WO2023116759A1 - Anti-bcma antibody and use thereof - Google Patents

Anti-bcma antibody and use thereof Download PDF

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WO2023116759A1
WO2023116759A1 PCT/CN2022/140660 CN2022140660W WO2023116759A1 WO 2023116759 A1 WO2023116759 A1 WO 2023116759A1 CN 2022140660 W CN2022140660 W CN 2022140660W WO 2023116759 A1 WO2023116759 A1 WO 2023116759A1
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seq
amino acid
acid sequence
chain variable
light chain
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PCT/CN2022/140660
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Chinese (zh)
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WO2023116759A9 (en
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徐维丽
张继全
李帅
盛香香
张洁
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上海君实生物医药科技股份有限公司
上海君实生物工程有限公司
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Publication of WO2023116759A1 publication Critical patent/WO2023116759A1/en
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    • 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
    • C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6854—Immunoglobulins
    • 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
    • C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
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    • C07K2317/515—Complete light chain, i.e. VL + CL
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    • 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
    • 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
    • C07K2317/565—Complementarity determining region [CDR]
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70578—NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30 CD40 or CD95

Definitions

  • the application belongs to the field of biomedicine, and in particular relates to an antibody capable of specifically binding to BCMA or an antigen-binding fragment thereof and use thereof.
  • B cells are lymphocytes that play an important role in adaptive humoral immunity and the production of antibodies that specifically recognize antigens.
  • the three subclasses of B cells are naive B cells, memory B cells, and plasma cells.
  • VDJ recombination in which two or three segments of DNA are selected from a genomic library and recombined to produce a combinatorial array of antibody variable domains, by which variable domains encoded by B cells of different lineages are further Alterations result in as many as 109 unique B cell lineages that produce and uniquely target antibodies with specificity.
  • Various diseases involve B cells. Malignant transformation of B cells leads to cancers, including some lymphomas such as multiple myeloma and Hodgkin's lymphoma.
  • B cells including systemic lupus erythematosus (SLE) and IgA nephropathy.
  • SLE systemic lupus erythematosus
  • IgA nephropathy IgA nephropathy.
  • Cancers and autoimmune diseases involving B cells can be considered to be dysfunctional B cells, so a possible strategy to control such diseases is the use of antibodies targeting pathological B cells.
  • BCMA B cell maturation antigen BCMA
  • CD269 or TNFRSF17 is a member of the tumor necrosis factor superfamily, mainly expressed on plasma cells and some mature B cells.
  • Human BCMA is a type III transmembrane protein composed of 184 amino acid residues.
  • BCMA can specifically bind to proliferation-inducing ligand (APRIL) and B cell activating factor (BAFF) to activate NF- ⁇ B and MAPK8/JNK signaling pathways; it can also bind to various TRAF family members to promote the development of B cells at different developmental stages Involved in the regulation of humoral immunity, B cell development and homeostasis.
  • APRIL proliferation-inducing ligand
  • BAFF B cell activating factor
  • BCMA is highly expressed on the surface of various tumor cells, such as multiple myeloma, Hodgkin's lymphoma, acute lymphoblastic leukemia (ALL), but not expressed in hematopoietic stem cells and other normal tissue cells, so it is Ideal target for targeted cancer therapy.
  • tumor cells such as multiple myeloma, Hodgkin's lymphoma, acute lymphoblastic leukemia (ALL), but not expressed in hematopoietic stem cells and other normal tissue cells, so it is Ideal target for targeted cancer therapy.
  • ADCs antibody-drug conjugates of BCMA such as belantamab mafodotin (GSK) are currently used to treat some cancers and are being tested for other anti-cancer indications, there is still a need Develop more novel BCMA antibody drugs.
  • GSK belantamab mafodotin
  • the purpose of the present application is to provide an antibody capable of specifically binding to BCMA (i.e., an anti-BCMA antibody) or an antigen-binding fragment thereof, a polynucleotide molecule encoding the antibody of the present application or an antigen-binding fragment thereof, for expressing the present application
  • BCMA i.e., an anti-BCMA antibody
  • an antigen-binding fragment thereof a polynucleotide molecule encoding the antibody of the present application or an antigen-binding fragment thereof, for expressing the present application
  • the first aspect of the present application provides an antibody or an antigen-binding fragment thereof capable of specifically binding to BCMA, which comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3;
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, or respectively have the amino acid sequences shown in SEQ ID NO: 4, SEQ ID NO: 5 and the amino acid sequence shown in SEQ ID NO: 6, or have respectively the amino acid sequence shown in SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 9, or have the amino acid sequence shown in SEQ ID NO: 10, SEQ ID NO: 10, SEQ ID NO: 9 respectively
  • Said LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequence shown in SEQ ID NO:25, SEQ ID NO:26 and SEQ ID NO:27, or respectively have such as SEQ ID NO:28, SEQ ID NO:29 and SEQ ID NO:29 and SEQ ID NO:27
  • At least one of said SEQ ID NO: 1-48 can be replaced with a variant having 1, 2 or 3 amino acid differences;
  • the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO:8 has the amino acid sequence shown in SEQ ID NO:49 or SEQ ID NO:50;
  • the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO: 9 has the amino acid sequence shown in SEQ ID NO: 178;
  • the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO: 11 has the amino acid sequence shown in SEQ ID NO: 51;
  • the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO: 15 has the amino acid sequence shown in SEQ ID NO: 52;
  • the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO:29 has the amino acid sequence shown in SEQ ID NO:53;
  • the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO:31 has the amino acid sequence shown in SEQ ID NO:54 or SEQ ID NO:179;
  • the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO:32 has the amino acid sequence shown in SEQ ID NO:55;
  • the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO:36 has the amino acid sequence shown in SEQ ID NO:180;
  • the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO:40 has the amino acid sequence shown in SEQ ID NO:56;
  • the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO:41 has the amino acid sequence shown in SEQ ID NO:57.
  • the antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively:
  • HCDR1 NYDMA
  • HCDR2 SISRX1GDX2X3X4YRDSVX5G, where X1 is F or S, X2 is S or T, X3 is F or T, X4 is Y or Q or D, X5 is K or E;
  • HCDR3 QDYGYX6WVWFAY, where X6 is K or D or N;
  • LCDR1 X7AX8EX9ISNDLX10, where X7 is R or L, X8 is S or N, X9 is D or G, X10 is V or A;
  • LCDR2 X11X12SRLX13X14, where X11 is G or A, X12 is T or A, X13 is Q or P, X14 is D or E or S;
  • LCDR3 QQX15YKYPFT, where X15 is T or S;
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 28.
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 28, SEQ ID NO: 28, SEQ ID NO: The amino acid sequence shown in ID NO:53 and SEQ ID NO:30; or
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 9, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 31, SEQ ID NO: 31, SEQ ID NO: The amino acid sequence shown in ID NO:32 and SEQ ID NO:33; or
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 178
  • the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 179, SEQ ID NO: 179 and SEQ ID NO: 178 respectively.
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 49 and SEQ ID NO: 9, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 31, SEQ ID NO: 31, SEQ ID NO: The amino acid sequence shown in ID NO:32 and SEQ ID NO:33; or
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 50 and SEQ ID NO: 9, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 54, SEQ ID NO: 54, SEQ ID NO: Amino acid sequences shown in ID NO:55 and SEQ ID NO:33.
  • the antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively:
  • HCDR2 FIRNKANX1YTTEYNPSVKG, where X1 is G or A;
  • HCDR3 FQHSYYFDY
  • LCDR2 DATSLAY
  • LCDR3 LQTYSX2PPT, where X2 is T or S;
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 34.
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 34, SEQ ID NO: 34 and SEQ ID NO: 12 respectively. the amino acid sequence shown in ID NO:35 and SEQ ID NO:180; or
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 10, SEQ ID NO: 51 and SEQ ID NO: 12, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 34, SEQ ID NO: 34 and SEQ ID NO: 12 respectively. Amino acid sequences shown in ID NO:35 and SEQ ID NO:36.
  • the antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively:
  • HCDR1 IYGMY
  • HCDR2 WINTETGTPTYATDFKG
  • HCDR3 EDX1GYFDY, where X1 is G or A;
  • LCDR1 RASQSVTISRYNFMN;
  • LCDR2 RASNLPS
  • LCDR3 QQNRESPRT
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 15, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 37.
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 52
  • the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 37, SEQ ID NO: 37 and SEQ ID NO: 52 respectively.
  • the antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively:
  • HCDR1 NYDIS
  • HCDR2 GINPGSGGTAYNEKFKD
  • HCDR3 WDYGGDYNWFTY
  • LCDR1 LASEGISNX1LA, where X1 is G or A;
  • LCDR2 AASRLQDX2, where X2 is E or does not exist;
  • LCDR3 QQNYRYPLT
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 40.
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 56, SEQ ID NO: 56 and SEQ ID NO: 18 respectively. Amino acid sequences shown in ID NO:57 and SEQ ID NO:42.
  • the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 3 respectively. the amino acid sequences set forth in ID NO:25, SEQ ID NO:26 and SEQ ID NO:27; or
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 28, SEQ ID NO: 28, SEQ ID NO: The amino acid sequence shown in ID NO:29 and SEQ ID NO:30; or
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 28, SEQ ID NO: 28, SEQ ID NO: The amino acid sequence shown in ID NO:53 and SEQ ID NO:30; or
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 9, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 31, SEQ ID NO: 31, SEQ ID NO: The amino acid sequence shown in ID NO:32 and SEQ ID NO:33; or
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 178
  • the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 179, SEQ ID NO: 179 and SEQ ID NO: 178 respectively.
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 49 and SEQ ID NO: 9, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 31, SEQ ID NO: 31, SEQ ID NO: The amino acid sequence shown in ID NO:32 and SEQ ID NO:33; or
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 50 and SEQ ID NO: 9, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 54, SEQ ID NO: 54, SEQ ID NO: The amino acid sequence shown in ID NO:55 and SEQ ID NO:33; or
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 34, SEQ ID NO: 34 and SEQ ID NO: 12 respectively.
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 34, SEQ ID NO: 34 and SEQ ID NO: 12 respectively. the amino acid sequence shown in ID NO:35 and SEQ ID NO:180; or
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 10, SEQ ID NO: 51 and SEQ ID NO: 12, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 34, SEQ ID NO: 34 and SEQ ID NO: 12 respectively.
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 15, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 37, SEQ ID NO: 37 and SEQ ID NO: 15 respectively.
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 52, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 37, SEQ ID NO: 37 and SEQ ID NO: 52 respectively.
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 40, SEQ ID NO: 40 and SEQ ID NO: 18 respectively.
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 56, SEQ ID NO: 56 and SEQ ID NO: 18 respectively. the amino acid sequence shown in ID NO:57 and SEQ ID NO:42; or
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 19, SEQ ID NO: 20 and SEQ ID NO: 21, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 43, SEQ ID NO: 43 and SEQ ID NO: 21 respectively.
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 22, SEQ ID NO: 23 and SEQ ID NO: 24, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 46, SEQ ID NO: 46 and SEQ ID NO: 24 respectively. Amino acid sequences shown in ID NO:47 and SEQ ID NO:48.
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • amino acid sequence of the heavy chain variable region shown in SEQ ID NO: 183 and the amino acid sequence of the light chain variable region shown in SEQ ID NO: 184.
  • the antibody or antigen-binding fragment thereof further comprises a human heavy chain constant region and a human light chain constant region
  • the human heavy chain constant region is selected from the constant heavy chain region of human IgG1, IgG2, IgG3 or IgG4.
  • Region, preferably the heavy chain constant region of human IgG1; the human light chain constant region is selected from the light chain constant region of lambda light chain or kappa light chain.
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • amino acid sequence is the heavy chain shown in SEQ ID NO: 176, and the amino acid sequence is the light chain shown in SEQ ID NO: 177.
  • the antibody comprises at least one of a monoclonal antibody and a multispecific antibody
  • the antigen-binding fragment comprises at least one of a Fab, Fab', F(ab')2, Fv, scFv, and sdAb .
  • the second aspect of the present application provides an isolated antibody or antigen-binding fragment thereof, which has at least one of the following characteristics:
  • the antibody or antigen-binding fragment thereof provided in the first aspect of the present application binds to the same epitope of human BCMA protein, or completely overlaps or partially overlaps;
  • the third aspect of the present application provides a polynucleotide molecule, which comprises the antibody encoding the antibody or antigen-binding fragment thereof provided in the first aspect of the application, or encoding the isolated antibody or antigen-binding fragment thereof provided in the second aspect of the application At least one of a nucleotide sequence or its complementary sequence.
  • the fourth aspect of the present application provides an expression vector comprising the polynucleotide molecule provided in the third aspect of the present application, preferably, the expression vector is a eukaryotic expression vector.
  • the fifth aspect of the present application provides a host cell, which comprises the polynucleotide molecule provided in the third aspect of the present application, or the expression vector provided in the fourth aspect of the present application, preferably, the host cell is a eukaryotic cell, more Mammalian cells are preferred.
  • the host cell is used to express the antibody or antigen-binding fragment thereof of the first aspect of the present application or the isolated antibody or antigen-binding fragment thereof of the second aspect of the present application.
  • the sixth aspect of the present application provides a method for preparing the antibody or antigen-binding fragment thereof of the first aspect of the present application or the isolated antibody or antigen-binding fragment thereof of the second aspect of the present application, which includes the method provided in the fifth aspect of the present application expressing the antibody or antigen-binding fragment thereof in a host cell, and recovering the expressed antibody or antigen-binding fragment thereof from the host cell.
  • the seventh aspect of the present application provides an anti-BCMA antibody drug conjugate (ADC) or a pharmaceutically acceptable salt thereof, which comprises:
  • a coupling moiety coupled to the antibody moiety being selected from at least one of detectable labels, drugs, toxins, cytokines, radionuclides and enzymes.
  • the antibody moiety is coupled to the coupling moiety via a chemical bond or linker.
  • the eighth aspect of the present application provides a pharmaceutical composition comprising the antibody or antigen-binding fragment thereof provided in the first aspect of the present application or the isolated antibody or antigen-binding fragment thereof provided in the second aspect of the present application or the antibody or antigen-binding fragment thereof provided in the second aspect of the present application.
  • the ninth aspect of the application provides the antibody or antigen-binding fragment thereof in the first aspect of the application or the isolated antibody or antigen-binding fragment thereof in the second aspect of the application or the polynucleotide molecule provided in the third aspect of the application or the antibody or antigen-binding fragment thereof in the third aspect of the application
  • the expression vector provided in the fourth aspect or the host cell provided in the fifth aspect of the application or the drug conjugate provided in the seventh aspect of the application or the pharmaceutical composition provided in the eighth aspect of the application is used in the preparation of the treatment or prevention of BCMA-mediated Use in medicine for disease.
  • the tenth aspect of the application provides the antibody or antigen-binding fragment thereof in the first aspect of the application or the isolated antibody or antigen-binding fragment thereof in the second aspect of the application or the polynucleotide molecule provided in the third aspect of the application or the antibody or antigen-binding fragment thereof in the third aspect of the application.
  • the expression vector provided in the fourth aspect or the host cell provided in the fifth aspect of the application or the drug conjugate provided in the seventh aspect of the application or the pharmaceutical composition provided in the eighth aspect of the application in the treatment or prevention of BCMA-mediated diseases use.
  • the eleventh aspect of the present application provides a method for treating or preventing BCMA-mediated diseases or disorders, which includes administering the antibody or antigen-binding fragment thereof provided in the first aspect of the present application or the present application to a subject in need.
  • the drug conjugate provided in the seventh aspect or the pharmaceutical composition provided in the eighth aspect of the present application.
  • the BCMA-mediated disease is cancer or an autoimmune disease.
  • the twelfth aspect of the present application provides a kit comprising the antibody or antigen-binding fragment thereof provided in the first aspect of the present application or the isolated antibody or antigen-binding fragment thereof provided in the second aspect of the present application or the antibody or antigen-binding fragment thereof provided in the second aspect of the present application
  • the thirteenth aspect of the present application provides a method for detecting BCMA using the antibody or antigen-binding fragment thereof provided in the first aspect of the present application or the isolated antibody or antigen-binding fragment thereof provided in the second aspect of the present application, which includes using The antibody or antigen-binding fragment thereof is contacted with the sample, the binding of the antibody or antigen-binding fragment thereof to BCMA is detected, and optionally the binding is quantified.
  • the antibody or antigen-binding fragment thereof that can specifically bind to BCMA provided by the application can specifically bind to human BCMA, has high affinity, excellent ADCC activity and obvious tumor suppression effect, and can be used to treat BCMA-mediated diseases, Examples include cancer or autoimmune diseases.
  • Figure 1A to Figure 1G respectively show the test results of the activity test of the anti-human BCMA chimeric antibody in Example 2 of the present application for binding to human BCMA.
  • Fig. 2A to Fig. 2F respectively show the test results of blocking the binding between BAFF and BCMA by the anti-human BCMA chimeric antibody in Example 3 of the present application.
  • 3A to 3I respectively show the test results of the binding activity of the humanized anti-human BCMA antibody to MM.1S in Example 5 of the present application.
  • Figure 4A to Figure 4C respectively show the ADCC activity test results (reporter gene method) of the anti-human BCMA chimeric antibody in Example 7 of the present application.
  • Figure 5A to Figure 5E respectively show the ADCC activity test results (PBMC method) of the anti-human BCMA chimeric antibody in Example 7 of the present application.
  • Figure 6A to Figure 6H respectively show the ADCC activity test results (reporter gene method) of the humanized antibody against human BCMA antibody in Example 7 of the present application.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • BCMA refers to B cell maturation antigen.
  • BCMA also known as TNFRSF17, BCM or CD269
  • TNFRSF17 BCM
  • CD269 B-cell activating factor (BAFF)
  • APRIL proliferation-inducing ligand
  • BAFF B-cell activating factor
  • APRIL proliferation-inducing ligand
  • the protein BCMA is encoded by the gene TNFRSF17. Exemplary BCMA sequences are available in the Uniprot database under accession number Q02223.
  • Antibodies provided herein, or antigen-binding portions thereof, can also bind BCMA from species other than humans, eg, cynomolgus monkey BCMA.
  • cynomolgus BCMA may refer to BCMA having the complete amino acid sequence of cynomolgus BCMA with Genbank accession number EHH60172.1.
  • percent (%) amino acid sequence identity or simply “identity” is defined as aligning amino acid sequences (and introducing gaps where necessary) for maximum percent sequence identity and not considering any conservative substitutions as Following a portion of sequence identity, the percentage of amino acid residues in a candidate amino acid sequence that are identical to those in a reference amino acid sequence. Alignment of sequences to determine percent amino acid sequence identity can be performed using various methods in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGN (DNASTAR) 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.
  • immune response refers to selective damage from the body through the action of, for example, lymphocytes, antigen-presenting cells, phagocytes, granulocytes, and soluble macromolecules (including antibodies, cytokines, and complement) produced by the above cells or the liver , destruction or elimination of invading pathogens, pathogen-infected cells or tissues, cancer cells, or in the case of autoimmunity or pathological inflammation, damage, destruction or elimination of normal human cells or tissues.
  • lymphocytes for example, lymphocytes, antigen-presenting cells, phagocytes, granulocytes, and soluble macromolecules (including antibodies, cytokines, and complement) produced by the above cells or the liver , destruction or elimination of invading pathogens, pathogen-infected cells or tissues, cancer cells, or in the case of autoimmunity or pathological inflammation, damage, destruction or elimination of normal human cells or tissues.
  • signal transduction pathway or “signal transduction activity” refers to a biochemical causal relationship, usually initiated by protein-protein interactions, such as the binding of a growth factor to a receptor, that results in the transmission of a signal from one part of a cell to another part of the cell. part.
  • delivery involves specific phosphorylation of one or more tyrosine, serine, or threonine residues on one or more proteins in a cascade of reactions resulting in signal transduction.
  • the penultimate process often involves nuclear events, resulting in changes in gene expression.
  • activity or “biological activity” or the terms “biological property” or “biological signature” are used interchangeably in this application and include, but are not limited to, epitope or antigen affinity, specificity, in vivo or in vitro neutralization or The ability to antagonize the activity of BCMA, the half-inhibitory concentration (IC 50 ), the stability of the antibody in vivo, and the immunogenicity of the antibody, etc.
  • Other identifiable biological properties or characteristics of antibodies known in the art include, for example, cross-reactivity (such as with non-human homologues of the targeting peptide, or with other proteins or tissues), and retention of mammalian The ability of a cell to express a protein at a high level.
  • ELISA enzyme-linked immunosorbent assay
  • FACS flow cytometry sorting
  • BIACORE plasma resonance analysis Any in vitro or in vivo neutralization assays, receptor binding assays, cytokine or growth factor production and/or secretion assays, signal transduction assays, and analysis of tissue sections of different origin, including human, primate, or any other origin Immunohistochemical analysis, etc.
  • antibody refers to any form of antibody that possesses the desired biological activity. Accordingly, it is used in the broadest sense and specifically includes, but is not limited to, monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (such as bispecific antibodies), humanized antibodies, fully human antibodies, Chimeric antibodies and camelized single domain antibodies, etc.
  • the basic antibody structural unit is known to comprise tetramers, each tetramer comprising two identical pairs of polypeptide chains, each pair having a "light” chain (L, approximately 25 kDa) and a "heavy” chain ( H, about 50-70 kDa).
  • the amino-terminal portion or fragment of each chain may include a variable region of about 100-110 or more amino acids primarily responsible for antigen recognition.
  • the carboxy-terminal portion or fragment of each chain may define a constant region primarily responsible for effector function.
  • Human light chains are generally classified as kappa and lambda light chains.
  • human heavy chains are usually classified into five types: ⁇ , ⁇ , ⁇ , ⁇ , or ⁇ , and the antibody isotypes are defined as IgM, IgD, IgG, IgA, and IgE according to the heavy chains.
  • the respective variable and constant regions are joined by a "J" region of about 12 or more amino acids, with the heavy chain also including a "D” region of about 10 more amino acids. See generally Chapter 7 of Fundamental Immunology (Paul, W. ed., 2nd ed. Raven Press, N.Y. (1989)).
  • the term “isolated antibody” means that the antibody is substantially free of other cellular components associated with its natural state, such as nucleic acids, proteins, lipids, sugars or other substances such as cell debris and growth medium. It can be understood that the isolated antibody is in a substantially purified state, preferably in a homogeneous state, and the isolated antibody can be in a dry or aqueous solution. Antibody purity and homogeneity can often be determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. The term “isolated” does not mean the complete absence of the above substances or the absence of water, buffers or salts, unless they are present in an amount that significantly interferes with the experimental or therapeutic application of the antibody of the present application.
  • the term "monoclonal antibody” is an antibody made from highly identical immune cells that are all clones of a single parental cell. Monoclonal antibodies have monovalent affinity because they bind to the same epitope (the part of the antibody that recognizes an antigen). The monoclonal antibodies may also contain minor amounts of naturally occurring mutations. In contrast, the term “polyclonal antibody” binds multiple epitopes, usually consists of several different lineages of plasma cells (antibody-secreting immune cells), and can be understood as a hybrid of multiple monoclonal antibodies. The modifier "monoclonal” should not be construed as requiring that the antibody be produced by any particular method.
  • multispecific antibody means comprising two or more antigen binding domains, capable of binding two or more different epitopes (e.g., two, three, four or more different epitope) antibodies.
  • the epitopes to which specific antibodies bind can be on the same or different antigens.
  • multispecific antibodies include "bispecific antibodies” that bind two different epitopes.
  • binding domain or "antigen-binding domain” or “antigen-binding site” refers to a region in an antibody that can specifically bind to a part or all of an antigen and is complementary to a part or all of the antigen. When an antigen is large, antibodies may only be able to bind to a specific part of the antigen, called an epitope.
  • the binding domain may comprise the variable domains of the heavy and light chains, namely the heavy chain variable region VH and the light chain variable region VL, each comprising four conserved framework regions (FR) and three complementarity determining regions (CDRs). ).
  • the CDRs can vary in sequence and determine specificity for a particular antigen.
  • full-length antibody refers to an immunoglobulin molecule that, as it occurs in nature, comprises four peptide chains: two heavy chains (approximately 50-70 kDa in overall length) and two light chains (approximately 25 kDa in overall length) which are disulfide-bonded interconnected.
  • Each heavy chain is composed of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region (abbreviated herein as CH).
  • the heavy chain constant region consists of three domains CH1, CH2 and CH3.
  • Each light chain is composed of a light chain variable region (abbreviated herein as VL) and a light chain constant region (abbreviated herein as CL).
  • the light chain constant region consists of one domain, CL.
  • the VH and VL regions can be further subdivided into highly variable complementarity-determining regions (CDRs) and spaced apart from the complementarity-determining regions, more conserved framework regions (FRs).
  • CDRs complementarity-determining regions
  • FRs conserved framework regions
  • the sequence of domains from the amino terminus to the carboxyl terminus of each VH or VL is FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.
  • the variable regions of the heavy and light chains each contain a binding domain that interacts with the antigen.
  • the constant regions of the antibodies may mediate the binding of the antibodies to tissues of the host or to various cells of the immune system (e.g., effector cells) and to the first component (Clq) of the classical complement system.
  • heavy chain constant region or "CH”, which is used interchangeably in this application, comprises at least three heavy chain constant domains (CH1, CH2 and CH3).
  • exemplary, human heavy chain constant regions include gamma, delta, alpha, epsilon, and mu, each heavy chain constant region corresponding to an antibody isotype.
  • an antibody containing a gamma constant region is an IgG antibody
  • an antibody containing a delta constant region is an IgD antibody
  • an antibody containing an alpha constant region is an IgA antibody
  • an antibody containing a mu constant region is an IgM antibody
  • an antibody containing an epsilon constant region is an IgE Antibody.
  • IgG antibodies include, but are not limited to, IgG1 (comprising the ⁇ 1 constant region), IgG2 (comprising the ⁇ 2 constant region), IgG3 (comprising the ⁇ 3 constant region), and IgG4 (comprising the ⁇ 4 constant region );
  • IgA antibodies include but are not limited to IgA1 (comprising the ⁇ 1 constant region) and IgA2 (comprising the ⁇ 2 constant region);
  • IgM antibodies include but are not limited to IgM1 and IgM2.
  • Isoforms may also include modifications that alter Fc function, eg, enhance or reduce effector function or enhance or reduce binding to Fc receptors.
  • light chain constant region or "CL” is used interchangeably in this application, which comprises a light chain constant domain, CL.
  • CL light chain constant region
  • antigen-binding fragment of an antibody includes a fragment of an antibody or a derivative of an antibody, and the antibody corresponding to the "antigen-binding fragment” can be referred to as a parent antibody.
  • An antigen-binding fragment of an antibody typically comprises at least a fragment of the antigen-binding or variable region of the parent antibody that retains at least some of the binding specificity of the parent antibody.
  • antigen-binding fragments include, but are not limited to, Fab, Fab', F(ab')2 and single chain Fv fragments, diabodies, linear antibodies, domain antibodies, single chain antibody molecules such as scFv; nanobodies formed from antibody fragments Antibody (nanobody) and multispecific antibody, etc.
  • the antigen-binding fragment can retain at least 10%, at least 20%, 50%, 70%, 80%, 90%, 95% or 100% or more of the antigen-binding activity of the parent antibody.
  • antigen-binding fragments of antibodies may also include conservative or non-conservative amino acid substitutions that do not significantly alter their biological activity (referred to as “conservative variants” or “functionally conservative variants” of the antibody).
  • single-chain Fv or "scFv” antibody refers to an antibody fragment comprising the VH and VL domains of an antibody, wherein these domains are present in a single polypeptide chain.
  • Fv polypeptides generally also comprise a polypeptide linker between the VH and VL domains, which enables the scFv to form the desired structure for antigen binding.
  • domain antibody refers to an immunologically functional immunoglobulin fragment containing only the variable region of the heavy chain or the variable region of the light chain.
  • two or more VH regions are covalently linked with a peptide linker to form a bivalent domain antibody.
  • the two VH regions of a bivalent domain antibody can target the same or different antigens.
  • antigen refers to a molecule or a part of a molecule capable of being bound by an antibody of the present application.
  • An antigen may have one or more than one epitope.
  • diabody refers to a small antibody fragment with two antigen-binding sites, said fragment comprising a heavy chain variable domain (VH) connected to a light chain variable domain (VL) in the same polypeptide chain, The two said fragments pass a linker that is too short to allow pairing between the two domains of the same chain, forcing this domain to pair with the complementary domain in the other fragment and creating two antigen-binding sites.
  • VH heavy chain variable domain
  • VL light chain variable domain
  • the terms “specific binding” and “selective binding” refer to the binding of an antibody to a predetermined epitope on an antigen.
  • an antibody is used as a ligand
  • SPR surface plasmon resonance
  • the antibody has a particle size of about less than 10 ⁇ 7 M or even smaller
  • KD equilibrium dissociation constant
  • the equilibrium dissociation constant (KD) binds to a predetermined antigen or its epitope, and the binding affinity of the antibody to the predetermined antigen or its epitope is at least twice that of its binding affinity to other non-specific antigens (such as BSA, etc.).
  • the term “recognizes an antigen” is used interchangeably with the term “specifically binds” in this application.
  • epitope refers to the region of an antigen to which an antibody binds. Epitopes can be formed from contiguous amino acids or non-contiguous amino acids juxtaposed by the tertiary folding of the protein.
  • Affinity or "binding affinity” refers to the intrinsic binding affinity that reflects the interaction between members of a binding pair (eg, antigen and antibody). Affinity can generally be expressed by the equilibrium dissociation constant (KD), which is the ratio of the dissociation rate constant and the association rate constant (kdis and kon, respectively). Affinity can be measured by common methods known in the art, for example, it can be determined using ForteBio Biological Molecular Interaction Workstation.
  • not binding to proteins or cells refers to not binding to proteins or cells, or not binding to them with high affinity, that is, the KD of binding proteins or cells is 1.0 ⁇ 10 -6 M or higher, more preferably 1.0 ⁇ 10 -6 5 M or higher, more preferably 1.0 ⁇ 10 -4 M or higher, 1.0 ⁇ 10 -3 M or higher, more preferably 1.0 ⁇ 10 -2 M or higher.
  • high affinity for an IgG antibody means that the KD for the antigen is 1.0 ⁇ 10 -6 M or lower, preferably 5.0 ⁇ 10 -8 M or lower, more preferably 1.0 ⁇ 10 -8 M or lower, 5.0 ⁇ 10 -9 M or lower, more preferably 1.0 ⁇ 10 -9 M or lower.
  • "High affinity" binding may vary for other antibody subtypes.
  • "high affinity" binding of IgM subtype means a KD of 10 -6 M or lower, preferably 10 -7 M or lower, more preferably 10 -8 M or lower.
  • nucleic acid refers to deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) and polymers thereof in single- or double-stranded form.
  • nucleic acid or “polynucleotide” also include nucleic acids that contain known analogs of natural nucleotides that have binding properties similar to those of a reference nucleic acid and that are similar to naturally occurring nucleosides. Uridine is metabolized in a similar manner (see, U.S. Patent No.
  • Construction refers to any recombinant polynucleotide molecule (e.g., plasmid, cosmid, virus, autonomously replicating polynucleotide molecule, bacteriophage, linear or circular single- or double-stranded DNA or RNA polynucleotide molecule), which can be Derived from any source, capable of integrating into the genome or replicating autonomously, it may be operably linked to one or more polynucleotide molecules.
  • plasmid plasmid, cosmid, virus, autonomously replicating polynucleotide molecule, bacteriophage, linear or circular single- or double-stranded DNA or RNA polynucleotide molecule
  • a construct is generally a polynucleotide molecule of the present application, which is operably linked to transcriptional initiation regulatory sequences, and these sequences will direct the transcription of the polynucleotide molecule of the present application in a host cell.
  • Expression of the nucleic acids of the present application may be directed using heterologous or endogenous promoters.
  • Vector refers to any recombinant polynucleotide construct that can be used for the purpose of transformation (ie, the introduction of heterologous DNA into a host cell).
  • plasmid refers to a circular double-stranded DNA loop into which additional DNA segments can be ligated.
  • viral vector which can incorporate additional DNA segments into the viral genome.
  • Certain vectors are capable of autonomous replication in the host cell into which they are introduced (eg, bacterial vectors with a bacterial origin of replication and episomal mammalian vectors).
  • Other vectors eg, non-episomal mammalian vectors) are integrated into the genome of the host cell after introduction into the host cell, where they replicate together with the host genome.
  • expression vector refers to a nucleic acid molecule capable of replicating and expressing a gene of interest upon transformation, transfection or transduction into a host cell.
  • Expression vectors typically contain one or more phenotypic selectable markers and an origin of replication for maintenance of the vector and, if desired, amplification within the host.
  • activation may have the same meaning, for example, cells or receptors are activated, stimulated or treated with a ligand, unless otherwise specified.
  • Ligand includes natural and synthetic ligands such as cytokines, cytokine variants or analogs, muteins, and antibody-derived binding compounds (eg, antibodies and binding fragments thereof).
  • Ligand also includes small molecules, such as peptidomimetics of cytokines and peptidomimetics of antibodies.
  • Activation can refer to cellular activation regulated by internal mechanisms as well as external or environmental factors.
  • Response or “response”, such as that of a cell, tissue, organ, or organism, includes changes in biochemical or physiological behavior, such as the concentration, density, viscosity, Accompanied by changes in migration, gene expression rates, or differentiation status, which changes may be associated with activation, stimulation, or processing.
  • treatment may refer to improving the disease or condition in one embodiment, such as slowing down, arresting or reducing the progression of the disease, or the clinical symptoms of the disease, etc.; In one embodiment, it may refer to alleviation or improvement of at least one physical parameter that may not show improvement in overt disease symptoms; in another embodiment, it may refer to physical (e.g., discernible stabilization of symptoms), physiologically (eg, stabilization of body parameters), or both. Unless explicitly described herein, methods for assessing treatment and/or prevention of disease are generally known in the art.
  • the "subject” includes any human or non-human animal.
  • non-human animal includes all vertebrates, eg, mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, and the like.
  • Administration "in conjunction with” one or more other therapeutic agents includes simultaneous or co-administration, or sequential administration in any order.
  • “Therapeutically effective dose”, “therapeutically effective dose” and “effective dose” refer to the dosage, when the anti-BCMA antibody or antigen-binding fragment thereof of the present application is administered to cells, tissues or subjects alone or in combination with other therapeutic drugs, Effective in preventing or ameliorating the symptoms of at least one disease or condition, or preventing or ameliorating the development of at least one disease or condition.
  • a therapeutically effective dose can also refer to an amount of an antibody or antigen-binding fragment thereof sufficient to result in amelioration of symptoms (eg, treatment, cure, prevention or amelioration of an associated medical condition or an increase in the rate of treatment, cure, prevention or amelioration of such a condition).
  • the therapeutically effective dose refers to that ingredient alone;
  • An effective amount of a therapeutic agent will result in an increase in diagnostic criteria or parameters of at least 10%; usually at least 20%; preferably at least about 30%; more preferably at least 40%, most preferably at least 50%.
  • Cancer and “cancerous” refer to a physiological condition in mammals, often characterized by unregulated cell growth, and include within this definition benign tumors, malignant cancers, and dormant tumors or micrometastases. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia.
  • cancers include squamous cell carcinoma, lung cancer (including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma), peritoneal cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, Cervical cancer, ovarian cancer, liver cancer, bladder cancer, icteric liver tumors, breast cancer, colon cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, and All types of head and neck cancer, as well as B-cell lymphomas (eg, low-grade/follicular non-Hodgkin lymphoma (NHL), small lymphocytic (SL) NHL, intermediate-grade/follicular NHL, intermediate-grade diffuse NHL, Immunoblastic NHL, lymphoblastic NHL, small anucleated cleaved NHL, storage disease NHL, mantle cell lymphoma, AIDS-related lymphoma, and
  • autoimmune disease is used interchangeably with the term "autoimmune disorder” and refers to a condition in a patient characterized by the development of cells, tissues and/or organ damage.
  • inflammatory disease is used interchangeably with the term “inflammatory disorder” and refers to a condition of a patient characterized by inflammation, preferably chronic inflammation.
  • Autoimmune disorders may or may not be accompanied by inflammation. Additionally, inflammation may or may not be caused by an autoimmune disorder.
  • certain diseases can have both autoimmune and inflammatory features. Examples of autoimmune diseases include, but are not limited to, lupus erythematosus, IgA nephropathy, and rheumatoid arthritis.
  • the first aspect of the present application provides an antibody or an antigen-binding fragment thereof capable of specifically binding to BCMA, which comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3;
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, or respectively have the amino acid sequences shown in SEQ ID NO: 4, SEQ ID NO: 5 and the amino acid sequence shown in SEQ ID NO: 6, or have respectively the amino acid sequence shown in SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 9, or have the amino acid sequence shown in SEQ ID NO: 10, SEQ ID NO: 10, SEQ ID NO: 9 respectively
  • Said LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequence shown in SEQ ID NO:25, SEQ ID NO:26 and SEQ ID NO:27, or respectively have such as SEQ ID NO:28, SEQ ID NO:29 and SEQ ID NO:29 and SEQ ID NO:27
  • At least one of said SEQ ID NO: 1-48 can be replaced with a variant having 1, 2 or 3 amino acid differences;
  • the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO:8 has the amino acid sequence shown in SEQ ID NO:49 or SEQ ID NO:50;
  • the variant having 1, 2 or 3 amino acid differences with the amino acid sequence shown in SEQ ID NO: 9 has the amino acid sequence shown in SEQ ID NO: 178;
  • the variant having 1, 2 or 3 amino acid differences with the amino acid sequence shown in SEQ ID NO: 11 has the amino acid sequence shown in SEQ ID NO: 51;
  • the variant having 1, 2 or 3 amino acid differences with the amino acid sequence shown in SEQ ID NO: 15 has the amino acid sequence shown in SEQ ID NO: 52;
  • the variant having 1, 2 or 3 amino acid differences with the amino acid sequence shown in SEQ ID NO:29 has the amino acid sequence shown in SEQ ID NO:53;
  • the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO:31 has the amino acid sequence shown in SEQ ID NO:54 or SEQ ID NO:179;
  • the variant having 1, 2 or 3 amino acid differences with the amino acid sequence shown in SEQ ID NO:32 has the amino acid sequence shown in SEQ ID NO:55;
  • the variant having 1, 2 or 3 amino acid differences with the amino acid sequence shown in SEQ ID NO:36 has the amino acid sequence shown in SEQ ID NO:180;
  • the variant having 1, 2 or 3 amino acid differences with the amino acid sequence shown in SEQ ID NO:40 has the amino acid sequence shown in SEQ ID NO:56;
  • the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO:41 has the amino acid sequence shown in SEQ ID NO:57.
