analog synthesized in-house based on the sequences disclosed in U.S. Patent No. US 8,802,091, was used as a control.
- FIGS 1A and 1B show that the top 11 clones bound to human and cynomolgus B7H3, respectively.
- the sequences of the top clones were identified and used to make bivalent VHH-Fc antibodies by adding human IgG1 Fc region including constant heavy chain 2 (CH2) and constant heavy chain 3 (CH3) domains.
- the VHH-Fc antibodies were expressed in ExpiCHO cells, and proteins in supernatants were harvested and purified by Protein A.
- top 11 binders and their CDRs and VHs are shown in the Sequence Table (SEQ ID NOs: 1-44) .
- the binding kinetics of the top clones in the VHH-Fc form were evaluated by Octet binding assays, and the data are shown in Table 3.
- One representative clone 19c10 was selected for humanization of its framework. Briefly, Igblast was performed using the sequences of the clone to search database of human germline genes. Ideal germline sequences were selected, and mutations of framework sequences were made to change the framework sequences from llama to human. Two humanized clones, 19c10-V2 and 19c10-V3 were made, where 19c10-V2 contained humanized FR1, FR3 and FR4, and 19c10-V3 further humanized FR2 based on 19c10-V2. Another humanized clone, 19c10-V4 was made by introducing back mutation and reducing the number of lysine residues around the CDR2 region. The constructs were cloned into expression vectors, and antibody proteins were produced by transient transfection of ExpiCHO and purified by protein A.
- B7H3 positive human tumor cells B7H3 positive cells, A498 (human kidney carcinoma cells) or negative control cells, Jurkat (human leukemia cells) and Raji cells, were seeded in equal amount (1*10 ⁇ 4 cell/well, 100ul per well) in a 96-well plate with FACS buffer (PBS with 1.5%FBS) .
- FACS buffer PBS with 1.5%FBS
- the top 11 anti-B7H3 antibody clones showed higher binding affinity (lower EC50) to B7H3 positive A498 cells compared to Reference Ab 1 (an enoblituzumab analog) .
- the humanized anti-B7H3 antibody clones also showed binding affinity comparable to the parental clone and Reference Ab 1.
- Reference Ab 4 is a negative control that does not bind to B7H3.
- Figure 2C shows that 19c10-V4 had higher binding affinity (lower EC50) to B7H3 positive A498 cells compared to 19c10-V3.
- 19c10-V4 showed higher binding affinity (lower EC50) to B7H3 positive A498 cells compared to both Reference Ab 1 (an enoblituzumab analog) and Reference Ab 2 (an h1702 analog) .
- Figure 2E showed that none of the anti-B7H3 antibodies bound to the B7H3 negative Jurkat cells.
- Figure 2F showed that none of 19c10-V4, Reference Ab 1 or Reference Ab 2 bound to the B7H3 negative Raji cells, whereas an anti-CD47 antibody served as a positive control.
- ADCC antibody-dependent cellular cytotoxicity
- VHH antibody clones Five of the top 11 anti-B7H3 VHH antibody clones (5H8, 6H4, 14C4, 18B5 and 19C10) were selected for the ADCC evaluation. It was reported that the ADCC functions of enoblituzumab was one of the main mechanisms of its antitumor efficacy. Therefore, Reference Ab 1, an enoblituzumab analog, was used as a positive control for the ADCC evaluation. To ensure an accurate comparison of the antigen binding regions with the enoblituzumab analog, the VHH antibodies’ Fc regions were replaced with the Fc region of enoblituzumab to rule out any different effect caused by the difference of the Fc regions.
- B7H3 positive A498 human kidney carcinoma cells were seeded in 96-well plate and incubate with cell culture medium (Eagle’s Minimum Essential Medium, ATCC 30-2003, with 10%FBS, 1%Penicillin/Streptomycin, and 1%L-glutamine) overnight.
- the anti-B7H3 antibodies were then diluted by A498 culture medium and incubated with the cells in 37°Cincubator for 30 minutes.
- the primary human peripheral blood mononuclear cells (PBMCs) were added to the antibody-A498 mixture for incubation overnight.
- the cell viability was then detected by VICTOR X3 multilabel plate reader (PerkinElmer) every hour for 6 hours and was calculated using GraphPad PRISM.
