WO2020228604A1 - Anticorps anti-trop-2, fragment de liaison à l'antigène de celui-ci et utilisation médicale associée - Google Patents

Anticorps anti-trop-2, fragment de liaison à l'antigène de celui-ci et utilisation médicale associée Download PDF

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WO2020228604A1
WO2020228604A1 PCT/CN2020/089179 CN2020089179W WO2020228604A1 WO 2020228604 A1 WO2020228604 A1 WO 2020228604A1 CN 2020089179 W CN2020089179 W CN 2020089179W WO 2020228604 A1 WO2020228604 A1 WO 2020228604A1
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seq
antibody
trop
antigen
cancer
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PCT/CN2020/089179
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Chinese (zh)
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花海清
包如迪
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江苏豪森药业集团有限公司
上海翰森生物医药科技有限公司
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Priority to CN202080003175.1A priority Critical patent/CN112243443B/zh
Publication of WO2020228604A1 publication Critical patent/WO2020228604A1/fr

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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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells

Definitions

  • the present application relates to an anti-TROP-2 antibody that is specifically immunoreactive to human TROP-2 receptor, and antigen-binding fragments thereof, a chimeric antibody containing the CDR region of the anti-TROP-2 antibody, and humanized Antibodies, and pharmaceutical compositions containing human anti-TROP-2 antibodies and antigen-binding fragments thereof, and their use as anti-cancer drugs and tumor detection or diagnosis.
  • Molecular targeted therapy of tumors is a new treatment mode that is different from traditional surgery, radiotherapy, and chemotherapy.
  • the advantage is that drugs usually only bind to the corresponding target, and directly affect the function of the target molecule or carry it.
  • the physical or chemical effector molecules to achieve the effect of killing or inhibiting target cells. Because the target site is clear, the drug usually has a high selectivity, which can effectively kill or inhibit the target cell, but also produces no or only minor toxic side effects on normal tissue cells. Therefore, the development of molecularly targeted drugs has become a hot spot in tumor clinical research.
  • TROP-2 Human trophoblast cell surface antigen 2
  • TROP-2 consists of 323 amino acids, including 26 amino acids in signal peptide, 248 amino acids in extracellular region, 23 amino acids in transmembrane region, and 26 amino acids in cytoplasmic region.
  • the extracellular domain has a characteristic thyroglobulin (TY) sequence, which is generally believed to be related to the proliferation, infiltration and metastasis of cancer cells.
  • TY thyroglobulin
  • the physiological ligand of TROP-2 has not been identified, and the molecular function has not been elucidated.
  • the intracellular Serine 303 residue is phosphorylated by protein kinase C (PKC), which is a Ca2+ dependent protein kinase, and intracellular The domain has a PIP2 binding sequence, indicating that it has a signal transmission function in tumor cells.
  • PLC protein kinase C
  • TROP-2 is overexpressed in gastric cancer, lung cancer, colon, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, liver cancer, esophageal cancer and other epithelial cancers.
  • TROP-2 is rarely expressed or not expressed in normal adult tissues, only a small amount of expression in cells in the epithelial area, and the expression level is also lower than that in cancer, indicating that TROP-2 is related to tumor formation.
  • the overexpression of TROP-2 in tumor tissues is closely related to the poor prognosis of patients and the metastasis of cancer cells, and affects the overall survival rate of patients. Therefore, TROP-2 has become an attractive target in tumor molecular targeted therapy.
  • US Patent No. 5840854 reports the cytotoxicity of anti-hTROP-2 monoclonal antibody (BR110) bound to cytotoxin on human cancer cell lines H3619, H2987, MCF-7, H3396 and H2981.
  • U.S. Patent No. 6653104 discloses an antibody (RS7), which was tested in an in vivo model using an antibody labeled with a radioactive substance, and showed anti-tumor activity in a nude mouse xenograft model, but there is no report of only naked antibody Timely anti-tumor effect.
  • US Patent No. 7420040 also reported that the isolated monoclonal antibody produced by the hybridoma cell line AR47A6.4.2 or AR52A301.5 obtained by immunizing mice with human ovarian cancer tissue binds to hTROP-2 and is xenotransplanted in nude mice. The model showed anti-tumor activity.
  • CN102827282A discloses a human anti-TROP-2 genetically engineered antibody IgG and its application. In vitro test results show that the anti-TROP-2 antibody IgG has a significant inhibitory effect on the proliferation of pancreatic cancer cells.
  • CN104114580A discloses an antibody (especially a humanized antibody) that specifically reacts with hTROP-2 and has anti-tumor activity in the body; and a hybridoma that produces the antibody, a complex of the antibody and a drug, and diagnostic use for tumors Or therapeutic pharmaceutical composition, tumor detection method, tumor detection or diagnostic kit.
  • the present invention provides new anti-TROP-2 antibodies or antigen-binding fragments thereof with enhanced tumor cell killing effect.