  • the antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively:
  • HCDR1 NYDMA
  • HCDR2 SISRX1GDX2X3X4YRDSVX5G, where X1 is F or S, X2 is S or T, X3 is F or T, X4 is Y or Q or D, X5 is K or E;
  • HCDR3 QDYGYX6WVWFAY, where X6 is K or D or N;
  • LCDR1 X7AX8EX9ISNDLX10, where X7 is R or L, X8 is S or N, X9 is D or G, X10 is V or A;
  • LCDR2 X11X12SRLX13X14, where X11 is G or A, X12 is T or A, X13 is Q or P, X14 is D or E or S;
  • LCDR3 QQX15YKYPFT, where X15 is T or S;
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 28.
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 28, SEQ ID NO: 28, SEQ ID NO: The amino acid sequence shown in ID NO:53 and SEQ ID NO:30; or
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 9, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 31, SEQ ID NO: 31, SEQ ID NO: The amino acid sequence shown in ID NO:32 and SEQ ID NO:33; or
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 178
  • the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 179, SEQ ID NO: 179 and SEQ ID NO: 178 respectively.
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 49 and SEQ ID NO: 9, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 31, SEQ ID NO: 31, SEQ ID NO: The amino acid sequence shown in ID NO:32 and SEQ ID NO:33; or
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 50 and SEQ ID NO: 9, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 54, SEQ ID NO: 54, SEQ ID NO: Amino acid sequences shown in ID NO:55 and SEQ ID NO:33.
  • the antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively:
  • HCDR2 FIRNKANX1YTTEYNPSVKG, where X1 is G or A;
  • HCDR3 FQHSYYFDY
  • LCDR2 DATSLAY
  • LCDR3 LQTYSX2PPT, where X2 is T or S;
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 34.
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 34, SEQ ID NO: 34 and SEQ ID NO: 12 respectively. the amino acid sequence shown in ID NO:35 and SEQ ID NO:180; or
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 10, SEQ ID NO: 51 and SEQ ID NO: 12, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 34, SEQ ID NO: 34 and SEQ ID NO: 12 respectively. Amino acid sequences shown in ID NO:35 and SEQ ID NO:36.
  • the antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively:
  • HCDR1 IYGMY
  • HCDR2 WINTETGTPTYATDFKG
  • HCDR3 EDX1GYFDY, where X1 is G or A;
  • LCDR1 RASQSVTISRYNFMN;
  • LCDR2 RASNLPS
  • LCDR3 QQNRESPRT
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 15, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 37.
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 52
  • the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 37, SEQ ID NO: 37 and SEQ ID NO: 52 respectively.
  • the antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively:
  • HCDR1 NYDIS
  • HCDR2 GINPGSGGTAYNEKFKD
  • HCDR3 WDYGGDYNWFTY
  • LCDR1 LASEGISNX1LA, where X1 is G or A;
  • LCDR2 AASRLQD, where X2 is E or does not exist;
  • LCDR3 QQNYRYPLT
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 40.
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 56, SEQ ID NO: 56 and SEQ ID NO: 18 respectively. Amino acid sequences shown in ID NO:57 and SEQ ID NO:42.
  • the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 3 respectively. the amino acid sequences set forth in ID NO:25, SEQ ID NO:26 and SEQ ID NO:27; or
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 28, SEQ ID NO: 28, SEQ ID NO: The amino acid sequence shown in ID NO:29 and SEQ ID NO:30; or
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 28, SEQ ID NO: 28, SEQ ID NO: The amino acid sequence shown in ID NO:53 and SEQ ID NO:30; or
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 9, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 31, SEQ ID NO: 31, SEQ ID NO: The amino acid sequence shown in ID NO:32 and SEQ ID NO:33; or
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 178
  • the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 179, SEQ ID NO: 179 and SEQ ID NO: 178 respectively.
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 49 and SEQ ID NO: 9, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 31, SEQ ID NO: 31, SEQ ID NO: The amino acid sequence shown in ID NO:32 and SEQ ID NO:33; or
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 50 and SEQ ID NO: 9, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 54, SEQ ID NO: 54, SEQ ID NO: The amino acid sequence shown in ID NO:55 and SEQ ID NO:33; or
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 34, SEQ ID NO: 34 and SEQ ID NO: 12 respectively.
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 34, SEQ ID NO: 34 and SEQ ID NO: 12 respectively. the amino acid sequence shown in ID NO:35 and SEQ ID NO:180; or
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 10, SEQ ID NO: 51 and SEQ ID NO: 12, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 34, SEQ ID NO: 34 and SEQ ID NO: 12 respectively.
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 15, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 37, SEQ ID NO: 37 and SEQ ID NO: 15 respectively.
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 52, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 37, SEQ ID NO: 37 and SEQ ID NO: 52 respectively.
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 40, SEQ ID NO: 40 and SEQ ID NO: 18 respectively.
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 56, SEQ ID NO: 56 and SEQ ID NO: 18 respectively. the amino acid sequence shown in ID NO:57 and SEQ ID NO:42; or
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 19, SEQ ID NO: 20 and SEQ ID NO: 21, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 43, SEQ ID NO: 43 and SEQ ID NO: 21 respectively.
  • the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 22, SEQ ID NO: 23 and SEQ ID NO: 24, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 46, SEQ ID NO: 46 and SEQ ID NO: 24 respectively. Amino acid sequences shown in ID NO:47 and SEQ ID NO:48.
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • amino acid sequence of the heavy chain variable region shown in SEQ ID NO: 183 and the amino acid sequence of the light chain variable region shown in SEQ ID NO: 184.
  • the antibody or antigen-binding fragment thereof further comprises a human heavy chain constant region and a human light chain constant region
  • the human heavy chain constant region is selected from the constant heavy chain region of human IgG1, IgG2, IgG3 or IgG4.
  • Region, preferably the heavy chain constant region of human IgG1; the human light chain constant region is selected from the light chain constant region of lambda light chain or kappa light chain.
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the amino acid sequence is the heavy chain shown in SEQ ID NO: 176, and the amino acid sequence is the light chain shown in SEQ ID NO: 177.
  • the antibody comprises at least one of a monoclonal antibody and a multispecific antibody, and the antigen-binding fragment comprises at least one of a Fab, Fab', F(ab')2, Fv, scFv, and sdAb .
  • the second aspect of the present application provides an isolated antibody or antigen-binding fragment thereof, which has at least one of the following characteristics:
  • the antibody or antigen-binding fragment thereof provided in the first aspect of the present application binds to the same epitope of human BCMA protein, or completely overlaps or partially overlaps;
  • the epitope that completely overlaps with the antibody of the present application or its antigen-binding fragment indicates that the antigenic epitope bound by the antibody includes the binding epitope of the antibody of the present application or its antigen-binding fragment;
  • the partially overlapping epitope bound by the binding fragment means that a part of the epitope bound by the antibody is the same as a part of the binding epitope of the antibody or antigen-binding fragment thereof of the present application.
  • the precise amino acid sequence boundaries of the complementarity determining region CDR of an antibody can be defined according to known methods, such as Chothia based on the three-dimensional structure of the antibody and the topology of the CDR loop (Chothia et al., Nature 342:877-883, 1989; Al-Lazikani et al., Journal of Molecular Biology, 273:927-948, 1997); or Kabat based on antibody sequence variability (Kabat et al., Sequences of Proteins of Immunological Interest, 4th ed., U.S.
  • the boundaries of the CDRs of the same antibody obtained based on different definition methods may be different, that is, the CDR sequences of the variable region of the same antibody obtained by different definition methods are different. Therefore, when specific CDR sequences as defined in this application are used to define an antibody, said antibody also includes sequences whose CDR sequences comprise the CDRs described in this application, only because of the different ways of defining CDR boundaries. Antibodies with CDR boundaries that differ from the specific CDR boundaries defined herein.
  • Antibodies with different specificities have different CDRs.
  • CDRs are different from antibody to antibody, only a limited number of amino acid positions within CDRs are directly involved in antigen binding, and the smallest overlapping region of antibody CDRs and antigen binding is also called the "minimum binding unit" for antigen binding , can be determined using at least two of the Kabat, Chothia, AbM, Contact and North methods. The smallest binding unit can be a portion of a CDR.
  • the structure and protein folding of the antibody will determine the residues of the remainder of the CDR sequence, and therefore, this application also contemplates any CDR variant, e.g., in a CDR variant, the minimum The amino acid residues of the binding unit can remain unchanged, while the remaining CDR residues according to the Kabat or Chothia definition can be replaced by conservative amino acid residues.
  • murine CDR regions can be inserted into human germline framework regions using methods known in the art. See US Patent No. 5,225,539 to Winter et al. and US Patent Nos. 5,530,101; 5,585,089; 5,693,762 and 6,180,370 to Queen et al.
  • amino acid differences may result from amino acid changes, including amino acid deletions, insertions, or substitutions.
  • the anti-BCMA antibody or antigen-binding fragment thereof of the present application includes amino acid deletion, insertion or substitution mutations, but is still compatible with the antibody or antigen-binding fragment thereof (especially described in the above sequence) CDR regions) have amino acid sequences that are at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical.
  • Fc region variants may include human Fc region sequences (eg, human IgGl, IgG2, IgG3 or IgG4 Fc regions) with amino acid modifications (eg, substitutions) at one or more amino acid positions.
  • the antibody or antigen-binding fragment thereof comprises a cysteine-engineered antibody or antigen-binding fragment thereof, such as a "thioMAb", wherein one or more of the antibody or antigen-binding fragment thereof residues were replaced by cysteine residues.
  • the antibodies or antigen-binding fragments thereof may be further modified to contain other non-proteinaceous moieties known in the art and readily available, such as water-soluble polymers.
  • water-soluble polymers include, but are not limited to: polyethylene glycol (PEG), ethylene glycol/propylene glycol copolymer, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1 , 3-dioxane, poly-1,3,6-trioxane, ethylene/maleic anhydride copolymer, polyamino acid (homopolymer or random copolymer), and dextran or poly(N-vinylpyrrole alk) polyethylene glycol, propylene glycol homopolymer, polypropylene oxide/ethylene oxide copolymer, polyoxyethylated polyols (eg glycerol), polyvinyl alcohol, and mixtures thereof.
  • PEG polyethylene glycol
  • Another aspect of the present application provides a polynucleotide molecule, which comprises at least one of the nucleotide sequence encoding the antibody or antigen-binding fragment thereof provided in the present application or its complementary sequence.
  • a polynucleotide molecule in the present application includes double-stranded or single-stranded DNA or RNA.
  • the antibody or antigen-binding fragment thereof provided in the present application includes the antibody or antigen-binding fragment thereof in the first aspect of the application and the isolated antibody or antigen-binding fragment thereof in the second aspect of the application.
  • the polynucleotide molecule encoding the antibody of the present application or an antigen-binding fragment thereof may also include a CDR that has a nucleotide deletion, insertion or substitution mutation, but is still consistent with the antibody of the present application or an antigen-binding fragment thereof
  • the corresponding coding regions are polynucleotide sequences that are at least about 60%, 70%, 80%, 90%, 95%, or 100% identical.
  • the present application provides an expression vector comprising the polynucleotide molecule of the present application, preferably, the expression vector is a eukaryotic expression vector.
  • the present application provides a host cell comprising the polynucleotide molecule or expression vector of the present application; preferably, the host cell is a eukaryotic cell, more preferably a mammalian cell.
  • the host cells are used to express the antibodies or antigen-binding fragments thereof provided herein.
  • the mammalian host cells provided herein for expressing the antibodies or antigen-binding fragments thereof of the present application include various immortalized cell lines available from the American Type Culture Collection (ATCC). Exemplary, it can include Chinese hamster ovary (CHO) cells, NSO, SP2/0 cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells, A549 cells, 293T cells and many other cell lines. Mammalian host cells can include human, mouse, rat, dog, monkey, pig, goat, bovine, horse and hamster cells. One skilled in the art can select particularly preferred cell lines by determining which cell lines have high expression levels.
  • ATCC American Type Culture Collection
  • the present application provides a method for preparing the antibody or antigen-binding fragment thereof of the present application, comprising expressing the antibody or antigen-binding fragment thereof in the host cell provided in the present application, and extracting the antibody or antigen-binding fragment thereof from the host cell The expressed antibody or antigen-binding fragment thereof is recovered.
  • the application provides a method for preparing the antibody or antigen-binding fragment thereof of the application may include:
  • polynucleotide molecules or expression vectors of the present application are introduced into the host cells described in the present application by known methods, such as lipofection, electroporation, transformation, etc.; Cultivating the host cell under the condition of fragment expression, so that the host cell expresses the antibody or its antigen-binding fragment; using methods known in the art, such as polyacrylamide gel electrophoresis, recovering the expressed antibody from the host cell Antibodies or antigen-binding fragments thereof.
  • the host cell used to express the antibody or its antigen-binding fragment in the present application may be an isolated cell, or a cell that still exists in the host body, for example, different cell lines may be used to express the antibody or its antigen-binding fragment , or using transgenic animals to express the antibody or antigen-binding fragment thereof.
  • Antibodies or antigen-binding fragments thereof expressed by different cell lines or expressed in different transgenic animals may have different glycosylation modifications. It should be noted that, regardless of the glycosylation of these antibodies, all antibodies encoded by the polynucleotide molecules provided by the application or comprising the amino acid sequences provided by the application are part of the application. Likewise, in certain embodiments, the antibody or antigen-binding fragment thereof is preferably a non-fucosylated antibody or antigen-binding fragment thereof. And in vivo than fucosylated antibodies or their antigen-binding fragments have stronger efficacy, in addition, because these different sugar structures are normal components of natural human serum IgG, so there is no significant difference in their immunogenicity.
  • an anti-BCMA antibody drug conjugate or a pharmaceutically acceptable salt thereof, comprising:
  • a coupling moiety coupled to the antibody moiety being selected from at least one of detectable labels, drugs, toxins, cytokines, radionuclides and enzymes.
  • the antibody moiety is coupled to the coupling moiety via a chemical bond or linker.
  • the application provides a pharmaceutical composition (or called pharmaceutical preparation, preparation), which comprises the antibody or antigen-binding fragment thereof, polynucleotide molecule, expression vector, host cell or drug provided in the application A conjugate, and a pharmaceutically acceptable carrier or excipient.
  • antibodies or pharmaceutical compositions thereof provided herein can be administered in combination with appropriate carriers, excipients and other agents in formulations, so as to provide improved transfer, delivery, tolerance and the like.
  • the active ingredients in the pharmaceutical composition exist in a form with effective biological activity, and do not contain ingredients with unacceptable toxicity to the subject of the pharmaceutical composition.
  • the antibody or antigen-binding fragment thereof of the present application having the required purity and one or more optional pharmaceutical excipients (see Remington's Pharmaceutical Sciences, 16th edition, Osol, A. Editor, 1980) mixed to prepare the pharmaceutical composition of the present application, preferably, the pharmaceutical composition of the present application may be in the form of an aqueous solution or a lyophilized formulation.
  • the pharmaceutical composition or preparation of the present application may also contain one or more other active ingredients, which can be selected according to specific indications, preferably, the active ingredients will not adversely affect each other's activities.
  • other active ingredients can be chemotherapeutic agents, immune checkpoint inhibitors, growth inhibitors, antibiotics or various known anti-tumor or anti-cancer agents, and the active ingredients can be effective for the intended use Quantitative combinations exist.
  • the present application provides a kit comprising the antibody or antigen-binding fragment thereof, polynucleotide molecule, expression vector, host cell, drug conjugate or pharmaceutical composition of the present application.
  • the application provides the antibody or its antigen-binding fragment, polynucleotide molecule, expression vector, host cell, drug conjugate or pharmaceutical composition of the application in the preparation for the treatment or prevention of BCMA-mediated diseases or use in medicine for a disease.
  • the application provides the antibody or its antigen-binding fragment, polynucleotide molecule, expression vector, host cell, drug conjugate or pharmaceutical composition of the application for the treatment or prevention of BCMA-mediated diseases or disorders the use of.
  • the present application provides a method for treating or preventing BCMA-mediated diseases or disorders, comprising administering the antibody or its antigen-binding fragment or polynucleotide molecule provided in the present application to a subject in need , expression vector, host cell, drug conjugate or pharmaceutical composition.
  • the BCMA-mediated disease is cancer or an autoimmune disease.
  • modes of administration include, but are not limited to, oral, intravenous, subcutaneous, intramuscular, intraarterial, intraarticular (e.g., in arthritic joints), inhalation drug delivery, aerosol delivery or intratumoral administration, etc.
  • the application provides a method for detecting BCMA using the antibody or antigen-binding fragment thereof of the application, comprising contacting the antibody or antigen-binding fragment thereof with a sample, detecting the antibody or antigen-binding fragment thereof and Conjugates formed by BCMA, and optionally quantifying said conjugates.
  • detection as used in this application may include quantitative or qualitative detection.
  • the sample is a biological sample.
  • the biological sample is blood, serum, or other liquid sample of biological origin.
  • a biological sample comprises cells or tissues.
  • the present application provides a method for detecting BCMA using the antibody or antigen-binding fragment thereof of the present application, comprising contacting the antibody or antigen-binding fragment thereof with a sample, detecting the antibody or antigen-binding fragment thereof and Conjugates formed by BCMA, and optionally quantifying said conjugates.
  • detection as used in this application may include quantitative or qualitative detection.
  • the sample is a biological sample.
  • the biological sample is blood, serum, or other liquid sample of biological origin.
  • a biological sample comprises cells or tissues. This application does not limit the method for detecting the conjugate formed by the antibody or its antigen-binding fragment and BCMA; this application does not limit the method for "quantitatively determining the conjugate".
  • mice (Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) and 6-8 weeks old Rats (Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) were immunized.
  • complete Freund's adjuvant was used according to the dose of 50 micrograms of human recombinant BCMA protein antigen per mouse, and the second and subsequent immunizations were mixed with incomplete Freund's adjuvant with 25 micrograms of human recombinant BCMA protein antigen per mouse. Dosing is carried out. The mice were immunized at day 0, day 14, day 28 and day 49, respectively.
  • the mouse tail blood was taken and the titer of BCMA antibody in the serum was detected.
  • the mouse or rat with the highest titer of BCMA antibody in the serum was selected, and its spleen cells were isolated, and then fused with mouse myeloma cell SP2/0 , plated and cultured in HAT selection medium for 10-14 days, select the wells with double positive binding to human BCMA and cynomolgus monkey BCMA from the culture supernatant for subcloning, and then select the subclones to maintain the double positive binding to human BCMA and cynomolgus monkey BCMA
  • the monoclonal sequence of the anti-human BCMA murine antibody was obtained by sanger sequencing. The amino acid sequences of the light and heavy chain variable regions and CDRs of the anti-human BCMA murine antibody are shown in Table 1.
  • Table 1 CDR and variable region amino acid sequences of anti-human BCMA murine antibody (KABAT scheme)
  • Embodiment 2 the binding detection experiment of anti-human BCMA chimeric antibody and BCMA
  • variable region sequence of the anti-human BCMA mouse monoclonal antibody was subcloned into the backbone of human IgG1/Kappa, expressed and purified in the HEK293 system to obtain anti-human BCMA chimeric antibodies BCMA-005, BCMA-011, BCMA- 017, BCMA-021, BCMA-027, BCMA-037, BCMA-040, BCMA-050, BCMA-051 and BCMA-060.
  • the binding activity of the chimeric antibody to human BCMA (hBCMA) and cynomolgus monkey BCMA (cynoBCMA) was detected by ELISA, and the detection method was as follows.
  • Belantamab is a positive control antibody whose sequence is from INN10797 and made by Junshi Biotechnology (see patents WO2012163805A1 and CN103562225B).
  • Figure 1A to Figure 1G show the binding situation of 10 anti-human BCMA chimeric antibodies and hBCMA respectively, and the corresponding EC 50 (half maximum effect concentration) values are listed in Table 2A to Table 2G;
  • the binding conditions of human BCMA chimeric antibody and cynomolgus monkey BCMA, and the corresponding EC 50 values are summarized in Table 2A to Table 2G.
  • the results showed that 10 anti-human BCMA chimeric antibodies had good binding activity to hBCMA and cynoBCMA.
  • Table 2A Binding activity of anti-human BCMA chimeric antibodies to hBCMA and cynoBCMA
  • Table 2B Binding activity of anti-human BCMA chimeric antibodies to hBCMA and cynoBCMA
  • Table 2C Binding activity of anti-human BCMA chimeric antibodies to hBCMA and cynoBCMA
  • Table 2D Binding activity of anti-human BCMA chimeric antibodies to hBCMA and cynoBCMA
  • Table 2E Binding activity of anti-human BCMA chimeric antibodies to hBCMA and cynoBCMA
  • Table 2F Binding activity of anti-human BCMA chimeric antibodies to hBCMA and cynoBCMA
  • Table 2G Binding activity of anti-human BCMA chimeric antibodies to hBCMA and cynoBCMA
  • Example 3 Competitive binding experiment between anti-human BCMA chimeric antibody and BCMA ligand APRIL (proliferation-inducing ligand) and BAFF (B cell activating factor)
  • the ELISA method was used to detect the activity of the anti-human BCMA chimeric antibody competitively binding to BCMA with the BCMA ligands APRIL and BAFF, and the detection method was specifically described as follows.
  • Belantamab is a positive control antibody whose sequence is from INN10797, made by Junshi Biotech (see patents WO2012163805A1 and CN103562225B).
  • the corresponding IC 50 (half inhibitory concentration) values of 10 anti-human BCMA chimeric antibodies to the blocking effect of APRIL on BCMA are listed in Table 3A to Table 3F;
  • Figure 2A to Figure 2F respectively show the blocking effect of 10 anti-human BCMA chimeric antibodies on the binding of BAFF to BCMA.
  • the corresponding IC 50 values are listed in the table 3A to Table 3F. The results showed that all 10 anti-human BCMA chimeric antibodies could effectively block the binding of BCMA to ligands APRIL and BAFF.
  • Table 3A The activity of anti-human BCMA chimeric antibodies to compete for the binding of APRIL and BAFF to hBCMA
  • Table 3C The activity of anti-human BCMA chimeric antibodies to compete for the binding of APRIL and BAFF to hBCMA
  • Anti-human BCMA chimeric antibodies BCMA-005, BCMA-017, BCMA-021, BCMA-027, BCMA-040, BCMA-050, BCMA-051 and BCMA-060 were selected for humanization.
  • the selected germline (germline mutation) and reverse mutation sites for antibody humanization are shown in Table 4, the CDR sequence is underlined, and the transplanted sequence before the heavy chain CDR1 (the first 5 amino acids of hCDR1) is italicized Bold marks, PTM mutations are marked in bold font, back mutations are marked in italics.
  • the sequences of humanized antibodies against human BCMA are shown in Table 5-1 and Table 5-2.
  • the CDR (Kabat numbering system) of the murine antibody and the first 5 amino acids of the heavy chain CDR1 are grafted onto the human germline to obtain the humanized antibody sequence.
  • the prefix hu when naming a humanized antibody that maintains a humanized antibody represents humanization, and the following number represents the sequence number of the humanized antibody. For example, BCMA-005-hu160, BCMA-005-hu178, BCMA-005-hu190, the last letter represents the PTM mutation.
  • the humanized antibody sequence was cloned into the backbone of human IgG1/kappa, expressed and purified in the HEK293 expression system.
  • Table 4 Variable region sequences of humanized antibodies against human BCMA
  • Table 5-1 CDR amino acid sequences of humanized antibodies against human BCMA (KABAT scheme)
  • Table 5-2 Variable regions and full-length amino acid sequences of humanized antibodies against human BCMA
  • Example 5 Cell surface BCMA binding detection of humanized antibodies against human BCMA antibodies
  • the FACs method was used to measure the binding of the humanized antibody against human BCMA antibody to the MM.1S cells expressing human BCMA, and the specific method was as follows.
  • the well-grown MM1S cells were centrifuged at 1000 rpm and the cells were harvested, and the cell density was adjusted to 50000 cells per well with FACs solution (DPBS (Duchener's phosphate buffered saline) + 2v/v% FBS (fetal bovine serum)). Incubate the serially diluted humanized antibody against human BCMA antibody (initial concentration 20 ⁇ g/mL, 3-fold serial dilution) with MM.1S cells for 60 minutes on ice.
  • FACs solution DPBS (Duchener's phosphate buffered saline) + 2v/v% FBS (fetal bovine serum)
  • the cells were washed twice with pre-cooled FACs solution, and then incubated with PE (fluorescein)-labeled anti-human IgG secondary antibody (cat#: 409304, biolegend) diluted 1:1000 on ice for half an hour. After two washes, resuspend, use Sartorius Fluorescence signal was detected by iQue3 flow cytometer.
  • PE fluorescein-labeled anti-human IgG secondary antibody
  • Belantamab is a positive control antibody whose sequence is from INN10797, made by Junshi Biotech (see patents WO2012163805A1 and CN103562225B).
  • Figure 3A to Figure 3I respectively show the binding of the humanized antibody against human BCMA antibody to MM.1S cells, and the corresponding EC 50 statistics are listed in Table 6A to Table 6I. The results showed that all the humanized antibodies against human BCMA antibodies could bind to MM.1S cells expressing human BCMA with high affinity, which was equivalent to or better than the control antibody.
  • Table 6A Binding of humanized antibodies against human BCMA antibodies to MM.1S cells
  • Table 6B Binding of humanized antibodies against human BCMA antibodies to MM.1S cells
  • Table 6C Binding of humanized antibodies against human BCMA antibodies to MM.1S cells
  • Table 6D Binding of humanized antibodies against human BCMA antibodies to MM.1S cells
  • Table 6F Binding of humanized antibodies against human BCMA antibodies to MM.1S cells
  • Antibody EC50 ( ⁇ g/mL) Belantamab 1.992 BCMA-051-hu601-FT 0.6569 BCMA-051-hu601 0.6637
  • Human-BCMA-his (cat#: BCA-H522y, acrobiosystems) and Cyno-BCMA-his (cat#: BAR-C52H4, acrobiosystems) were diluted 2-fold from 100nM down to 8 concentration gradients with human anti-human BCMA antibody
  • the derivatized antibody was combined and dissociated in 1 ⁇ HBS-EP+, and the association and dissociation signals were measured using Biacore 8K (Cytiva) to obtain the association rate constant (ka) and dissociation rate constant (kd).
  • Affinity KD values were determined using software to fit a 1:1 model.
  • Table 7A and Table 7B show that all anti-human BCMA humanized antibodies have good affinity to human BCMA and cynomolgus monkey BCMA protein.
  • Table 7B Binding affinity of humanized antibodies of anti-human BCMA antibodies to cynomolgus monkey BCMA protein
  • Embodiment 7 ADCC detection experiment of anti-human BCMA antibody
  • Antibody-dependent cell-mediated cytotoxicity means that the Fab segment of the antibody specifically binds to the epitope of the target cell, while the Fc segment of the antibody interacts with the killer cells (NK cells, Fc receptors on the surface of macrophages, etc.) mediate killer cells to directly kill target cells, and NK cells are the main effector cells that play ADCC.
  • the present application adopts two experimental systems for in vitro detection of ADCC effect.
  • One is the Jurkat-ADCC reporter gene detection system.
  • the effector cells are Jurkat-ADCC cells overexpressing Fc ⁇ RIIIa and downstream fluorescent reporter genes.
  • the target cells are three multiple myeloma cell lines NCI-H929 and MM.
  • MM.1S both purchased from the ATCC cell bank
  • PBMC peripheral blood mononuclear cells
  • the density of effector cells and target cells was adjusted to 7.5 ⁇ 10 6 cells/mL, and the density of target cells was adjusted to 3.75 ⁇ 10 6 cells/mL. Then the effector cells and target cells were mixed at a volume ratio of 1:1, and 40 ⁇ L of the cell mixture was added to a 96-well cell culture plate, wherein each well contained 150,000 effector cells and 75,000 target cells.
  • Belantamab is a positive control antibody whose sequence is from INN10797, made by Junshi Biotech (see patents WO2012163805A1 and CN103562225B).
  • Figure 4A to Figure 4C show the results of the detection of six anti-human BCMA chimeric antibodies in the case of NCI-H929, MM.1R and MM.1S respectively in the ADCC reporter gene method, where isotype ctrl For the same type control group.
  • the corresponding EC 50 values are listed in Table 8, and the results show that the ADCC activities of the six anti-human BCMA chimeric antibodies are better than those of the control antibody.
  • this application uses the co-cultivation of PBMC with the target cell MM.1R, and the lysis of the target cell is mediated by adding BCMA-017, BCMA-027, BCMA-040 and Belantamab respectively, and finally by detecting the target cell
  • the lysis ratio of the cells was used to compare the ADCC effects of these several anti-human BCMA chimeric antibodies.
  • target cells MM.1R were fluorescently labeled with Cell Trace Far Red (Cell Far Infrared Dye, Thermo Fisher Scientific) at a final concentration of 1 ⁇ M, and then the labeled target cells were adjusted to a density of 3 ⁇ 10 5 with complete medium cells/mL, and then 50 ⁇ L per well was added to a 96-well plate. According to the effect-to-target ratio of 20:1, 50 ⁇ L of PBMC (density of 6 ⁇ 10 6 cells/mL) was added to a 96-well cell culture plate, and the effector cells and target cells were gently mixed.
  • Cell Trace Far Red Cell Far Infrared Dye, Thermo Fisher Scientific
  • the initial concentration is 10 ⁇ g/mL, 5-fold dilution, 8 concentration gradients.
  • the cells were mixed and cultured for 4 hours, washed once with staining buffer, resuspended in staining buffer containing 1 ⁇ g/mL PI (propidium iodide), and detected on a BD fortessa flow cytometer. Use flowjo to analyze the data. First, gate on the target cell population positive for Cell Trace Far Red, and then look at the percentage of cells in the target cell population that are PI+. This ratio is the ADCC target cell lysis ratio.
  • Belantamab is a positive control antibody whose sequence is from INN10797, made by Junshi Biotech (see patents WO2012163805A1 and CN103562225B).
  • Figure 5A to Figure 5E respectively show the killing ratio of target cells mediated by PBMC from 5 different donors, wherein isotype ctrl is the isotype control group.
  • PBMCs from different donors showed a large difference in killing target cells.
  • Table 9 lists the EC 50 values of these three antibodies in different donors. The results show that the ADCC activity of the anti-human BCMA chimeric antibody is better than that of the control antibody .
  • the humanized antibodies against human BCMA were further detected by ADCC reporter gene method, including BCMA-005, BCMA-017, BCMA-021, BCMA-027, BCMA-040, BCMA-050, BCMA-051 and BCMA-060.
  • the specific detection method is the same as 7.1 Detection of ADCC effect of anti-human BCMA chimeric antibody (reporter gene method), and the target cells are NCI-H929 cells.
  • Belantamab is a positive control antibody whose sequence is from INN10797, made by Junshi Biotech (see patents WO2012163805A1 and CN103562225B).
  • Figure 6A to Figure 6H respectively show the ADCC activities of different humanized antibodies against human BCMA, where isotype ctrl is the isotype control group; the corresponding EC 50 values are shown in Table 10A to Table 10H, and the results show that the humanized antibodies against human BCMA ADCC activity was comparable or superior to control antibodies.
  • Table 10A ADCC effect of humanized antibodies against human BCMA (reporter gene method)
  • Table 10B ADCC effect of humanized antibodies against human BCMA (reporter gene method)
  • Table 10C ADCC effect of humanized antibodies against human BCMA (reporter gene method)
  • Table 10D ADCC effect of humanized antibodies against human BCMA (reporter gene method)
  • Table 10F ADCC effect of humanized antibodies against human BCMA (reporter gene method)

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Abstract

Provided are an antibody capable of specifically binding to BCMA or an antigen-binding fragment of the antibody, and a pharmaceutical composition comprising same. Also provided are a polynucleotide molecule encoding the antibody or the antigen-binding fragment thereof, an expression vector and a host cell for expressing the antibody or the antigen-binding fragment thereof, and a use of the antibody or the antigen-binding fragment thereof.

Description

抗BCMA抗体及其用途Anti-BCMA antibodies and uses thereof
本申请要求于2021年12月22日提交中国专利局、申请号为202111578280.0发明名称为“抗BCMA抗体及其用途”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。This application claims the priority of a Chinese patent application with the application number 202111578280.0 filed on December 22, 2021, entitled "Anti-BCMA Antibody and Its Use" with the Chinese Patent Office, the entire contents of which are incorporated herein by reference.
技术领域technical field
本申请属于生物医药领域，特别是涉及能够与BCMA特异性结合的抗体或其抗原结合片段及其用途。The application belongs to the field of biomedicine, and in particular relates to an antibody capable of specifically binding to BCMA or an antigen-binding fragment thereof and use thereof.
背景技术Background technique
B细胞是淋巴细胞，其在自适应体液免疫和特异性识别抗原的抗体的产生中发挥重要的作用。B细胞的三种亚类是幼稚B细胞、记忆B细胞和浆细胞。在VDJ重组的过程中，其中DNA的两种或三种片段选自基因组文库，并且重组以产生抗体可变结构域的组合阵列，通过其由不同谱系的B细胞编码的可变结构域进一步的改变导致多至10 9种独特的B细胞谱系，其产生和独特靶向具有特异性的抗体。多种疾病涉及B细胞。B细胞的恶性转化导致癌症，包括一些淋巴瘤，如多发性骨髓瘤和霍奇金氏淋巴瘤。自身免疫性疾病也会涉及到B细胞，包括系统性红斑狼疮(SLE)和IgA肾病。涉及B细胞的癌症和自家免疫性疾病可被认为B细胞功能异常，因此控制这类疾病的可能的策略是使用靶向病理B细胞的抗体。 B cells are lymphocytes that play an important role in adaptive humoral immunity and the production of antibodies that specifically recognize antigens. The three subclasses of B cells are naive B cells, memory B cells, and plasma cells. During VDJ recombination, in which two or three segments of DNA are selected from a genomic library and recombined to produce a combinatorial array of antibody variable domains, by which variable domains encoded by B cells of different lineages are further Alterations result in as many as 109 unique B cell lineages that produce and uniquely target antibodies with specificity. Various diseases involve B cells. Malignant transformation of B cells leads to cancers, including some lymphomas such as multiple myeloma and Hodgkin's lymphoma. Autoimmune diseases also involve B cells, including systemic lupus erythematosus (SLE) and IgA nephropathy. Cancers and autoimmune diseases involving B cells can be considered to be dysfunctional B cells, so a possible strategy to control such diseases is the use of antibodies targeting pathological B cells.
B细胞成熟抗原BCMA(CD269或TNFRSF17)是肿瘤坏死因子超家族的成员，主要在浆细胞和一部分成熟的B细胞上表达，人BCMA是由184个氨基酸残基组成的III型跨膜蛋白。BCMA能与增殖诱导配体(APRIL)和B细胞激活因子(BAFF)特异性结合，激活NF-κB和MAPK8/JNK信号通路；也能与多种TRAF家族成员结合，促进B细胞在不同发育阶段的存活，参与调节体液免疫、B细胞发育和稳态。B cell maturation antigen BCMA (CD269 or TNFRSF17) is a member of the tumor necrosis factor superfamily, mainly expressed on plasma cells and some mature B cells. Human BCMA is a type III transmembrane protein composed of 184 amino acid residues. BCMA can specifically bind to proliferation-inducing ligand (APRIL) and B cell activating factor (BAFF) to activate NF-κB and MAPK8/JNK signaling pathways; it can also bind to various TRAF family members to promote the development of B cells at different developmental stages Involved in the regulation of humoral immunity, B cell development and homeostasis.
据报道，BCMA高表达于多种肿瘤细胞表面，如多发性骨髓瘤、霍奇金氏淋巴瘤、急性淋巴细胞性白血病(ALL)，而在造血干细胞和其他正常组织细胞中不表达，因此是癌症靶向性治疗的理想靶点。According to reports, BCMA is highly expressed on the surface of various tumor cells, such as multiple myeloma, Hodgkin's lymphoma, acute lymphoblastic leukemia (ALL), but not expressed in hematopoietic stem cells and other normal tissue cells, so it is Ideal target for targeted cancer therapy.
尽管目前已有BCMA的抗体药物偶联物(ADC)如贝兰他单抗莫福汀(Belantamab mafodotin，葛兰素史克)用于治疗一些癌症，并且正在测试其他抗癌适应症，但是仍需要开发更多的新型BCMA抗体药物。Although antibody-drug conjugates (ADCs) of BCMA such as belantamab mafodotin (GSK) are currently used to treat some cancers and are being tested for other anti-cancer indications, there is still a need Develop more novel BCMA antibody drugs.
发明内容Contents of the invention
本申请的目的在于提供一种能够与BCMA特异性结合的抗体(即抗BCMA抗体)或其抗原结合片段，编码本申请的抗体或其抗原结合片段的多核苷酸分子，用于表达本申请的抗体或其抗原结合片段的表达载体和宿主细胞，以及本申请的抗体或其抗原结合片段的用途。The purpose of the present application is to provide an antibody capable of specifically binding to BCMA (i.e., an anti-BCMA antibody) or an antigen-binding fragment thereof, a polynucleotide molecule encoding the antibody of the present application or an antigen-binding fragment thereof, for expressing the present application Expression vectors and host cells of antibodies or antigen-binding fragments thereof, and uses of the antibodies or antigen-binding fragments thereof of the present application.