- the anti-B7H3 antibodies’ antitumor effects were further evaluated in vivo using A549 xenograft mouse models.
- the A549 is a human lung cancer cell line purchased from ATCC.
- the A549 cells were maintained in vitro as a monolayer culture in F-12K medium supplemented with 10%heat inactivated fetal bovine serum at 37°C in an atmosphere of 5%CO 2 in air. Cells were routinely sub-cultured three times weekly by 0.25%trypsin-EDTA digestion. After three times of passage, 5 million A549 cells were subcutaneously inoculated into each mouse. Animals were randomized, and treatment started when average tumor volume reached around 100mm 3 (Day 1) . The treatment was carried out twice per week for three weeks (Table 4) .
- TGI (%) [1- (V treat-t -V treat-0 ) / (V control-t -V control-0 ) ] , represents antitumor effectiveness, in which V treat-0 and V control-0 are the mean volumes of the treated and control groups on grouping day; V treat-t and V control-t are the mean volumes of the treated and control groups on a given day.
- T/C% TRTV/CRTV ⁇ 100% (TRTV: treated groups RTV; CRTV: control groups RTV) .
- mice treated with the anti-B7H3 antibodies showed better tumor growth inhibition (TGI) compared to control mice.
- 19c10V4 showed better TGI (38.46%) than reference antibodies including an hl702 analog (21.19%) and MGA-271, a enoblituzumab analog (27.14%) on day 45. No significant body weight lost was observed in any group ( Figure4B) .
- the results demonstrated that 19c10V4 antibody has superior antitumor efficacy compared to the hl702 analog and the enoblituzumab analog in A549 xenograft model.
- B7H3 is highly expressed in many types of EGFR positive solid tumors.
- a bispecific antibody targeting both B7H3 and EGFR can provide specific targeting of those tumor cells and thereby increase the efficacy and reduce the side effects of anti-EGFR antibody treatment.
- anti-B7H3/EGFR bispecific antibodies were generated using the anti-B7H3 antibodies described above and an anti-EGFR antibody described in PCT/US2015/033402 (published as International Publication WO2015184403A2) .
- anti-B7H3 VHH clone 19c10, 19c10-V3 and 19c10-V4 were fused to the N-terminus of anti-EGFR antibody heavy chains to generate 19c10xanti-EGFR, 19c10-V3xanti-EGFR and 19c10-V4xanti-EGFR.
- the protein sequences are shown in SEQ ID NOs: 125-128.
- the bispecific antibodies were produced from transfected ExpiCHO cells and purified by Protein A affinity column for further analyses.
- the bispecific antibodies showed high binding affinity to both B7H3 and EGFR, and 19C10v4xanti-EGFR showed higher binding affinity to B7H3 compared to 19c10V3xanti-EGFR.
- FIGS. 5A-5D showed ADCC effects of 19C10v3xanti-EGFR.
- B7H3/EGFR double positive tumor cells (A498 human kidney carcinoma cell, Detroit 562 human HSNCC cell, HCT116 human colon cancer cell, and A549 human lung cancer cell) were seeded in 96-well plate and incubate with cell culture medium (Eagle’s Minimum Essential Medium, ATCC 30-2003, with 10%FBS, 1%Penicillin/Streptomycin, and 1%L-glutamine) overnight.
- 19C10v3xanti-EGFR was then diluted by cell culture medium and incubated with the cells in 37°C incubator for 30 minutes.
- PBMCs peripheral blood mononuclear cells
- the bispecific antibody induced lysis of all types of the tumor cells through the ADCC function, and the bispecific antibody showed superior ADCC effects compared to each of its monospecific antibody components and the combination thereof.
- Figure 6 compares the ADCC effects of 19C10v3xanti-EGFR and 19C10v4xanti-EGFR.
- B7H3/EGFR double positive tumor cells A549 human lung cancer cells
- cell culture medium Dulbecco’s Modified Eagle’s Medium, ATCC 30-2002, with 10%FBS, 1%Penicillin/Streptomycin, and 1%L-glutamine
- the bispecific antibodies were then diluted by A549 culture medium and incubated with the cells in 37°C incubator for 30 minutes.
- the NK92-CD16a cell were added to the antibody-A549 mixture for 5 hours incubation.