  • an anti-TROP-2 antibody or an antigen-binding fragment thereof which comprises an antibody heavy chain variable region and an antibody light chain variable region, wherein the antibody heavy chain variable region comprises At least one HCDR is selected from the following sequences: SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5; and the antibody light chain variable region includes at least one HCDR selected from the following sequences LCDR: SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8.
  • the heavy chain variable region of the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application comprises:
  • the light chain variable region of the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application comprises:
  • the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application comprises:
  • the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application is selected from: murine antibody, chimeric antibody, human antibody, humanized antibody.
  • the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application further comprises a heavy chain constant region derived from human IgG1, IgG2, IgG3 or IgG4 or a variant thereof.
  • the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application further comprises an IgG1 heavy chain constant region derived from amino acid mutations that has enhanced ADCC toxicity.
  • the applied anti-TROP-2 antibody or antigen-binding fragment thereof further comprises an IgG1 heavy chain constant region introduced with E239D and M241L mutations.
  • the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application comprises a sequence selected from SEQ ID NO: 48 or SEQ ID NO: 49 heavy chain constant region.
  • the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application further comprises a human kappa chain, a lambda chain or a variant thereof. In some embodiments, the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application further comprises a constant region selected from SEQ ID NO:50.
  • the heavy chain variable region of the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application is selected from the heavy chain variable regions shown in the following sequences: SEQ ID NO: 9, SEQ ID NO :11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 23, SEQ ID NO: 25, or at least 70 %, 75%, 80%, 85%, 90%, 95% or 99% homology of the heavy chain variable region sequence.
  • the light chain variable region of the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application is selected from the light chain variable regions shown in the following sequences: SEQ ID NO: 10, SEQ ID NO :12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, or at least 70 %, 75%, 80%, 85%, 90%, 95% or 99% homology of the light chain variable region sequence.
  • the heavy chain of the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application is selected from heavy chains containing the following sequences: SEQ ID NO: 27, SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 47, or similar
  • the light chain of the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application is selected from light chains containing the following sequences: SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, or at least 80%, 85%, 90%, 95 % Or 99% homology of the full-length light chain sequence.
  • the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application, wherein:
  • the heavy chain variable region of the anti-TROP-2 antibody is shown in SEQ ID NO: 9;
  • the light chain variable region of the anti-TROP-2 antibody is shown in SEQ ID NO: 10.
  • the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application, wherein:
  • the heavy chain variable region of the anti-TROP-2 antibody is shown in SEQ ID NO: 11;
  • the light chain variable region of the anti-TROP-2 antibody is shown in SEQ ID NO: 12.
  • the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application, wherein:
  • the heavy chain variable region of the anti-TROP-2 antibody is shown in SEQ ID NO: 13;
  • the light chain variable region of the anti-TROP-2 antibody is shown in SEQ ID NO: 14.
  • the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application, wherein:
  • the heavy chain variable region of the anti-TROP-2 antibody is shown in SEQ ID NO: 15;
  • the light chain variable region of the anti-TROP-2 antibody is shown in SEQ ID NO: 16.
  • the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application, wherein:
  • the heavy chain variable region of the anti-TROP-2 antibody is shown in SEQ ID NO: 17;
  • the light chain variable region of the anti-TROP-2 antibody is shown in SEQ ID NO: 18.
  • the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application, wherein:
  • the heavy chain variable region of the anti-TROP-2 antibody is shown in SEQ ID NO: 19;
  • the light chain variable region of the anti-TROP-2 antibody is shown in SEQ ID NO: 20.
  • the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application, wherein:
  • the heavy chain variable region of the anti-TROP-2 antibody is shown in SEQ ID NO: 21;
  • the light chain variable region of the anti-TROP-2 antibody is shown in SEQ ID NO: 22.
  • the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application, wherein:
  • the heavy chain variable region of the anti-TROP-2 antibody is shown in SEQ ID NO: 23;
  • the light chain variable region of the anti-TROP-2 antibody is shown in SEQ ID NO: 24.
  • the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application, wherein:
  • the heavy chain variable region of the anti-TROP-2 antibody is shown in SEQ ID NO: 25;
  • the light chain variable region of the anti-TROP-2 antibody is shown in SEQ ID NO: 26.
  • the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application, wherein:
  • the heavy chain of the anti-TROP-2 antibody is shown in SEQ ID NO: 27;
  • the light chain of the anti-TROP-2 antibody is shown in SEQ ID NO: 28.
  • the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application, wherein:
  • the heavy chain of the anti-TROP-2 antibody is shown in SEQ ID NO: 29;
  • the light chain of the anti-TROP-2 antibody is shown in SEQ ID NO: 30.
  • the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application, wherein:
  • the heavy chain of the anti-TROP-2 antibody is shown in SEQ ID NO: 31;
  • the light chain of the anti-TROP-2 antibody is shown in SEQ ID NO: 32.
  • the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application, wherein:
  • the heavy chain of the anti-TROP-2 antibody is shown in SEQ ID NO: 33;
  • the light chain of the anti-TROP-2 antibody is shown in SEQ ID NO: 34.