本申请第一方面提供了一种能够与BCMA特异性结合的抗体或其抗原结合片段，其包含HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3；The first aspect of the present application provides an antibody or an antigen-binding fragment thereof capable of specifically binding to BCMA, which comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3;
其中，所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3所示的氨基酸序列，或者分别具有如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示的氨基酸序列，或者分别具有如SEQ ID NO:7、SEQ ID NO:8和SEQ ID NO:9所示的氨基酸序列，或者分别具有如SEQ ID NO:10、SEQ ID NO:11和SEQ ID NO:12所示的氨基酸序列，或者分别具有如SEQ ID NO:13、SEQ ID NO:14和SEQ ID NO:15所示的氨基酸序列，或者分别具有如SEQ ID NO:16、SEQ ID NO:17和SEQ ID NO:18所示的氨 基酸序列，或者分别具有如SEQ ID NO:19、SEQ ID NO:20和SEQ ID NO:21所示的氨基酸序列，或者分别具有如SEQ ID NO:22、SEQ ID NO:23和SEQ ID NO:24所示的氨基酸序列；Wherein, the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, or respectively have the amino acid sequences shown in SEQ ID NO: 4, SEQ ID NO: 5 and the amino acid sequence shown in SEQ ID NO: 6, or have respectively the amino acid sequence shown in SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 9, or have the amino acid sequence shown in SEQ ID NO: 10, SEQ ID NO: 10, SEQ ID NO: 9 respectively The amino acid sequence shown in ID NO: 11 and SEQ ID NO: 12, or have the amino acid sequence shown in SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 15 respectively, or have the amino acid sequence shown in SEQ ID NO respectively : 16, the amino acid sequence shown in SEQ ID NO: 17 and SEQ ID NO: 18, or have the amino acid sequence shown in SEQ ID NO: 19, SEQ ID NO: 20 and SEQ ID NO: 21 respectively, or have respectively Amino acid sequences as shown in SEQ ID NO:22, SEQ ID NO:23 and SEQ ID NO:24;
所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:25、SEQ ID NO:26和SEQ ID NO:27所示的氨基酸序列，或者分别具有如SEQ ID NO:28、SEQ ID NO:29和SEQ ID NO:30所示的氨基酸序列，或者分别具有如SEQ ID NO:31、SEQ ID NO:32和SEQ ID NO:33所示的氨基酸序列，或者分别具有如SEQ ID NO:34、SEQ ID NO:35和SEQ ID NO:36所示的氨基酸序列，或者分别具有如SEQ ID NO:37、SEQ ID NO:38和SEQ ID NO:39所示的氨基酸序列，或者分别具有如SEQ ID NO:40、SEQ ID NO:41和SEQ ID NO:42所示的氨基酸序列，或者分别具有如SEQ ID NO:43、SEQ ID NO:44和SEQ ID NO:45所示的氨基酸序列，或者分别具有如SEQ ID NO:46、SEQ ID NO:47和SEQ ID NO:48所示的氨基酸序列；Said LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequence shown in SEQ ID NO:25, SEQ ID NO:26 and SEQ ID NO:27, or respectively have such as SEQ ID NO:28, SEQ ID NO:29 and SEQ ID NO:29 and SEQ ID NO:27 The amino acid sequence shown in ID NO: 30, or have the amino acid sequence shown in SEQ ID NO: 31, SEQ ID NO: 32 and SEQ ID NO: 33 respectively, or have the amino acid sequence shown in SEQ ID NO: 34, SEQ ID NO respectively Amino acid sequences shown in: 35 and SEQ ID NO: 36, or respectively have the amino acid sequences shown in SEQ ID NO: 37, SEQ ID NO: 38 and SEQ ID NO: 39, or have respectively the amino acid sequences shown in SEQ ID NO: 40 , the amino acid sequence shown in SEQ ID NO: 41 and SEQ ID NO: 42, or have the amino acid sequence shown in SEQ ID NO: 43, SEQ ID NO: 44 and SEQ ID NO: 45 respectively, or have the amino acid sequence shown in SEQ ID NO: 45 respectively The amino acid sequences shown in ID NO:46, SEQ ID NO:47 and SEQ ID NO:48;
其中，所述SEQ ID NO:1-48中的至少一个可以替换为与其具有1、2或3个氨基酸差异的变体；Wherein, at least one of said SEQ ID NO: 1-48 can be replaced with a variant having 1, 2 or 3 amino acid differences;
优选地，所述与SEQ ID NO:8所示的氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:49或SEQ ID NO:50所示的氨基酸序列；Preferably, the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO:8 has the amino acid sequence shown in SEQ ID NO:49 or SEQ ID NO:50;
优选地，所述与SEQ ID NO:9所示的氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:178所示的氨基酸序列；Preferably, the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO: 9 has the amino acid sequence shown in SEQ ID NO: 178;
优选地，所述与SEQ ID NO:11所示的氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:51所示的氨基酸序列；Preferably, the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO: 11 has the amino acid sequence shown in SEQ ID NO: 51;
优选地，所述与SEQ ID NO:15所示的氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:52所示的氨基酸序列；Preferably, the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO: 15 has the amino acid sequence shown in SEQ ID NO: 52;
优选地，所述与SEQ ID NO:29所示的氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:53所示的氨基酸序列；Preferably, the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO:29 has the amino acid sequence shown in SEQ ID NO:53;
优选地，所述与SEQ ID NO:31所示的氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:54或SEQ ID NO:179所示的氨基酸序列；Preferably, the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO:31 has the amino acid sequence shown in SEQ ID NO:54 or SEQ ID NO:179;
优选地，所述与SEQ ID NO:32所示的氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:55所示的氨基酸序列；Preferably, the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO:32 has the amino acid sequence shown in SEQ ID NO:55;
优选地，所述与SEQ ID NO:36所示的氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:180所示的氨基酸序列；Preferably, the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO:36 has the amino acid sequence shown in SEQ ID NO:180;
优选地，所述与SEQ ID NO:40所示的氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:56所示的氨基酸序列；Preferably, the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO:40 has the amino acid sequence shown in SEQ ID NO:56;
优选地，所述与SEQ ID NO:41所示的氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:57所示的氨基酸序列。Preferably, the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO:41 has the amino acid sequence shown in SEQ ID NO:57.
在一些实施方式中，所述抗体或其抗原结合片段包含的HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3分别为：In some embodiments, the antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively:
HCDR1：NYDMA；HCDR1: NYDMA;
HCDR2：SISRX1GDX2X3X4YRDSVX5G，其中，X1为F或S，X2为S或T，X3为F或T，X4为Y或Q或D，X5为K或E；HCDR2: SISRX1GDX2X3X4YRDSVX5G, where X1 is F or S, X2 is S or T, X3 is F or T, X4 is Y or Q or D, X5 is K or E;
HCDR3：QDYGYX6WVWFAY，其中，X6为K或D或N；HCDR3: QDYGYX6WVWFAY, where X6 is K or D or N;
LCDR1：X7AX8EX9ISNDLX10，其中，X7为R或L，X8为S或N，X9为D或G，X10为V或A；LCDR1: X7AX8EX9ISNDLX10, where X7 is R or L, X8 is S or N, X9 is D or G, X10 is V or A;
LCDR2：X11X12SRLX13X14，其中，X11为G或A，X12为T或A，X13为Q或P，X14为D或E或S；LCDR2: X11X12SRLX13X14, where X11 is G or A, X12 is T or A, X13 is Q or P, X14 is D or E or S;
LCDR3：QQX15YKYPFT，其中，X15为T或S；LCDR3: QQX15YKYPFT, where X15 is T or S;
优选地，所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:28、SEQ ID NO:29和SEQ ID NO:30所示的氨基酸序列；或者Preferably, the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 28. The amino acid sequence shown in SEQ ID NO: 29 and SEQ ID NO: 30; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:28、SEQ ID NO:53和SEQ ID NO:30所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 28, SEQ ID NO: 28, SEQ ID NO: The amino acid sequence shown in ID NO:53 and SEQ ID NO:30; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:7、SEQ ID NO:8和SEQ ID NO:9所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:31、SEQ ID NO:32和SEQ ID NO:33所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 9, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 31, SEQ ID NO: 31, SEQ ID NO: The amino acid sequence shown in ID NO:32 and SEQ ID NO:33; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:7、SEQ ID NO:8和SEQ ID NO:178所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:179、SEQ ID NO:32和SEQ ID NO:33所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 178, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 179, SEQ ID NO: 179 and SEQ ID NO: 178 respectively. The amino acid sequence shown in ID NO:32 and SEQ ID NO:33; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:7、SEQ ID NO:49和SEQ ID NO:9所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:31、SEQ ID NO:32和SEQ ID NO:33所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 49 and SEQ ID NO: 9, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 31, SEQ ID NO: 31, SEQ ID NO: The amino acid sequence shown in ID NO:32 and SEQ ID NO:33; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:7、SEQ ID NO:50和SEQ ID NO:9所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:54、SEQ ID NO:55和SEQ ID NO:33所示的氨基酸序列。The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 50 and SEQ ID NO: 9, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 54, SEQ ID NO: 54, SEQ ID NO: Amino acid sequences shown in ID NO:55 and SEQ ID NO:33.
在一些实施方式中，所述抗体或其抗原结合片段包含的HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3分别为：In some embodiments, the antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively:
HCDR1：DFYMN；HCDR1:DFYMN;
HCDR2：FIRNKANX1YTTEYNPSVKG，其中，X1为G或A；HCDR2: FIRNKANX1YTTEYNPSVKG, where X1 is G or A;
HCDR3：FQHSYYFDY；HCDR3: FQHSYYFDY;
LCDR1：KASQDIDDYLS；LCDR1:KASQDIDDYLS;
LCDR2：DATSLAY；LCDR2: DATSLAY;
LCDR3：LQTYSX2PPT，其中，X2为T或S；LCDR3: LQTYSX2PPT, where X2 is T or S;
优选地，所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:10、SEQ ID NO:11和SEQ ID NO:12所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:34、SEQ ID NO:35和SEQ ID NO:36所示的氨基酸序列；或者Preferably, the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 34. The amino acid sequence shown in SEQ ID NO: 35 and SEQ ID NO: 36; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:10、SEQ ID NO:11和SEQ ID NO:12所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:34、SEQ ID NO:35和SEQ ID NO:180所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 34, SEQ ID NO: 34 and SEQ ID NO: 12 respectively. the amino acid sequence shown in ID NO:35 and SEQ ID NO:180; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:10、SEQ ID NO:51和SEQ ID NO:12所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:34、SEQ ID NO:35和SEQ ID NO:36所示的氨基酸序列。The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 10, SEQ ID NO: 51 and SEQ ID NO: 12, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 34, SEQ ID NO: 34 and SEQ ID NO: 12 respectively. Amino acid sequences shown in ID NO:35 and SEQ ID NO:36.
在一些实施方式中，所述抗体或其抗原结合片段包含的HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3分别为：In some embodiments, the antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively:
HCDR1：IYGMY；HCDR1: IYGMY;
HCDR2：WINTETGTPTYATDFKG；HCDR2: WINTETGTPTYATDFKG;
HCDR3：EDX1GYFDY，其中，X1为G或A；HCDR3: EDX1GYFDY, where X1 is G or A;
LCDR1：RASQSVTISRYNFMN；LCDR1: RASQSVTISRYNFMN;
LCDR2：RASNLPS；LCDR2: RASNLPS;
LCDR3：QQNRESPRT；LCDR3: QQNRESPRT;
优选地，所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:13、SEQ ID NO:14和SEQ ID NO:15所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:37、SEQ ID NO:38和SEQ ID NO:39所示的氨基酸序列；或者Preferably, the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 15, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 37. The amino acid sequence shown in SEQ ID NO: 38 and SEQ ID NO: 39; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:13、SEQ ID NO:14和SEQ ID NO:52所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:37、SEQ ID NO:38和SEQ ID NO:39所示的氨基酸序列。The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 52, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 37, SEQ ID NO: 37 and SEQ ID NO: 52 respectively. Amino acid sequences shown in ID NO:38 and SEQ ID NO:39.
在一些实施方式中，所述抗体或其抗原结合片段包含的HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3分别为：In some embodiments, the antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively:
HCDR1：NYDIS；HCDR1: NYDIS;
HCDR2：GINPGSGGTAYNEKFKD；HCDR2: GINPGSGGTAYNEKFKD;
HCDR3：WDYGGDYNWFTY；HCDR3: WDYGGDYNWFTY;
LCDR1：LASEGISNX1LA，其中，X1为G或A；LCDR1: LASEGISNX1LA, where X1 is G or A;
LCDR2：AASRLQDX2，其中，X2为E或不存在；LCDR2: AASRLQDX2, where X2 is E or does not exist;
LCDR3：QQNYRYPLT；LCDR3: QQNYRYPLT;
优选地，所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:16、SEQ ID NO:17和SEQ ID NO:18所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:40、SEQ ID NO:41和SEQ ID NO:42所示的氨基酸序列；或者Preferably, the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 40. The amino acid sequence shown in SEQ ID NO: 41 and SEQ ID NO: 42; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:16、SEQ ID NO:17和SEQ ID NO:18所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:56、SEQ ID NO:57和SEQ ID NO:42所示的氨基酸序列。The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 56, SEQ ID NO: 56 and SEQ ID NO: 18 respectively. Amino acid sequences shown in ID NO:57 and SEQ ID NO:42.
在一些实施方式中，所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:25、SEQ ID NO:26和SEQ ID NO:27所示的氨基酸序列；或者In some embodiments, the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 3 respectively. the amino acid sequences set forth in ID NO:25, SEQ ID NO:26 and SEQ ID NO:27; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:28、SEQ ID NO:29和SEQ ID NO:30所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 28, SEQ ID NO: 28, SEQ ID NO: The amino acid sequence shown in ID NO:29 and SEQ ID NO:30; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:28、SEQ ID NO:53和SEQ ID NO:30所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 28, SEQ ID NO: 28, SEQ ID NO: The amino acid sequence shown in ID NO:53 and SEQ ID NO:30; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:7、SEQ ID NO:8和SEQ ID NO:9所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:31、SEQ ID NO:32和SEQ ID NO:33所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 9, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 31, SEQ ID NO: 31, SEQ ID NO: The amino acid sequence shown in ID NO:32 and SEQ ID NO:33; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:7、SEQ ID NO:8和SEQ ID NO:178所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:179、SEQ ID NO:32和SEQ ID NO:33所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 178, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 179, SEQ ID NO: 179 and SEQ ID NO: 178 respectively. The amino acid sequence shown in ID NO:32 and SEQ ID NO:33; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:7、SEQ ID NO:49和SEQ ID NO:9所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:31、SEQ ID NO:32和SEQ ID NO:33所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 49 and SEQ ID NO: 9, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 31, SEQ ID NO: 31, SEQ ID NO: The amino acid sequence shown in ID NO:32 and SEQ ID NO:33; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:7、SEQ ID NO:50和SEQ ID NO:9所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:54、SEQ ID NO:55和SEQ ID NO:33所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 50 and SEQ ID NO: 9, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 54, SEQ ID NO: 54, SEQ ID NO: The amino acid sequence shown in ID NO:55 and SEQ ID NO:33; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:10、SEQ ID NO:11和SEQ ID NO:12所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:34、SEQ ID NO:35和SEQ ID NO:36所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 34, SEQ ID NO: 34 and SEQ ID NO: 12 respectively. The amino acid sequence shown in ID NO:35 and SEQ ID NO:36; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:10、SEQ ID NO:11和SEQ ID NO:12所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:34、SEQ ID NO:35和SEQ ID NO:180所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 34, SEQ ID NO: 34 and SEQ ID NO: 12 respectively. the amino acid sequence shown in ID NO:35 and SEQ ID NO:180; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:10、SEQ ID NO:51和SEQ ID NO:12所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:34、SEQ ID NO:35和SEQ ID NO:36所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 10, SEQ ID NO: 51 and SEQ ID NO: 12, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 34, SEQ ID NO: 34 and SEQ ID NO: 12 respectively. The amino acid sequence shown in ID NO:35 and SEQ ID NO:36; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:13、SEQ ID NO:14和SEQ ID NO:15所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:37、SEQ ID NO:38和SEQ ID NO:39所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 15, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 37, SEQ ID NO: 37 and SEQ ID NO: 15 respectively. The amino acid sequence shown in ID NO:38 and SEQ ID NO:39; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:13、SEQ ID NO:14和SEQ ID NO:52所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:37、SEQ ID NO:38和SEQ ID NO:39所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 52, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 37, SEQ ID NO: 37 and SEQ ID NO: 52 respectively. The amino acid sequence shown in ID NO:38 and SEQ ID NO:39; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:16、SEQ ID NO:17和SEQ ID NO:18所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:40、SEQ ID NO:41和SEQ ID NO:42所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 40, SEQ ID NO: 40 and SEQ ID NO: 18 respectively. The amino acid sequence shown in ID NO:41 and SEQ ID NO:42; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:16、SEQ ID NO:17和SEQ ID NO:18所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:56、SEQ ID NO:57和SEQ ID NO:42所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 56, SEQ ID NO: 56 and SEQ ID NO: 18 respectively. the amino acid sequence shown in ID NO:57 and SEQ ID NO:42; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:19、SEQ ID NO:20和SEQ ID NO:21所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:43、SEQ ID NO:44和SEQ ID NO:45所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 19, SEQ ID NO: 20 and SEQ ID NO: 21, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 43, SEQ ID NO: 43 and SEQ ID NO: 21 respectively. The amino acid sequence shown in ID NO:44 and SEQ ID NO:45; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:22、SEQ ID NO:23和SEQ ID NO:24所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:46、SEQ ID NO:47和SEQ ID NO:48所示的氨基酸序列。The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 22, SEQ ID NO: 23 and SEQ ID NO: 24, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 46, SEQ ID NO: 46 and SEQ ID NO: 24 respectively. Amino acid sequences shown in ID NO:47 and SEQ ID NO:48.
在一些实施方式中，所述的抗体或其抗原结合片段包含：In some embodiments, the antibody or antigen-binding fragment thereof comprises:
与SEQ ID NO:58所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:92所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:58 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO:92 light chain variable regions of sequence identity; or
与SEQ ID NO:59所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:93所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:59 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO:93 light chain variable regions of sequence identity; or
与SEQ ID NO:60所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:94所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:60 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO:94 light chain variable regions of sequence identity; or
与SEQ ID NO:61所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:95所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:61 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO:95 light chain variable regions of sequence identity; or
与SEQ ID NO:62所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:96所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％ 序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:62 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO:96 light chain variable regions of sequence identity; or
与SEQ ID NO:63所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:97所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:63 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO:97 light chain variable regions of sequence identity; or
与SEQ ID NO:64所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:98所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:64 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO:98 light chain variable regions of sequence identity; or
与SEQ ID NO:65所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:99所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:65 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO:99 light chain variable regions of sequence identity; or
与SEQ ID NO:66所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:100所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:66 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 100 light chain variable regions of sequence identity; or
与SEQ ID NO:67所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:101所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:67 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 101 light chain variable regions of sequence identity; or
与SEQ ID NO:68所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:102所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:68 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 102 light chain variable regions of sequence identity; or
与SEQ ID NO:69所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:103所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 69 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 103 light chain variable regions of sequence identity; or
与SEQ ID NO:70所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:104所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:70 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 104 light chain variable regions of sequence identity; or
与SEQ ID NO:71所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:105所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:71 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 105 light chain variable regions of sequence identity; or
与SEQ ID NO:72所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:106所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:72 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 106 light chain variable regions of sequence identity; or
与SEQ ID NO:73所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:107所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％ 序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:73 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 107 light chain variable regions of sequence identity; or
与SEQ ID NO:74所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:108所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:74 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 108 light chain variable regions of sequence identity; or
与SEQ ID NO:75所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:109所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:75 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 109 light chain variable regions of sequence identity; or
与SEQ ID NO:76所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:110所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:76 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 110 light chain variable regions of sequence identity; or
与SEQ ID NO:77所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:111所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:77 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 111 light chain variable regions of sequence identity; or
与SEQ ID NO:78所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:112所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:78 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 112 light chain variable regions of sequence identity; or
与SEQ ID NO:79所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:113所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:79 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 113 light chain variable regions of sequence identity; or
与SEQ ID NO:80所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:114所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 80 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 114 light chain variable regions of sequence identity; or
与SEQ ID NO:81所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:115所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 81 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 115 light chain variable regions of sequence identity; or
与SEQ ID NO:82所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:116所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:82 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 116 light chain variable regions of sequence identity; or
与SEQ ID NO:83所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:117所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:83 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 117 light chain variable regions of sequence identity; or
与SEQ ID NO:84所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:118所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％ 序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:84 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 118 light chain variable regions of sequence identity; or
与SEQ ID NO:85所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:119所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:85 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 119 light chain variable regions of sequence identity; or
与SEQ ID NO:86所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:120所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:86 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 120 light chain variable regions of sequence identity; or
与SEQ ID NO:87所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:121所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:87 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 121 light chain variable regions of sequence identity; or
与SEQ ID NO:88所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:122所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:88 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 122 light chain variable regions of sequence identity; or
与SEQ ID NO:89所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:123所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 89 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 123 light chain variable regions of sequence identity; or
与SEQ ID NO:90所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:124所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:90 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 124 light chain variable regions of sequence identity; or
与SEQ ID NO:91所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:125所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:91 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 125 light chain variable regions of sequence identity; or
与SEQ ID NO:181所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:182所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 181 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 182 light chain variable regions of sequence identity; or
与SEQ ID NO:183所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:184所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区。A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 183 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the amino acid sequence shown in SEQ ID NO: 184 Sequence identity of the light chain variable region.
在一些实施方式中，所述的抗体或其抗原结合片段包含：In some embodiments, the antibody or antigen-binding fragment thereof comprises:
氨基酸序列如SEQ ID NO:58所示的重链可变区，和氨基酸序列如SEQ ID NO:92所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:58, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:92; or
氨基酸序列如SEQ ID NO:59所示的重链可变区，和氨基酸序列如SEQ ID NO:93所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:59, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:93; or
氨基酸序列如SEQ ID NO:60所示的重链可变区，和氨基酸序列如SEQ ID NO:94所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:60, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:94; or
氨基酸序列如SEQ ID NO:61所示的重链可变区，和氨基酸序列如SEQ ID NO:95所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:61, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:95; or
氨基酸序列如SEQ ID NO:62所示的重链可变区，和氨基酸序列如SEQ ID NO:96所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:62, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:96; or
氨基酸序列如SEQ ID NO:63所示的重链可变区，和氨基酸序列如SEQ ID NO:97所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:63, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:97; or
氨基酸序列如SEQ ID NO:64所示的重链可变区，和氨基酸序列如SEQ ID NO:98所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:64, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:98; or
氨基酸序列如SEQ ID NO:65所示的重链可变区，和氨基酸序列如SEQ ID NO:99所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:65, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:99; or
氨基酸序列如SEQ ID NO:66所示的重链可变区，和氨基酸序列如SEQ ID NO:100所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:66, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:100; or
氨基酸序列如SEQ ID NO:67所示的重链可变区，和氨基酸序列如SEQ ID NO:101所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:67, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:101; or
氨基酸序列如SEQ ID NO:68所示的重链可变区，和氨基酸序列如SEQ ID NO:102所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:68, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:102; or
氨基酸序列如SEQ ID NO:69所示的重链可变区，和氨基酸序列如SEQ ID NO:103所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:69, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:103; or
氨基酸序列如SEQ ID NO:70所示的重链可变区，和氨基酸序列如SEQ ID NO:104所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:70, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:104; or
氨基酸序列如SEQ ID NO:71所示的重链可变区，和氨基酸序列如SEQ ID NO:105所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:71, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:105; or
氨基酸序列如SEQ ID NO:72所示的重链可变区，和氨基酸序列如SEQ ID NO:106所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO:72, and a light chain variable region having an amino acid sequence as shown in SEQ ID NO:106; or
氨基酸序列如SEQ ID NO:73所示的重链可变区，和氨基酸序列如SEQ ID NO:107所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:73, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:107; or
氨基酸序列如SEQ ID NO:74所示的重链可变区，和氨基酸序列如SEQ ID NO:108所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:74, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:108; or
氨基酸序列如SEQ ID NO:75所示的重链可变区，和氨基酸序列如SEQ ID NO:109所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:75, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:109; or
氨基酸序列如SEQ ID NO:76所示的重链可变区，和氨基酸序列如SEQ ID NO:110所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:76, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:110; or
氨基酸序列如SEQ ID NO:77所示的重链可变区，和氨基酸序列如SEQ ID NO:111所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:77, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:111; or
氨基酸序列如SEQ ID NO:78所示的重链可变区，和氨基酸序列如SEQ ID NO:112所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:78, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:112; or
氨基酸序列如SEQ ID NO:79所示的重链可变区，和氨基酸序列如SEQ ID NO:113所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:79, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:113; or
氨基酸序列如SEQ ID NO:80所示的重链可变区，和氨基酸序列如SEQ ID NO:114所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO:80, and a light chain variable region having an amino acid sequence as shown in SEQ ID NO:114; or
氨基酸序列如SEQ ID NO:81所示的重链可变区，和氨基酸序列如SEQ ID NO:115所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:81, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:115; or
氨基酸序列如SEQ ID NO:82所示的重链可变区，和氨基酸序列如SEQ ID NO:116所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:82, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:116; or
氨基酸序列如SEQ ID NO:83所示的重链可变区，和氨基酸序列如SEQ ID NO:117所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:83, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:117; or
氨基酸序列如SEQ ID NO:84所示的重链可变区，和氨基酸序列如SEQ ID NO:118所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:84, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:118; or
氨基酸序列如SEQ ID NO:85所示的重链可变区，和氨基酸序列如SEQ ID NO:119所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:85, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:119; or
氨基酸序列如SEQ ID NO:86所示的重链可变区，和氨基酸序列如SEQ ID NO:120所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:86, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:120; or
氨基酸序列如SEQ ID NO:87所示的重链可变区，和氨基酸序列如SEQ ID NO:121所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:87, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:121; or
氨基酸序列如SEQ ID NO:88所示的重链可变区，和氨基酸序列如SEQ ID NO:122所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:88, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:122; or
氨基酸序列如SEQ ID NO:89所示的重链可变区，和氨基酸序列如SEQ ID NO:123所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:89, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:123; or
氨基酸序列如SEQ ID NO:90所示的重链可变区，和氨基酸序列如SEQ ID NO:124所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:90, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:124; or
氨基酸序列如SEQ ID NO:91所示的重链可变区，和氨基酸序列如SEQ ID NO:125所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:91, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:125; or
氨基酸序列如SEQ ID NO:181所示的重链可变区，和氨基酸序列如SEQ ID NO:182所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 181, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO: 182; or
氨基酸序列如SEQ ID NO:183所示的重链可变区，和氨基酸序列如SEQ ID NO:184所示的轻链可变区。The amino acid sequence of the heavy chain variable region shown in SEQ ID NO: 183, and the amino acid sequence of the light chain variable region shown in SEQ ID NO: 184.
在一些实施方式中，所述的抗体或其抗原结合片段还包含人重链恒定区和人轻链恒定区，所述人重链恒定区选自人IgG1、IgG2、IgG3或IgG4的重链恒定区，优选为人IgG1的重链恒定区；所述人轻链恒定区选自λ轻链或κ轻链的轻链恒定区。In some embodiments, the antibody or antigen-binding fragment thereof further comprises a human heavy chain constant region and a human light chain constant region, and the human heavy chain constant region is selected from the constant heavy chain region of human IgG1, IgG2, IgG3 or IgG4. Region, preferably the heavy chain constant region of human IgG1; the human light chain constant region is selected from the light chain constant region of lambda light chain or kappa light chain.
在一些实施方式中，所述的抗体或其抗原结合片段包含：In some embodiments, the antibody or antigen-binding fragment thereof comprises:
与SEQ ID NO:126所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:127所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 126 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 127 light chain; or
与SEQ ID NO:128所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:129所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 128 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 129 light chain; or
与SEQ ID NO:130所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:131所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 130 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 131 light chain; or
与SEQ ID NO:132所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:133所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 132 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 133 light chain; or
与SEQ ID NO:134所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:135所示氨基酸序列 具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 134 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 135 light chain; or
与SEQ ID NO:136所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:137所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 136 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 137 light chain; or
与SEQ ID NO:138所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:139所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 138 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 139 light chain; or
与SEQ ID NO:140所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:141所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 140 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 141 light chain; or
与SEQ ID NO:142所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:143所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 142 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 143 light chain; or
与SEQ ID NO:144所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:145所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 144 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 145 light chain; or
与SEQ ID NO:146所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:147所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 146 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 147 light chain; or
与SEQ ID NO:148所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:149所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 148 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 149 light chain; or
与SEQ ID NO:150所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:151所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 150 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 151 light chain; or
与SEQ ID NO:152所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:153所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 152 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 153 light chain; or
与SEQ ID NO:154所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:155所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 154 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 155 light chain; or
与SEQ ID NO:156所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:157所示氨基酸序列 具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 156 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 157 light chain; or
与SEQ ID NO:158所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:159所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 158 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 159 light chain; or
与SEQ ID NO:160所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:161所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 160 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 161 light chain; or
与SEQ ID NO:162所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:163所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 162 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 163 light chain; or
与SEQ ID NO:164所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:165所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 164 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 165 light chain; or
与SEQ ID NO:166所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:167所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 166 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 167 light chain; or
与SEQ ID NO:168所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:169所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 168 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 169 light chain; or
与SEQ ID NO:170所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:171所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 170 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 171 light chain; or
与SEQ ID NO:172所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:173所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 172 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 173 light chain; or
与SEQ ID NO:174所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:175所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 174 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 175 light chain; or
与SEQ ID NO:176所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:177所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链。A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 176 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 177 light chain.
在一些实施方式中，所述抗体或其抗原结合片段包含：In some embodiments, the antibody or antigen-binding fragment thereof comprises:
氨基酸序列如SEQ ID NO:126所示的重链，和氨基酸序列如SEQ ID NO:127所示的轻 链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 126, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 127; or
氨基酸序列如SEQ ID NO:128所示的重链，和氨基酸序列如SEQ ID NO:129所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 128, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 129; or
氨基酸序列如SEQ ID NO:130所示的重链，和氨基酸序列如SEQ ID NO:131所示的轻链；或A heavy chain having an amino acid sequence as set forth in SEQ ID NO:130, and a light chain having an amino acid sequence as set forth in SEQ ID NO:131; or
氨基酸序列如SEQ ID NO:132所示的重链，和氨基酸序列如SEQ ID NO:133所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 132, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 133; or
氨基酸序列如SEQ ID NO:134所示的重链，和氨基酸序列如SEQ ID NO:135所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 134, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 135; or
氨基酸序列如SEQ ID NO:136所示的重链，和氨基酸序列如SEQ ID NO:137所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 136, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 137; or
氨基酸序列如SEQ ID NO:138所示的重链，和氨基酸序列如SEQ ID NO:139所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 138, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 139; or
氨基酸序列如SEQ ID NO:140所示的重链，和氨基酸序列如SEQ ID NO:141所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 140, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 141; or
氨基酸序列如SEQ ID NO:142所示的重链，和氨基酸序列如SEQ ID NO:143所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 142, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 143; or
氨基酸序列如SEQ ID NO:144所示的重链，和氨基酸序列如SEQ ID NO:145所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 144, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 145; or
氨基酸序列如SEQ ID NO:146所示的重链，和氨基酸序列如SEQ ID NO:147所示的轻链；或a heavy chain having an amino acid sequence set forth in SEQ ID NO: 146, and a light chain having an amino acid sequence set forth in SEQ ID NO: 147; or
氨基酸序列如SEQ ID NO:148所示的重链，和氨基酸序列如SEQ ID NO:149所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 148, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 149; or
氨基酸序列如SEQ ID NO:150所示的重链，和氨基酸序列如SEQ ID NO:151所示的轻链；或A heavy chain having an amino acid sequence as set forth in SEQ ID NO:150, and a light chain having an amino acid sequence as set forth in SEQ ID NO:151; or
氨基酸序列如SEQ ID NO:152所示的重链，和氨基酸序列如SEQ ID NO:153所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 152, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 153; or
氨基酸序列如SEQ ID NO:154所示的重链，和氨基酸序列如SEQ ID NO:155所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 154, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 155; or
氨基酸序列如SEQ ID NO:156所示的重链，和氨基酸序列如SEQ ID NO:157所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 156, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 157; or
氨基酸序列如SEQ ID NO:158所示的重链，和氨基酸序列如SEQ ID NO:159所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 158, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 159; or
氨基酸序列如SEQ ID NO:160所示的重链，和氨基酸序列如SEQ ID NO:161所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 160, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 161; or
氨基酸序列如SEQ ID NO:162所示的重链，和氨基酸序列如SEQ ID NO:163所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 162, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 163; or
氨基酸序列如SEQ ID NO:164所示的重链，和氨基酸序列如SEQ ID NO:165所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 164, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 165; or
氨基酸序列如SEQ ID NO:166所示的重链，和氨基酸序列如SEQ ID NO:167所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 166, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 167; or
氨基酸序列如SEQ ID NO:168所示的重链，和氨基酸序列如SEQ ID NO:169所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 168, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 169; or
氨基酸序列如SEQ ID NO:170所示的重链，和氨基酸序列如SEQ ID NO:171所示的轻 链；或A heavy chain having an amino acid sequence as shown in SEQ ID NO: 170, and a light chain having an amino acid sequence as shown in SEQ ID NO: 171; or
氨基酸序列如SEQ ID NO:172所示的重链，和氨基酸序列如SEQ ID NO:173所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 172, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 173; or
氨基酸序列如SEQ ID NO:174所示的重链，和氨基酸序列如SEQ ID NO:175所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 174, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 175; or
氨基酸序列如SEQ ID NO:176所示的重链，和氨基酸序列如SEQ ID NO:177所示的轻链。The amino acid sequence is the heavy chain shown in SEQ ID NO: 176, and the amino acid sequence is the light chain shown in SEQ ID NO: 177.
在一些实施方式中，所述抗体包括单克隆抗体和多特异性抗体的至少一种，所述抗原结合片段包括Fab、Fab'、F(ab')2、Fv、scFv和sdAb的至少一种。In some embodiments, the antibody comprises at least one of a monoclonal antibody and a multispecific antibody, and the antigen-binding fragment comprises at least one of a Fab, Fab', F(ab')2, Fv, scFv, and sdAb .
本申请第二方面提供了一种分离的抗体或其抗原结合片段，其具有以下特性中的至少一种：The second aspect of the present application provides an isolated antibody or antigen-binding fragment thereof, which has at least one of the following characteristics:
(Ⅰ)与本申请第一方面所提供的抗体或其抗原结合片段结合相同的、或者完全重叠或部分重叠的人BCMA蛋白的表位；(I) the antibody or antigen-binding fragment thereof provided in the first aspect of the present application binds to the same epitope of human BCMA protein, or completely overlaps or partially overlaps;
(Ⅱ)与本申请第一方面所提供的抗体或其抗原结合片段竞争结合人BCMA蛋白的表位。(II) Compete with the antibody or antigen-binding fragment thereof provided in the first aspect of the present application for binding to the epitope of human BCMA protein.
本申请第三方面提供了一种多核苷酸分子，其包含编码本申请第一方面提供的抗体或其抗原结合片段，或编码本申请第二方面所提供的分离的抗体或其抗原结合片段的核苷酸序列或其互补序列的至少一种。The third aspect of the present application provides a polynucleotide molecule, which comprises the antibody encoding the antibody or antigen-binding fragment thereof provided in the first aspect of the application, or encoding the isolated antibody or antigen-binding fragment thereof provided in the second aspect of the application At least one of a nucleotide sequence or its complementary sequence.
本申请第四方面提供了一种表达载体，其包含本申请第三方面提供的多核苷酸分子，优选地，所述表达载体为真核表达载体。The fourth aspect of the present application provides an expression vector comprising the polynucleotide molecule provided in the third aspect of the present application, preferably, the expression vector is a eukaryotic expression vector.
本申请第五方面提供了一种宿主细胞，其包含本申请第三方面提供的多核苷酸分子，或本申请第四方面提供的表达载体，优选地，所述宿主细胞是真核细胞，更优选哺乳动物细胞。The fifth aspect of the present application provides a host cell, which comprises the polynucleotide molecule provided in the third aspect of the present application, or the expression vector provided in the fourth aspect of the present application, preferably, the host cell is a eukaryotic cell, more Mammalian cells are preferred.
在一些实施方式中，所述宿主细胞用于表达本申请第一方面的抗体或其抗原结合片段或本申请第二方面的分离的抗体或其抗原结合片段。In some embodiments, the host cell is used to express the antibody or antigen-binding fragment thereof of the first aspect of the present application or the isolated antibody or antigen-binding fragment thereof of the second aspect of the present application.
本申请第六方面提供了一种制备本申请第一方面的抗体或其抗原结合片段或本申请第二方面的分离的抗体或其抗原结合片段的方法，其包括在本申请第五方面所提供的宿主细胞中表达所述的抗体或其抗原结合片段，并从所述宿主细胞回收所表达的抗体或其抗原结合片段。The sixth aspect of the present application provides a method for preparing the antibody or antigen-binding fragment thereof of the first aspect of the present application or the isolated antibody or antigen-binding fragment thereof of the second aspect of the present application, which includes the method provided in the fifth aspect of the present application expressing the antibody or antigen-binding fragment thereof in a host cell, and recovering the expressed antibody or antigen-binding fragment thereof from the host cell.