- the cell viability was then detected by VICTOR X3 multilabel plate reader (PerkinElmer) and was calculated using GraphPad PRISM.
- the bispecific antibodies induced lysis of the tumor cells through the ADCC function more effectively compared to monospecific anti-B7H3 antibodies, and 19C10v4xanti-EGFR showed superior ADCC effects compared to 19C10v3xanti-EGFR.
- the anti-B7H3/EGFR bispecific antibodies exhibited superior ADCC function compared to anti-B7H3 and anti-EGFR monospecific antibodies and their combinations, which indicates improved therapeutic effects for tumor eradication.
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Abstract
L'invention concerne des anticorps et des dérivés d'anticorps qui se lient à B7H3 (également connue sous le nom de CD276) et des procédés d'utilisation de ceux-ci. L'anticorps ou le dérivé d'anticorps comprend un anticorps à domaine unique qui se lie à B7H3. Le dérivé d'anticorps est un anticorps multispécifique qui se lie à B7H3 et un antigène supplémentaire, par exemple l'EGFR.
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015104406A2 (fr) * | 2014-01-13 | 2015-07-16 | Pieris Ag | Polypeptide multi-spécifique utilisé pour l'immunomodulation tumorale localisée |
WO2015184403A2 (fr) * | 2014-05-30 | 2015-12-03 | Henlius Biotech Co., Ltd. | Anticorps anti-récepteurs du facteur de croissance épidermique (egfr) |
WO2018160671A1 (fr) * | 2017-02-28 | 2018-09-07 | Harpoon Therapeutics, Inc. | Inhibiteurs de point de contrôle ciblés et méthodes d'utilisation |
WO2021089609A1 (fr) * | 2019-11-04 | 2021-05-14 | Numab Therapeutics AG | Anticorps multispécifiques |
CN113166261A (zh) * | 2018-10-11 | 2021-07-23 | 印希比股份有限公司 | B7h3单域抗体及其治疗性组合物 |
US20210403575A1 (en) * | 2018-10-22 | 2021-12-30 | Shanghai Yichen Biomed Co. Ltd | Bispecific antibody |
CN114729041A (zh) * | 2019-10-22 | 2022-07-08 | 美国政府(由卫生和人类服务部的部长所代表) | 用于治疗多种实体瘤的靶向b7h3(cd276)的高亲和力纳米抗体 |
-
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- 2023-09-21 WO PCT/CN2023/120239 patent/WO2024061297A1/fr unknown
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015104406A2 (fr) * | 2014-01-13 | 2015-07-16 | Pieris Ag | Polypeptide multi-spécifique utilisé pour l'immunomodulation tumorale localisée |
WO2015184403A2 (fr) * | 2014-05-30 | 2015-12-03 | Henlius Biotech Co., Ltd. | Anticorps anti-récepteurs du facteur de croissance épidermique (egfr) |
WO2018160671A1 (fr) * | 2017-02-28 | 2018-09-07 | Harpoon Therapeutics, Inc. | Inhibiteurs de point de contrôle ciblés et méthodes d'utilisation |
CN113166261A (zh) * | 2018-10-11 | 2021-07-23 | 印希比股份有限公司 | B7h3单域抗体及其治疗性组合物 |
US20210403575A1 (en) * | 2018-10-22 | 2021-12-30 | Shanghai Yichen Biomed Co. Ltd | Bispecific antibody |
CN114729041A (zh) * | 2019-10-22 | 2022-07-08 | 美国政府(由卫生和人类服务部的部长所代表) | 用于治疗多种实体瘤的靶向b7h3(cd276)的高亲和力纳米抗体 |
WO2021089609A1 (fr) * | 2019-11-04 | 2021-05-14 | Numab Therapeutics AG | Anticorps multispécifiques |
Non-Patent Citations (1)
Title |
---|
MA JIABING, MO YICHENG, TANG MENGLIN, SHEN JUNJIE, QI YANAN, ZHAO WENXU, HUANG YI, XU YANMIN, QIAN CHENG: "Bispecific Antibodies: From Research to Clinical Application", FRONTIERS IN IMMUNOLOGY, vol. 12, XP055936885, DOI: 10.3389/fimmu.2021.626616 * |
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