  • the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application, wherein:
  • the heavy chain of the anti-TROP-2 antibody is shown in SEQ ID NO: 35;
  • the light chain of the anti-TROP-2 antibody is shown in SEQ ID NO: 36.
  • the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application, wherein:
  • the heavy chain of the anti-TROP-2 antibody is shown in SEQ ID NO: 37;
  • the light chain of the anti-TROP-2 antibody is shown in SEQ ID NO: 38.
  • the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application, wherein:
  • the heavy chain of the anti-TROP-2 antibody is shown in SEQ ID NO: 39;
  • the light chain of the anti-TROP-2 antibody is shown in SEQ ID NO: 40.
  • the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application, wherein:
  • the heavy chain of the anti-TROP-2 antibody is shown in SEQ ID NO: 41;
  • the light chain of the anti-TROP-2 antibody is shown in SEQ ID NO: 42.
  • the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application, wherein:
  • the heavy chain of the anti-TROP-2 antibody is shown in SEQ ID NO: 43;
  • the light chain of the anti-TROP-2 antibody is shown in SEQ ID NO: 44.
  • the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application, wherein:
  • the heavy chain of the anti-TROP-2 antibody is shown in SEQ ID NO: 45;
  • the light chain of the anti-TROP-2 antibody is shown in SEQ ID NO: 38.
  • the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application, wherein:
  • the heavy chain of the anti-TROP-2 antibody is shown in SEQ ID NO: 47;
  • the light chain of the anti-TROP-2 antibody is shown in SEQ ID NO: 28.
  • a polynucleotide which encodes the anti-TROP-2 antibody or antigen-binding fragment thereof of the present application.
  • an expression vector which contains the polynucleotide of the application.
  • a host cell is provided, which is introduced into or contains the expression vector of the present application.
  • the host cell is bacteria, preferably Escherichia coli.
  • the host cell is yeast, preferably Pichia pastoris.
  • the host cell is a mammalian cell, preferably a CHO cell or HEK293 cell.
  • a method for producing an anti-TROP-2 antibody including the steps of culturing a host cell according to the present application, isolating the antibody from the culture, and purifying the antibody.
  • a pharmaceutical composition which contains the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application and a pharmaceutically acceptable excipient, diluent or carrier.
  • a detection or diagnosis kit which contains the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application.
  • the use of the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application in the preparation of a medicament for the treatment or prevention of a disease or disorder mediated by TROP-2.
  • the use of the anti-TROP-2 antibody or antigen-binding fragment thereof according to the present application in the preparation of reagents, wherein the reagents are used for detecting or diagnosing diseases or disorders mediated by TROP-2.
  • the disease or condition is cancer.
  • the disease or condition is a cancer that expresses TROP-2.
  • the disease or condition is selected from breast cancer, non-small cell lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, liver cancer, stomach cancer, colon cancer, bladder cancer, esophageal cancer , Cervical cancer, gallbladder cancer, glioblastoma and melanoma.
  • a method for treating or preventing TROP-2 mediated diseases including the steps of: providing a subject with a therapeutically effective amount or a preventively effective amount of an anti-TROP-2 antibody according to the present application Or its antigen-binding fragment.
  • a method for treating or preventing TROP-2 mediated diseases including the steps of: providing a subject with a therapeutically effective amount or a preventively effective amount of the pharmaceutical composition according to the present application.
  • the subject is suspected of having, has suffered from, or is susceptible to a TROP-2 mediated disease, which is selected from breast cancer, non-small cell lung cancer, ovarian cancer, prostate cancer, pancreatic cancer , Kidney cancer, lung cancer, liver cancer, stomach cancer, colon cancer, bladder cancer, esophageal cancer, cervical cancer, gallbladder cancer, glioblastoma and melanoma.
  • TROP-2 mediated disease which is selected from breast cancer, non-small cell lung cancer, ovarian cancer, prostate cancer, pancreatic cancer , Kidney cancer, lung cancer, liver cancer, stomach cancer, colon cancer, bladder cancer, esophageal cancer, cervical cancer, gallbladder cancer, glioblastoma and melanoma.
  • Figure 1 ELISA in vitro binding experiment of antibodies, showing the binding activity of 11 humanized anti-TROP-2 antibodies to human TROP-2 antigen.
  • antibody refers to an immunoglobulin, which is a tetrapeptide chain structure composed of two identical heavy chains and two identical light chains connected by interchain disulfide bonds.
  • the amino acid composition and sequence of the constant region of the immunoglobulin heavy chain are different, so their antigenicity is also different.
  • immunoglobulins can be divided into five categories, or isotypes of immunoglobulins, namely IgM, IgD, IgG, IgA and IgE.
  • the corresponding heavy chains are ⁇ chain, ⁇ chain, and ⁇ chain. , ⁇ chain and ⁇ chain.
  • IgG can be divided into IgG1, IgG2, IgG3, and IgG4.