本申请第七方面提供了一种抗BCMA抗体的药物偶联物(ADC)或其药学上可接受的盐，其包含：The seventh aspect of the present application provides an anti-BCMA antibody drug conjugate (ADC) or a pharmaceutically acceptable salt thereof, which comprises:
(a)抗体部分，所述抗体部分为本申请第一方面提供的抗体或其抗原结合片段；和(a) an antibody part, which is the antibody or antigen-binding fragment thereof provided in the first aspect of the application; and
(b)与所述抗体部分偶联的偶联部分，所述偶联部分选自可检测标记物、药物、毒素、细胞因子、放射性核素和酶中的至少一种。(b) a coupling moiety coupled to the antibody moiety, the coupling moiety being selected from at least one of detectable labels, drugs, toxins, cytokines, radionuclides and enzymes.
在一些实施方式中，所述的抗体部分与所述的偶联部分通过化学键或接头进行偶联。In some embodiments, the antibody moiety is coupled to the coupling moiety via a chemical bond or linker.
本申请第八方面提供了一种药物组合物，其包含本申请第一方面所提供的抗体或其抗原结合片段或本申请第二方面所提供的分离的抗体或其抗原结合片段或本申请第三方面提供的多核苷酸分子或本申请第四方面提供的表达载体或本申请第五方面提供的宿主细胞或本申请第七方面提供的药物偶联物，和药学上可接受的载体或赋形剂。The eighth aspect of the present application provides a pharmaceutical composition comprising the antibody or antigen-binding fragment thereof provided in the first aspect of the present application or the isolated antibody or antigen-binding fragment thereof provided in the second aspect of the present application or the antibody or antigen-binding fragment thereof provided in the second aspect of the present application The polynucleotide molecule provided in the third aspect or the expression vector provided in the fourth aspect of the application or the host cell provided in the fifth aspect of the application or the drug conjugate provided in the seventh aspect of the application, and a pharmaceutically acceptable carrier or excipient Forming agent.
本申请第九方面提供了本申请第一方面的抗体或其抗原结合片段或本申请第二方面的分离的抗体或其抗原结合片段或本申请第三方面提供的多核苷酸分子或本申请第四方面提供的表达载体或本申请第五方面提供的宿主细胞或本申请第七方面提供的药物偶联物或本申请第八方面提供的药物组合物在制备用于治疗或预防BCMA介导的疾病的药物中的用途。The ninth aspect of the application provides the antibody or antigen-binding fragment thereof in the first aspect of the application or the isolated antibody or antigen-binding fragment thereof in the second aspect of the application or the polynucleotide molecule provided in the third aspect of the application or the antibody or antigen-binding fragment thereof in the third aspect of the application The expression vector provided in the fourth aspect or the host cell provided in the fifth aspect of the application or the drug conjugate provided in the seventh aspect of the application or the pharmaceutical composition provided in the eighth aspect of the application is used in the preparation of the treatment or prevention of BCMA-mediated Use in medicine for disease.
本申请第十方面提供了本申请第一方面的抗体或其抗原结合片段或本申请第二方面 的分离的抗体或其抗原结合片段或本申请第三方面提供的多核苷酸分子或本申请第四方面提供的表达载体或本申请第五方面提供的宿主细胞或本申请第七方面提供的药物偶联物或本申请第八方面提供的药物组合物在治疗或预防BCMA介导的疾病中的用途。The tenth aspect of the application provides the antibody or antigen-binding fragment thereof in the first aspect of the application or the isolated antibody or antigen-binding fragment thereof in the second aspect of the application or the polynucleotide molecule provided in the third aspect of the application or the antibody or antigen-binding fragment thereof in the third aspect of the application. The expression vector provided in the fourth aspect or the host cell provided in the fifth aspect of the application or the drug conjugate provided in the seventh aspect of the application or the pharmaceutical composition provided in the eighth aspect of the application in the treatment or prevention of BCMA-mediated diseases use.
本申请第十一方面提供了一种治疗或预防BCMA介导的疾病或病症的方法，其包括向有需要的受试者施用本申请第一方面所提供的抗体或其抗原结合片段或本申请第二方面所提供的分离的抗体或其抗原结合片段或本申请第三方面提供的多核苷酸分子或本申请第四方面提供的表达载体或本申请第五方面提供的宿主细胞或本申请第七方面提供的药物偶联物或本申请第八方面提供的药物组合物。The eleventh aspect of the present application provides a method for treating or preventing BCMA-mediated diseases or disorders, which includes administering the antibody or antigen-binding fragment thereof provided in the first aspect of the present application or the present application to a subject in need. The isolated antibody or antigen-binding fragment thereof provided in the second aspect or the polynucleotide molecule provided in the third aspect of the application or the expression vector provided in the fourth aspect of the application or the host cell provided in the fifth aspect of the application or the host cell provided in the fifth aspect of the application The drug conjugate provided in the seventh aspect or the pharmaceutical composition provided in the eighth aspect of the present application.
在一些实施方式中，所述BCMA介导的疾病为癌症或自身免疫病。In some embodiments, the BCMA-mediated disease is cancer or an autoimmune disease.
本申请第十二方面提供了一种试剂盒，其包括本申请第一方面所提供的抗体或其抗原结合片段或本申请第二方面所提供的分离的抗体或其抗原结合片段或本申请第三方面提供的多核苷酸分子或本申请第四方面提供的表达载体或本申请第五方面提供的宿主细胞或本申请第七方面提供的药物偶联物或本申请第八方面所提供的药物组合物。The twelfth aspect of the present application provides a kit comprising the antibody or antigen-binding fragment thereof provided in the first aspect of the present application or the isolated antibody or antigen-binding fragment thereof provided in the second aspect of the present application or the antibody or antigen-binding fragment thereof provided in the second aspect of the present application The polynucleotide molecule provided in the third aspect or the expression vector provided in the fourth aspect of the application or the host cell provided in the fifth aspect of the application or the drug conjugate provided in the seventh aspect of the application or the drug provided in the eighth aspect of the application combination.
本申请第十三方面提供了一种使用本申请第一方面所提供的抗体或其抗原结合片段或本申请第二方面所提供的分离的抗体或其抗原结合片段检测BCMA的方法，其包括使所述抗体或其抗原结合片段与样品接触，检测所述抗体或其抗原结合片段与BCMA形成的结合物，以及任选地对所述结合物进行定量测定。The thirteenth aspect of the present application provides a method for detecting BCMA using the antibody or antigen-binding fragment thereof provided in the first aspect of the present application or the isolated antibody or antigen-binding fragment thereof provided in the second aspect of the present application, which includes using The antibody or antigen-binding fragment thereof is contacted with the sample, the binding of the antibody or antigen-binding fragment thereof to BCMA is detected, and optionally the binding is quantified.
本申请提供的能够与BCMA特异性结合的抗体或其抗原结合片段，可以与人BCMA特异性结合，具有高亲和力、优异的ADCC活性以及明显的肿瘤抑制作用，可用于治疗BCMA介导的疾病，例如癌症或自身免疫病。The antibody or antigen-binding fragment thereof that can specifically bind to BCMA provided by the application can specifically bind to human BCMA, has high affinity, excellent ADCC activity and obvious tumor suppression effect, and can be used to treat BCMA-mediated diseases, Examples include cancer or autoimmune diseases.
附图说明Description of drawings
此处所说明的附图用来提供对本申请的进一步理解，构成本申请的一部分，本申请的示意性实施例及其说明用于解释本申请，并不构成对本申请的不当限定。The drawings described here are used to provide a further understanding of the application and constitute a part of the application. The schematic embodiments and descriptions of the application are used to explain the application and do not constitute an improper limitation to the application.
图1A至图1G分别显示了本申请实施例2中抗人BCMA嵌合抗体结合人BCMA的活性测试结果。Figure 1A to Figure 1G respectively show the test results of the activity test of the anti-human BCMA chimeric antibody in Example 2 of the present application for binding to human BCMA.
图2A至图2F分别显示了本申请实施例3中抗人BCMA嵌合抗体阻断BAFF与BCMA的结合测试结果。Fig. 2A to Fig. 2F respectively show the test results of blocking the binding between BAFF and BCMA by the anti-human BCMA chimeric antibody in Example 3 of the present application.
图3A至图3I分别显示了本申请实施例5中抗人BCMA抗体的人源化抗体对MM.1S的结合活性测试结果。3A to 3I respectively show the test results of the binding activity of the humanized anti-human BCMA antibody to MM.1S in Example 5 of the present application.
图4A至图4C分别显示了本申请实施例7中抗人BCMA嵌合抗体的ADCC活性测试结果(报告基因法)。Figure 4A to Figure 4C respectively show the ADCC activity test results (reporter gene method) of the anti-human BCMA chimeric antibody in Example 7 of the present application.
图5A至图5E分别显示了本申请实施例7中抗人BCMA嵌合抗体的ADCC活性测试结果(PBMC法)。Figure 5A to Figure 5E respectively show the ADCC activity test results (PBMC method) of the anti-human BCMA chimeric antibody in Example 7 of the present application.
图6A至图6H分别显示了本申请实施例7中抗人BCMA抗体的人源化抗体的ADCC活性测试结果(报告基因法)。Figure 6A to Figure 6H respectively show the ADCC activity test results (reporter gene method) of the humanized antibody against human BCMA antibody in Example 7 of the present application.
具体实施方式Detailed ways
为使本申请的目的、技术方案、及优点更加清楚明白，以下参照附图并举实施例，对本申请进一步详细说明。显然，所描述的实施例仅仅是本申请一部分实施例，而不是全部的实施例。基于本申请中的实施例，本领域普通技术人员所获得的所有其他实施例，都属于本申请保护的范围。In order to make the purpose, technical solution, and advantages of the present application clearer, the present application will be further described in detail below with reference to the accompanying drawings and examples. Apparently, the described embodiments are only some of the embodiments of this application, not all of them. All other embodiments obtained by persons of ordinary skill in the art based on the embodiments in this application belong to the protection scope of this application.
定义definition
除非另有说明，本申请的实施将采用分子生物学(包括重组技术)、微生物学、细胞生物学、生物化学和免疫学的常规技术，这些都在本领域的技术范围内。The practice of this application will employ, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are within the skill of the art.
为了可以更容易地理解本申请，某些科技术语具体定义如下。除非本文其它部分另有明确定义，否则本文所用的科技术语都具有本申请所属领域普通技术人员通常理解的含义。关于本领域的定义及术语，专业人员具体可参考Current Protocolsin Molecular Biology(Ausubel)。氨基酸残基的缩写是本领域中所用的指代20个常用L-氨基酸之一的标准3字母和/或1字母代码。本文(包括权利要求书)所用单数形式包括其相应的复数形式，除非文中另有明确规定。In order to make this application easier to understand, certain technical terms are specifically defined as follows. Unless otherwise clearly defined elsewhere herein, the scientific and technical terms used herein have the meanings commonly understood by those of ordinary skill in the art to which the application belongs. For definitions and terms in this field, professionals can refer to Current Protocols in Molecular Biology (Ausubel). Abbreviations for amino acid residues are the standard 3-letter and/or 1-letter codes used in the art to refer to one of the 20 commonly used L-amino acids. As used herein (including the claims), singular forms include their corresponding plural forms unless the context clearly dictates otherwise.
术语“约”在与数字数值联合使用时意为涵盖具有比指定数字数值小5％的下限和比指定数字数值大5％的上限的范围内的数字数值，包括但不限于±5％、±2％、±1％和±0.1％。The term "about" when used in conjunction with a numerical value is meant to encompass a numerical value within a range having a lower limit of 5% less and an upper limit of 5% greater than the indicated numerical value, including but not limited to ±5%, ± 2%, ±1%, and ±0.1%.
术语“和/或”应理解为意指可选项中的任一项或可选项中的任意两项或更多项的组合。The term "and/or" should be understood as meaning any one of the optional items or a combination of any two or more of the optional items.
术语“ADCC”或“抗体依赖性细胞介导的细胞毒性”是指细胞介导的反应，其中表达FcγR的非特异性细胞毒性细胞识别靶细胞上的结合抗体并且随后导致所述靶细胞的裂解。The term "ADCC" or "antibody-dependent cell-mediated cytotoxicity" refers to a cell-mediated response in which non-specific cytotoxic cells expressing FcγRs recognize bound antibodies on target cells and subsequently cause lysis of said target cells.
术语“BCMA”是指B细胞成熟抗原。BCMA(也称为TNFRSF17、BCM或CD269)是肿瘤坏死受体(TNFR)家族的成员，并且主要在终末分化的B细胞(例如记忆B细胞和浆细胞)上表达。其配体包括B细胞活化因子(BAFF)和增殖诱导配体(APRIL)。蛋白质BCMA由基因TNFRSF17编码。示例性BCMA序列可获得于Uniprot数据库，登录号为Q02223。The term "BCMA" refers to B cell maturation antigen. BCMA (also known as TNFRSF17, BCM or CD269) is a member of the tumor necrosis receptor (TNFR) family and is predominantly expressed on terminally differentiated B cells such as memory B cells and plasma cells. Its ligands include B-cell activating factor (BAFF) and proliferation-inducing ligand (APRIL). The protein BCMA is encoded by the gene TNFRSF17. Exemplary BCMA sequences are available in the Uniprot database under accession number Q02223.
本申请所提供的抗体或其抗原结合部分也可以结合来自除人之外的物种的BCMA，例如食蟹猴BCMA。术语“食蟹猴BCMA”可以指具有Genbank登录号EHH60172.1蟹猴BCMA的完整氨基酸序列的BCMA。Antibodies provided herein, or antigen-binding portions thereof, can also bind BCMA from species other than humans, eg, cynomolgus monkey BCMA. The term "cynomolgus BCMA" may refer to BCMA having the complete amino acid sequence of cynomolgus BCMA with Genbank accession number EHH60172.1.
术语“百分比(％)氨基酸序列同一性”或简称“同一性”定义为在将氨基酸序列进行比对(并在必要时导入空位)以获取最大百分比序列同一性，且不将任何保守取代视为序列同一性的一部分之后，候选氨基酸序列中的氨基酸残基与参比氨基酸序列中的相同氨基酸残基的百分比。可使用本领域各种方法进行序列比对以便测定百分比氨基酸序列同一性，例如，使用公众可得到的计算机软件如BLAST、BLAST-2、ALIGN或MEGALIGN(DNASTAR)软件。本领域技术人员可以决定测量比对的适宜参数，包括对所比较的序列全长获得最大比对所需的任何算法。The term "percent (%) amino acid sequence identity" or simply "identity" is defined as aligning amino acid sequences (and introducing gaps where necessary) for maximum percent sequence identity and not considering any conservative substitutions as Following a portion of sequence identity, the percentage of amino acid residues in a candidate amino acid sequence that are identical to those in a reference amino acid sequence. Alignment of sequences to determine percent amino acid sequence identity can be performed using various methods in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGN (DNASTAR) 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.
术语“免疫应答”是指通过例如淋巴细胞、抗原呈递细胞、吞噬细胞、粒细胞和由上述细胞或肝产生的可溶性大分子(包括抗体、细胞因子和补体)的作用，导致从人体选择性损害、破坏或清除侵入的病原体、感染病原体的细胞或组织、癌细胞，或者在自体免疫或病理性炎症的情况下，对正常人细胞或组织的损害、破坏或清除。The term "immune response" refers to selective damage from the body through the action of, for example, lymphocytes, antigen-presenting cells, phagocytes, granulocytes, and soluble macromolecules (including antibodies, cytokines, and complement) produced by the above cells or the liver , destruction or elimination of invading pathogens, pathogen-infected cells or tissues, cancer cells, or in the case of autoimmunity or pathological inflammation, damage, destruction or elimination of normal human cells or tissues.
术语“信号转导途径”或“信号转导活性”是指通常由蛋白质间相互作用诸如生长因子对受体的结合启动的生化因果关系，所述关系导致信号从细胞的一部分传递至细胞的另一部分。一般地，传递包括引起信号转导的系列反应中的一种或多种蛋白质上的一个或多个酪氨酸、丝氨酸或苏氨酸残基的特定磷酸化。倒数第二过程通常包括细胞核事件，从而导致基因表达的变化。The term "signal transduction pathway" or "signal transduction activity" refers to a biochemical causal relationship, usually initiated by protein-protein interactions, such as the binding of a growth factor to a receptor, that results in the transmission of a signal from one part of a cell to another part of the cell. part. Typically, delivery involves specific phosphorylation of one or more tyrosine, serine, or threonine residues on one or more proteins in a cascade of reactions resulting in signal transduction. The penultimate process often involves nuclear events, resulting in changes in gene expression.
术语“活性”或“生物活性”或术语“生物性质”或“生物特征”在本申请中可互换使用，其包括但不限于表位或抗原亲和力、特异性、在体内或体外中和或拮抗BCMA活性的能力、半抑制浓度(IC 50)、抗体的体内稳定性和抗体的免疫原性等。本领域公知的抗体的其它可鉴定的生物性质或特征包括，例如，交叉反应性(如与靶定肽的非人同源物，或与其它蛋白质或组织的交叉反应性)，和保持哺乳动物细胞中蛋白质高水平表达的能力。使用本领域公知的技术观察、测定或评估前面提及的性质或特征，所述技术包括但不局限于酶联免疫吸附(ELISA)、流式细胞分选(FACS)或BIACORE等离子体共振分析、任意的体外或体内中和测定、受体结合测试、细胞因子或生长因子的产生和/或分泌测试、信 号转导测试以及不同来源(包括人类、灵长类或任何其它来源)的组织切片的免疫组织化学分析等。 The terms "activity" or "biological activity" or the terms "biological property" or "biological signature" are used interchangeably in this application and include, but are not limited to, epitope or antigen affinity, specificity, in vivo or in vitro neutralization or The ability to antagonize the activity of BCMA, the half-inhibitory concentration (IC 50 ), the stability of the antibody in vivo, and the immunogenicity of the antibody, etc. Other identifiable biological properties or characteristics of antibodies known in the art include, for example, cross-reactivity (such as with non-human homologues of the targeting peptide, or with other proteins or tissues), and retention of mammalian The ability of a cell to express a protein at a high level. The aforementioned properties or characteristics are observed, measured or evaluated using techniques well known in the art including, but not limited to, enzyme-linked immunosorbent assay (ELISA), flow cytometry sorting (FACS) or BIACORE plasma resonance analysis, Any in vitro or in vivo neutralization assays, receptor binding assays, cytokine or growth factor production and/or secretion assays, signal transduction assays, and analysis of tissue sections of different origin, including human, primate, or any other origin Immunohistochemical analysis, etc.
术语“抗体”是指具有所需生物活性的任何形式的抗体。因此，其以最广义使用，具体包括但不限于单克隆抗体(包括全长单克隆抗体)、多克隆抗体、多特异性抗体(例如双特异性抗体)、人源化抗体、全人抗体、嵌合抗体和骆驼源化单结构域抗体等。已知基本的抗体结构单位包含四聚体，每个四聚体包括两个相同的多肽链对，每各多肽链对具有一条“轻”链(L，约25kDa)和一条“重”链(H，约50-70kDa)。每条链的氨基端部分或片段可包括主要负责抗原识别的约100-110个或更多个氨基酸的可变区。每条链的羧基端部分或片段可限定主要负责效应子功能的恒定区。通常将人轻链归类为κ轻链和λ轻链。此外，通常将人重链归类为μ、δ、γ、α或ε五类，并依据重链的不同将抗体的同种型分别定义为IgM、IgD、IgG、IgA和IgE。在轻链和重链内，各自的可变区和恒定区通过约12个或更多个氨基酸的“J”区连接，其中重链还包括约10多个氨基酸的“D”区。一般参见Fundamental Immunology第7章(Paul，W.主编，第2版。Raven Press，N.Y.(1989))。The term "antibody" refers to any form of antibody that possesses the desired biological activity. Accordingly, it is used in the broadest sense and specifically includes, but is not limited to, monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (such as bispecific antibodies), humanized antibodies, fully human antibodies, Chimeric antibodies and camelized single domain antibodies, etc. The basic antibody structural unit is known to comprise tetramers, each tetramer comprising two identical pairs of polypeptide chains, each pair having a "light" chain (L, approximately 25 kDa) and a "heavy" chain ( H, about 50-70 kDa). The amino-terminal portion or fragment of each chain may include a variable region of about 100-110 or more amino acids primarily responsible for antigen recognition. The carboxy-terminal portion or fragment of each chain may define a constant region primarily responsible for effector function. Human light chains are generally classified as kappa and lambda light chains. In addition, human heavy chains are usually classified into five types: μ, δ, γ, α, or ε, and the antibody isotypes are defined as IgM, IgD, IgG, IgA, and IgE according to the heavy chains. Within light and heavy chains, the respective variable and constant regions are joined by a "J" region of about 12 or more amino acids, with the heavy chain also including a "D" region of about 10 more amino acids. See generally Chapter 7 of Fundamental Immunology (Paul, W. ed., 2nd ed. Raven Press, N.Y. (1989)).
相对于抗体，术语“分离的抗体”表示该抗体基本上不含与其天然状态相关的其他细胞组分，例如核酸、蛋白质、脂质、糖或其它物质例如细胞碎片和生长培养基。可以理解为，所述分离的抗体为基本上纯化的状态，优选所述分离的抗体处于均质状态，所述分离的抗体可以是干燥或水性溶液。通常可以使用分析化学技术，例如聚丙烯酰胺凝胶电泳或高效液相色谱法来测定抗体的纯度和均质性。术语“分离(的)”并非意指完全不存在上述物质或不存在水、缓冲液或盐，除非它们以明显干扰本申请的抗体的实验或治疗应用的量存在。With respect to an antibody, the term "isolated antibody" means that the antibody is substantially free of other cellular components associated with its natural state, such as nucleic acids, proteins, lipids, sugars or other substances such as cell debris and growth medium. It can be understood that the isolated antibody is in a substantially purified state, preferably in a homogeneous state, and the isolated antibody can be in a dry or aqueous solution. Antibody purity and homogeneity can often be determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. The term "isolated" does not mean the complete absence of the above substances or the absence of water, buffers or salts, unless they are present in an amount that significantly interferes with the experimental or therapeutic application of the antibody of the present application.
术语“单克隆抗体”是由高度一致的免疫细胞制成的抗体，这些免疫细胞是单一亲本细胞的所有克隆。单克隆抗体具有单价亲和力，因为它们结合相同的表位(抗体识别抗原的部位)。所述单克隆抗体也可能包括少量天然存在的突变。相比之下，术语“多克隆抗体”结合多个表位，通常由几个不同的浆细胞(分泌抗体的免疫细胞)谱系组成，可以理解为是多种单克隆抗体的混杂物。修饰语“单克隆”不得解释为需要通过任何特定方法产生抗体。The term "monoclonal antibody" is an antibody made from highly identical immune cells that are all clones of a single parental cell. Monoclonal antibodies have monovalent affinity because they bind to the same epitope (the part of the antibody that recognizes an antigen). The monoclonal antibodies may also contain minor amounts of naturally occurring mutations. In contrast, the term "polyclonal antibody" binds multiple epitopes, usually consists of several different lineages of plasma cells (antibody-secreting immune cells), and can be understood as a hybrid of multiple monoclonal antibodies. The modifier "monoclonal" should not be construed as requiring that the antibody be produced by any particular method.
术语“多特异性抗体”意指包含两个或更多个抗原结合结构域，能够结合两个或更多个不同的表位(例如，两个、三个、四个或更多个不同的表位)的抗体。可特异性抗体结合的表位可以在相同或不同的抗原上。多特异性抗体的示例包括结合两个不同表位的“双特异性抗体”。The term "multispecific antibody" means comprising two or more antigen binding domains, capable of binding two or more different epitopes (e.g., two, three, four or more different epitope) antibodies. The epitopes to which specific antibodies bind can be on the same or different antigens. Examples of multispecific antibodies include "bispecific antibodies" that bind two different epitopes.
术语“结合结构域”或“抗原结合结构域”或“抗原结合位点”系指抗体中能够特异地与抗原的一部分或全部结合，并与抗原的一部分或全部互补的区域。当抗原很大时，抗体可能只能结合到抗原的一个特定的部分，该部分被称为表位。结合结构域可包含重链和轻链的可变结构域，即重链可变区VH和轻链可变区VL，其各自包括四个保守框架区(FR)和三个互补决定区(CDR)。CDR在序列上可变化并确定对特定抗原的特异性。The term "binding domain" or "antigen-binding domain" or "antigen-binding site" refers to a region in an antibody that can specifically bind to a part or all of an antigen and is complementary to a part or all of the antigen. When an antigen is large, antibodies may only be able to bind to a specific part of the antigen, called an epitope. The binding domain may comprise the variable domains of the heavy and light chains, namely the heavy chain variable region VH and the light chain variable region VL, each comprising four conserved framework regions (FR) and three complementarity determining regions (CDRs). ). The CDRs can vary in sequence and determine specificity for a particular antigen.
术语“全长”抗体，是指在天然存在时包含四条肽链的免疫球蛋白分子：两条重链(全长约50-70kDa)和两条轻链(全长约25kDa)通过二硫键互相连接。每一条重链由重链可变区(在本文中缩写为VH)和重链恒定区(在本文中缩写为CH)组成。重链恒定区由3个结构域CH1、CH2和CH3组成。每一条轻链由轻链可变区(在本文中缩写为VL)和轻链恒定区(在本文中缩写为CL)组成。轻链恒定区由一个结构域CL组成。VH和VL区可被进一步细分为具有高可变性的互补决定区(CDR)和与互补决定区间隔分布的，具有更高保守性的框架区(FR)。每一个VH或VL从氨基末端至羧基末端的结构域排列顺序为FR1、CDR1、FR2、CDR2、FR3、CDR3和FR4。重链和轻链的可变区分别含有与抗原相互作用的结合结构域。抗体的恒定区可介导抗体对宿主的组织或免疫系统的各种细胞 (例如，效应细胞)和经典补体系统的第一组分(C1q)的结合。The term "full-length" antibody refers to an immunoglobulin molecule that, as it occurs in nature, comprises four peptide chains: two heavy chains (approximately 50-70 kDa in overall length) and two light chains (approximately 25 kDa in overall length) which are disulfide-bonded interconnected. Each heavy chain is composed of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region (abbreviated herein as CH). The heavy chain constant region consists of three domains CH1, CH2 and CH3. Each light chain is composed of a light chain variable region (abbreviated herein as VL) and a light chain constant region (abbreviated herein as CL). The light chain constant region consists of one domain, CL. The VH and VL regions can be further subdivided into highly variable complementarity-determining regions (CDRs) and spaced apart from the complementarity-determining regions, more conserved framework regions (FRs). The sequence of domains from the amino terminus to the carboxyl terminus of each VH or VL is FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. The variable regions of the heavy and light chains each contain a binding domain that interacts with the antigen. The constant regions of the antibodies may mediate the binding of the antibodies to tissues of the host or to various cells of the immune system (e.g., effector cells) and to the first component (Clq) of the classical complement system.
术语“重链恒定区”或“CH”在本申请中可互换使用，其包含至少三个重链恒定结构域(CH1、CH2和CH3)。示例性的，人重链恒定区包括γ、δ、α、ε和μ，各重链恒定区对应于抗体同种型。例如，包含γ恒定区的抗体是IgG抗体，包含δ恒定区的抗体是IgD抗体，包含α恒定区的抗体是IgA抗体，包含μ恒定区的抗体是IgM抗体，包含ε恒定区的抗体是IgE抗体。某些同种型可以进一步再分成亚类，例如，IgG抗体包括但不限于IgG1(包含γ1恒定区)、IgG2(包含γ2恒定区)、IgG3(包含γ3恒定区)和IgG4(包含γ4恒定区)；IgA抗体包括但不限于IgA1(包含α1恒定区)和IgA2(包含α2恒定区)；IgM抗体包括但不限于IgM1和IgM2。同种型还可以包括一些修饰形式，所述修饰可以改变Fc功能，例如增强或减弱效应子功能或增强或减弱其对Fc受体的结合。The term "heavy chain constant region" or "CH", which is used interchangeably in this application, comprises at least three heavy chain constant domains (CH1, CH2 and CH3). Exemplary, human heavy chain constant regions include gamma, delta, alpha, epsilon, and mu, each heavy chain constant region corresponding to an antibody isotype. For example, an antibody containing a gamma constant region is an IgG antibody, an antibody containing a delta constant region is an IgD antibody, an antibody containing an alpha constant region is an IgA antibody, an antibody containing a mu constant region is an IgM antibody, and an antibody containing an epsilon constant region is an IgE Antibody. Certain isotypes can be further subdivided into subclasses, for example, IgG antibodies include, but are not limited to, IgG1 (comprising the γ1 constant region), IgG2 (comprising the γ2 constant region), IgG3 (comprising the γ3 constant region), and IgG4 (comprising the γ4 constant region ); IgA antibodies include but are not limited to IgA1 (comprising the α1 constant region) and IgA2 (comprising the α2 constant region); IgM antibodies include but are not limited to IgM1 and IgM2. Isoforms may also include modifications that alter Fc function, eg, enhance or reduce effector function or enhance or reduce binding to Fc receptors.
术语“轻链恒定区”或“CL”在本申请中可互换使用，其包含1个轻链恒定结构域CL。示例性的，根据轻链恒定区的不同，轻链可分为λ和κ两类。The term "light chain constant region" or "CL" is used interchangeably in this application, which comprises a light chain constant domain, CL. Exemplarily, light chains can be classified into λ and κ according to the light chain constant region.
术语抗体的“抗原结合片段”包括抗体的片段或抗体的衍生物，所述“抗原结合片段”对应的抗体可称为亲代抗体。抗体的抗原结合片段通常包含亲代抗体的抗原结合区或可变区的至少一个片段，其保持亲代抗体的至少一些结合特异性。抗原结合片段的实例包括但不限于Fab、Fab'、F(ab')2和单链Fv片段，双抗体，线性抗体，结构域抗体，单链抗体分子，例如scFv；由抗体片段形成的纳米抗体(nanobody)和多特异性抗体等。相同摩尔浓度下，抗原结合片段至少能够保持亲代抗体抗原结合活性的10％，至少20％、50％、70％、80％、90％、95％或100％或更高。此外，抗体的抗原结合片段还可以包括不明显改变其生物活性的保守或非保守氨基酸取代(称为抗体的“保守变体”或“功能保守变体”)。The term "antigen-binding fragment" of an antibody includes a fragment of an antibody or a derivative of an antibody, and the antibody corresponding to the "antigen-binding fragment" can be referred to as a parent antibody. An antigen-binding fragment of an antibody typically comprises at least a fragment of the antigen-binding or variable region of the parent antibody that retains at least some of the binding specificity of the parent antibody. Examples of antigen-binding fragments include, but are not limited to, Fab, Fab', F(ab')2 and single chain Fv fragments, diabodies, linear antibodies, domain antibodies, single chain antibody molecules such as scFv; nanobodies formed from antibody fragments Antibody (nanobody) and multispecific antibody, etc. At the same molar concentration, the antigen-binding fragment can retain at least 10%, at least 20%, 50%, 70%, 80%, 90%, 95% or 100% or more of the antigen-binding activity of the parent antibody. In addition, antigen-binding fragments of antibodies may also include conservative or non-conservative amino acid substitutions that do not significantly alter their biological activity (referred to as "conservative variants" or "functionally conservative variants" of the antibody).
术语“单链Fv”或“scFv”抗体是指包含抗体的VH和VL结构域的抗体片段，其中，这些结构域存在于单条多肽链中。Fv多肽一般还包含VH和VL结构域之间的多肽接头，其使scFv能够形成用于抗原结合的所需结构。The term "single-chain Fv" or "scFv" antibody refers to an antibody fragment comprising the VH and VL domains of an antibody, wherein these domains are present in a single polypeptide chain. Fv polypeptides generally also comprise a polypeptide linker between the VH and VL domains, which enables the scFv to form the desired structure for antigen binding.
术语“结构域抗体”是指只含有重链可变区或轻链可变区的免疫功能性免疫球蛋白片段。在某些情况下，两个或更多个VH区与肽接头共价连接形成二价结构域抗体。二价结构域抗体的2个VH区可靶向相同或不同的抗原。The term "domain antibody" refers to an immunologically functional immunoglobulin fragment containing only the variable region of the heavy chain or the variable region of the light chain. In certain instances, two or more VH regions are covalently linked with a peptide linker to form a bivalent domain antibody. The two VH regions of a bivalent domain antibody can target the same or different antigens.
术语“抗原”系指能够被本申请的抗体所结合的分子或分子的一部分。抗原可有一个或多于一个表位。The term "antigen" refers to a molecule or a part of a molecule capable of being bound by an antibody of the present application. An antigen may have one or more than one epitope.
术语“双抗体”是指具有两个抗原结合部位的小抗体片段，所述片段包含在同一多肽链中，与轻链可变结构域(VL)连接的重链可变结构域(VH)，两个所述片段通过短得不允许在同一链的两个结构域之间配对的接头，迫使该结构域与另一片段中的互补结构域配对并产生两个抗原结合部位。The term "diabody" refers to a small antibody fragment with two antigen-binding sites, said fragment comprising a heavy chain variable domain (VH) connected to a light chain variable domain (VL) in the same polypeptide chain, The two said fragments pass a linker that is too short to allow pairing between the two domains of the same chain, forcing this domain to pair with the complementary domain in the other fragment and creating two antigen-binding sites.
术语“特异性结合”、“选择性结合”是指抗体与预定的抗原上的表位结合。通常，当使用重组人BCMA或其表位作为分析物并使用抗体作为配体，在仪器中通过表面等离子体共振(SPR)技术测定时，抗体以大约低于10 -7M或甚至更小的平衡解离常数(KD)与预定的抗原或其表位结合，并且抗体与预定抗原或其表位结合的亲和力是其与其他非特异性抗原(如BSA等)结合的亲和力的至少两倍。术语“识别抗原”在本申请中可以与术语“特异性结合”互换使用。 The terms "specific binding" and "selective binding" refer to the binding of an antibody to a predetermined epitope on an antigen. Usually, when recombinant human BCMA or its epitope is used as an analyte and an antibody is used as a ligand, when the surface plasmon resonance (SPR) technique is used in an instrument, the antibody has a particle size of about less than 10 −7 M or even smaller The equilibrium dissociation constant (KD) binds to a predetermined antigen or its epitope, and the binding affinity of the antibody to the predetermined antigen or its epitope is at least twice that of its binding affinity to other non-specific antigens (such as BSA, etc.). The term "recognizes an antigen" is used interchangeably with the term "specifically binds" in this application.
术语“表位”是指抗体所结合的抗原区域。表位可以由连续的氨基酸形成或者通过蛋白的三级折叠而并置的非连续氨基酸形成。The term "epitope" refers to the region of an antigen to which an antibody binds. Epitopes can be formed from contiguous amino acids or non-contiguous amino acids juxtaposed by the tertiary folding of the protein.
“亲和力”或“结合亲和力”指反映结合对子的成员(如抗原和抗体)之间相互作用的固有结合亲和力。亲和力可以通常由平衡解离常数(KD)表示，平衡解离常数是解离速率常数和结合速率常数(分别是kdis和kon)的比值。亲和力可以由本领域已知的常见方法测量，例如可采用ForteBio生物学分子相互作用工作站测定。"Affinity" or "binding affinity" refers to the intrinsic binding affinity that reflects the interaction between members of a binding pair (eg, antigen and antibody). Affinity can generally be expressed by the equilibrium dissociation constant (KD), which is the ratio of the dissociation rate constant and the association rate constant (kdis and kon, respectively). Affinity can be measured by common methods known in the art, for example, it can be determined using ForteBio Biological Molecular Interaction Workstation.
术语“不结合”蛋白或细胞是指，不与蛋白或细胞结合，或者不以高亲和力与其结合，即结合蛋白或细胞的KD为1.0×10 -6M或更高，更优选1.0×10 -5M或更高，更优选1.0×10 -4M或更高、1.0×10 -3M或更高，更优选1.0×10 -2M或更高。 The term "not binding" to proteins or cells refers to not binding to proteins or cells, or not binding to them with high affinity, that is, the KD of binding proteins or cells is 1.0×10 -6 M or higher, more preferably 1.0×10 -6 5 M or higher, more preferably 1.0×10 -4 M or higher, 1.0×10 -3 M or higher, more preferably 1.0×10 -2 M or higher.
术语“高亲和性”对于IgG抗体而言，是指对于抗原的KD为1.0×10 -6M或更低，优选5.0×10 -8M或更低，更优选1.0×10 -8M或更低、5.0×10 -9M或更低，更优选1.0×10 -9M或更低。对于其他抗体亚型，“高亲和性”结合可能会变化。例如，IgM亚型的“高亲和性”结合是指KD为10 -6M或更低，优选10 -7M或更低，更优选10 -8M或更低。 The term "high affinity" for an IgG antibody means that the KD for the antigen is 1.0×10 -6 M or lower, preferably 5.0×10 -8 M or lower, more preferably 1.0×10 -8 M or lower, 5.0×10 -9 M or lower, more preferably 1.0×10 -9 M or lower. "High affinity" binding may vary for other antibody subtypes. For example, "high affinity" binding of IgM subtype means a KD of 10 -6 M or lower, preferably 10 -7 M or lower, more preferably 10 -8 M or lower.
术语“核酸”或“多核苷酸”是指脱氧核糖核酸(DNA)或核糖核酸(RNA)及其呈单链或双链形式的聚合物。除非明确地限制，否则术语“核酸”或“多核苷酸”还包括含有已知的天然核苷酸的类似物的核酸，其具有与参照核酸相似的结合性质，并且以与天然存在的核苷酸相似的方式被代谢(参见，属于Kariko等人的美国专利No.8278036，其公开了尿苷被假尿苷替代的mRNA分子，合成所述mRNA分子的方法以及用于在体内递送治疗性蛋白的方法)。除非另有所指，否则特定核酸序列还隐含地包括其保守修饰的变体(例如，简并密码子取代)、等位基因、直系同源物、单核苷酸多态性(SNP)和互补序列以及明确指出的序列。The term "nucleic acid" or "polynucleotide" refers to deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) and polymers thereof in single- or double-stranded form. Unless expressly limited, the terms "nucleic acid" or "polynucleotide" also include nucleic acids that contain known analogs of natural nucleotides that have binding properties similar to those of a reference nucleic acid and that are similar to naturally occurring nucleosides. Uridine is metabolized in a similar manner (see, U.S. Patent No. 8,278,036 to Kariko et al., which discloses mRNA molecules in which uridine is replaced by pseudouridine, methods of synthesizing said mRNA molecules, and methods for delivering therapeutic proteins in vivo Methods). Unless otherwise indicated, a particular nucleic acid sequence also implicitly includes conservatively modified variants thereof (e.g., degenerate codon substitutions), alleles, orthologs, single nucleotide polymorphisms (SNPs) and complementary sequences as well as clearly indicated sequences.