  • the light chain is divided into ⁇ chain or ⁇ chain by the difference of the constant region.
  • Each of the five types of Ig can have a kappa chain or a lambda chain.
  • the antibody light chain variable region described in the present application may further include a light chain constant region, and the light chain constant region includes human or murine ⁇ , ⁇ chains or variants thereof.
  • the antibody heavy chain variable region described in this application may further include a heavy chain constant region, and the heavy chain constant region includes human or murine IgG1, IgG2, IgG3, IgG4 or its variants. body.
  • variable region The sequence of about 110 amino acids near the N-terminus of the antibody heavy and light chains varies greatly and is the variable region (V region); the remaining amino acid sequences near the C-terminus are relatively stable and are the constant region (C region).
  • the variable region includes 3 hypervariable regions (HVR) and 4 framework regions (FR) with relatively conservative sequences. Three hypervariable regions determine the specificity of the antibody, also known as complementarity determining regions (CDR).
  • CDR complementarity determining regions
  • Each light chain variable region (VL) and heavy chain variable region (VH) is composed of 3 CDR regions and 4 FR regions.
  • the sequence from amino terminal to carboxy terminal is FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the 3 CDR regions of the light chain refer to LCDR1, LCDR2, and LCDR3; the 3 CDR regions of the heavy chain refer to HCDR1, HCDR2, and HCDR3.
  • the number and position of the CDR amino acid residues of the VL region and VH region of the antibody or antigen-binding fragment described in this application comply with the known Kabat numbering rules and Kabat or ABM definition rules (http://bioinf.org.uk/abs /).
  • APC antigen presenting cell
  • DC dendritic cells
  • PBMC topical blood mononuclear cells
  • monocytes B lymphoblasts
  • monocyte-derived dendritic cells monocyte-derived dendritic cells
  • antigen presentation refers to the process by which APC captures antigens and enables them to be recognized by T cells, for example as a component of MHC-I/MHC-II conjugates.
  • TROP-2 includes any variant or isoform of TROP-2 that is naturally expressed by the cell.
  • the antibodies of the application can cross-react with TROP-2 derived from non-human species.
  • the antibody may also be human TROP-2 specific, and may not show cross-reactivity with other species.
  • TROP-2 or any variants or isoforms thereof can be isolated from the cells or tissues that naturally express them, or can be produced by recombinant techniques using techniques commonly used in the art and those described herein.
  • the anti-TROP-2 antibody targets human TROP-2 with a normal glycosylation pattern.
  • recombinant human antibody includes human antibodies prepared, expressed, created or isolated by recombinant methods, and the techniques and methods involved are well known in the art, such as:
  • Antibodies isolated from host cells transformed to express antibodies such as transfectomas;
  • Antibodies prepared, expressed, created or isolated by splicing human immunoglobulin gene sequences to other DNA sequences.
  • Such recombinant human antibodies contain variable and constant regions, which utilize specific human germline immunoglobulin sequences encoded by germline genes, but also include subsequent rearrangements and mutations that occur during antibody maturation.
  • murine antibody in this application is a monoclonal antibody to human TROP-2 prepared according to the knowledge and skills in the art. During preparation, the test subject is injected with TROP-2 antigen, and then hybridomas expressing antibodies with the desired sequence or functional properties are isolated.
  • the murine TROP-2 antibody or antigen-binding fragment thereof may further comprise the light chain constant region of murine kappa, lambda chains or variants thereof, or further comprise murine IgG1 , IgG2, IgG3 or IgG4 or variants of the heavy chain constant region.
  • human antibody includes antibodies having variable and constant regions of human germline immunoglobulin sequences.
  • the human antibodies of the present application may include amino acid residues not encoded by human germline immunoglobulin sequences (such as mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo).
  • the term “human antibody” does not include antibodies in which CDR sequences derived from the germline of another mammalian species (such as a mouse) have been grafted onto human framework sequences (ie, "humanized antibodies”) .
  • humanized antibody also known as CDR-grafted antibody, refers to an antibody produced by grafting mouse CDR sequences into a human antibody variable region framework.
  • Humanized antibodies can overcome the shortcomings of a strong immune response induced by chimeric antibodies that carry a large amount of mouse protein components.
  • the variable region of the human antibody can be subjected to minimal reverse mutation to maintain activity.
  • chimeric antibody refers to an antibody formed by fusing the variable region of a murine antibody with the constant region of a human antibody, which can reduce the immune response induced by the murine antibody.
  • To establish a chimeric antibody it is necessary to select a hybridoma that secretes a murine specific monoclonal antibody, and then clone the variable region gene from the mouse hybridoma cell, and then clone the constant region gene of the human antibody as needed, and change the mouse variable
  • the region gene and the human constant region gene are connected to form a chimeric gene and then inserted into a human vector, and finally the chimeric antibody molecule is expressed in a eukaryotic industrial system or a prokaryotic industrial system.
  • the constant region of a human antibody can be selected from the heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 or variants thereof, preferably comprising human IgG1, IgG2 or IgG4 heavy chain constant region, or using amino acid mutations to enhance ADCC (antibody -dependent cell-mediated cytotoxicity, antibody-dependent cell-mediated cytotoxicity) toxic IgG1 heavy chain constant region.
  • ADCC antibody -dependent cell-mediated cytotoxicity, antibody-dependent cell-mediated cytotoxicity
  • antigen-binding fragment refers to antigen-binding fragments and antibody analogs of antibodies, which usually include at least part of the antigen-binding region or variable region (for example, one or more CDRs) of a parental antibody.
  • Antibody fragments retain at least some of the binding specificity of the parent antibody. Generally, when the activity is expressed on a mole basis, the antibody fragment retains at least 10% of the parent binding activity. Preferably, the antibody fragment retains at least 20%, 50%, 70%, 80%, 90%, 95% or 100% or more of the binding affinity of the parent antibody to the target.
  • antigen-binding fragments include, but are not limited to: Fab, Fab', F(ab')2, Fv fragments, linear antibodies, single-chain antibodies, nanobodies, domain antibodies, and multispecific antibodies.
  • the engineered antibody variants are reviewed in Holliger and Hudson, 2005, Nat. Biotechnol. 23:1126-1136.
  • the "Fab fragment” consists of the CH1 and variable regions of one light chain and one heavy chain.
  • the heavy chain of a Fab molecule cannot form a disulfide bond with another heavy chain molecule.
  • the "Fc" region contains two heavy chain fragments containing the CH1 and CH2 domains of the antibody.
  • the two heavy chain fragments are held together by two or more disulfide bonds and by the hydrophobic effect of the CH3 domain.
  • the "Fab' fragment” contains a light chain and a portion of a heavy chain that contains the VH domain, the CH1 domain, and the region between the CH1 and CH2 domains, so that it can be between the two heavy chains of the two Fab' fragments The formation of interchain disulfide bonds to form F(ab')2 molecules.
  • the "F(ab')2 fragment” contains two light chains and two heavy chains containing a portion of the constant region between the CH1 and CH2 domains, thereby forming an interchain disulfide bond between the two heavy chains. Therefore, the F(ab')2 fragment is composed of two Fab' fragments held together by the disulfide bond between the two heavy chains.
  • the "Fv region” contains variable regions from both the heavy and light chains, but lacks the constant region.
  • multispecific antibody is used in its broadest sense to encompass antibodies with polyepitope specificity.
  • These multispecific antibodies include, but are not limited to: antibodies comprising a heavy chain variable region VH and a light chain variable region VL, wherein the VH-VL unit has polyepitope specificity; having two or more VL and VH regions Antibodies, each VH-VL unit binds to a different target or a different epitope of the same target; an antibody with two or more single variable regions, each single variable region with a different target Or binding to different epitopes of the same target; full-length antibodies, antibody fragments, diabodies, bispecific diabodies and triabodies, antibody fragments that have been covalently or non-covalently linked together Wait.
  • single-chain antibody is a single-chain recombinant protein formed by connecting the heavy chain variable region VH and the light chain variable region VL of an antibody through a connecting peptide. It is the smallest antibody fragment with a complete antigen-binding site.
  • domain antibody fragment is an immunoglobulin fragment with immunological functions that only contains a heavy chain variable region or a light chain variable region chain.
  • two or more VH regions are covalently linked to a peptide linker to form a bivalent domain antibody fragment.
  • the two VH regions of the bivalent domain antibody fragment can target the same or different antigens.
  • binding to TROP-2 refers to the ability to interact with human TROP-2.
  • antigen-binding site in the present application refers to a three-dimensional site recognized by the antibody or antigen-binding fragment of the present application.
  • epitope refers to a site on an antigen that specifically binds to an immunoglobulin or antibody.
  • Epitopes can be formed by adjacent amino acids, or non-adjacent amino acids juxtaposed by tertiary folding of the protein. Epitopes formed by adjacent amino acids are usually maintained after exposure to a denaturing solvent, while epitopes formed by tertiary folding are usually lost after treatment with a denaturing solvent.
  • Epitopes usually include at least 3-15 amino acids in a unique spatial conformation. Methods to determine what epitope is bound by a given antibody are well known in the art, including immunoblotting and immunoprecipitation detection analysis. Methods for determining the spatial conformation of an epitope include the techniques in the art and the techniques described herein, such as X-ray crystal analysis and two-dimensional nuclear magnetic resonance.
  • binding and “selective binding” as used in this application refer to the binding of an antibody to an epitope on a predetermined antigen.
  • an antibody when measured by surface plasmon resonance (SPR) technology in the instrument, the antibody dissociates at an equilibrium of about less than 10 -7 M or even less
  • the constant (K D ) binds to a predetermined antigen, and its binding affinity to the predetermined antigen is at least twice its binding affinity to non-specific antigens (such as BSA, etc.) other than the predetermined antigen or closely related antigens.