“构建体”是指任何重组多核苷酸分子(例如质粒、粘粒、病毒、自主复制多核苷酸分子、噬菌体、线性或环状单链或双链DNA或RNA多核苷酸分子)，其可衍生自任何来源，能够与基因组整合或自主复制，其可以以可操作的方式连接一或多个多核苷酸分子。本申请中，构建体通常本申请的多核苷酸分子，其可操作地连接至转录起始调节序列，这些序列会导引本申请的多核苷酸分子在宿主细胞中的转录。可使用异源启动子或内源启动子导引本申请的核酸的表达。"Construct" refers to any recombinant polynucleotide molecule (e.g., plasmid, cosmid, virus, autonomously replicating polynucleotide molecule, bacteriophage, linear or circular single- or double-stranded DNA or RNA polynucleotide molecule), which can be Derived from any source, capable of integrating into the genome or replicating autonomously, it may be operably linked to one or more polynucleotide molecules. In the present application, a construct is generally a polynucleotide molecule of the present application, which is operably linked to transcriptional initiation regulatory sequences, and these sequences will direct the transcription of the polynucleotide molecule of the present application in a host cell. Expression of the nucleic acids of the present application may be directed using heterologous or endogenous promoters.
“载体”是指任何重组多核苷酸构建体，该构建体可用于转化的目的(即将异源DNA引入到宿主细胞中)。一种类型的载体为“质粒”，是指环状双链DNA环，可将额外DNA区段连接至该环中。另一类型的载体为病毒载体，其可将额外DNA区段连接至病毒基因组中。某些载体能够在被引入到的宿主细胞(例如，具有细菌复制起点的细菌载体及游离型哺乳动物载体)中自主复制。另一些载体(例如，非游离型哺乳动物载体)在引入到宿主细胞中后，被整合至宿主细胞的基因组中，与宿主基因组一起复制。"Vector" refers to any recombinant polynucleotide construct that can be used for the purpose of transformation (ie, the introduction of heterologous DNA into a host cell). One type of vector is a "plasmid", which refers to a circular double-stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a viral vector, which can incorporate additional DNA segments into the viral genome. Certain vectors are capable of autonomous replication in the host cell into which they are introduced (eg, bacterial vectors with a bacterial origin of replication and episomal mammalian vectors). Other vectors (eg, non-episomal mammalian vectors) are integrated into the genome of the host cell after introduction into the host cell, where they replicate together with the host genome.
本文所用术语“表达载体”是指能够在转化、转染或转导至宿主细胞中时复制及表达目的基因的核酸分子。表达载体通常包含一或多个表型选择标记和复制起点，用于维护载体及在需要的情况下在宿主内进行扩增。The term "expression vector" as used herein refers to a nucleic acid molecule capable of replicating and expressing a gene of interest upon transformation, transfection or transduction into a host cell. Expression vectors typically contain one or more phenotypic selectable markers and an origin of replication for maintenance of the vector and, if desired, amplification within the host.
本申请中，除非另有明确规定，用于细胞或受体的“活化”、“刺激”和“处理”可具有相同含义，例如细胞或受体用配体活化、刺激或处理。“配体”包括天然和合成配体，例如细胞因子、细胞因子变体或类似物、突变蛋白以及来源于抗体的结合化合物(如抗体及其结合片段)。“配体”还包括小分子，例如细胞因子的肽模拟物和抗体的肽模拟物。“活化”可指通过内部机制以及外部或环境因素调节的细胞活化。“应答”或“反应”，例如细胞、组织、器官或生物体的应答，包括生化或生理行为的改变，例如生物区室(如组织、细胞、细胞器等)内的部分成分浓度、密度、粘附或迁移、基因表达速率或分化状态的改变，其改变可以与活化、刺激或处理相关。In the present application, "activation", "stimulation" and "treatment" for cells or receptors may have the same meaning, for example, cells or receptors are activated, stimulated or treated with a ligand, unless otherwise specified. "Ligand" includes natural and synthetic ligands such as cytokines, cytokine variants or analogs, muteins, and antibody-derived binding compounds (eg, antibodies and binding fragments thereof). "Ligand" also includes small molecules, such as peptidomimetics of cytokines and peptidomimetics of antibodies. "Activation" can refer to cellular activation regulated by internal mechanisms as well as external or environmental factors. "Response" or "response", such as that of a cell, tissue, organ, or organism, includes changes in biochemical or physiological behavior, such as the concentration, density, viscosity, Accompanied by changes in migration, gene expression rates, or differentiation status, which changes may be associated with activation, stimulation, or processing.
如本文中所用，术语任何疾病或病症的“治疗”或“医治”在一个实施方式中可以是指改善疾病或病症，例如减缓、阻止或减少疾病的进展，或疾病的临床症状等；在另一个实施方式中，可以是指缓解或改善至少一个身体参数，这些参数可能并不表现出明显的疾病症状的改善；在另一个实施方式中，其可以是指在身体上(例如，可辨别的症状的稳定)、生理上(例如，身体参数的稳定)或在这两方面调节疾病或病症。除非在本文中明确描述，否则用于评估疾病的治疗和/或预防的方法在本领域中通常是已知的。As used herein, the term "treatment" or "treatment" of any disease or condition may refer to improving the disease or condition in one embodiment, such as slowing down, arresting or reducing the progression of the disease, or the clinical symptoms of the disease, etc.; In one embodiment, it may refer to alleviation or improvement of at least one physical parameter that may not show improvement in overt disease symptoms; in another embodiment, it may refer to physical (e.g., discernible stabilization of symptoms), physiologically (eg, stabilization of body parameters), or both. Unless explicitly described herein, methods for assessing treatment and/or prevention of disease are generally known in the art.
本申请中，所述“受试者”包括任何的人或非人动物。术语“非人动物”包括所有脊椎动物，例如哺乳动物和非哺乳动物，诸如非人灵长类动物、绵羊、狗、猫、马、牛、鸡、两栖动物、爬行动物等。In this application, the "subject" includes any human or non-human animal. The term "non-human animal" includes all vertebrates, eg, mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, and the like.
“联合”一种或多种其它治疗剂的施用包括同时施用或共同施用，或任意次序的连续施用。Administration "in conjunction with" one or more other therapeutic agents includes simultaneous or co-administration, or sequential administration in any order.
“治疗有效量”、“治疗有效剂量”和“有效量”是指该剂量下，本申请的抗BCMA抗体或其抗原结合片段单独或与其它治疗药物组合给予细胞、组织或受试者时，能够有效预防或改善至少一种疾病或病况的症状，或预防或改善至少一种疾病或病况的发展。治疗有效剂量还可以指足以导致症状改善(例如治疗、治愈、预防或改善相关医学病况或者提高这类病况的治疗、治愈、预防或改善的速度)的抗体或其抗原结合片段的量。当对个体施用单独给予的活性成分(如抗体或其抗原结合片段)时，治疗有效剂量仅是指该成分；当组合施用时，不论是依次药还是同时给药，治疗有效剂量是均指引起治疗效果的所有活性成分的综合量。治疗剂的有效量将导致诊断标准或参数提高至少10％；通常至少20％；优选至少约30％；更优选至少40％，最优选至少50％。"Therapeutically effective dose", "therapeutically effective dose" and "effective dose" refer to the dosage, when the anti-BCMA antibody or antigen-binding fragment thereof of the present application is administered to cells, tissues or subjects alone or in combination with other therapeutic drugs, Effective in preventing or ameliorating the symptoms of at least one disease or condition, or preventing or ameliorating the development of at least one disease or condition. A therapeutically effective dose can also refer to an amount of an antibody or antigen-binding fragment thereof sufficient to result in amelioration of symptoms (eg, treatment, cure, prevention or amelioration of an associated medical condition or an increase in the rate of treatment, cure, prevention or amelioration of such a condition). When the active ingredient (such as an antibody or antigen-binding fragment thereof) is administered to a subject alone, the therapeutically effective dose refers to that ingredient alone; The combined amount of all active ingredients for a therapeutic effect. An effective amount of a therapeutic agent will result in an increase in diagnostic criteria or parameters of at least 10%; usually at least 20%; preferably at least about 30%; more preferably at least 40%, most preferably at least 50%.
“癌症”和“癌性”指哺乳动物中特征通常为细胞生长不受调控的生理疾患，此定义中包括良性肿瘤、恶性癌症以及休眠肿瘤或微转移。癌症的例子包括但不限于癌、淋巴瘤、母细胞瘤、肉瘤和白血病。此类癌症的更具体例子包括鳞状细胞癌、肺癌(包括小细胞肺癌、非小细胞肺癌、肺腺癌、肺鳞癌)、腹膜癌、胃肠癌、胰腺癌、成胶质细胞瘤、宫颈癌、卵巢癌、肝癌、膀胱癌、黄疸型肝肿瘤、乳腺癌、结肠癌、结肠直肠癌、子宫内膜癌或子宫癌、唾液腺癌、肾癌、前列腺癌、外阴癌、甲状腺癌、及各种类型的头颈癌，以及B细胞淋巴瘤(如低级/滤泡性非霍奇金淋巴瘤(NHL)、小淋巴细胞性(SL)NHL、中级/滤泡性NHL、中级弥漫性NHL、成免疫细胞性NHL、成淋巴细胞性NHL、小无核裂细胞性NHL、贮积病NHL、套细胞淋巴瘤、AIDS相关淋巴瘤和瓦尔登斯特伦氏(Waldenstrom)巨球蛋白血症)、慢性淋巴细胞性白血病(CLL)、急性成淋巴细胞性白血病(ALL)、毛细胞性白血病、慢性成髓细胞性白血病、移植后淋巴增殖性病症(PTLD)，以及与瘢痣病(phakomatoses)，与脑瘤有关的水肿和梅格斯氏综合征(Meigs)有关的异常血管增殖。"Cancer" and "cancerous" refer to a physiological condition in mammals, often characterized by unregulated cell growth, and include within this definition benign tumors, malignant cancers, and dormant tumors or micrometastases. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More specific examples of such cancers include squamous cell carcinoma, lung cancer (including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma), peritoneal cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, Cervical cancer, ovarian cancer, liver cancer, bladder cancer, icteric liver tumors, breast cancer, colon cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, and All types of head and neck cancer, as well as B-cell lymphomas (eg, low-grade/follicular non-Hodgkin lymphoma (NHL), small lymphocytic (SL) NHL, intermediate-grade/follicular NHL, intermediate-grade diffuse NHL, Immunoblastic NHL, lymphoblastic NHL, small anucleated cleaved NHL, storage disease NHL, mantle cell lymphoma, AIDS-related lymphoma, and Waldenstrom's macroglobulinemia) , chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia, chronic myeloblastic leukemia, post-transplant lymphoproliferative disorder (PTLD), and phakomatoses , edema associated with brain tumors and abnormal vascular proliferation associated with Meigs syndrome (Meigs).
“自身免疫性疾病”与术语“自身免疫病症”互换使用，指患者的一种状态，其特征是患者对其自身细胞、组织和/或器官的免疫反应从而产生的细胞、组织和/或器官损伤。术语“炎症性疾病”与术语“炎症性病症”互换使用，指患者的一种状态，其特征是炎症，优选为慢性炎症。自身免疫病症可能伴随或不伴随炎症。另外，炎症可以是或不是由自身免疫病症引起的。因此，某些疾病可以同时具有自身免疫和炎症的特征。自身免疫病的例子包括但不限于红斑狼疮、IgA肾病和风湿性关节炎。"Autoimmune disease" is used interchangeably with the term "autoimmune disorder" and refers to a condition in a patient characterized by the development of cells, tissues and/or organ damage. The term "inflammatory disease" is used interchangeably with the term "inflammatory disorder" and refers to a condition of a patient characterized by inflammation, preferably chronic inflammation. Autoimmune disorders may or may not be accompanied by inflammation. Additionally, inflammation may or may not be caused by an autoimmune disorder. Thus, certain diseases can have both autoimmune and inflammatory features. Examples of autoimmune diseases include, but are not limited to, lupus erythematosus, IgA nephropathy, and rheumatoid arthritis.
抗体Antibody
本申请第一方面提供了一种能够与BCMA特异性结合的抗体或其抗原结合片段，其包含HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3；The first aspect of the present application provides an antibody or an antigen-binding fragment thereof capable of specifically binding to BCMA, which comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3;
其中，所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3所示的氨基酸序列，或者分别具有如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示的氨基酸序列，或者分别具有如SEQ ID NO:7、SEQ ID NO:8和SEQ ID NO:9所示的氨基酸序列，或者分别具有如SEQ ID NO:10、SEQ ID NO:11和SEQ ID NO:12所示的氨基酸序列，或者分别具有如SEQ ID NO:13、SEQ ID NO:14和SEQ ID NO:15所示的氨基酸序列，或者分别具有如SEQ ID NO:16、SEQ ID NO:17和SEQ ID NO:18所示的氨基酸序列，或者分别具有如SEQ ID NO:19、SEQ ID NO:20和SEQ ID NO:21所示的氨基酸序列，或者分别具有如SEQ ID NO:22、SEQ ID NO:23和SEQ ID NO:24所示的氨基酸序列；Wherein, the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, or respectively have the amino acid sequences shown in SEQ ID NO: 4, SEQ ID NO: 5 and the amino acid sequence shown in SEQ ID NO: 6, or have respectively the amino acid sequence shown in SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 9, or have the amino acid sequence shown in SEQ ID NO: 10, SEQ ID NO: 10, SEQ ID NO: 9 respectively The amino acid sequence shown in ID NO: 11 and SEQ ID NO: 12, or have the amino acid sequence shown in SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 15 respectively, or have the amino acid sequence shown in SEQ ID NO respectively : 16, the amino acid sequence shown in SEQ ID NO: 17 and SEQ ID NO: 18, or have the amino acid sequence shown in SEQ ID NO: 19, SEQ ID NO: 20 and SEQ ID NO: 21 respectively, or have respectively Amino acid sequences as shown in SEQ ID NO:22, SEQ ID NO:23 and SEQ ID NO:24;
所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:25、SEQ ID NO:26和SEQ ID NO:27所示的氨基酸序列，或者分别具有如SEQ ID NO:28、SEQ ID NO:29和SEQ ID NO:30所示的氨基酸序列，或者分别具有如SEQ ID NO:31、SEQ ID NO:32和SEQ ID NO:33所示的氨基酸序列，或者分别具有如SEQ ID NO:34、SEQ ID NO:35和SEQ ID NO:36所示的氨基酸序列，或者分别具有如SEQ ID NO:37、SEQ ID NO:38和SEQ ID NO:39所示的氨基酸序列，或者分别具有如SEQ ID NO:40、SEQ ID NO:41和SEQ ID NO:42所示的氨基酸序列，或者分别具有如SEQ ID NO:43、SEQ ID NO:44和SEQ ID NO:45所示的氨基酸序列，或者分别具有如SEQ ID NO:46、SEQ ID NO:47和SEQ ID NO:48所示的氨基酸序列；Said LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequence shown in SEQ ID NO:25, SEQ ID NO:26 and SEQ ID NO:27, or respectively have such as SEQ ID NO:28, SEQ ID NO:29 and SEQ ID NO:29 and SEQ ID NO:27 The amino acid sequence shown in ID NO: 30, or have the amino acid sequence shown in SEQ ID NO: 31, SEQ ID NO: 32 and SEQ ID NO: 33 respectively, or have the amino acid sequence shown in SEQ ID NO: 34, SEQ ID NO respectively Amino acid sequences shown in: 35 and SEQ ID NO: 36, or respectively have the amino acid sequences shown in SEQ ID NO: 37, SEQ ID NO: 38 and SEQ ID NO: 39, or have respectively the amino acid sequences shown in SEQ ID NO: 40 , the amino acid sequence shown in SEQ ID NO: 41 and SEQ ID NO: 42, or have the amino acid sequence shown in SEQ ID NO: 43, SEQ ID NO: 44 and SEQ ID NO: 45 respectively, or have the amino acid sequence shown in SEQ ID NO: 45 respectively The amino acid sequences shown in ID NO:46, SEQ ID NO:47 and SEQ ID NO:48;
其中，所述SEQ ID NO:1-48中的至少一个可以替换为与其具有1、2或3个氨基酸差异的变体；Wherein, at least one of said SEQ ID NO: 1-48 can be replaced with a variant having 1, 2 or 3 amino acid differences;
优选地，所述与SEQ ID NO:8所示的氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:49或SEQ ID NO:50所示的氨基酸序列；Preferably, the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO:8 has the amino acid sequence shown in SEQ ID NO:49 or SEQ ID NO:50;
优选地，所述与SEQ ID NO:9所示氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:178所示的氨基酸序列；Preferably, the variant having 1, 2 or 3 amino acid differences with the amino acid sequence shown in SEQ ID NO: 9 has the amino acid sequence shown in SEQ ID NO: 178;
优选地，所述与SEQ ID NO:11所示氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:51所示的氨基酸序列；Preferably, the variant having 1, 2 or 3 amino acid differences with the amino acid sequence shown in SEQ ID NO: 11 has the amino acid sequence shown in SEQ ID NO: 51;
优选地，所述与SEQ ID NO:15所示氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:52所示的氨基酸序列；Preferably, the variant having 1, 2 or 3 amino acid differences with the amino acid sequence shown in SEQ ID NO: 15 has the amino acid sequence shown in SEQ ID NO: 52;
优选地，所述与SEQ ID NO:29所示氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:53所示的氨基酸序列；Preferably, the variant having 1, 2 or 3 amino acid differences with the amino acid sequence shown in SEQ ID NO:29 has the amino acid sequence shown in SEQ ID NO:53;
优选地，所述与SEQ ID NO:31所示氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:54或SEQ ID NO:179所示的氨基酸序列；Preferably, the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO:31 has the amino acid sequence shown in SEQ ID NO:54 or SEQ ID NO:179;
优选地，所述与SEQ ID NO:32所示氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:55所示的氨基酸序列；Preferably, the variant having 1, 2 or 3 amino acid differences with the amino acid sequence shown in SEQ ID NO:32 has the amino acid sequence shown in SEQ ID NO:55;
优选地，所述与SEQ ID NO:36所示氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:180所示的氨基酸序列；Preferably, the variant having 1, 2 or 3 amino acid differences with the amino acid sequence shown in SEQ ID NO:36 has the amino acid sequence shown in SEQ ID NO:180;
优选地，所述与SEQ ID NO:40所示氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:56所示的氨基酸序列；Preferably, the variant having 1, 2 or 3 amino acid differences with the amino acid sequence shown in SEQ ID NO:40 has the amino acid sequence shown in SEQ ID NO:56;
优选地，所述与SEQ ID NO:41所示氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:57所示的氨基酸序列。Preferably, the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO:41 has the amino acid sequence shown in SEQ ID NO:57.
在一些实施方式中，所述抗体或其抗原结合片段包含的HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3分别为：In some embodiments, the antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively:
HCDR1：NYDMA；HCDR1: NYDMA;
HCDR2：SISRX1GDX2X3X4YRDSVX5G，其中，X1为F或S，X2为S或T，X3为F或T，X4为Y或Q或D，X5为K或E；HCDR2: SISRX1GDX2X3X4YRDSVX5G, where X1 is F or S, X2 is S or T, X3 is F or T, X4 is Y or Q or D, X5 is K or E;
HCDR3：QDYGYX6WVWFAY，其中，X6为K或D或N；HCDR3: QDYGYX6WVWFAY, where X6 is K or D or N;
LCDR1：X7AX8EX9ISNDLX10，其中，X7为R或L，X8为S或N，X9为D或G，X10为V或A；LCDR1: X7AX8EX9ISNDLX10, where X7 is R or L, X8 is S or N, X9 is D or G, X10 is V or A;
LCDR2：X11X12SRLX13X14，其中，X11为G或A，X12为T或A，X13为Q或P，X14为D或E或S；LCDR2: X11X12SRLX13X14, where X11 is G or A, X12 is T or A, X13 is Q or P, X14 is D or E or S;
LCDR3：QQX15YKYPFT，其中，X15为T或S；LCDR3: QQX15YKYPFT, where X15 is T or S;
优选地，所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID  NO:28、SEQ ID NO:29和SEQ ID NO:30所示的氨基酸序列；或者Preferably, the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 28. The amino acid sequence shown in SEQ ID NO: 29 and SEQ ID NO: 30; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:28、SEQ ID NO:53和SEQ ID NO:30所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 28, SEQ ID NO: 28, SEQ ID NO: The amino acid sequence shown in ID NO:53 and SEQ ID NO:30; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:7、SEQ ID NO:8和SEQ ID NO:9所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:31、SEQ ID NO:32和SEQ ID NO:33所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 9, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 31, SEQ ID NO: 31, SEQ ID NO: The amino acid sequence shown in ID NO:32 and SEQ ID NO:33; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:7、SEQ ID NO:8和SEQ ID NO:178所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:179、SEQ ID NO:32和SEQ ID NO:33所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 178, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 179, SEQ ID NO: 179 and SEQ ID NO: 178 respectively. The amino acid sequence shown in ID NO:32 and SEQ ID NO:33; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:7、SEQ ID NO:49和SEQ ID NO:9所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:31、SEQ ID NO:32和SEQ ID NO:33所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 49 and SEQ ID NO: 9, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 31, SEQ ID NO: 31, SEQ ID NO: The amino acid sequence shown in ID NO:32 and SEQ ID NO:33; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:7、SEQ ID NO:50和SEQ ID NO:9所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:54、SEQ ID NO:55和SEQ ID NO:33所示的氨基酸序列。The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 50 and SEQ ID NO: 9, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 54, SEQ ID NO: 54, SEQ ID NO: Amino acid sequences shown in ID NO:55 and SEQ ID NO:33.
在一些实施方式中，所述抗体或其抗原结合片段包含的HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3分别为：In some embodiments, the antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively:
HCDR1：DFYMN；HCDR1:DFYMN;
HCDR2：FIRNKANX1YTTEYNPSVKG，其中，X1为G或A；HCDR2: FIRNKANX1YTTEYNPSVKG, where X1 is G or A;
HCDR3：FQHSYYFDY；HCDR3: FQHSYYFDY;
LCDR1：KASQDIDDYLS；LCDR1:KASQDIDDYLS;
LCDR2：DATSLAY；LCDR2: DATSLAY;
LCDR3：LQTYSX2PPT，其中，X2为T或S；LCDR3: LQTYSX2PPT, where X2 is T or S;
优选地，所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:10、SEQ ID NO:11和SEQ ID NO:12所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:34、SEQ ID NO:35和SEQ ID NO:36所示的氨基酸序列；或者Preferably, the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 34. The amino acid sequence shown in SEQ ID NO: 35 and SEQ ID NO: 36; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:10、SEQ ID NO:11和SEQ ID NO:12所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:34、SEQ ID NO:35和SEQ ID NO:180所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 34, SEQ ID NO: 34 and SEQ ID NO: 12 respectively. the amino acid sequence shown in ID NO:35 and SEQ ID NO:180; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:10、SEQ ID NO:51和SEQ ID NO:12所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:34、SEQ ID NO:35和SEQ ID NO:36所示的氨基酸序列。The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 10, SEQ ID NO: 51 and SEQ ID NO: 12, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 34, SEQ ID NO: 34 and SEQ ID NO: 12 respectively. Amino acid sequences shown in ID NO:35 and SEQ ID NO:36.
在一些实施方式中，所述抗体或其抗原结合片段包含的HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3分别为：In some embodiments, the antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively:
HCDR1：IYGMY；HCDR1: IYGMY;
HCDR2：WINTETGTPTYATDFKG；HCDR2: WINTETGTPTYATDFKG;
HCDR3：EDX1GYFDY，其中，X1为G或A；HCDR3: EDX1GYFDY, where X1 is G or A;
LCDR1：RASQSVTISRYNFMN；LCDR1: RASQSVTISRYNFMN;
LCDR2：RASNLPS；LCDR2: RASNLPS;
LCDR3：QQNRESPRT；LCDR3: QQNRESPRT;
优选地，所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:13、SEQ ID NO:14和SEQ ID NO:15所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:37、SEQ ID NO:38和SEQ ID NO:39所示的氨基酸序列；或者Preferably, the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 15, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 37. The amino acid sequence shown in SEQ ID NO: 38 and SEQ ID NO: 39; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:13、SEQ ID NO:14和SEQ ID NO:52所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:37、SEQ ID NO:38和SEQ ID NO:39所示的氨基酸序列。The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 52, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 37, SEQ ID NO: 37 and SEQ ID NO: 52 respectively. Amino acid sequences shown in ID NO:38 and SEQ ID NO:39.
在一些实施方式中，所述抗体或其抗原结合片段包含的HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3分别为：In some embodiments, the antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively:
HCDR1：NYDIS；HCDR1: NYDIS;
HCDR2：GINPGSGGTAYNEKFKD；HCDR2: GINPGSGGTAYNEKFKD;
HCDR3：WDYGGDYNWFTY；HCDR3: WDYGGDYNWFTY;
LCDR1：LASEGISNX1LA，其中，X1为G或A；LCDR1: LASEGISNX1LA, where X1 is G or A;
LCDR2：AASRLQD，其中，X2为E或不存在；LCDR2: AASRLQD, where X2 is E or does not exist;
LCDR3：QQNYRYPLT；LCDR3: QQNYRYPLT;
优选地，所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:16、SEQ ID NO:17和SEQ ID NO:18所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:40、SEQ ID NO:41和SEQ ID NO:42所示的氨基酸序列；或者Preferably, the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 40. The amino acid sequence shown in SEQ ID NO: 41 and SEQ ID NO: 42; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:16、SEQ ID NO:17和SEQ ID NO:18所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:56、SEQ ID NO:57和SEQ ID NO:42所示的氨基酸序列。The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 56, SEQ ID NO: 56 and SEQ ID NO: 18 respectively. Amino acid sequences shown in ID NO:57 and SEQ ID NO:42.
在一些实施方式中，所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:25、SEQ ID NO:26和SEQ ID NO:27所示的氨基酸序列；或者In some embodiments, the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 3 respectively. the amino acid sequences set forth in ID NO:25, SEQ ID NO:26 and SEQ ID NO:27; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:28、SEQ ID NO:29和SEQ ID NO:30所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 28, SEQ ID NO: 28, SEQ ID NO: The amino acid sequence shown in ID NO:29 and SEQ ID NO:30; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:28、SEQ ID NO:53和SEQ ID NO:30所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 28, SEQ ID NO: 28, SEQ ID NO: The amino acid sequence shown in ID NO:53 and SEQ ID NO:30; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:7、SEQ ID NO:8和SEQ ID NO:9所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:31、SEQ ID NO:32和SEQ ID NO:33所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 9, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 31, SEQ ID NO: 31, SEQ ID NO: The amino acid sequence shown in ID NO:32 and SEQ ID NO:33; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:7、SEQ ID NO:8和SEQ ID NO:178所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:179、SEQ ID NO:32和SEQ ID NO:33所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 178, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 179, SEQ ID NO: 179 and SEQ ID NO: 178 respectively. The amino acid sequence shown in ID NO:32 and SEQ ID NO:33; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:7、SEQ ID NO:49和SEQ ID NO:9所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:31、SEQ ID NO:32和SEQ ID NO:33所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 49 and SEQ ID NO: 9, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 31, SEQ ID NO: 31, SEQ ID NO: The amino acid sequence shown in ID NO:32 and SEQ ID NO:33; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:7、SEQ ID NO:50和SEQ ID NO:9所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:54、SEQ ID NO:55和SEQ ID NO:33所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 50 and SEQ ID NO: 9, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 54, SEQ ID NO: 54, SEQ ID NO: The amino acid sequence shown in ID NO:55 and SEQ ID NO:33; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:10、SEQ ID NO:11和SEQ ID NO:12所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:34、SEQ ID NO:35和SEQ ID NO:36所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 34, SEQ ID NO: 34 and SEQ ID NO: 12 respectively. The amino acid sequence shown in ID NO:35 and SEQ ID NO:36; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:10、SEQ ID NO:11和SEQ ID NO:12所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:34、SEQ ID NO:35和SEQ ID NO:180所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 34, SEQ ID NO: 34 and SEQ ID NO: 12 respectively. the amino acid sequence shown in ID NO:35 and SEQ ID NO:180; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:10、SEQ ID NO:51和SEQ ID NO:12所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:34、SEQ ID NO:35和SEQ ID NO:36所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 10, SEQ ID NO: 51 and SEQ ID NO: 12, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 34, SEQ ID NO: 34 and SEQ ID NO: 12 respectively. The amino acid sequence shown in ID NO:35 and SEQ ID NO:36; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:13、SEQ ID NO:14和SEQ ID NO:15所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:37、SEQ ID NO:38和SEQ ID NO:39所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 15, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 37, SEQ ID NO: 37 and SEQ ID NO: 15 respectively. The amino acid sequence shown in ID NO:38 and SEQ ID NO:39; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:13、SEQ ID NO:14和SEQ ID NO:52所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:37、SEQ ID NO:38和SEQ ID NO:39所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 52, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 37, SEQ ID NO: 37 and SEQ ID NO: 52 respectively. The amino acid sequence shown in ID NO:38 and SEQ ID NO:39; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:16、SEQ ID NO:17和SEQ ID NO:18所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:40、SEQ ID NO:41和SEQ ID NO:42所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 40, SEQ ID NO: 40 and SEQ ID NO: 18 respectively. The amino acid sequence shown in ID NO:41 and SEQ ID NO:42; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:16、SEQ ID NO:17和SEQ ID NO:18所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:56、SEQ ID NO:57和SEQ ID NO:42所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 56, SEQ ID NO: 56 and SEQ ID NO: 18 respectively. the amino acid sequence shown in ID NO:57 and SEQ ID NO:42; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:19、SEQ ID NO:20和SEQ ID NO:21所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:43、SEQ ID NO:44和SEQ ID NO:45所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 19, SEQ ID NO: 20 and SEQ ID NO: 21, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 43, SEQ ID NO: 43 and SEQ ID NO: 21 respectively. The amino acid sequence shown in ID NO:44 and SEQ ID NO:45; or
所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:22、SEQ ID NO:23和SEQ ID NO:24所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:46、SEQ ID NO:47和SEQ ID NO:48所示的氨基酸序列。The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 22, SEQ ID NO: 23 and SEQ ID NO: 24, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 46, SEQ ID NO: 46 and SEQ ID NO: 24 respectively. Amino acid sequences shown in ID NO:47 and SEQ ID NO:48.
在一些实施方式中，所述的抗体或其抗原结合片段包含：In some embodiments, the antibody or antigen-binding fragment thereof comprises:
与SEQ ID NO:58所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:92所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:58 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO:92 light chain variable regions of sequence identity; or
与SEQ ID NO:59所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:93所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:59 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO:93 light chain variable regions of sequence identity; or
与SEQ ID NO:60所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:94所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:60 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO:94 light chain variable regions of sequence identity; or
与SEQ ID NO:61所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:95所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:61 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO:95 light chain variable regions of sequence identity; or
与SEQ ID NO:62所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:96所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:62 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO:96 light chain variable regions of sequence identity; or
与SEQ ID NO:63所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:97所示氨基 酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:63 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO:97 light chain variable regions of sequence identity; or
与SEQ ID NO:64所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:98所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:64 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO:98 light chain variable regions of sequence identity; or
与SEQ ID NO:65所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:99所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:65 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO:99 light chain variable regions of sequence identity; or
与SEQ ID NO:66所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:100所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:66 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 100 light chain variable regions of sequence identity; or
与SEQ ID NO:67所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:101所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:67 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 101 light chain variable regions of sequence identity; or
与SEQ ID NO:68所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:102所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:68 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 102 light chain variable regions of sequence identity; or
与SEQ ID NO:69所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:103所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 69 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 103 light chain variable regions of sequence identity; or
与SEQ ID NO:70所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:104所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:70 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 104 light chain variable regions of sequence identity; or
与SEQ ID NO:71所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:105所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:71 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 105 light chain variable regions of sequence identity; or
与SEQ ID NO:72所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:106所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:72 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 106 light chain variable regions of sequence identity; or
与SEQ ID NO:73所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:107所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:73 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 107 light chain variable regions of sequence identity; or
与SEQ ID NO:74所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:108所示氨基 酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:74 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 108 light chain variable regions of sequence identity; or
与SEQ ID NO:75所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:109所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:75 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 109 light chain variable regions of sequence identity; or
与SEQ ID NO:76所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:110所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:76 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 110 light chain variable regions of sequence identity; or
与SEQ ID NO:77所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:111所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:77 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 111 light chain variable regions of sequence identity; or
与SEQ ID NO:78所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:112所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:78 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 112 light chain variable regions of sequence identity; or
与SEQ ID NO:79所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:113所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:79 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 113 light chain variable regions of sequence identity; or
与SEQ ID NO:80所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:114所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 80 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 114 light chain variable regions of sequence identity; or
与SEQ ID NO:81所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:115所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 81 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 115 light chain variable regions of sequence identity; or
与SEQ ID NO:82所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:116所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:82 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 116 light chain variable regions of sequence identity; or
与SEQ ID NO:83所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:117所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:83 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 117 light chain variable regions of sequence identity; or
与SEQ ID NO:84所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:118所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:84 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 118 light chain variable regions of sequence identity; or
与SEQ ID NO:85所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:119所示氨基 酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:85 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 119 light chain variable regions of sequence identity; or
与SEQ ID NO:86所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:120所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:86 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 120 light chain variable regions of sequence identity; or
与SEQ ID NO:87所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:121所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:87 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 121 light chain variable regions of sequence identity; or
与SEQ ID NO:88所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:122所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:88 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 122 light chain variable regions of sequence identity; or
与SEQ ID NO:89所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:123所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 89 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 123 light chain variable regions of sequence identity; or
与SEQ ID NO:90所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:124所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:90 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 124 light chain variable regions of sequence identity; or
与SEQ ID NO:91所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:125所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:91 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 125 light chain variable regions of sequence identity; or
与SEQ ID NO:181所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:182所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 181 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 182 light chain variable regions of sequence identity; or
与SEQ ID NO:183所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:184所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区。A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 183 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the amino acid sequence shown in SEQ ID NO: 184 Sequence identity of the light chain variable region.
在一些实施方式中，所述的抗体或其抗原结合片段包含：In some embodiments, the antibody or antigen-binding fragment thereof comprises:
氨基酸序列如SEQ ID NO:58所示的重链可变区，和氨基酸序列如SEQ ID NO:92所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:58, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:92; or
氨基酸序列如SEQ ID NO:59所示的重链可变区，和氨基酸序列如SEQ ID NO:93所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:59, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:93; or
氨基酸序列如SEQ ID NO:60所示的重链可变区，和氨基酸序列如SEQ ID NO:94所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:60, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:94; or
氨基酸序列如SEQ ID NO:61所示的重链可变区，和氨基酸序列如SEQ ID NO:95所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:61, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:95; or
氨基酸序列如SEQ ID NO:62所示的重链可变区，和氨基酸序列如SEQ ID NO:96所示 的轻链可变区；或A heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:62, and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:96; or
氨基酸序列如SEQ ID NO:63所示的重链可变区，和氨基酸序列如SEQ ID NO:97所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:63, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:97; or
氨基酸序列如SEQ ID NO:64所示的重链可变区，和氨基酸序列如SEQ ID NO:98所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:64, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:98; or
氨基酸序列如SEQ ID NO:65所示的重链可变区，和氨基酸序列如SEQ ID NO:99所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:65, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:99; or
氨基酸序列如SEQ ID NO:66所示的重链可变区，和氨基酸序列如SEQ ID NO:100所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:66, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:100; or
氨基酸序列如SEQ ID NO:67所示的重链可变区，和氨基酸序列如SEQ ID NO:101所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:67, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:101; or
氨基酸序列如SEQ ID NO:68所示的重链可变区，和氨基酸序列如SEQ ID NO:102所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:68, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:102; or
氨基酸序列如SEQ ID NO:69所示的重链可变区，和氨基酸序列如SEQ ID NO:103所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:69, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:103; or
氨基酸序列如SEQ ID NO:70所示的重链可变区，和氨基酸序列如SEQ ID NO:104所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:70, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:104; or
氨基酸序列如SEQ ID NO:71所示的重链可变区，和氨基酸序列如SEQ ID NO:105所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:71, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:105; or
氨基酸序列如SEQ ID NO:72所示的重链可变区，和氨基酸序列如SEQ ID NO:106所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO:72, and a light chain variable region having an amino acid sequence as shown in SEQ ID NO:106; or
氨基酸序列如SEQ ID NO:73所示的重链可变区，和氨基酸序列如SEQ ID NO:107所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:73, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:107; or
氨基酸序列如SEQ ID NO:74所示的重链可变区，和氨基酸序列如SEQ ID NO:108所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:74, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:108; or
氨基酸序列如SEQ ID NO:75所示的重链可变区，和氨基酸序列如SEQ ID NO:109所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:75, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:109; or
氨基酸序列如SEQ ID NO:76所示的重链可变区，和氨基酸序列如SEQ ID NO:110所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:76, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:110; or
氨基酸序列如SEQ ID NO:77所示的重链可变区，和氨基酸序列如SEQ ID NO:111所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:77, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:111; or
氨基酸序列如SEQ ID NO:78所示的重链可变区，和氨基酸序列如SEQ ID NO:112所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:78, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:112; or
氨基酸序列如SEQ ID NO:79所示的重链可变区，和氨基酸序列如SEQ ID NO:113所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:79, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:113; or
氨基酸序列如SEQ ID NO:80所示的重链可变区，和氨基酸序列如SEQ ID NO:114所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO:80, and a light chain variable region having an amino acid sequence as shown in SEQ ID NO:114; or
氨基酸序列如SEQ ID NO:81所示的重链可变区，和氨基酸序列如SEQ ID NO:115所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:81, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:115; or
氨基酸序列如SEQ ID NO:82所示的重链可变区，和氨基酸序列如SEQ ID NO:116所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:82, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:116; or
氨基酸序列如SEQ ID NO:83所示的重链可变区，和氨基酸序列如SEQ ID NO:117所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:83, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:117; or
氨基酸序列如SEQ ID NO:84所示的重链可变区，和氨基酸序列如SEQ ID NO:118所 示的轻链可变区；或A heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:84, and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:118; or
氨基酸序列如SEQ ID NO:85所示的重链可变区，和氨基酸序列如SEQ ID NO:119所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:85, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:119; or
氨基酸序列如SEQ ID NO:86所示的重链可变区，和氨基酸序列如SEQ ID NO:120所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:86, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:120; or
氨基酸序列如SEQ ID NO:87所示的重链可变区，和氨基酸序列如SEQ ID NO:121所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:87, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:121; or
氨基酸序列如SEQ ID NO:88所示的重链可变区，和氨基酸序列如SEQ ID NO:122所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:88, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:122; or
氨基酸序列如SEQ ID NO:89所示的重链可变区，和氨基酸序列如SEQ ID NO:123所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:89, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:123; or
氨基酸序列如SEQ ID NO:90所示的重链可变区，和氨基酸序列如SEQ ID NO:124所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:90, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:124; or
氨基酸序列如SEQ ID NO:91所示的重链可变区，和氨基酸序列如SEQ ID NO:125所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:91, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:125; or
氨基酸序列如SEQ ID NO:181所示的重链可变区，和氨基酸序列如SEQ ID NO:182所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 181, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO: 182; or
氨基酸序列如SEQ ID NO:183所示的重链可变区，和氨基酸序列如SEQ ID NO:184所示的轻链可变区。The amino acid sequence of the heavy chain variable region shown in SEQ ID NO: 183, and the amino acid sequence of the light chain variable region shown in SEQ ID NO: 184.