  • the term "antibody that recognizes an antigen” can be used interchangeably with the term “antibody that specifically binds” herein.
  • cross-reactivity refers to the ability of the antibodies of the present application to bind to TROP-2 from different species.
  • the antibody of the present application that binds to human TROP-2 can also bind to TROP-2 of another species.
  • Cross-reactivity is measured by detecting specific reactivity with purified antigens in binding assays such as SPR and ELISA, or binding or functional interaction with cells that physiologically express TROP-2.
  • Methods of determining cross-reactivity include standard binding assays as described herein, such as surface plasmon resonance (SPR) analysis, or flow cytometry.
  • SPR surface plasmon resonance
  • inhibition or “blocking” are used interchangeably and encompass both partial and complete inhibition/blocking.
  • the inhibition/blocking of the ligand preferably reduces or alters the normal level or type of activity that occurs when ligand binding occurs without inhibition or blocking.
  • Inhibition and blocking are also intended to include any measurable decrease in ligand binding affinity when contacted with an anti-TROP-2 antibody compared to a ligand not contacted with an anti-TROP-2 antibody.
  • inhibition of growth is intended to include any measurable decrease in cell growth.
  • inducing an immune response and “enhancing an immune response” are used interchangeably and refer to the stimulation (ie, passive or adaptive) of an immune response to a specific antigen.
  • induction for inducing CDC or ADCC refers to stimulating a specific direct cell killing mechanism.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • cells expressing Fc receptors directly kill the antibody-coated cells by recognizing the Fc segment of the antibody.
  • the target cells are.
  • the ADCC effect function of the antibody can be enhanced or reduced by modifying the Fc segment of IgG.
  • the modification refers to mutations in the constant region of the heavy chain of the antibody.
  • mice can be immunized with human TROP-2 or fragments thereof, and the obtained antibodies can be renatured, purified, and amino acid sequencing can be performed by conventional methods.
  • Antigen-binding fragments can also be prepared by conventional methods.
  • the antibody or antigen-binding fragment of the invention is genetically engineered to add one or more human FR regions to the non-human CDR region.
  • the human FR germline sequence can be obtained from the website http://imgt.cines.fr of ImmunoGeneTics (IMGT), or from the Journal of Immunoglobulin, 2001ISBN012441351.
  • the engineered antibody or antigen-binding fragment of the application can be prepared and purified by conventional methods.
  • the cDNA sequence of the corresponding antibody can be cloned and recombined into a GS expression vector.
  • the recombinant immunoglobulin expression vector can be stably transfected into CHO cells.
  • mammalian expression systems can lead to glycosylation of antibodies, especially at the highly conserved N-terminus of the FC region.
  • Stable clones are obtained by expressing antibodies that specifically bind to human antigens. Positive clones are expanded in the serum-free medium of the bioreactor to produce antibodies.
  • the antibody-secreted culture medium can be purified and collected by conventional techniques.
  • the antibody can be filtered and concentrated by conventional methods. Soluble mixtures and polymers can also be removed by conventional methods, such as molecular sieves and ion exchange.
  • the resulting product needs to be frozen immediately, such as -70°C, or lyophilized.
  • the antibody in this application refers to a monoclonal antibody.
  • the monoclonal antibody (mAb) described in this application refers to an antibody obtained from a single cloned cell line, and the cell line is not limited to a eukaryotic, prokaryotic or phage cloned cell line.
  • Monoclonal antibodies or antigen-binding fragments can be obtained by recombination using, for example, hybridoma technology, recombination technology, phage display technology, synthesis technology (such as CDR-grafting), or other existing technologies.
  • administering when applied to animals, humans, experimental subjects, cells, tissues, organs or biological fluids refer to exogenous drugs, therapeutic agents, diagnostic agents or compositions and animals , Human, subject, cell, tissue, organ or biological fluid contact.
  • administering can refer to, for example, treatment, pharmacokinetics, diagnosis, research, and experimental methods.
  • the treatment of cells includes contact of reagents with cells, and contact of reagents with fluids, where the fluids are in contact with cells.
  • administering “administration” and “treatment” also mean the treatment of, for example, cells by reagents, diagnostics, binding compositions, or by another cell in vitro and ex vivo.
  • Treatment when applied to human, veterinary or research subjects, refers to treatment, preventive or preventive measures, research and diagnostic applications.
  • Treatment means administering an internal or external therapeutic agent, such as containing any of the antibodies of the present application, to a patient who has one or more disease symptoms, and the therapeutic agent is known to have a therapeutic effect on these symptoms.
  • the therapeutic agent is administered in the patient or population to be treated in an amount effective to alleviate one or more disease symptoms, whether by inducing the regression of such symptoms or inhibiting the development of such symptoms to any clinically measured extent.
  • the amount of the therapeutic agent effective to alleviate the symptoms of any particular disease can vary depending on various factors, such as the patient's disease state, age and weight, and the ability of the drug to produce the desired therapeutic effect in the patient.