在一些实施方式中，所述的抗体或其抗原结合片段还包含人重链恒定区和人轻链恒定区，所述人重链恒定区选自人IgG1、IgG2、IgG3或IgG4的重链恒定区，优选为人IgG1的重链恒定区；所述人轻链恒定区选自λ轻链或κ轻链的轻链恒定区。In some embodiments, the antibody or antigen-binding fragment thereof further comprises a human heavy chain constant region and a human light chain constant region, and the human heavy chain constant region is selected from the constant heavy chain region of human IgG1, IgG2, IgG3 or IgG4. Region, preferably the heavy chain constant region of human IgG1; the human light chain constant region is selected from the light chain constant region of lambda light chain or kappa light chain.
在一些实施方式中，所述的抗体或其抗原结合片段包含：In some embodiments, the antibody or antigen-binding fragment thereof comprises:
与SEQ ID NO:126所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:127所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 126 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 127 light chain; or
与SEQ ID NO:128所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:129所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 128 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 129 light chain; or
与SEQ ID NO:130所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:131所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 130 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 131 light chain; or
与SEQ ID NO:132所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:133所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 132 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 133 light chain; or
与SEQ ID NO:134所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:135所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 134 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 135 light chain; or
与SEQ ID NO:136所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、 96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:137所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 136 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 137 light chain; or
与SEQ ID NO:138所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:139所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 138 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 139 light chain; or
与SEQ ID NO:140所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:141所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 140 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 141 light chain; or
与SEQ ID NO:142所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:143所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 142 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 143 light chain; or
与SEQ ID NO:144所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:145所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 144 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 145 light chain; or
与SEQ ID NO:146所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:147所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 146 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 147 light chain; or
与SEQ ID NO:148所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:149所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 148 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 149 light chain; or
与SEQ ID NO:150所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:151所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 150 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 151 light chain; or
与SEQ ID NO:152所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:153所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 152 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 153 light chain; or
与SEQ ID NO:154所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:155所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 154 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 155 light chain; or
与SEQ ID NO:156所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:157所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 156 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 157 light chain; or
与SEQ ID NO:158所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、 96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:159所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 158 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 159 light chain; or
与SEQ ID NO:160所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:161所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 160 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 161 light chain; or
与SEQ ID NO:162所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:163所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 162 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 163 light chain; or
与SEQ ID NO:164所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:165所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 164 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 165 light chain; or
与SEQ ID NO:166所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:167所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 166 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 167 light chain; or
与SEQ ID NO:168所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:169所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 168 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 169 light chain; or
与SEQ ID NO:170所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:171所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 170 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 171 light chain; or
与SEQ ID NO:172所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:173所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 172 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 173 light chain; or
与SEQ ID NO:174所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:175所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 174 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 175 light chain; or
与SEQ ID NO:176所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:177所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链。A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 176 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 177 light chain.
在一些实施方式中，所述抗体或其抗原结合片段包含：In some embodiments, the antibody or antigen-binding fragment thereof comprises:
氨基酸序列如SEQ ID NO:126所示的重链，和氨基酸序列如SEQ ID NO:127所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 126, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 127; or
氨基酸序列如SEQ ID NO:128所示的重链，和氨基酸序列如SEQ ID NO:129所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 128, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 129; or
氨基酸序列如SEQ ID NO:130所示的重链，和氨基酸序列如SEQ ID NO:131所示的轻链；或A heavy chain having an amino acid sequence as set forth in SEQ ID NO:130, and a light chain having an amino acid sequence as set forth in SEQ ID NO:131; or
氨基酸序列如SEQ ID NO:132所示的重链，和氨基酸序列如SEQ ID NO:133所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 132, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 133; or
氨基酸序列如SEQ ID NO:134所示的重链，和氨基酸序列如SEQ ID NO:135所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 134, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 135; or
氨基酸序列如SEQ ID NO:136所示的重链，和氨基酸序列如SEQ ID NO:137所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 136, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 137; or
氨基酸序列如SEQ ID NO:138所示的重链，和氨基酸序列如SEQ ID NO:139所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 138, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 139; or
氨基酸序列如SEQ ID NO:140所示的重链，和氨基酸序列如SEQ ID NO:141所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 140, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 141; or
氨基酸序列如SEQ ID NO:142所示的重链，和氨基酸序列如SEQ ID NO:143所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 142, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 143; or
氨基酸序列如SEQ ID NO:144所示的重链，和氨基酸序列如SEQ ID NO:145所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 144, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 145; or
氨基酸序列如SEQ ID NO:146所示的重链，和氨基酸序列如SEQ ID NO:147所示的轻链；或a heavy chain having an amino acid sequence set forth in SEQ ID NO: 146, and a light chain having an amino acid sequence set forth in SEQ ID NO: 147; or
氨基酸序列如SEQ ID NO:148所示的重链，和氨基酸序列如SEQ ID NO:149所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 148, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 149; or
氨基酸序列如SEQ ID NO:150所示的重链，和氨基酸序列如SEQ ID NO:151所示的轻链；或A heavy chain having an amino acid sequence as set forth in SEQ ID NO:150, and a light chain having an amino acid sequence as set forth in SEQ ID NO:151; or
氨基酸序列如SEQ ID NO:152所示的重链，和氨基酸序列如SEQ ID NO:153所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 152, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 153; or
氨基酸序列如SEQ ID NO:154所示的重链，和氨基酸序列如SEQ ID NO:155所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 154, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 155; or
氨基酸序列如SEQ ID NO:156所示的重链，和氨基酸序列如SEQ ID NO:157所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 156, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 157; or
氨基酸序列如SEQ ID NO:158所示的重链，和氨基酸序列如SEQ ID NO:159所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 158, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 159; or
氨基酸序列如SEQ ID NO:160所示的重链，和氨基酸序列如SEQ ID NO:161所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 160, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 161; or
氨基酸序列如SEQ ID NO:162所示的重链，和氨基酸序列如SEQ ID NO:163所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 162, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 163; or
氨基酸序列如SEQ ID NO:164所示的重链，和氨基酸序列如SEQ ID NO:165所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 164, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 165; or
氨基酸序列如SEQ ID NO:166所示的重链，和氨基酸序列如SEQ ID NO:167所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 166, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 167; or
氨基酸序列如SEQ ID NO:168所示的重链，和氨基酸序列如SEQ ID NO:169所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 168, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 169; or
氨基酸序列如SEQ ID NO:170所示的重链，和氨基酸序列如SEQ ID NO:171所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 170, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 171; or
氨基酸序列如SEQ ID NO:172所示的重链，和氨基酸序列如SEQ ID NO:173所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 172, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 173; or
氨基酸序列如SEQ ID NO:174所示的重链，和氨基酸序列如SEQ ID NO:175所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 174, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 175; or
氨基酸序列如SEQ ID NO:176所示的重链，和氨基酸序列如SEQ ID NO:177所示的轻链。在一些实施方式中，所述抗体包括单克隆抗体和多特异性抗体的至少一种，所述抗原结合片段包括Fab、Fab'、F(ab')2、Fv、scFv和sdAb的至少一种。The amino acid sequence is the heavy chain shown in SEQ ID NO: 176, and the amino acid sequence is the light chain shown in SEQ ID NO: 177. In some embodiments, the antibody comprises at least one of a monoclonal antibody and a multispecific antibody, and the antigen-binding fragment comprises at least one of a Fab, Fab', F(ab')2, Fv, scFv, and sdAb .
本申请第二方面提供了一种分离的抗体或其抗原结合片段，其具有以下特性中的至少一种：The second aspect of the present application provides an isolated antibody or antigen-binding fragment thereof, which has at least one of the following characteristics:
(Ⅰ)与本申请第一方面所提供的抗体或其抗原结合片段结合相同的、或者完全重叠或部分重叠的人BCMA蛋白的表位；(I) the antibody or antigen-binding fragment thereof provided in the first aspect of the present application binds to the same epitope of human BCMA protein, or completely overlaps or partially overlaps;
(Ⅱ)与本申请第一方面所提供的抗体或其抗原结合片段竞争结合人BCMA蛋白的表位。(II) Compete with the antibody or antigen-binding fragment thereof provided in the first aspect of the present application for binding to the epitope of human BCMA protein.
其中，与本申请的抗体或其抗原结合片段结合完全重叠的表位表示该抗体结合的抗原表位包含了本申请的抗体或其抗原结合片段的结合表位；与本申请的抗体或其抗原结合片段结合部分重叠的表位表示该抗体结合的抗原表位的一部分与本申请的抗体或其抗原结合片段的结合表位的一部分相同。Wherein, the epitope that completely overlaps with the antibody of the present application or its antigen-binding fragment indicates that the antigenic epitope bound by the antibody includes the binding epitope of the antibody of the present application or its antigen-binding fragment; The partially overlapping epitope bound by the binding fragment means that a part of the epitope bound by the antibody is the same as a part of the binding epitope of the antibody or antigen-binding fragment thereof of the present application.
对于抗体的互补决定区CDR的精确氨基酸序列边界，可根据公知方法来定义，例如基于抗体的三维结构和CDR环的拓扑学的Chothia(Chothia等，Nature 342:877-883，1989；Al-Lazikani等，Journal of Molecular Biology，273:927-948，1997)；或者基于抗体序列可变性的Kabat(Kabat等，Sequences of Proteins of Immunological Interest，第4版，U.S.Department of Health and Human Services，National Institutes of Health，1987)、AbM(University of Bath)、Contact(University College London)以及IMGT(the international ImMunoGeneTics database，1999Nucleic Acids Research,27,209-212)；或者基于利用大量晶体结构的近邻传播聚类(affinity propagation clustering)的North CDR定义。本申请中抗体的CDR可以由本领域技术人员根据本领域的任何方案(例如上述任选的定义方法)确定边界。The precise amino acid sequence boundaries of the complementarity determining region CDR of an antibody can be defined according to known methods, such as Chothia based on the three-dimensional structure of the antibody and the topology of the CDR loop (Chothia et al., Nature 342:877-883, 1989; Al-Lazikani et al., Journal of Molecular Biology, 273:927-948, 1997); or Kabat based on antibody sequence variability (Kabat et al., Sequences of Proteins of Immunological Interest, 4th ed., U.S. Department of Health and Human Services, National Institutes of Health, 1987), AbM (University of Bath), Contact (University College London) and IMGT (the international ImMunoGeneTics database, 1999 Nucleic Acids Research, 27, 209-212); or based on affinity propagation clustering using a large number of crystal structures ) North CDR definition. The boundaries of the CDRs of the antibodies in the present application can be determined by those skilled in the art according to any scheme in the art (such as the optional definition method mentioned above).
应该注意的是，基于不同定义方式获得的同一抗体的CDR的边界可能有所差异，即不同定义方式下获得的同一抗体可变区的CDR序列有所不同。因此，当采用本申请定义的具体CDR序列限定抗体时，所述抗体还包括其互补决定区序列包含本申请所述的CDR的序列，只是由于采用了不同的CDR边界定义方式而导致其所声称的CDR边界与本申请所定义的具体CDR边界不同的抗体。It should be noted that the boundaries of the CDRs of the same antibody obtained based on different definition methods may be different, that is, the CDR sequences of the variable region of the same antibody obtained by different definition methods are different. Therefore, when specific CDR sequences as defined in this application are used to define an antibody, said antibody also includes sequences whose CDR sequences comprise the CDRs described in this application, only because of the different ways of defining CDR boundaries. Antibodies with CDR boundaries that differ from the specific CDR boundaries defined herein.
具有不同特异性(即，针对不同的抗原结合位点)的抗体具有不同的CDR。然而，尽管CDR在抗体与抗体之间是不同的，但是CDR内只有有限数量的氨基酸位置直接参与抗原结合，抗体CDR与抗原结合的最小重叠区域也称为用于抗原结合的“最小结合单位”，可使用Kabat、Chothia、AbM、Contact和North方法中的至少两种来确定。最小结合单位可以是CDR的一部分。正如本领域技术人员所明了的，通过抗体的结构和蛋白折叠，可以确定CDR序列其余部分的残基，因此，本申请也考虑任何CDR的变体，例如，在一个CDR的变体中，最小结合单位的氨基酸残基可以保持不变，而根据Kabat或Chothia定义的其余CDR残基可以被保守氨基酸残基替代。Antibodies with different specificities (ie, directed against different antigen combining sites) have different CDRs. However, although CDRs are different from antibody to antibody, only a limited number of amino acid positions within CDRs are directly involved in antigen binding, and the smallest overlapping region of antibody CDRs and antigen binding is also called the "minimum binding unit" for antigen binding , can be determined using at least two of the Kabat, Chothia, AbM, Contact and North methods. The smallest binding unit can be a portion of a CDR. As will be apparent to those skilled in the art, the structure and protein folding of the antibody will determine the residues of the remainder of the CDR sequence, and therefore, this application also contemplates any CDR variant, e.g., in a CDR variant, the minimum The amino acid residues of the binding unit can remain unchanged, while the remaining CDR residues according to the Kabat or Chothia definition can be replaced by conservative amino acid residues.
本申请所述的人源化抗体，可以使用本领域已知的方法将鼠源CDR区插入人种系框架区。参见Winter等人的美国专利No.5225539及Queen等人的美国专利No.5530101；5585089；5693762和6180370。For the humanized antibodies described herein, murine CDR regions can be inserted into human germline framework regions using methods known in the art. See US Patent No. 5,225,539 to Winter et al. and US Patent Nos. 5,530,101; 5,585,089; 5,693,762 and 6,180,370 to Queen et al.
在一些实施方式中，氨基酸差异可以由氨基酸的变化造成，所述变化包括氨基酸缺失、插入或置换。在一些实施方式中，本申请的抗BCMA抗体或其抗原结合片段包括具有已通过氨基酸缺失、插入或置换突变的，但仍与所述抗体或其抗原结合片段(特别地在上述序列中描述的CDR区中)具有至少约90％、91％、92％、93％、94％、95％、96％、97％、98％、 99％或100％同一性的氨基酸序列的抗体。In some embodiments, amino acid differences may result from amino acid changes, including amino acid deletions, insertions, or substitutions. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof of the present application includes amino acid deletion, insertion or substitution mutations, but is still compatible with the antibody or antigen-binding fragment thereof (especially described in the above sequence) CDR regions) have amino acid sequences that are at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical.
在一些实施方式中，可在本文中所提供抗体的Fc区中引入一个或多个氨基酸修饰，以此产生Fc区变体。Fc区变体可包括在一或多个氨基酸位置处存在氨基酸修饰(例如置换)的人Fc区序列(例如人IgG1、IgG2、IgG3或IgG4Fc区)。In some embodiments, one or more amino acid modifications can be introduced into the Fc region of the antibodies provided herein to generate Fc region variants. Fc region variants may include human Fc region sequences (eg, human IgGl, IgG2, IgG3 or IgG4 Fc regions) with amino acid modifications (eg, substitutions) at one or more amino acid positions.
在一些实施方式中，所述抗体或其抗原结合片段包括经半胱氨酸工程改造的抗体或其抗原结合片段，例如“硫代MAb”，其中所述抗体或其抗原结合片段的一或多个残基被半胱氨酸残基置换。In some embodiments, the antibody or antigen-binding fragment thereof comprises a cysteine-engineered antibody or antigen-binding fragment thereof, such as a "thioMAb", wherein one or more of the antibody or antigen-binding fragment thereof residues were replaced by cysteine residues.
在一些实施方式中，所述抗体或其抗原结合片段可进一步经修饰为含有本领域已知且可轻易获得的其他非蛋白质部分，例如水溶性聚合物。所述水溶性聚合物的实例包括但不限于：聚乙二醇(PEG)、乙二醇/丙二醇共聚物、羧甲基纤维素、葡聚糖、聚乙烯醇、聚乙烯吡咯烷酮、聚-1，3-二烷、聚-1，3，6-三烷、乙烯/马来酸酐共聚物、聚氨基酸(均聚物或无规共聚物)、及葡聚糖或聚(N-乙烯基吡咯烷)聚乙二醇、丙二醇均聚物、聚环氧丙烷/氧化乙烯共聚物、聚氧乙基化多元醇(例如甘油)、聚乙烯醇、及其混合物。In some embodiments, the antibodies or antigen-binding fragments thereof may be further modified to contain other non-proteinaceous moieties known in the art and readily available, such as water-soluble polymers. Examples of such water-soluble polymers include, but are not limited to: polyethylene glycol (PEG), ethylene glycol/propylene glycol copolymer, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1 , 3-dioxane, poly-1,3,6-trioxane, ethylene/maleic anhydride copolymer, polyamino acid (homopolymer or random copolymer), and dextran or poly(N-vinylpyrrole alk) polyethylene glycol, propylene glycol homopolymer, polypropylene oxide/ethylene oxide copolymer, polyoxyethylated polyols (eg glycerol), polyvinyl alcohol, and mixtures thereof.
抗体表达Antibody expression
本申请另一个方面提供了一种多核苷酸分子，其包含编码本申请所提供的抗体或其抗原结合片段的核苷酸序列或其互补序列的至少一种。本申请中的多核苷酸分子包括双链或单链的DNA或RNA。本申请所提供的抗体或其抗原结合片段包括了本申请第一方面的抗体或其抗原结合片段和本申请第二方面的分离的抗体或其抗原结合片段。Another aspect of the present application provides a polynucleotide molecule, which comprises at least one of the nucleotide sequence encoding the antibody or antigen-binding fragment thereof provided in the present application or its complementary sequence. A polynucleotide molecule in the present application includes double-stranded or single-stranded DNA or RNA. The antibody or antigen-binding fragment thereof provided in the present application includes the antibody or antigen-binding fragment thereof in the first aspect of the application and the isolated antibody or antigen-binding fragment thereof in the second aspect of the application.
在一些实施方式中，编码本申请的抗体或其抗原结合片段的多核苷酸分子还可以包括存在核苷酸缺失、插入或置换突变的，但仍与本申请的抗体或其抗原结合片段的CDR对应的编码区具有至少约60％、70％、80％、90％、95％或100％同一性的多核苷酸序列。In some embodiments, the polynucleotide molecule encoding the antibody of the present application or an antigen-binding fragment thereof may also include a CDR that has a nucleotide deletion, insertion or substitution mutation, but is still consistent with the antibody of the present application or an antigen-binding fragment thereof The corresponding coding regions are polynucleotide sequences that are at least about 60%, 70%, 80%, 90%, 95%, or 100% identical.
在又一个方面，本申请提供了一种表达载体，其包含本申请的多核苷酸分子，优选地，所述表达载体为真核表达载体。In yet another aspect, the present application provides an expression vector comprising the polynucleotide molecule of the present application, preferably, the expression vector is a eukaryotic expression vector.
在又一个方面，本申请提供了一种宿主细胞，其包含本申请的多核苷酸分子或表达载体；优选地，所述宿主细胞是真核细胞，更优选哺乳动物细胞。In yet another aspect, the present application provides a host cell comprising the polynucleotide molecule or expression vector of the present application; preferably, the host cell is a eukaryotic cell, more preferably a mammalian cell.
在一些实施方式中，所述宿主细胞用于表达本申请所提供的抗体或其抗原结合片段。In some embodiments, the host cells are used to express the antibodies or antigen-binding fragments thereof provided herein.
本申请所提供的用于表达本申请的抗体或其抗原结合片段的哺乳动物宿主细胞，包括可获自美国典型培养物保藏中心(ATCC)的多种永生化细胞系。示例性的，可以包括中国仓鼠卵巢(CHO)细胞、NS0、SP2/0细胞、HeLa细胞、幼仓鼠肾(BHK)细胞、猴肾细胞(COS)、人肝细胞癌细胞、A549细胞、293T细胞和许多其它细胞系。哺乳动物宿主细胞可以包括人、小鼠、大鼠、狗、猴、猪、山羊、牛、马和仓鼠细胞。本领域技术人员可以通过测定哪种细胞系具有高表达水平来选择特别优选的细胞系。The mammalian host cells provided herein for expressing the antibodies or antigen-binding fragments thereof of the present application include various immortalized cell lines available from the American Type Culture Collection (ATCC). Exemplary, it can include Chinese hamster ovary (CHO) cells, NSO, SP2/0 cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells, A549 cells, 293T cells and many other cell lines. Mammalian host cells can include human, mouse, rat, dog, monkey, pig, goat, bovine, horse and hamster cells. One skilled in the art can select particularly preferred cell lines by determining which cell lines have high expression levels.
在又一个方面，本申请提供了一种制备本申请的抗体或其抗原结合片段的方法，包括在本申请所提供的宿主细胞中表达所述抗体或其抗原结合片段，并从所述宿主细胞回收所表达的抗体或其抗原结合片段。In yet another aspect, the present application provides a method for preparing the antibody or antigen-binding fragment thereof of the present application, comprising expressing the antibody or antigen-binding fragment thereof in the host cell provided in the present application, and extracting the antibody or antigen-binding fragment thereof from the host cell The expressed antibody or antigen-binding fragment thereof is recovered.
具体地，本申请提供了一种制备本申请的抗体或其抗原结合片段的方法可以包括：Specifically, the application provides a method for preparing the antibody or antigen-binding fragment thereof of the application may include:
将本申请的多核苷酸分子或表达载体采用公知的方法，例如脂质体转染、电转染、转化等方式导入本申请所述的宿主细胞中；在适合于所述抗体或其抗原结合片段表达的条件下培养所述的宿主细胞，使所述宿主细胞表达所述抗体或其抗原结合片段；采用本领域公知的方法，例如聚丙烯酰胺凝胶电泳，从所述宿主细胞回收所表达的抗体或其抗原结合片段。The polynucleotide molecules or expression vectors of the present application are introduced into the host cells described in the present application by known methods, such as lipofection, electroporation, transformation, etc.; Cultivating the host cell under the condition of fragment expression, so that the host cell expresses the antibody or its antigen-binding fragment; using methods known in the art, such as polyacrylamide gel electrophoresis, recovering the expressed antibody from the host cell Antibodies or antigen-binding fragments thereof.
需要说明的是，由于采用的表达载体或宿主细胞的不同，本领域技术人员可根据具体情况选择适合于所述抗体或其抗原结合片段表达的条件，本申请在此不做限定。It should be noted that due to the differences in the expression vectors or host cells used, those skilled in the art can choose the conditions suitable for the expression of the antibody or its antigen-binding fragment according to the specific situation, which is not limited in this application.
本申请中的用于表达所述抗体或其抗原结合片段的宿主细胞可以是分离的细胞，也可 以是仍存在与宿主体内的细胞，例如可以采用不同细胞系表达所述抗体或其抗原结合片段，或者采用转基因动物表达所述抗体或其抗原结合片段。The host cell used to express the antibody or its antigen-binding fragment in the present application may be an isolated cell, or a cell that still exists in the host body, for example, different cell lines may be used to express the antibody or its antigen-binding fragment , or using transgenic animals to express the antibody or antigen-binding fragment thereof.
由不同细胞系表达或在不同转基因动物中表达的抗体或其抗原结合片段可能具有不同的糖基化修饰。需要说明的是，不论这些抗体的糖基化如何，这些由本申请提供的多核苷酸分子编码的，或包含本申请提供的氨基酸序列的所有抗体均是本申请的组成部分。同样，在某些实施方式中，所述抗体或其抗原结合片段优选为非岩藻糖基化抗体或其抗原结合片段，发明人发现，非岩藻糖基化抗体或其抗原结合片段在体外和体内比岩藻糖基化的抗体或其抗原结合片段具有更强力的功效，此外，由于这些不同的糖结构都是天然人血清IgG的正常组分，因此其免疫原性并无明显差异。Antibodies or antigen-binding fragments thereof expressed by different cell lines or expressed in different transgenic animals may have different glycosylation modifications. It should be noted that, regardless of the glycosylation of these antibodies, all antibodies encoded by the polynucleotide molecules provided by the application or comprising the amino acid sequences provided by the application are part of the application. Likewise, in certain embodiments, the antibody or antigen-binding fragment thereof is preferably a non-fucosylated antibody or antigen-binding fragment thereof. And in vivo than fucosylated antibodies or their antigen-binding fragments have stronger efficacy, in addition, because these different sugar structures are normal components of natural human serum IgG, so there is no significant difference in their immunogenicity.
药物偶联物drug conjugate
在又一方面，本申请提供了一种抗BCMA抗体的药物偶联物(ADC)或其药学上可接受的盐，其包含：In yet another aspect, the application provides an anti-BCMA antibody drug conjugate (ADC) or a pharmaceutically acceptable salt thereof, comprising:
(a)抗体部分，所述抗体部分为本申请第一方面所提供的抗体或其抗原结合片段；和(a) an antibody part, which is the antibody or antigen-binding fragment thereof provided in the first aspect of the application; and
(b)与所述抗体部分偶联的偶联部分，所述偶联部分选自可检测标记物、药物、毒素、细胞因子、放射性核素和酶中的至少一种。(b) a coupling moiety coupled to the antibody moiety, the coupling moiety being selected from at least one of detectable labels, drugs, toxins, cytokines, radionuclides and enzymes.
在一些实施方式中，所述的抗体部分与所述的偶联部分通过化学键或接头进行偶联。In some embodiments, the antibody moiety is coupled to the coupling moiety via a chemical bond or linker.
药物组合物或药物制剂pharmaceutical composition or pharmaceutical preparation
在又一个方面，本申请提供了一种药物组合物(或称为药物制剂、制剂)，其包含本申请所提供的抗体或其抗原结合片段、多核苷酸分子、表达载体、宿主细胞或药物偶联物，和药学上可接受的载体或赋形剂。In yet another aspect, the application provides a pharmaceutical composition (or called pharmaceutical preparation, preparation), which comprises the antibody or antigen-binding fragment thereof, polynucleotide molecule, expression vector, host cell or drug provided in the application A conjugate, and a pharmaceutically acceptable carrier or excipient.
应理解，本申请提供的抗体或其药物组合物可以整合制剂中合适的载体、赋形剂和其他试剂以联合给药，从而提供改善的转移、递送、耐受性能等。It should be understood that the antibodies or pharmaceutical compositions thereof provided herein can be administered in combination with appropriate carriers, excipients and other agents in formulations, so as to provide improved transfer, delivery, tolerance and the like.
本申请中，所述药物组合物中的活性成分以其生物学活性有效的形式存在，并且不包含对所述药物组合物的受试者具有不可接受的毒性的成分。In the present application, the active ingredients in the pharmaceutical composition exist in a form with effective biological activity, and do not contain ingredients with unacceptable toxicity to the subject of the pharmaceutical composition.
在本申请的一些实施方式中，可以通过将具有所需纯度的本申请的抗体或其抗原结合片段与一种或多种任选的药用辅料(参见Remington's Pharmaceutical Sciences，第16版，Osol,A.编辑，1980)混合来制备本申请的药物组合物，优选地，本申请的药物组合物可以是水溶液或冻干制剂的形式。In some embodiments of the present application, the antibody or antigen-binding fragment thereof of the present application having the required purity and one or more optional pharmaceutical excipients (see Remington's Pharmaceutical Sciences, 16th edition, Osol, A. Editor, 1980) mixed to prepare the pharmaceutical composition of the present application, preferably, the pharmaceutical composition of the present application may be in the form of an aqueous solution or a lyophilized formulation.
本申请的药物组合物或制剂还可以包含一种或多种其它活性成分，所述活性成分可以根据特定适应症选择，优选地，所述活性成分不会不利地影响彼此的活性。在一些实施方式中，其它的活性成分可以为化疗剂、免疫检查点抑制剂、生长抑制剂、抗生素或已知的各种抗肿瘤或抗癌剂，所述活性成分可以以对于目的用途有效的量组合存在。The pharmaceutical composition or preparation of the present application may also contain one or more other active ingredients, which can be selected according to specific indications, preferably, the active ingredients will not adversely affect each other's activities. In some embodiments, other active ingredients can be chemotherapeutic agents, immune checkpoint inhibitors, growth inhibitors, antibiotics or various known anti-tumor or anti-cancer agents, and the active ingredients can be effective for the intended use Quantitative combinations exist.
在又一个方面，本申请提供了一种试剂盒，其包括本申请的抗体或其抗原结合片段、多核苷酸分子、表达载体、宿主细胞、药物偶联物或药物组合物。In yet another aspect, the present application provides a kit comprising the antibody or antigen-binding fragment thereof, polynucleotide molecule, expression vector, host cell, drug conjugate or pharmaceutical composition of the present application.
医药用途medical use
在又一个方面，本申请提供了本申请的抗体或其抗原结合片段、多核苷酸分子、表达载体、宿主细胞、药物偶联物或药物组合物在制备用于治疗或预防BCMA介导的疾病或病症的药物中的用途。In yet another aspect, the application provides the antibody or its antigen-binding fragment, polynucleotide molecule, expression vector, host cell, drug conjugate or pharmaceutical composition of the application in the preparation for the treatment or prevention of BCMA-mediated diseases or use in medicine for a disease.
在又一个方面，本申请提供了本申请的抗体或其抗原结合片段、多核苷酸分子、表达载体、宿主细胞、药物偶联物或药物组合物用于治疗或预防BCMA介导的疾病或病症的用途。In yet another aspect, the application provides the antibody or its antigen-binding fragment, polynucleotide molecule, expression vector, host cell, drug conjugate or pharmaceutical composition of the application for the treatment or prevention of BCMA-mediated diseases or disorders the use of.
在又一个方面，本申请提供了一种治疗或预防BCMA介导的疾病或病症的方法，其包括向有需要的受试者施用本申请所提供的抗体或其抗原结合片段、多核苷酸分子、表达载 体、宿主细胞、药物偶联物或药物组合物。In yet another aspect, the present application provides a method for treating or preventing BCMA-mediated diseases or disorders, comprising administering the antibody or its antigen-binding fragment or polynucleotide molecule provided in the present application to a subject in need , expression vector, host cell, drug conjugate or pharmaceutical composition.
在一些实施方式中，所述BCMA介导的疾病为癌症或自身免疫病。In some embodiments, the BCMA-mediated disease is cancer or an autoimmune disease.
在一些实施方式中，给药方式包括但不限于口服、静脉内给药、皮下给药、肌内给药、动脉内给药、关节内给药(例如在关节炎关节中给药)、吸入给药、气雾剂递送或肿瘤内给药等。In some embodiments, modes of administration include, but are not limited to, oral, intravenous, subcutaneous, intramuscular, intraarterial, intraarticular (e.g., in arthritic joints), inhalation drug delivery, aerosol delivery or intratumoral administration, etc.
用于诊断和检测的方法Methods for diagnosis and detection
在又一个方面，本申请提供了一种使用本申请的抗体或其抗原结合片段检测BCMA的方法，包括使所述抗体或其抗原结合片段与样品接触，检测所述抗体或其抗原结合片段与BCMA形成的结合物，以及任选地对所述结合物进行定量测定。术语“检测”用于本申请中时，可以包括定量或定性检测。在一些实施方式中，所述样品是生物样品。在某些实施方式中，生物样品是血、血清或生物来源的其他液体样品。在某些实施方式中，生物样品包含细胞或组织。本申请对检测所述抗体或其抗原结合片段与BCMA形成的结合物的方法不做限定；本申请对所述“对所述结合物进行定量测定”的方法不做限定。In yet another aspect, the application provides a method for detecting BCMA using the antibody or antigen-binding fragment thereof of the application, comprising contacting the antibody or antigen-binding fragment thereof with a sample, detecting the antibody or antigen-binding fragment thereof and Conjugates formed by BCMA, and optionally quantifying said conjugates. The term "detection" as used in this application may include quantitative or qualitative detection. In some embodiments, the sample is a biological sample. In certain embodiments, the biological sample is blood, serum, or other liquid sample of biological origin. In certain embodiments, a biological sample comprises cells or tissues. This application does not limit the method for detecting the conjugate formed by the antibody or its antigen-binding fragment and BCMA; this application does not limit the method for "quantitatively determining the conjugate".
在又一个方面，本申请提供了一种使用本申请的抗体或其抗原结合片段检测BCMA的方法，包括使所述抗体或其抗原结合片段与样品接触，检测所述抗体或其抗原结合片段与BCMA形成的结合物，以及任选地对所述结合物进行定量测定。术语“检测”用于本申请中时，可以包括定量或定性检测。在一些实施方式中，所述样品是生物样品。在某些实施方式中，生物样品是血、血清或生物来源的其他液体样品。在某些实施方式中，生物样品包含细胞或组织。本申请对检测所述抗体或其抗原结合片段与BCMA形成的结合物的方法不做限定；本申请对所述“对所述结合物进行定量测定”的方法不做限定。In yet another aspect, the present application provides a method for detecting BCMA using the antibody or antigen-binding fragment thereof of the present application, comprising contacting the antibody or antigen-binding fragment thereof with a sample, detecting the antibody or antigen-binding fragment thereof and Conjugates formed by BCMA, and optionally quantifying said conjugates. The term "detection" as used in this application may include quantitative or qualitative detection. In some embodiments, the sample is a biological sample. In certain embodiments, the biological sample is blood, serum, or other liquid sample of biological origin. In certain embodiments, a biological sample comprises cells or tissues. This application does not limit the method for detecting the conjugate formed by the antibody or its antigen-binding fragment and BCMA; this application does not limit the method for "quantitatively determining the conjugate".
为使本申请的目的、技术方案、及优点更加清楚明白，以下参照附图并举实施例，对本申请进一步详细说明。显然，所描述的实施例仅仅是本申请一部分实施例，而不是全部的实施例。本领域普通技术人员基于本申请中的实施例所获得的所有其他实施例，都属于本申请保护的范围。In order to make the purpose, technical solution, and advantages of the present application clearer, the present application will be further described in detail below with reference to the accompanying drawings and examples. Apparently, the described embodiments are only some of the embodiments of this application, not all of them. All other embodiments obtained by persons of ordinary skill in the art based on the embodiments in this application belong to the protection scope of this application.
实施例1：杂交瘤的方法产生抗人BCMA的单克隆抗体Example 1: Hybridoma Method to Produce Monoclonal Antibody Against Human BCMA
采用重组人BCMA抗原蛋白的胞外区(序列参考Uniprot数据库，编号Q02223)蛋白的三聚体(his标签)对6-8周龄的小鼠(北京维通利华实验动物技术有限公司)和大鼠(北京维通利华实验动物技术有限公司)进行免疫。首次用完全弗氏佐剂按照50微克人重组BCMA蛋白抗原每只小鼠的剂量进行，第2次以及后续的免疫采用不完全弗氏佐剂混合25微克人重组BCMA蛋白抗原每只小鼠的剂量进行。小鼠免疫时间点分别在第0天、第14天、第28天和第49天。Using the trimer (his tag) of the extracellular region of recombinant human BCMA antigen protein (sequence reference Uniprot database, numbering Q02223) protein to mice (Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) and 6-8 weeks old Rats (Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) were immunized. For the first time, complete Freund's adjuvant was used according to the dose of 50 micrograms of human recombinant BCMA protein antigen per mouse, and the second and subsequent immunizations were mixed with incomplete Freund's adjuvant with 25 micrograms of human recombinant BCMA protein antigen per mouse. Dosing is carried out. The mice were immunized at day 0, day 14, day 28 and day 49, respectively.
免疫4次后取小鼠尾血并检测血清中BCMA抗体的滴度，选择血清中BCMA抗体滴度最高的小鼠或者大鼠，分离其脾脏细胞，之后与小鼠骨髓瘤细胞SP2/0融合，铺板并在HAT选择培养基中培养10～14天后，选择培养上清跟人BCMA和食蟹猴BCMA结合双阳性的孔进行亚克隆，然后选择亚克隆后保持人BCMA和食蟹猴BCMA结合双阳性的单克隆，用sanger测序法获得抗人BCMA鼠源抗体的可变区序列。抗人BCMA鼠源抗体的轻链和重链可变区及CDR的氨基酸序列如表1所示。After 4 times of immunization, the mouse tail blood was taken and the titer of BCMA antibody in the serum was detected. The mouse or rat with the highest titer of BCMA antibody in the serum was selected, and its spleen cells were isolated, and then fused with mouse myeloma cell SP2/0 , plated and cultured in HAT selection medium for 10-14 days, select the wells with double positive binding to human BCMA and cynomolgus monkey BCMA from the culture supernatant for subcloning, and then select the subclones to maintain the double positive binding to human BCMA and cynomolgus monkey BCMA The monoclonal sequence of the anti-human BCMA murine antibody was obtained by sanger sequencing. The amino acid sequences of the light and heavy chain variable regions and CDRs of the anti-human BCMA murine antibody are shown in Table 1.
表1：抗人BCMA鼠源抗体的CDR和可变区氨基酸序列(KABAT方案)Table 1: CDR and variable region amino acid sequences of anti-human BCMA murine antibody (KABAT scheme)
Figure PCTCN2022140660-appb-000001
Figure PCTCN2022140660-appb-000001
Figure PCTCN2022140660-appb-000002
Figure PCTCN2022140660-appb-000002
实施例2：抗人BCMA嵌合抗体和BCMA的结合检测实验Embodiment 2: the binding detection experiment of anti-human BCMA chimeric antibody and BCMA
将抗人BCMA鼠源单克隆抗体的可变区序列亚克隆到人IgG1/Kappa的骨架上，在HEK293系统中表达并纯化，得到抗人BCMA嵌合抗体BCMA-005、BCMA-011、BCMA-017、BCMA-021、BCMA-027、BCMA-037、BCMA-040、BCMA-050、BCMA-051和BCMA-060。用ELISA的方法检测嵌合抗体对人BCMA(hBCMA)和食蟹猴BCMA(cynoBCMA)的结合活性，检测方法如下。The variable region sequence of the anti-human BCMA mouse monoclonal antibody was subcloned into the backbone of human IgG1/Kappa, expressed and purified in the HEK293 system to obtain anti-human BCMA chimeric antibodies BCMA-005, BCMA-011, BCMA- 017, BCMA-021, BCMA-027, BCMA-037, BCMA-040, BCMA-050, BCMA-051 and BCMA-060. The binding activity of the chimeric antibody to human BCMA (hBCMA) and cynomolgus monkey BCMA (cynoBCMA) was detected by ELISA, and the detection method was as follows.
加入1μg/mL兔抗his抗体(cat#：A01856，金斯瑞)于ELISA板中，4度包被过夜。第二天用PBS*T(PBS(磷酸盐缓冲液)+0.5v/v‰吐温20)洗板3次，加入含有5wt％脱脂奶粉的PBS(磷酸盐缓冲液)，室温封闭1小时。随后PBS*T洗板三次，加入1μg/mL人BCMA-his(cat#：BCA-H522y，acrobiosystems)溶液，室温孵育一小时。随后PBS*T洗板三次，加入梯度稀释的抗人BCMA嵌合抗体溶液(起始浓度20μg/mL，3倍梯度稀释)，室温孵育一小时。随后PBS*T洗板三次，加入1：5000稀释的辣根过氧化物酶标记的山羊抗人IgG抗体(cat#：SAB3701274，sigma)，室温孵育1小时。PBS*T洗板三次，加入TMB(3,3',5,5'-四甲基联苯胺)显色5分钟，并用酶标仪读取OD 450nm数值。 Add 1 μg/mL rabbit anti-his antibody (cat#: A01856, GenScript) to the ELISA plate, and coat at 4 degrees overnight. The next day, the plate was washed 3 times with PBS*T (PBS (phosphate buffer saline)+0.5v/v‰Tween 20), added PBS (phosphate buffer saline) containing 5wt% skim milk powder, and blocked at room temperature for 1 hour. Then the plate was washed three times with PBS*T, 1 μg/mL human BCMA-his (cat#: BCA-H522y, acrobiosystems) solution was added, and incubated at room temperature for one hour. Then the plate was washed three times with PBS*T, and a serially diluted anti-human BCMA chimeric antibody solution (initial concentration 20 μg/mL, 3-fold serial dilution) was added, and incubated at room temperature for one hour. Then wash the plate three times with PBS*T, add 1:5000 dilution of horseradish peroxidase-labeled goat anti-human IgG antibody (cat#: SAB3701274, sigma), and incubate at room temperature for 1 hour. Wash the plate three times with PBS*T, add TMB (3,3',5,5'-tetramethylbenzidine) to develop color for 5 minutes, and read the OD 450nm value with a microplate reader.
Belantamab(贝兰他单抗)为阳性对照抗体，序列来自于INN10797，君实生物自制(参见专利WO2012163805A1和CN103562225B)。Belantamab (Belantamab) is a positive control antibody whose sequence is from INN10797 and made by Junshi Biotechnology (see patents WO2012163805A1 and CN103562225B).
图1A至图1G分别展示了10个抗人BCMA嵌合抗体和hBCMA的结合情况，相应的EC 50(半最大效应浓度)值统计在了表2A至表2G中；采用同样的检测方法检测抗人BCMA嵌合抗体和食蟹猴BCMA的结合情况，相应的EC 50值统计在了表2A至表2G中。结果显示10个抗人BCMA嵌合抗体与hBCMA和cynoBCMA均有较好的结合活性。 Figure 1A to Figure 1G show the binding situation of 10 anti-human BCMA chimeric antibodies and hBCMA respectively, and the corresponding EC 50 (half maximum effect concentration) values are listed in Table 2A to Table 2G; The binding conditions of human BCMA chimeric antibody and cynomolgus monkey BCMA, and the corresponding EC 50 values are summarized in Table 2A to Table 2G. The results showed that 10 anti-human BCMA chimeric antibodies had good binding activity to hBCMA and cynoBCMA.
表2A：抗人BCMA嵌合抗体与hBCMA和cynoBCMA的结合活性Table 2A: Binding activity of anti-human BCMA chimeric antibodies to hBCMA and cynoBCMA
Figure PCTCN2022140660-appb-000003
Figure PCTCN2022140660-appb-000003
表2B：抗人BCMA嵌合抗体与hBCMA和cynoBCMA的结合活性Table 2B: Binding activity of anti-human BCMA chimeric antibodies to hBCMA and cynoBCMA
Figure PCTCN2022140660-appb-000004
Figure PCTCN2022140660-appb-000004
表2C：抗人BCMA嵌合抗体与hBCMA和cynoBCMA的结合活性Table 2C: Binding activity of anti-human BCMA chimeric antibodies to hBCMA and cynoBCMA
Figure PCTCN2022140660-appb-000005
Figure PCTCN2022140660-appb-000005
表2D：抗人BCMA嵌合抗体与hBCMA和cynoBCMA的结合活性Table 2D: Binding activity of anti-human BCMA chimeric antibodies to hBCMA and cynoBCMA
Figure PCTCN2022140660-appb-000006
Figure PCTCN2022140660-appb-000006
表2E：抗人BCMA嵌合抗体与hBCMA和cynoBCMA的结合活性Table 2E: Binding activity of anti-human BCMA chimeric antibodies to hBCMA and cynoBCMA
Figure PCTCN2022140660-appb-000007
Figure PCTCN2022140660-appb-000007
表2F：抗人BCMA嵌合抗体与hBCMA和cynoBCMA的结合活性Table 2F: Binding activity of anti-human BCMA chimeric antibodies to hBCMA and cynoBCMA
Figure PCTCN2022140660-appb-000008
Figure PCTCN2022140660-appb-000008
表2G：抗人BCMA嵌合抗体与hBCMA和cynoBCMA的结合活性Table 2G: Binding activity of anti-human BCMA chimeric antibodies to hBCMA and cynoBCMA
Figure PCTCN2022140660-appb-000009
Figure PCTCN2022140660-appb-000009
实施例3：抗人BCMA嵌合抗体与BCMA配体APRIL(增殖诱导配体)和BAFF(B细胞活化因子)竞争性结合实验Example 3: Competitive binding experiment between anti-human BCMA chimeric antibody and BCMA ligand APRIL (proliferation-inducing ligand) and BAFF (B cell activating factor)
采用ELISA方法检测抗人BCMA嵌合抗体与BCMA配体APRIL和BAFF竞争性结合BCMA的活性，检测方法具体描述如下。The ELISA method was used to detect the activity of the anti-human BCMA chimeric antibody competitively binding to BCMA with the BCMA ligands APRIL and BAFF, and the detection method was specifically described as follows.
加入1μg/mL兔抗his抗体(cat#：A01856，金斯瑞)于ELISA板中，4度包被过夜。第二天用PBS*T洗包被板3次，加入含有5wt％脱脂奶粉的PBS，室温封闭1小时。PBS*T洗板三次，加入1μg/mL人BCMA-his溶液(cat#：BCA-H522y，acrobiosystems)，室温孵育一小时。PBS*T洗板三次，加入梯度稀释的抗人BCMA嵌合抗体溶液(起始浓度20μg/mL， 3倍梯度稀释)，室温孵育一小时。PBS*T洗板三次，加入1μg/mL生物素标记的APRIL(cat#：APL-H82F5，acrobiosystems)，室温孵育一小时。PBS*T洗板三次，加入1：1000稀释的辣根过氧化物酶标记的山羊抗生物素抗体(cat#：A4541，sigma)，室温孵育1小时。PBS*T洗板三次，加入TMB显色并用酶标仪读取OD 450nm的数值。 Add 1 μg/mL rabbit anti-his antibody (cat#: A01856, GenScript) to the ELISA plate, and coat at 4 degrees overnight. The next day, the coated plate was washed 3 times with PBS*T, PBS containing 5 wt% skimmed milk powder was added, and blocked at room temperature for 1 hour. Wash the plate three times with PBS*T, add 1 μg/mL human BCMA-his solution (cat#: BCA-H522y, acrobiosystems), and incubate at room temperature for one hour. Wash the plate three times with PBS*T, add a serially diluted anti-human BCMA chimeric antibody solution (initial concentration 20 μg/mL, 3-fold serial dilution), and incubate at room temperature for one hour. Wash the plate three times with PBS*T, add 1 μg/mL biotin-labeled APRIL (cat#: APL-H82F5, acrobiosystems), and incubate at room temperature for one hour. Wash the plate three times with PBS*T, add horseradish peroxidase-labeled goat anti-biotin antibody (cat#: A4541, sigma) diluted 1:1000, and incubate at room temperature for 1 hour. Wash the plate three times with PBS*T, add TMB for color development and read the value of OD 450nm with a microplate reader.
Belantamab为阳性对照抗体，序列来自于INN10797，君实生物自制(参见专利WO2012163805A1和CN103562225B)。Belantamab is a positive control antibody whose sequence is from INN10797, made by Junshi Biotech (see patents WO2012163805A1 and CN103562225B).
10个抗人BCMA嵌合抗体对APRIL结合BCMA的阻断作用相应的IC 50(半抑制浓度)值统计在表3A至表3F中；采用同样的检测条件检测10个抗人BCMA嵌合抗体对BAFF(cat#：BAF-H82F3，acrobiosystems)结合BCMA的阻断作用，图2A至图2F分别展示了10个抗人BCMA嵌合抗体阻断BAFF与BCMA结合情况，相应的IC 50值统计在表3A至表3F中。结果显示10个抗人BCMA嵌合抗体均能够有效阻断BCMA与配体APRIL和BAFF的结合。 The corresponding IC 50 (half inhibitory concentration) values of 10 anti-human BCMA chimeric antibodies to the blocking effect of APRIL on BCMA are listed in Table 3A to Table 3F; The blocking effect of BAFF (cat#: BAF-H82F3, acrobiosystems) binding to BCMA. Figure 2A to Figure 2F respectively show the blocking effect of 10 anti-human BCMA chimeric antibodies on the binding of BAFF to BCMA. The corresponding IC 50 values are listed in the table 3A to Table 3F. The results showed that all 10 anti-human BCMA chimeric antibodies could effectively block the binding of BCMA to ligands APRIL and BAFF.
表3A：抗人BCMA嵌合抗体竞争APRIL和BAFF与hBCMA结合的活性Table 3A: The activity of anti-human BCMA chimeric antibodies to compete for the binding of APRIL and BAFF to hBCMA
Figure PCTCN2022140660-appb-000010
Figure PCTCN2022140660-appb-000010
表3B：抗人BCMA嵌合抗体竞争APRIL和BAFF与hBCMA结合的活性Table 3B: Anti-human BCMA chimeric antibodies compete for the binding activity of APRIL and BAFF to hBCMA
Figure PCTCN2022140660-appb-000011
Figure PCTCN2022140660-appb-000011
表3C：抗人BCMA嵌合抗体竞争APRIL和BAFF与hBCMA结合的活性Table 3C: The activity of anti-human BCMA chimeric antibodies to compete for the binding of APRIL and BAFF to hBCMA
Figure PCTCN2022140660-appb-000012
Figure PCTCN2022140660-appb-000012
表3D：抗人BCMA嵌合抗体竞争APRIL和BAFF与hBCMA结合的活性Table 3D: Anti-human BCMA chimeric antibodies compete for the binding activity of APRIL and BAFF to hBCMA
Figure PCTCN2022140660-appb-000013
Figure PCTCN2022140660-appb-000013
表3E：抗人BCMA嵌合抗体竞争APRIL和BAFF与hBCMA结合的活性Table 3E: Anti-human BCMA chimeric antibodies compete for the binding activity of APRIL and BAFF to hBCMA
Figure PCTCN2022140660-appb-000014
Figure PCTCN2022140660-appb-000014
表3F：抗人BCMA嵌合抗体竞争APRIL和BAFF与hBCMA结合的活性Table 3F: Anti-human BCMA chimeric antibodies compete for the binding activity of APRIL and BAFF to hBCMA
Figure PCTCN2022140660-appb-000015
Figure PCTCN2022140660-appb-000015
实施例4：抗人BCMA嵌合抗体的人源化Example 4: Humanization of anti-human BCMA chimeric antibody
选择抗人BCMA嵌合抗体BCMA-005、BCMA-017、BCMA-021、BCMA-027、BCMA-040、BCMA-050、BCMA-051和BCMA-060进行人源化。抗体的人源化所选择的germline(胚系突变)和回复突变的位点如表4所示，CDR序列用下划线标出，重链CDR1前的移植序列(hCDR1前面5个氨基酸)用斜体加粗标记，PTM突变为加粗字体标记，回复突变为斜体标记。抗人BCMA的人源化抗体的序列见表5-1和表5-2。Anti-human BCMA chimeric antibodies BCMA-005, BCMA-017, BCMA-021, BCMA-027, BCMA-040, BCMA-050, BCMA-051 and BCMA-060 were selected for humanization. The selected germline (germline mutation) and reverse mutation sites for antibody humanization are shown in Table 4, the CDR sequence is underlined, and the transplanted sequence before the heavy chain CDR1 (the first 5 amino acids of hCDR1) is italicized Bold marks, PTM mutations are marked in bold font, back mutations are marked in italics. The sequences of humanized antibodies against human BCMA are shown in Table 5-1 and Table 5-2.
以BCMA-005的人源化为例说明人源化的方法和步骤。利用MOE软件(分子模拟及药物设计综合软件)进行人源化设计，BCMA-005的重链和轻链的可变区序列导入MOE，并对其进行建模(模板为3U0W)，找出抗体的Framework(框架区)关键性位点，作为回复突变的参考。对人的germline的库进行搜索和对比，基于抗体序列的相似性程度，选择轻链IGKV1-39*01和重链IGHV3-7*01、3-21*01与IGHV3-23*04为模板，将鼠源抗体的CDR(Kabat编号系统)和重链CDR1之前5个氨基酸移植到人的germline上，获得人源化抗体序列。为保持人源化抗体的人源化抗体命名时的前缀hu代表人源化，后面的数字代表人源化抗体的序列号。比如BCMA-005-hu160，BCMA-005-hu178，BCMA-005-hu190，最后的字母代表PTM突变。将人源化抗体序列克隆进人IgG1/kappa的骨架中，在HEK293的表达系统中表达并纯化人源化抗体。Taking the humanization of BCMA-005 as an example to illustrate the method and steps of humanization. Use MOE software (molecular simulation and drug design comprehensive software) for humanization design, import the variable region sequences of the heavy chain and light chain of BCMA-005 into MOE, and model it (the template is 3U0W), and find out the antibody The key sites of the Framework (framework region) are used as a reference for back mutations. Search and compare the library of human germline, and select the light chain IGKV1-39*01 and the heavy chain IGHV3-7*01, 3-21*01 and IGHV3-23*04 as templates based on the similarity of antibody sequences. The CDR (Kabat numbering system) of the murine antibody and the first 5 amino acids of the heavy chain CDR1 are grafted onto the human germline to obtain the humanized antibody sequence. The prefix hu when naming a humanized antibody that maintains a humanized antibody represents humanization, and the following number represents the sequence number of the humanized antibody. For example, BCMA-005-hu160, BCMA-005-hu178, BCMA-005-hu190, the last letter represents the PTM mutation. The humanized antibody sequence was cloned into the backbone of human IgG1/kappa, expressed and purified in the HEK293 expression system.
表4：抗人BCMA的人源化抗体可变区序列Table 4: Variable region sequences of humanized antibodies against human BCMA
Figure PCTCN2022140660-appb-000016
Figure PCTCN2022140660-appb-000016
Figure PCTCN2022140660-appb-000017
Figure PCTCN2022140660-appb-000017
Figure PCTCN2022140660-appb-000018
Figure PCTCN2022140660-appb-000018
Figure PCTCN2022140660-appb-000019
Figure PCTCN2022140660-appb-000019
Figure PCTCN2022140660-appb-000020
Figure PCTCN2022140660-appb-000020
表5-1：抗人BCMA的人源化抗体的CDR氨基酸序列(KABAT方案)Table 5-1: CDR amino acid sequences of humanized antibodies against human BCMA (KABAT scheme)
Figure PCTCN2022140660-appb-000021
Figure PCTCN2022140660-appb-000021
Figure PCTCN2022140660-appb-000022
Figure PCTCN2022140660-appb-000022
表5-2：抗人BCMA的人源化抗体的可变区和全长氨基酸序列Table 5-2: Variable regions and full-length amino acid sequences of humanized antibodies against human BCMA
Figure PCTCN2022140660-appb-000023
Figure PCTCN2022140660-appb-000023
实施例5：抗人BCMA抗体的人源化抗体的细胞表面BCMA结合检测Example 5: Cell surface BCMA binding detection of humanized antibodies against human BCMA antibodies
采用FACs方法测定抗人BCMA抗体的人源化抗体与表达人BCMA的MM.1S细胞的结合，具体方法如下。The FACs method was used to measure the binding of the humanized antibody against human BCMA antibody to the MM.1S cells expressing human BCMA, and the specific method was as follows.
将生长良好的MM1S细胞1000rpm离心并收获细胞，用FACs溶液(DPBS(杜氏磷酸盐缓冲液)+2v/v％FBS(胎牛血清))将细胞密度调整为50000个每孔。在冰上将梯度稀释好的抗人BCMA抗体的人源化抗体(起始浓度20μg/mL，3倍梯度稀释)与MM.1S细胞孵育60分钟。用预冷的FACs溶液洗涤细胞两次，随后与1：1000稀释的PE(荧光素)标记的抗人IgG二抗(cat#：409304，biolegend)置于冰上孵育半小时。两次洗涤后，重悬，使用赛多利斯
Figure PCTCN2022140660-appb-000024
iQue3流式细胞仪检测荧光信号。 The well-grown MM1S cells were centrifuged at 1000 rpm and the cells were harvested, and the cell density was adjusted to 50000 cells per well with FACs solution (DPBS (Duchener's phosphate buffered saline) + 2v/v% FBS (fetal bovine serum)). Incubate the serially diluted humanized antibody against human BCMA antibody (initial concentration 20 μg/mL, 3-fold serial dilution) with MM.1S cells for 60 minutes on ice. The cells were washed twice with pre-cooled FACs solution, and then incubated with PE (fluorescein)-labeled anti-human IgG secondary antibody (cat#: 409304, biolegend) diluted 1:1000 on ice for half an hour. After two washes, resuspend, use Sartorius
Figure PCTCN2022140660-appb-000024
Fluorescence signal was detected by iQue3 flow cytometer.
Belantamab为阳性对照抗体，序列来自于INN10797，君实生物自制(参见专利WO2012163805A1和CN103562225B)。Belantamab is a positive control antibody whose sequence is from INN10797, made by Junshi Biotech (see patents WO2012163805A1 and CN103562225B).
图3A至图3I分别展示了抗人BCMA抗体的人源化抗体与MM.1S细胞的结合情况， 相应的EC 50统计在了表6A至表6I中。结果显示，抗人BCMA抗体的人源化抗体均能够以高亲和力结合表达人BCMA的MM.1S细胞，且相当或优于对照抗体。 Figure 3A to Figure 3I respectively show the binding of the humanized antibody against human BCMA antibody to MM.1S cells, and the corresponding EC 50 statistics are listed in Table 6A to Table 6I. The results showed that all the humanized antibodies against human BCMA antibodies could bind to MM.1S cells expressing human BCMA with high affinity, which was equivalent to or better than the control antibody.
表6A：抗人BCMA抗体的人源化抗体与MM.1S细胞的结合Table 6A: Binding of humanized antibodies against human BCMA antibodies to MM.1S cells
抗体Antibody EC 50(μg/mL) EC50 (μg/mL)
BelantamabBelantamab 1.3881.388
BCMA-005-hu160BCMA-005-hu160 1.8291.829
BCMA-005-hu178BCMA-005-hu178 1.5281.528
BCMA-005-hu190BCMA-005-hu190 1.421.42
表6B：抗人BCMA抗体的人源化抗体与MM.1S细胞的结合Table 6B: Binding of humanized antibodies against human BCMA antibodies to MM.1S cells
抗体Antibody EC 50(μg/mL) EC50 (μg/mL)
BelantamabBelantamab 2.6822.682
BCMA-017-hu914DEBCMA-017-hu914DE 1.7761.776
BCMA-017-hu923DEBCMA-017-hu923DE 1.9271.927
BCMA-017-hu937DEBCMA-017-hu937DE 1.5031.503
BCMA-017-hu938DEBCMA-017-hu938DE 2.0072.007
表6C：抗人BCMA抗体的人源化抗体与MM.1S细胞的结合Table 6C: Binding of humanized antibodies against human BCMA antibodies to MM.1S cells
抗体Antibody EC 50(μg/mL) EC50 (μg/mL)
BelantamabBelantamab 1.3881.388
BCMA-021-hu145BCMA-021-hu145 2.6092.609
BCMA-021-hu147BCMA-021-hu147 3.9213.921
BCMA-021-hu151BCMA-021-hu151 3.1033.103
表6D：抗人BCMA抗体的人源化抗体与MM.1S细胞的结合Table 6D: Binding of humanized antibodies against human BCMA antibodies to MM.1S cells
抗体Antibody EC 50(μg/mL) EC50 (μg/mL)
BelantamabBelantamab 1.0891.089
BCMA-027-hu215BCMA-027-hu215 1.1761.176
BCMA-027-hu216BCMA-027-hu216 1.611.61
BCMA-027-hu217BCMA-027-hu217 1.5761.576
表6E：抗人BCMA抗体的人源化抗体与MM.1S细胞的结合Table 6E: Binding of humanized antibodies against human BCMA antibodies to MM.1S cells
抗体Antibody EC 50(μg/mL) EC50 (μg/mL)
BelantamabBelantamab 2.2192.219
BCMA-040-hu304-DLT/DABCMA-040-hu304-DLT/DA 0.11630.1163
BCMA-040-hu306-DLT/DABCMA-040-hu306-DLT/DA 0.77010.7701
表6F：抗人BCMA抗体的人源化抗体与MM.1S细胞的结合Table 6F: Binding of humanized antibodies against human BCMA antibodies to MM.1S cells
抗体Antibody EC 50(μg/mL) EC50 (μg/mL)
BelantamabBelantamab 2.9422.942
BCMA-050-hu506-AEBCMA-050-hu506-AE 0.14560.1456
BCMA-050-hu514-AEBCMA-050-hu514-AE 0.54790.5479
BCMA-050-hu515-AEBCMA-050-hu515-AE 0.8670.867
BCMA-050-hu517-AEBCMA-050-hu517-AE 1.0631.063
表6G：抗人BCMA抗体的人源化抗体与MM.1S细胞的结合Table 6G: Binding of humanized antibodies against human BCMA antibodies to MM.1S cells
抗体Antibody EC 50(μg/mL) EC50 (μg/mL)
BelantamabBelantamab 1.0891.089
BCMA-051-hu601BCMA-051-hu601 1.4321.432
BCMA-051-hu609BCMA-051-hu609 0.50230.5023
BCMA-051-hu613BCMA-051-hu613 1.4821.482
表6H：抗人BCMA抗体的人源化抗体与MM.1S细胞的结合Table 6H: Binding of humanized antibodies against human BCMA antibodies to MM.1S cells
抗体Antibody EC 50(μg/mL) EC50 (μg/mL)
BelantamabBelantamab 1.9921.992
BCMA-051-hu601-FTBCMA-051-hu601-FT 0.65690.6569
BCMA-051-hu601BCMA-051-hu601 0.66370.6637
表6I：抗人BCMA抗体的人源化抗体与MM.1S细胞的结合Table 6I: Binding of humanized antibodies against human BCMA antibodies to MM.1S cells
抗体Antibody EC 50(μg/mL) EC50 (μg/mL)
BelantamabBelantamab 1.0891.089
BCMA-060-hu810BCMA-060-hu810 1.3471.347
BCMA-060-hu811BCMA-060-hu811 2.372.37
BCMA-060-hu823BCMA-060-hu823 1.7461.746
实施例6：抗人BCMA抗体的人源化抗体的亲和力测定Example 6: Affinity determination of humanized antibodies against human BCMA antibodies
使用Biacore 8K(Cytiva)仪器检测抗人BCMA抗体的人源化抗体与人BCMA(human BCMA)及食蟹猴BCMA(Cyno BCMA)蛋白的亲和力。Belantamab为阳性对照抗体，序列来自于INN10797，君实生物自制(参见专利WO2012163805A1和CN103562225B)。测定方法如下。The affinity of the humanized antibody against human BCMA antibody to human BCMA (human BCMA) and cynomolgus monkey BCMA (Cyno BCMA) protein was detected using a Biacore 8K (Cytiva) instrument. Belantamab is a positive control antibody whose sequence is from INN10797, made by Junshi Biotech (see patents WO2012163805A1 and CN103562225B). The measurement method is as follows.
抗体用1×HBS-EP+(10mM HEPES(4-羟乙基哌嗪乙磺酸)+150mM NaCl+3mM EDTA+0.05％(v/v)表面活性剂P20(吐温20)，pH7.4)稀释成25nM。Human-BCMA-his(cat#：BCA-H522y，acrobiosystems)及Cyno-BCMA-his(cat#：BAR-C52H4，acrobiosystems)从100nM往下2倍稀释设8个浓度梯度与抗人BCMA抗体的人源化抗体结合，于1×HBS-EP+中解离，使用Biacore 8K(Cytiva)测量结合与解离信号，得到缔合速率常数(ka)和解离速率常数(kd)。1×HBS-EP+(10mM HEPES (4-hydroxyethylpiperazineethanesulfonic acid)+150mM NaCl+3mM EDTA+0.05% (v/v) surfactant P20 (Tween 20), pH7.4) for antibody Dilute to 25nM. Human-BCMA-his (cat#: BCA-H522y, acrobiosystems) and Cyno-BCMA-his (cat#: BAR-C52H4, acrobiosystems) were diluted 2-fold from 100nM down to 8 concentration gradients with human anti-human BCMA antibody The derivatized antibody was combined and dissociated in 1×HBS-EP+, and the association and dissociation signals were measured using Biacore 8K (Cytiva) to obtain the association rate constant (ka) and dissociation rate constant (kd).
使用软件按1:1模型拟合来确定亲和力KD值。表7A和表7B显示所有抗人BCMA人源化抗体与人BCMA及食蟹猴BCMA蛋白均具有较好的亲和力。Affinity KD values were determined using software to fit a 1:1 model. Table 7A and Table 7B show that all anti-human BCMA humanized antibodies have good affinity to human BCMA and cynomolgus monkey BCMA protein.
表7A：抗人BCMA抗体的人源化抗体与人BCMA蛋白结合亲和力Table 7A: Binding affinity of humanized antibodies against human BCMA antibodies to human BCMA protein
Figure PCTCN2022140660-appb-000025
Figure PCTCN2022140660-appb-000025
Figure PCTCN2022140660-appb-000026
Figure PCTCN2022140660-appb-000026
表7B：抗人BCMA抗体的人源化抗体与食蟹猴BCMA蛋白结合亲和力Table 7B: Binding affinity of humanized antibodies of anti-human BCMA antibodies to cynomolgus monkey BCMA protein
Figure PCTCN2022140660-appb-000027
Figure PCTCN2022140660-appb-000027
实施例7：抗人BCMA抗体的ADCC检测实验Embodiment 7: ADCC detection experiment of anti-human BCMA antibody
抗体依赖性细胞介导的细胞毒性作用(antibody-dependent cell-mediated cytotoxicity，ADCC)是指抗体的Fab段特异性结合靶细胞的抗原表位，而抗体的Fc段则与杀伤细胞(NK细胞、巨噬细胞等)表面的Fc受体结合，介导杀伤细胞直接杀伤靶细胞，其中NK细胞是 发挥ADCC作用的主要效应细胞。基于该原理，本申请采用了两种体外检测ADCC效应的实验体系。一种是Jurkat-ADCC报告基因检测系统，效应细胞为过表达FcγRIIIa和下游荧光报告基因的Jurkat-ADCC细胞，靶细胞分别为三种高表达BCMA的多发性骨髓瘤细胞系NCI-H929、MM.1R以及MM.1S(均购自ATCC细胞库)，通过测定效应细胞的荧光报告基因的表达来反映抗体的ADCC活性。另一种是用人外周血单核细胞(peripheral blood mononuclear cell，PBMC)为效应细胞，通过测定靶细胞(NCI-H929、MM.1R、MM.1S)的杀伤来反映抗体的ADCC活性。Antibody-dependent cell-mediated cytotoxicity (ADCC) means that the Fab segment of the antibody specifically binds to the epitope of the target cell, while the Fc segment of the antibody interacts with the killer cells (NK cells, Fc receptors on the surface of macrophages, etc.) mediate killer cells to directly kill target cells, and NK cells are the main effector cells that play ADCC. Based on this principle, the present application adopts two experimental systems for in vitro detection of ADCC effect. One is the Jurkat-ADCC reporter gene detection system. The effector cells are Jurkat-ADCC cells overexpressing FcγRIIIa and downstream fluorescent reporter genes. The target cells are three multiple myeloma cell lines NCI-H929 and MM. 1R and MM.1S (both purchased from the ATCC cell bank) reflect the ADCC activity of the antibody by measuring the expression of the fluorescent reporter gene of the effector cells. The other is to use human peripheral blood mononuclear cells (PBMC) as effector cells to reflect the ADCC activity of the antibody by measuring the killing of target cells (NCI-H929, MM.1R, MM.1S).
7.1抗人BCMA嵌合抗体的ADCC效应检测(报告基因法)7.1 Detection of ADCC effect of anti-human BCMA chimeric antibody (reporter gene method)
按照效靶比2：1，将效应细胞和靶细胞密度分别调整为7.5×10 6细胞/mL，靶细胞调整为3.75×10 6细胞/mL。然后将效应细胞和靶细胞按体积1：1混合，向96孔细胞培养板中，加入40μL细胞混合液，其中每孔包括效应细胞150，000个，靶细胞75，000个。配置2倍分析浓度的抗人BCMA嵌合抗体溶液(起始浓度为10μg/mL，5倍浓度稀释，共8个点)，每孔加40μL相应的已配置好的抗体溶液，并于在37℃，5％CO 2(体积分数)条件下培养6小时。之后，取出96孔细胞培养板，室温平衡10～15分钟，然后每孔加入40μL ONE-GLO荧光素酶检测试剂(Promega)，并置于摇床上避光孵育5～10min(转速为350rpm)。最后用多功能酶标仪读板和GraphPad Prism软件进行数据分析处理。 According to the effect-to-target ratio of 2:1, the density of effector cells and target cells was adjusted to 7.5×10 6 cells/mL, and the density of target cells was adjusted to 3.75×10 6 cells/mL. Then the effector cells and target cells were mixed at a volume ratio of 1:1, and 40 μL of the cell mixture was added to a 96-well cell culture plate, wherein each well contained 150,000 effector cells and 75,000 target cells. Prepare an anti-human BCMA chimeric antibody solution at 2 times the concentration of the assay (initial concentration is 10 μg/mL, diluted 5 times, 8 points in total), add 40 μL of the corresponding prepared antibody solution to each well, and incubate at 37 Cultivate for 6 hours under the condition of 5% CO 2 (volume fraction). Afterwards, take out the 96-well cell culture plate, equilibrate at room temperature for 10-15 minutes, then add 40 μL ONE-GLO luciferase detection reagent (Promega) to each well, and incubate on a shaker in the dark for 5-10 minutes (350 rpm). Finally, the plate was read with a multifunctional microplate reader and the GraphPad Prism software was used for data analysis and processing.
Belantamab为阳性对照抗体，序列来自于INN10797，君实生物自制(参见专利WO2012163805A1和CN103562225B)。Belantamab is a positive control antibody whose sequence is from INN10797, made by Junshi Biotech (see patents WO2012163805A1 and CN103562225B).
图4A至图4C分别展示了6个抗人BCMA嵌合抗体在分别以NCI-H929、MM.1R以及MM.1S为靶细胞的情况下，在ADCC报告基因方法中检测的结果，其中isotype ctrl为同型对照组。相应EC 50值列在了在表8中，结果显示6个抗人BCMA嵌合抗体ADCC活性均优于对照抗体。 Figure 4A to Figure 4C show the results of the detection of six anti-human BCMA chimeric antibodies in the case of NCI-H929, MM.1R and MM.1S respectively in the ADCC reporter gene method, where isotype ctrl For the same type control group. The corresponding EC 50 values are listed in Table 8, and the results show that the ADCC activities of the six anti-human BCMA chimeric antibodies are better than those of the control antibody.
表8：嵌合抗体的ADCC效应(报告基因法)Table 8: ADCC effect of chimeric antibodies (reporter gene method)
Figure PCTCN2022140660-appb-000028
Figure PCTCN2022140660-appb-000028
7.2抗人BCMA嵌合抗体的ADCC效应检测(PBMC杀伤实验)7.2 Detection of ADCC effect of anti-human BCMA chimeric antibody (PBMC killing test)
为了进一步证实抗体的ADCC活性，本申请利用将PBMC与靶细胞MM.1R同培养，通过分别加入BCMA-017、BCMA-027、BCMA-040以及Belantamab来介导靶细胞的裂解，最后通过检测靶细胞的裂解比例来比较这几个抗人BCMA嵌合抗体的ADCC效应。In order to further confirm the ADCC activity of the antibody, this application uses the co-cultivation of PBMC with the target cell MM.1R, and the lysis of the target cell is mediated by adding BCMA-017, BCMA-027, BCMA-040 and Belantamab respectively, and finally by detecting the target cell The lysis ratio of the cells was used to compare the ADCC effects of these several anti-human BCMA chimeric antibodies.
首先，将靶细胞MM.1R用终浓度为1μM的Cell Trace Far Red(细胞远红外染料，Thermo Fisher Scientific)进行荧光标记，然后标记好的靶细胞用完全培养基将密度调整为3×10 5细胞/mL，然后按每孔50μL加入到96孔板中。按照效靶比20：1，加入50μL的PBMC(密度为6×10 6细胞/mL)到96孔细胞培养板中，将效应细胞和靶细胞轻轻混合。之后加入20μL的抗人BCMA嵌合抗体稀释液，起始终浓度为10μg/mL，5倍倍比稀释，8 个浓度梯度。细胞混合培养4小时，用染色缓冲液洗一次后，用含有1μg/mL PI(碘化丙啶)的染色缓冲液重悬细胞，在BD fortessa流式细胞仪上检测。用flowjo分析数据，首先圈门在Cell Trace Far Red阳性的靶细胞群上，之后再看靶细胞群中，有多少比例的细胞为PI+，这个比例即为ADCC靶细胞裂解比例。 First, target cells MM.1R were fluorescently labeled with Cell Trace Far Red (Cell Far Infrared Dye, Thermo Fisher Scientific) at a final concentration of 1 μM, and then the labeled target cells were adjusted to a density of 3×10 5 with complete medium cells/mL, and then 50 μL per well was added to a 96-well plate. According to the effect-to-target ratio of 20:1, 50 μL of PBMC (density of 6×10 6 cells/mL) was added to a 96-well cell culture plate, and the effector cells and target cells were gently mixed. Then add 20 μL of anti-human BCMA chimeric antibody diluent, the initial concentration is 10 μg/mL, 5-fold dilution, 8 concentration gradients. The cells were mixed and cultured for 4 hours, washed once with staining buffer, resuspended in staining buffer containing 1 μg/mL PI (propidium iodide), and detected on a BD fortessa flow cytometer. Use flowjo to analyze the data. First, gate on the target cell population positive for Cell Trace Far Red, and then look at the percentage of cells in the target cell population that are PI+. This ratio is the ADCC target cell lysis ratio.
Belantamab为阳性对照抗体，序列来自于INN10797，君实生物自制(参见专利WO2012163805A1和CN103562225B)。Belantamab is a positive control antibody whose sequence is from INN10797, made by Junshi Biotech (see patents WO2012163805A1 and CN103562225B).
图5A至图5E分别显示了来自于5个不同donor(供体)的PBMC介导的靶细胞的杀伤比例，其中isotype ctrl为同型对照组。不同donor来源的PBMC展现出较大的靶细胞杀伤差异，在表9中列出了这3个抗体在不同donor中的EC 50值，结果显示抗人BCMA嵌合抗体ADCC活性均优于对照抗体。 Figure 5A to Figure 5E respectively show the killing ratio of target cells mediated by PBMC from 5 different donors, wherein isotype ctrl is the isotype control group. PBMCs from different donors showed a large difference in killing target cells. Table 9 lists the EC 50 values of these three antibodies in different donors. The results show that the ADCC activity of the anti-human BCMA chimeric antibody is better than that of the control antibody .