  • any clinical testing methods commonly used by doctors or other professional health care professionals to evaluate the severity or progression of the symptoms can assess whether the symptoms of the disease have been alleviated.
  • the embodiments of this application may be ineffective in alleviating the symptoms of the target disease that each patient has, but according to any statistical test methods known in the art such as Student's t test, chi-square test, basis Mann and Whitney's U test, Kruskal-Wallis test (H test), Jonckheere-Terpstra test, and Wilcoxon test determined that they should alleviate the target disease symptoms in a statistically significant number of patients.
  • naturally occurring applied to an object as described in this application refers to the fact that the object can be found in nature.
  • polypeptide sequences or polynucleotide sequences that exist in organisms (including viruses) that can be isolated from natural sources and have not been intentionally modified by artificial in the laboratory are naturally occurring.
  • Effective amount includes an amount sufficient to improve or prevent the symptoms or conditions of medical conditions.
  • An effective amount also means an amount sufficient to allow or facilitate diagnosis.
  • the effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's general health, the method of administration and dosage, and the severity of side effects.
  • the effective amount can be the maximum dose or dosing schedule that avoids significant side effects or toxic effects.
  • Exogenous refers to substances that are produced outside organisms, cells, or humans depending on the background.
  • Endogenous refers to a substance produced in a cell, organism, or human body according to the background.
  • “Homology” refers to the sequence similarity between two polynucleotide sequences or between two polypeptides. When positions in two comparison sequences are occupied by the same base or amino acid monomer subunit, for example, if each position of two DNA molecules is occupied by adenine, then the molecules are homologous at that position .
  • the percentage 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 ⁇ 100%. For example, in the optimal sequence alignment, if there are 6 matches or homology in 10 positions in the two sequences, then the two sequences are 60% homologous. Generally speaking, the comparison is made when two sequences are aligned to obtain the maximum homogeneity percentage.
  • “Pharmaceutical composition” means containing one or more of the antibodies or antigen-binding fragments described herein, and other components such as physiological/pharmaceutically acceptable carriers and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredients and thus the biological activity.
  • TROP-2 (TROP-2-His) protein encoding His tag was synthesized by SinoBiologics (10428-H08H).
  • Example 2 Obtaining mouse hybridoma and antibody sequence
  • the indirect ELISA method as described in Example 3 was used for the immunized mouse serum to evaluate the serum titer and the ability to bind to cell surface antigens.
  • the detection of the titer (larger than 100,000 times dilution) determines the start of cell fusion.
  • the immunized mice with strong serum titer, affinity and FACS binding were selected for one final immunization and then sacrificed. Splenocytes and SP2/0 myeloma cells were fused and plated to obtain hybridomas.
  • the target hybridomas were screened by indirect ELISA, and The strain was established as a monoclonal cell strain by the limiting dilution method.
  • the obtained positive antibody strains are further screened using indirect ELISA to select hybridomas that bind the recombinant protein.
  • the logarithmic growth phase hybridoma cells were collected, RNA was extracted with Trizol (Invitrogen, 15596-018) and reverse transcribed (PrimeScript TM Reverse Transcriptase, Takara #2680A).
  • the cDNA obtained by reverse transcription was amplified by PCR using a mouse Ig-primer set (Novagen, TB326 Rev. B 0503) and then sequenced, and finally the sequence of the mouse antibody was obtained.
  • the heavy chain and light chain variable region sequences of murine monoclonal antibody M1 are as follows:
  • TROP-2His protein (Sino Biological Inc., cat#10428-H08H) with pH 7.4 PBS to a concentration of 1 ⁇ g/ml, add 100 ⁇ l/well to a 96-well high-affinity ELISA plate, and refrigerate at 4°C Incubate overnight (16-20 hours). After washing the plate with PBST (pH 7.4 PBS containing 0.05% Tween-20) 4 times, adding 150 ⁇ l/well of 3% bovine serum albumin (BSA) blocking solution diluted with PBST, and incubating for 1 hour at room temperature for blocking. After the blocking, discard the blocking solution, and wash the plate 4 times with PBST buffer.
  • BSA bovine serum albumin
  • Collect cultured TROP-2 high-expressing cells (CHO or 293 cells overexpressing TROP-2 and tumor cells expressing TROP-2, such as HCC-827, MDA-MB-468, etc.), adjust the cell density and spread them 96-well U bottom plate, 1 ⁇ 10 5 to 2 ⁇ 10 5 cells per well. Centrifuge at 1200g for 5min, remove the supernatant, add 100ul of serially diluted antibody solution or mouse immune serum, incubate at 4°C for 60min; centrifuge at 1200g for 5min, remove the supernatant, and wash the cells twice with PBS, add a fluorescently labeled secondary antibody (PE-GAM or PE-GAH) 100ul per well, incubate at 4°C for 60min. Centrifuge at 1200g for 5min to remove the supernatant. After washing the cells twice with PBS, resuspend them in PBS, use a flow cytometer to detect the signal, and make a concentration curve analysis result.
  • the humanization of the murine anti-human TROP-2 monoclonal antibody is carried out according to the methods published in many documents in the field. In short, a human constant domain is used instead of the parental (murine antibody) constant domain, and the human antibody sequence is selected based on the homology of the murine antibody and the human antibody. This application humanizes the murine antibody M1.
  • the heavy and light chain variable region sequences are compared with the human antibody germline database to obtain a human germline template with high homology.
  • the CDR region of the murine antibody M1 was transplanted to the selected corresponding humanized template. Then, based on the three-dimensional structure of the murine antibody, the embedded residues, the residues that directly interact with the CDR region, and the residues that have an important impact on the conformation of VL and VH were back-mutated. After expression testing and After comparing the number of back mutations, an antibody designed with a combination of humanized heavy chain variable region HCVR and light chain variable region LCVR sequences was selected. The sequence is as follows:
  • the obtained exemplary heavy chain and light chain sequences are as follows (where the HU1-HU9 heavy chain is derived from the sequence SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 23, SEQ ID NO: 25 are connected to the sequence SEQ ID NO: 49; the HU6DL and HU10 heavy chains are derived from the sequence of SEQ ID NO: 19 and SEQ ID NO: 9 are respectively connected to the sequence SEQ ID NO: 48):
  • CDNA fragments were synthesized based on the amino acid sequences of the light and heavy chains of the above humanized antibodies, and inserted into the pcDNA3.1 expression vector (Life Technologies Cat. No. V790-20).
  • the expression vector and transfection reagent PEI (Polysciences, Inc. Cat. No. 23966) were transfected into HEK293 cells (Life Technologies Cat. No. 11625019) at a ratio of 1:2, and incubated in a CO 2 incubator 4- 5 days.
  • Example 7 In order to detect the binding ability of each humanized antibody to the target protein TROP-2 on tumor cells, the in vitro cell binding experiment described in Example 3 (2) was used to test the humanized antibody against HCC827 tumor cells (not small The affinity (EC 50 ) of cell lung cancer) is shown in Table 7 below:
  • Humanized antibodies can kill tumor cells from many aspects, one of which is to mediate the killing effect of immune cells on tumor cells.
  • PBMC peripheral blood mononuclear cells
  • HCC827 tumor cells non-small cell lung cancer
  • Collect commercialized human PBMC cells after centrifugal counting, adjust the cell density to 2.2 ⁇ 10 6 cells/mL with complete medium, and spread them in the middle 60 wells of a white 96-well plate with HCC827 cells, each well is 90 ⁇ L, the number of cells is 200000. Add 200 ⁇ L of PBS to the remaining side holes, and place the cell plate in a 37°C, 5% CO2 incubator overnight. On the second day of the experiment, the humanized antibody solution was prepared in a 96-well V-bottom plate with PBS, starting at a concentration of 1000 nM, diluted 3 times, and 9 concentrations.
  • SW780 cells were trypsinized, the cells were collected and resuspended in pre-cooled PBS, and the cell concentration was adjusted to 1 ⁇ 10 6 cells/mL .
  • One tube will be taken out at different time points and placed on ice to pre-cool for 5 minutes. Centrifuge for all treatment groups and discard the supernatant (4°C, 1500rpm ⁇ 5min). ), wash once with PBS and remove the supernatant. Add 250 ⁇ L strip buffer to the tubes of all treatment groups except the 0min group, incubate at room temperature for 8min, centrifuge and discard the supernatant (4°C, 1500rpm ⁇ 5min), wash twice with PBS, and remove the supernatant. Add 100 ⁇ L of immunostaining fixative to all treatment groups, place them at 4°C for more than 30 minutes, and use flow cytometer DxFlex for detection.
  • the humanized antibody of the present invention has a very low inhibition rate on the binding of hRS7 antibody and TROP2 protein, suggesting that the humanized antibody of the present invention and hRS7 antibody do not compete for binding to the same epitope.

Abstract

L'invention concerne un anticorps anti-TROP-2, un fragment de liaison à l'antigène de celui-ci, et une utilisation médicale associée. En outre, l'invention concerne un anticorps chimérique et un anticorps humanisé comprenant une région CDR de l'anticorps anti-TROP-2, une composition pharmaceutique comprenant l'anticorps anti-TROP-2 ou un fragment de liaison à l'antigène de celui-ci, et une utilisation associée en tant que médicament anticancéreux. En particulier, la présente invention concerne un anticorps anti-TROP-2 humanisé, et une utilisation de celui-ci dans la préparation d'un médicament pour le traitement de maladies ou de symptômes à médiation par TROP-2 et une utilisation associée dans la détection et le diagnostic de tumeur.
PCT/CN2020/089179 2019-05-10 2020-05-08 Anticorps anti-trop-2, fragment de liaison à l'antigène de celui-ci et utilisation médicale associée WO2020228604A1 (fr)

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