表9：抗人BCMA嵌合抗体的ADCC效应(PBMC)Table 9: ADCC effect of anti-human BCMA chimeric antibody (PBMC)
Figure PCTCN2022140660-appb-000029
Figure PCTCN2022140660-appb-000029
7.3抗人BCMA的人源化抗体的ADCC效应检测(报告基因法)7.3 Detection of ADCC effect of humanized antibody against human BCMA (reporter gene method)
利用ADCC报告基因法进一步检测了抗人BCMA的人源化抗体，包括BCMA-005、BCMA-017、BCMA-021、BCMA-027、BCMA-040、BCMA-050、BCMA-051以及BCMA-060。具体检测方法同7.1抗人BCMA嵌合抗体的ADCC效应检测(报告基因法)，靶细胞为NCI-H929细胞。The humanized antibodies against human BCMA were further detected by ADCC reporter gene method, including BCMA-005, BCMA-017, BCMA-021, BCMA-027, BCMA-040, BCMA-050, BCMA-051 and BCMA-060. The specific detection method is the same as 7.1 Detection of ADCC effect of anti-human BCMA chimeric antibody (reporter gene method), and the target cells are NCI-H929 cells.
Belantamab为阳性对照抗体，序列来自于INN10797，君实生物自制(参见专利WO2012163805A1和CN103562225B)。Belantamab is a positive control antibody whose sequence is from INN10797, made by Junshi Biotech (see patents WO2012163805A1 and CN103562225B).
图6A至图6H分别展示了不同抗人BCMA的人源化抗体的ADCC活性，其中isotype ctrl为同型对照组；相应EC 50值见表10A至表10H，结果显示抗人BCMA的人源化抗体ADCC活性相当或优于对照抗体。 Figure 6A to Figure 6H respectively show the ADCC activities of different humanized antibodies against human BCMA, where isotype ctrl is the isotype control group; the corresponding EC 50 values are shown in Table 10A to Table 10H, and the results show that the humanized antibodies against human BCMA ADCC activity was comparable or superior to control antibodies.
表10A：抗人BCMA的人源化抗体的ADCC效应(报告基因法)Table 10A: ADCC effect of humanized antibodies against human BCMA (reporter gene method)
Figure PCTCN2022140660-appb-000030
Figure PCTCN2022140660-appb-000030
表10B：抗人BCMA的人源化抗体的ADCC效应(报告基因法)Table 10B: ADCC effect of humanized antibodies against human BCMA (reporter gene method)
Figure PCTCN2022140660-appb-000031
Figure PCTCN2022140660-appb-000031
Figure PCTCN2022140660-appb-000032
Figure PCTCN2022140660-appb-000032
表10C：抗人BCMA的人源化抗体的ADCC效应(报告基因法)Table 10C: ADCC effect of humanized antibodies against human BCMA (reporter gene method)
Figure PCTCN2022140660-appb-000033
Figure PCTCN2022140660-appb-000033
表10D：抗人BCMA的人源化抗体的ADCC效应(报告基因法)Table 10D: ADCC effect of humanized antibodies against human BCMA (reporter gene method)
Figure PCTCN2022140660-appb-000034
Figure PCTCN2022140660-appb-000034
表10E：抗人BCMA的人源化抗体的ADCC效应(报告基因法)Table 10E: ADCC effect of humanized antibodies against human BCMA (reporter gene method)
Figure PCTCN2022140660-appb-000035
Figure PCTCN2022140660-appb-000035
表10F：抗人BCMA的人源化抗体的ADCC效应(报告基因法)Table 10F: ADCC effect of humanized antibodies against human BCMA (reporter gene method)
Figure PCTCN2022140660-appb-000036
Figure PCTCN2022140660-appb-000036
Figure PCTCN2022140660-appb-000037
Figure PCTCN2022140660-appb-000037
表10G：抗人BCMA的人源化抗体的ADCC效应(报告基因法)Table 10G: ADCC effect of humanized antibodies against human BCMA (reporter gene method)
Figure PCTCN2022140660-appb-000038
Figure PCTCN2022140660-appb-000038
表10H：抗人BCMA的人源化抗体的ADCC效应(报告基因法)Table 10H: ADCC effect of humanized antibodies against human BCMA (reporter gene method)
Figure PCTCN2022140660-appb-000039
Figure PCTCN2022140660-appb-000039
以上所述仅为本申请的较佳实施例，并不用以限制本申请，凡在本申请的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本申请保护的范围之内。The above are only preferred embodiments of the application, and are not intended to limit the application. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the application shall be included in the protection of the application. within the range.

Claims (17)

  1. 一种能够与BCMA特异性结合的抗体或其抗原结合片段，其包含HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3；An antibody or antigen-binding fragment thereof capable of specifically binding to BCMA, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3;
    其中，所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3所示的氨基酸序列，或者分别具有如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示的氨基酸序列，或者分别具有如SEQ ID NO:7、SEQ ID NO:8和SEQ ID NO:9所示的氨基酸序列，或者分别具有如SEQ ID NO:10、SEQ ID NO:11和SEQ ID NO:12所示的氨基酸序列，或者分别具有如SEQ ID NO:13、SEQ ID NO:14和SEQ ID NO:15所示的氨基酸序列，或者分别具有如SEQ ID NO:16、SEQ ID NO:17和SEQ ID NO:18所示的氨基酸序列，或者分别具有如SEQ ID NO:19、SEQ ID NO:20和SEQ ID NO:21所示的氨基酸序列，或者分别具有如SEQ ID NO:22、SEQ ID NO:23和SEQ ID NO:24所示的氨基酸序列；Wherein, the HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, or respectively have the amino acid sequences shown in SEQ ID NO: 4, SEQ ID NO: 5 and the amino acid sequence shown in SEQ ID NO: 6, or have respectively the amino acid sequence shown in SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 9, or have the amino acid sequence shown in SEQ ID NO: 10, SEQ ID NO: 10, SEQ ID NO: 9 respectively The amino acid sequence shown in ID NO: 11 and SEQ ID NO: 12, or have the amino acid sequence shown in SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 15 respectively, or have the amino acid sequence shown in SEQ ID NO respectively : 16, the amino acid sequence shown in SEQ ID NO: 17 and SEQ ID NO: 18, or have the amino acid sequence shown in SEQ ID NO: 19, SEQ ID NO: 20 and SEQ ID NO: 21 respectively, or have respectively Amino acid sequences as shown in SEQ ID NO:22, SEQ ID NO:23 and SEQ ID NO:24;
    所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:25、SEQ ID NO:26和SEQ ID NO:27所示的氨基酸序列，或者分别具有如SEQ ID NO:28、SEQ ID NO:29和SEQ ID NO:30所示的氨基酸序列，或者分别具有如SEQ ID NO:31、SEQ ID NO:32和SEQ ID NO:33所示的氨基酸序列，或者分别具有如SEQ ID NO:34、SEQ ID NO:35和SEQ ID NO:36所示的氨基酸序列，或者分别具有如SEQ ID NO:37、SEQ ID NO:38和SEQ ID NO:39所示的氨基酸序列，或者分别具有如SEQ ID NO:40、SEQ ID NO:41和SEQ ID NO:42所示的氨基酸序列，或者分别具有如SEQ ID NO:43、SEQ ID NO:44和SEQ ID NO:45所示的氨基酸序列，或者分别具有如SEQ ID NO:46、SEQ ID NO:47和SEQ ID NO:48所示的氨基酸序列；Said LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequence shown in SEQ ID NO:25, SEQ ID NO:26 and SEQ ID NO:27, or respectively have such as SEQ ID NO:28, SEQ ID NO:29 and SEQ ID NO:29 and SEQ ID NO:27 The amino acid sequence shown in ID NO: 30, or have the amino acid sequence shown in SEQ ID NO: 31, SEQ ID NO: 32 and SEQ ID NO: 33 respectively, or have the amino acid sequence shown in SEQ ID NO: 34, SEQ ID NO respectively Amino acid sequences shown in: 35 and SEQ ID NO: 36, or respectively have the amino acid sequences shown in SEQ ID NO: 37, SEQ ID NO: 38 and SEQ ID NO: 39, or have respectively the amino acid sequences shown in SEQ ID NO: 40 , the amino acid sequence shown in SEQ ID NO: 41 and SEQ ID NO: 42, or have the amino acid sequence shown in SEQ ID NO: 43, SEQ ID NO: 44 and SEQ ID NO: 45 respectively, or have the amino acid sequence shown in SEQ ID NO: 45 respectively The amino acid sequences shown in ID NO:46, SEQ ID NO:47 and SEQ ID NO:48;
    其中，所述SEQ ID NO:1-48中的至少一个可以替换为与其具有1、2或3个氨基酸差异的变体；Wherein, at least one of said SEQ ID NO: 1-48 can be replaced with a variant having 1, 2 or 3 amino acid differences;
    优选地，所述与SEQ ID NO:8所示的氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:49或SEQ ID NO:50所示的氨基酸序列；Preferably, the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO:8 has the amino acid sequence shown in SEQ ID NO:49 or SEQ ID NO:50;
    优选地，所述与SEQ ID NO:9所示的氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:178所示的氨基酸序列；Preferably, the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO: 9 has the amino acid sequence shown in SEQ ID NO: 178;
    优选地，所述与SEQ ID NO:11所示的氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:51所示的氨基酸序列；Preferably, the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO: 11 has the amino acid sequence shown in SEQ ID NO: 51;
    优选地，所述与SEQ ID NO:15所示的氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:52所示的氨基酸序列；Preferably, the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO: 15 has the amino acid sequence shown in SEQ ID NO: 52;
    优选地，所述与SEQ ID NO:29所示的氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:53所示的氨基酸序列；Preferably, the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO:29 has the amino acid sequence shown in SEQ ID NO:53;
    优选地，所述与SEQ ID NO:31所示的氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:54或SEQ ID NO:179所示的氨基酸序列；Preferably, the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO:31 has the amino acid sequence shown in SEQ ID NO:54 or SEQ ID NO:179;
    优选地，所述与SEQ ID NO:32所示的氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:55所示的氨基酸序列；Preferably, the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO:32 has the amino acid sequence shown in SEQ ID NO:55;
    优选地，所述与SEQ ID NO:36所示的氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:180所示的氨基酸序列；Preferably, the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO:36 has the amino acid sequence shown in SEQ ID NO:180;
    优选地，所述与SEQ ID NO:40所示的氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:56所示的氨基酸序列；Preferably, the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO:40 has the amino acid sequence shown in SEQ ID NO:56;
    优选地，所述与SEQ ID NO:41所示的氨基酸序列具有1、2或3个氨基酸差异的变体具有如SEQ ID NO:57所示的氨基酸序列。Preferably, the variant having 1, 2 or 3 amino acid differences from the amino acid sequence shown in SEQ ID NO:41 has the amino acid sequence shown in SEQ ID NO:57.
  2. 根据权利要求1所述的抗体或其抗原结合片段，其中，The antibody or antigen-binding fragment thereof according to claim 1, wherein,
    所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:25、SEQ ID NO:26和SEQ ID NO:27所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 25, SEQ ID NO: 25, SEQ ID NO: The amino acid sequence shown in ID NO: 26 and SEQ ID NO: 27; or
    所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:28、SEQ ID NO:29和SEQ ID NO:30所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 28, SEQ ID NO: 28, SEQ ID NO: The amino acid sequence shown in ID NO:29 and SEQ ID NO:30; or
    所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:28、SEQ ID NO:53和SEQ ID NO:30所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 28, SEQ ID NO: 28, SEQ ID NO: The amino acid sequence shown in ID NO:53 and SEQ ID NO:30; or
    所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:7、SEQ ID NO:8和SEQ ID NO:9所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:31、SEQ ID NO:32和SEQ ID NO:33所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 9, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 31, SEQ ID NO: 31, SEQ ID NO: The amino acid sequence shown in ID NO:32 and SEQ ID NO:33; or
    所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:7、SEQ ID NO:8和SEQ ID NO:178所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:179、SEQ ID NO:32和SEQ ID NO:33所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 178, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 179, SEQ ID NO: 179 and SEQ ID NO: 178 respectively. The amino acid sequence shown in ID NO:32 and SEQ ID NO:33; or
    所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:7、SEQ ID NO:49和SEQ ID NO:9所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:31、SEQ ID NO:32和SEQ ID NO:33所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 49 and SEQ ID NO: 9, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 31, SEQ ID NO: 31, SEQ ID NO: The amino acid sequence shown in ID NO:32 and SEQ ID NO:33; or
    所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:7、SEQ ID NO:50和SEQ ID NO:9所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:54、SEQ ID NO:55和SEQ ID NO:33所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 7, SEQ ID NO: 50 and SEQ ID NO: 9, and the LCDR1, LCDR2 and LCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 54, SEQ ID NO: 54, SEQ ID NO: The amino acid sequence shown in ID NO:55 and SEQ ID NO:33; or
    所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:10、SEQ ID NO:11和SEQ ID NO:12所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:34、SEQ ID NO:35和SEQ ID NO:36所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 34, SEQ ID NO: 34 and SEQ ID NO: 12 respectively. The amino acid sequence shown in ID NO:35 and SEQ ID NO:36; or
    所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:10、SEQ ID NO:11和SEQ ID NO:12所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:34、SEQ ID NO:35和SEQ ID NO:180所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 34, SEQ ID NO: 34 and SEQ ID NO: 12 respectively. the amino acid sequence shown in ID NO:35 and SEQ ID NO:180; or
    所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:10、SEQ ID NO:51和SEQ ID NO:12所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:34、SEQ ID NO:35和SEQ ID NO:36所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 10, SEQ ID NO: 51 and SEQ ID NO: 12, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 34, SEQ ID NO: 34 and SEQ ID NO: 12 respectively. The amino acid sequence shown in ID NO:35 and SEQ ID NO:36; or
    所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:13、SEQ ID NO:14和SEQ ID NO:15所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:37、SEQ ID NO:38和SEQ ID NO:39所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 15, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 37, SEQ ID NO: 37 and SEQ ID NO: 15 respectively. The amino acid sequence shown in ID NO:38 and SEQ ID NO:39; or
    所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:13、SEQ ID NO:14和SEQ ID NO:52所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:37、SEQ ID NO:38和SEQ ID NO:39所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 52, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 37, SEQ ID NO: 37 and SEQ ID NO: 52 respectively. The amino acid sequence shown in ID NO:38 and SEQ ID NO:39; or
    所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:16、SEQ ID NO:17和SEQ ID NO:18所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:40、SEQ ID NO:41和SEQ ID NO:42所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 40, SEQ ID NO: 40 and SEQ ID NO: 18 respectively. The amino acid sequence shown in ID NO:41 and SEQ ID NO:42; or
    所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:16、SEQ ID NO:17和SEQ ID NO:18所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:56、SEQ ID NO:57和SEQ ID NO:42所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 56, SEQ ID NO: 56 and SEQ ID NO: 18 respectively. the amino acid sequence shown in ID NO:57 and SEQ ID NO:42; or
    所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:19、SEQ ID NO:20和SEQ ID NO:21所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:43、 SEQ ID NO:44和SEQ ID NO:45所示的氨基酸序列；或者The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 19, SEQ ID NO: 20 and SEQ ID NO: 21, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 43, SEQ ID NO: 43 and SEQ ID NO: 21 respectively. The amino acid sequence shown in ID NO:44 and SEQ ID NO:45; or
    所述HCDR1、HCDR2和HCDR3分别具有如SEQ ID NO:22、SEQ ID NO:23和SEQ ID NO:24所示的氨基酸序列，所述LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:46、SEQ ID NO:47和SEQ ID NO:48所示的氨基酸序列。The HCDR1, HCDR2 and HCDR3 respectively have the amino acid sequences shown in SEQ ID NO: 22, SEQ ID NO: 23 and SEQ ID NO: 24, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NO: 46, SEQ ID NO: 46 and SEQ ID NO: 24 respectively. Amino acid sequences shown in ID NO:47 and SEQ ID NO:48.
  3. 根据权利要求1所述的抗体或其抗原结合片段，其包含：The antibody or antigen-binding fragment thereof according to claim 1, comprising:
    与SEQ ID NO:58所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:92所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:58 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO:92 light chain variable regions of sequence identity; or
    与SEQ ID NO:59所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:93所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:59 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO:93 light chain variable regions of sequence identity; or
    与SEQ ID NO:60所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:94所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:60 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO:94 light chain variable regions of sequence identity; or
    与SEQ ID NO:61所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:95所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:61 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO:95 light chain variable regions of sequence identity; or
    与SEQ ID NO:62所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:96所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:62 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO:96 light chain variable regions of sequence identity; or
    与SEQ ID NO:63所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:97所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:63 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO:97 light chain variable regions of sequence identity; or
    与SEQ ID NO:64所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:98所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:64 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO:98 light chain variable regions of sequence identity; or
    与SEQ ID NO:65所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:99所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:65 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO:99 light chain variable regions of sequence identity; or
    与SEQ ID NO:66所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:100所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:66 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 100 light chain variable regions of sequence identity; or
    与SEQ ID NO:67所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:101所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％ 序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:67 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 101 light chain variable regions of sequence identity; or
    与SEQ ID NO:68所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:102所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:68 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 102 light chain variable regions of sequence identity; or
    与SEQ ID NO:69所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:103所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 69 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 103 light chain variable regions of sequence identity; or
    与SEQ ID NO:70所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:104所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:70 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 104 light chain variable regions of sequence identity; or
    与SEQ ID NO:71所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:105所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:71 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 105 light chain variable regions of sequence identity; or
    与SEQ ID NO:72所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:106所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:72 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 106 light chain variable regions of sequence identity; or
    与SEQ ID NO:73所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:107所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:73 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 107 light chain variable regions of sequence identity; or
    与SEQ ID NO:74所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:108所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:74 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 108 light chain variable regions of sequence identity; or
    与SEQ ID NO:75所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:109所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:75 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 109 light chain variable regions of sequence identity; or
    与SEQ ID NO:76所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:110所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:76 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 110 light chain variable regions of sequence identity; or
    与SEQ ID NO:77所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:111所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:77 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 111 light chain variable regions of sequence identity; or
    与SEQ ID NO:78所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:112所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％ 序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:78 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 112 light chain variable regions of sequence identity; or
    与SEQ ID NO:79所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:113所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:79 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 113 light chain variable regions of sequence identity; or
    与SEQ ID NO:80所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:114所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 80 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 114 light chain variable regions of sequence identity; or
    与SEQ ID NO:81所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:115所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 81 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 115 light chain variable regions of sequence identity; or
    与SEQ ID NO:82所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:116所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:82 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 116 light chain variable regions of sequence identity; or
    与SEQ ID NO:83所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:117所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:83 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 117 light chain variable regions of sequence identity; or
    与SEQ ID NO:84所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:118所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:84 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 118 light chain variable regions of sequence identity; or
    与SEQ ID NO:85所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:119所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:85 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 119 light chain variable regions of sequence identity; or
    与SEQ ID NO:86所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:120所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:86 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 120 light chain variable regions of sequence identity; or
    与SEQ ID NO:87所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:121所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:87 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 121 light chain variable regions of sequence identity; or
    与SEQ ID NO:88所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:122所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:88 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 122 light chain variable regions of sequence identity; or
    与SEQ ID NO:89所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:123所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％ 序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 89 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 123 light chain variable regions of sequence identity; or
    与SEQ ID NO:90所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:124所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:90 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 124 light chain variable regions of sequence identity; or
    与SEQ ID NO:91所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:125所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO:91 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 125 light chain variable regions of sequence identity; or
    与SEQ ID NO:181所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:182所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 181 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence shown in SEQ ID NO: 182 light chain variable regions of sequence identity; or
    与SEQ ID NO:183所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链可变区，和与SEQ ID NO:184所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链可变区；A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 183 chain variable region, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the amino acid sequence shown in SEQ ID NO: 184 light chain variable region of sequence identity;
    优选地，所述的抗体或其抗原结合片段包含：Preferably, the antibody or antigen-binding fragment thereof comprises:
    氨基酸序列如SEQ ID NO:58所示的重链可变区，和氨基酸序列如SEQ ID NO:92所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:58, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:92; or
    氨基酸序列如SEQ ID NO:59所示的重链可变区，和氨基酸序列如SEQ ID NO:93所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:59, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:93; or
    氨基酸序列如SEQ ID NO:60所示的重链可变区，和氨基酸序列如SEQ ID NO:94所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:60, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:94; or
    氨基酸序列如SEQ ID NO:61所示的重链可变区，和氨基酸序列如SEQ ID NO:95所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:61, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:95; or
    氨基酸序列如SEQ ID NO:62所示的重链可变区，和氨基酸序列如SEQ ID NO:96所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:62, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:96; or
    氨基酸序列如SEQ ID NO:63所示的重链可变区，和氨基酸序列如SEQ ID NO:97所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:63, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:97; or
    氨基酸序列如SEQ ID NO:64所示的重链可变区，和氨基酸序列如SEQ ID NO:98所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:64, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:98; or
    氨基酸序列如SEQ ID NO:65所示的重链可变区，和氨基酸序列如SEQ ID NO:99所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:65, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:99; or
    氨基酸序列如SEQ ID NO:66所示的重链可变区，和氨基酸序列如SEQ ID NO:100所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:66, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:100; or
    氨基酸序列如SEQ ID NO:67所示的重链可变区，和氨基酸序列如SEQ ID NO:101所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:67, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:101; or
    氨基酸序列如SEQ ID NO:68所示的重链可变区，和氨基酸序列如SEQ ID NO:102所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:68, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:102; or
    氨基酸序列如SEQ ID NO:69所示的重链可变区，和氨基酸序列如SEQ ID NO:103所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:69, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:103; or
    氨基酸序列如SEQ ID NO:70所示的重链可变区，和氨基酸序列如SEQ ID NO:104所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:70, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:104; or
    氨基酸序列如SEQ ID NO:71所示的重链可变区，和氨基酸序列如SEQ ID NO:105所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:71, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:105; or
    氨基酸序列如SEQ ID NO:72所示的重链可变区，和氨基酸序列如SEQ ID NO:106所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO:72, and a light chain variable region having an amino acid sequence as shown in SEQ ID NO:106; or
    氨基酸序列如SEQ ID NO:73所示的重链可变区，和氨基酸序列如SEQ ID NO:107所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:73, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:107; or
    氨基酸序列如SEQ ID NO:74所示的重链可变区，和氨基酸序列如SEQ ID NO:108所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:74, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:108; or
    氨基酸序列如SEQ ID NO:75所示的重链可变区，和氨基酸序列如SEQ ID NO:109所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:75, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:109; or
    氨基酸序列如SEQ ID NO:76所示的重链可变区，和氨基酸序列如SEQ ID NO:110所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:76, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:110; or
    氨基酸序列如SEQ ID NO:77所示的重链可变区，和氨基酸序列如SEQ ID NO:111所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:77, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:111; or
    氨基酸序列如SEQ ID NO:78所示的重链可变区，和氨基酸序列如SEQ ID NO:112所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:78, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:112; or
    氨基酸序列如SEQ ID NO:79所示的重链可变区，和氨基酸序列如SEQ ID NO:113所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:79, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:113; or
    氨基酸序列如SEQ ID NO:80所示的重链可变区，和氨基酸序列如SEQ ID NO:114所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO:80, and a light chain variable region having an amino acid sequence as shown in SEQ ID NO:114; or
    氨基酸序列如SEQ ID NO:81所示的重链可变区，和氨基酸序列如SEQ ID NO:115所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:81, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:115; or
    氨基酸序列如SEQ ID NO:82所示的重链可变区，和氨基酸序列如SEQ ID NO:116所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:82, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:116; or
    氨基酸序列如SEQ ID NO:83所示的重链可变区，和氨基酸序列如SEQ ID NO:117所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:83, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:117; or
    氨基酸序列如SEQ ID NO:84所示的重链可变区，和氨基酸序列如SEQ ID NO:118所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:84, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:118; or
    氨基酸序列如SEQ ID NO:85所示的重链可变区，和氨基酸序列如SEQ ID NO:119所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:85, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:119; or
    氨基酸序列如SEQ ID NO:86所示的重链可变区，和氨基酸序列如SEQ ID NO:120所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:86, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:120; or
    氨基酸序列如SEQ ID NO:87所示的重链可变区，和氨基酸序列如SEQ ID NO:121所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:87, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:121; or
    氨基酸序列如SEQ ID NO:88所示的重链可变区，和氨基酸序列如SEQ ID NO:122所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:88, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:122; or
    氨基酸序列如SEQ ID NO:89所示的重链可变区，和氨基酸序列如SEQ ID NO:123所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:89, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:123; or
    氨基酸序列如SEQ ID NO:90所示的重链可变区，和氨基酸序列如SEQ ID NO:124所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:90, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:124; or
    氨基酸序列如SEQ ID NO:91所示的重链可变区，和氨基酸序列如SEQ ID NO:125所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:91, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:125; or
    氨基酸序列如SEQ ID NO:181所示的重链可变区，和氨基酸序列如SEQ ID NO:182所示的轻链可变区；或a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 181, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO: 182; or
    氨基酸序列如SEQ ID NO:183所示的重链可变区，和氨基酸序列如SEQ ID NO:184所示的轻链可变区。The amino acid sequence of the heavy chain variable region shown in SEQ ID NO: 183, and the amino acid sequence of the light chain variable region shown in SEQ ID NO: 184.
  4. 根据权利要求1-3中任一项所述的抗体或其抗原结合片段，其还包含人重链恒定区和人轻链恒定区，所述人重链恒定区选自人IgG1、IgG2、IgG3或IgG4的重链恒定区，优选为人IgG1的重链恒定区；所述人轻链恒定区选自λ轻链或κ轻链的轻链恒定区。The antibody or antigen-binding fragment thereof according to any one of claims 1-3, further comprising a human heavy chain constant region and a human light chain constant region, the human heavy chain constant region being selected from human IgG1, IgG2, IgG3 Or the heavy chain constant region of IgG4, preferably the heavy chain constant region of human IgG1; the human light chain constant region is selected from the light chain constant region of lambda light chain or kappa light chain.
  5. 根据权利要求1-3中任一项所述的抗体或其抗原结合片段，其包含：The antibody or antigen-binding fragment thereof according to any one of claims 1-3, comprising:
    与SEQ ID NO:126所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:127所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 126 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 127 light chain; or
    与SEQ ID NO:128所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:129所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 128 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 129 light chain; or
    与SEQ ID NO:130所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:131所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 130 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 131 light chain; or
    与SEQ ID NO:132所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:133所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 132 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 133 light chain; or
    与SEQ ID NO:134所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:135所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 134 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 135 light chain; or
    与SEQ ID NO:136所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:137所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 136 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 137 light chain; or
    与SEQ ID NO:138所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:139所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 138 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 139 light chain; or
    与SEQ ID NO:140所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:141所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 140 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 141 light chain; or
    与SEQ ID NO:142所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:143所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 142 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 143 light chain; or
    与SEQ ID NO:144所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:145所示氨基酸序列 具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 144 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 145 light chain; or
    与SEQ ID NO:146所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:147所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 146 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 147 light chain; or
    与SEQ ID NO:148所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:149所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 148 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 149 light chain; or
    与SEQ ID NO:150所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:151所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 150 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 151 light chain; or
    与SEQ ID NO:152所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:153所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 152 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 153 light chain; or
    与SEQ ID NO:154所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:155所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 154 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 155 light chain; or
    与SEQ ID NO:156所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:157所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 156 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 157 light chain; or
    与SEQ ID NO:158所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:159所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 158 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 159 light chain; or
    与SEQ ID NO:160所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:161所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 160 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 161 light chain; or
    与SEQ ID NO:162所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:163所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 162 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 163 light chain; or
    与SEQ ID NO:164所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:165所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 164 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 165 light chain; or
    与SEQ ID NO:166所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:167所示氨基酸序列 具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 166 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 167 light chain; or
    与SEQ ID NO:168所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:169所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 168 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 169 light chain; or
    与SEQ ID NO:170所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:171所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 170 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 171 light chain; or
    与SEQ ID NO:172所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:173所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 172 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 173 light chain; or
    与SEQ ID NO:174所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:175所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；或A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 174 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 175 light chain; or
    与SEQ ID NO:176所示的氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的重链，和与SEQ ID NO:177所示氨基酸序列具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的轻链；A heavy compound having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 176 chain, and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO: 177 the light chain;
    优选地，所述抗体或其抗原结合片段包含：Preferably, the antibody or antigen-binding fragment thereof comprises:
    氨基酸序列如SEQ ID NO:126所示的重链，和氨基酸序列如SEQ ID NO:127所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 126, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 127; or
    氨基酸序列如SEQ ID NO:128所示的重链，和氨基酸序列如SEQ ID NO:129所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 128, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 129; or
    氨基酸序列如SEQ ID NO:130所示的重链，和氨基酸序列如SEQ ID NO:131所示的轻链；或A heavy chain having an amino acid sequence as set forth in SEQ ID NO:130, and a light chain having an amino acid sequence as set forth in SEQ ID NO:131; or
    氨基酸序列如SEQ ID NO:132所示的重链，和氨基酸序列如SEQ ID NO:133所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 132, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 133; or
    氨基酸序列如SEQ ID NO:134所示的重链，和氨基酸序列如SEQ ID NO:135所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 134, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 135; or
    氨基酸序列如SEQ ID NO:136所示的重链，和氨基酸序列如SEQ ID NO:137所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 136, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 137; or
    氨基酸序列如SEQ ID NO:138所示的重链，和氨基酸序列如SEQ ID NO:139所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 138, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 139; or
    氨基酸序列如SEQ ID NO:140所示的重链，和氨基酸序列如SEQ ID NO:141所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 140, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 141; or
    氨基酸序列如SEQ ID NO:142所示的重链，和氨基酸序列如SEQ ID NO:143所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 142, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 143; or
    氨基酸序列如SEQ ID NO:144所示的重链，和氨基酸序列如SEQ ID NO:145所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 144, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 145; or
    氨基酸序列如SEQ ID NO:146所示的重链，和氨基酸序列如SEQ ID NO:147所示的轻 链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 146, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 147; or
    氨基酸序列如SEQ ID NO:148所示的重链，和氨基酸序列如SEQ ID NO:149所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 148, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 149; or
    氨基酸序列如SEQ ID NO:150所示的重链，和氨基酸序列如SEQ ID NO:151所示的轻链；或A heavy chain having an amino acid sequence as set forth in SEQ ID NO:150, and a light chain having an amino acid sequence as set forth in SEQ ID NO:151; or
    氨基酸序列如SEQ ID NO:152所示的重链，和氨基酸序列如SEQ ID NO:153所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 152, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 153; or
    氨基酸序列如SEQ ID NO:154所示的重链，和氨基酸序列如SEQ ID NO:155所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 154, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 155; or
    氨基酸序列如SEQ ID NO:156所示的重链，和氨基酸序列如SEQ ID NO:157所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 156, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 157; or
    氨基酸序列如SEQ ID NO:158所示的重链，和氨基酸序列如SEQ ID NO:159所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 158, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 159; or
    氨基酸序列如SEQ ID NO:160所示的重链，和氨基酸序列如SEQ ID NO:161所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 160, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 161; or
    氨基酸序列如SEQ ID NO:162所示的重链，和氨基酸序列如SEQ ID NO:163所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 162, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 163; or
    氨基酸序列如SEQ ID NO:164所示的重链，和氨基酸序列如SEQ ID NO:165所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 164, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 165; or
    氨基酸序列如SEQ ID NO:166所示的重链，和氨基酸序列如SEQ ID NO:167所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 166, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 167; or
    氨基酸序列如SEQ ID NO:168所示的重链，和氨基酸序列如SEQ ID NO:169所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 168, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 169; or
    氨基酸序列如SEQ ID NO:170所示的重链，和氨基酸序列如SEQ ID NO:171所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 170, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 171; or
    氨基酸序列如SEQ ID NO:172所示的重链，和氨基酸序列如SEQ ID NO:173所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 172, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 173; or
    氨基酸序列如SEQ ID NO:174所示的重链，和氨基酸序列如SEQ ID NO:175所示的轻链；或a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 174, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 175; or
    氨基酸序列如SEQ ID NO:176所示的重链，和氨基酸序列如SEQ ID NO:177所示的轻链。The amino acid sequence is the heavy chain shown in SEQ ID NO: 176, and the amino acid sequence is the light chain shown in SEQ ID NO: 177.
  6. 根据权利要求1-3中任一项所述的抗体或其抗原结合片段，其中，所述抗体包括单克隆抗体和多特异性抗体的至少一种，所述抗原结合片段包括Fab、Fab'、F(ab')2、Fv、scFv和sdAb的至少一种。The antibody or antigen-binding fragment thereof according to any one of claims 1-3, wherein the antibody comprises at least one of a monoclonal antibody and a multispecific antibody, and the antigen-binding fragment comprises Fab, Fab', At least one of F(ab')2, Fv, scFv and sdAb.
  7. 一种分离的抗体或其抗原结合片段，其具有以下特性中的至少一种：An isolated antibody or antigen-binding fragment thereof having at least one of the following properties:
    (Ⅰ)与权利要求1-6中任一项所述的抗体或其抗原结合片段结合相同的、或者完全重叠或部分重叠的人BCMA蛋白的表位；(1) the epitope of the human BCMA protein that binds to the same or completely overlaps or partially overlaps with the antibody or antigen-binding fragment thereof according to any one of claims 1-6;
    (Ⅱ)与权利要求1-6中任一项所述的抗体或其抗原结合片段竞争结合人BCMA蛋白的表位。(II) Competing with the antibody or antigen-binding fragment thereof according to any one of claims 1-6 for binding to the epitope of human BCMA protein.
  8. 一种多核苷酸分子，其包含编码权利要求1-6中任一项所述的抗体或其抗原结合片段或编码权利要求7所述的分离的抗体或其抗原结合片段的核苷酸序列或其互补序列的至少一种。A polynucleotide molecule comprising a nucleotide sequence encoding the antibody or antigen-binding fragment thereof of any one of claims 1-6 or encoding the isolated antibody or antigen-binding fragment thereof of claim 7 or At least one of its complementary sequences.
  9. 一种表达载体，其包含根据权利要求8所述的多核苷酸分子，优选地，所述表达载体为真核表达载体。An expression vector comprising the polynucleotide molecule according to claim 8, preferably, the expression vector is a eukaryotic expression vector.
  10. 一种宿主细胞，其包含根据权利要求8所述的多核苷酸分子，或包含根据权利要求9所述的表达载体，优选地，所述宿主细胞是真核细胞，更优选哺乳动物细胞。A host cell comprising the polynucleotide molecule according to claim 8, or comprising the expression vector according to claim 9, preferably, the host cell is a eukaryotic cell, more preferably a mammalian cell.
  11. 根据权利要求10所述的宿主细胞，其用于表达根据权利要求1-6中任一项所述的抗体或其抗原结合片段或根据权利要求7所述的分离的抗体或其抗原结合片段。The host cell according to claim 10 for expressing the antibody or antigen-binding fragment thereof according to any one of claims 1-6 or the isolated antibody or antigen-binding fragment thereof according to claim 7.
  12. 一种制备根据权利要求1-6中任一项所述的抗体或其抗原结合片段，或根据权利要求7所述的分离的抗体或其抗原结合片段的方法，其包括在权利要求10所述的宿主细胞中表达所述的抗体或其抗原结合片段，并从所述宿主细胞回收所表达的抗体或其抗原结合片段。A method for preparing the antibody or antigen-binding fragment thereof according to any one of claims 1-6, or the isolated antibody or antigen-binding fragment thereof according to claim 7, which is included in claim 10 expressing the antibody or antigen-binding fragment thereof in a host cell, and recovering the expressed antibody or antigen-binding fragment thereof from the host cell.
  13. 一种抗BCMA抗体的药物偶联物或其药学上可接受的盐，其包含：A drug conjugate of an anti-BCMA antibody or a pharmaceutically acceptable salt thereof, comprising:
    (a)抗体部分，所述抗体部分为如权利要求1-6中任一项所述的抗体或其抗原结合片段；和(a) an antibody portion which is an antibody or antigen-binding fragment thereof according to any one of claims 1-6; and
    (b)与所述抗体部分偶联的偶联部分，所述偶联部分选自可检测标记物、药物、毒素、细胞因子、放射性核素和酶中的至少一种。(b) a coupling moiety coupled to the antibody moiety, the coupling moiety being selected from at least one of detectable labels, drugs, toxins, cytokines, radionuclides and enzymes.
  14. 一种药物组合物，其包含根据权利要求1-6中任一项所述的抗体或其抗原结合片段或根据权利要求7所述的分离的抗体或其抗原结合片段或根据权利要求8所述的多核苷酸分子或根据权利要求9所述的表达载体或根据权利要求10所述的宿主细胞或根据权利要求13所述的药物偶联物，和药学上可接受的载体或赋形剂。A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof according to any one of claims 1-6 or the isolated antibody or antigen-binding fragment thereof according to claim 7 or according to claim 8 The polynucleotide molecule or the expression vector according to claim 9 or the host cell according to claim 10 or the drug conjugate according to claim 13, and a pharmaceutically acceptable carrier or excipient.
  15. 根据权利要求1-6中任一项所述的抗体或其抗原结合片段或根据权利要求7所述的分离的抗体或其抗原结合片段或根据权利要求8所述的多核苷酸分子或根据权利要求9所述的表达载体或根据权利要求10所述的宿主细胞或根据权利要求13所述的药物偶联物或根据权利要求14所述的药物组合物在制备用于治疗或预防BCMA介导的疾病的药物中的用途；优选地，所述BCMA介导的疾病为癌症或自身免疫病。The antibody or antigen-binding fragment thereof according to any one of claims 1-6 or the isolated antibody or antigen-binding fragment thereof according to claim 7 or the polynucleotide molecule according to claim 8 or according to claim 8 The expression vector according to claim 9 or the host cell according to claim 10 or the drug conjugate according to claim 13 or the pharmaceutical composition according to claim 14 are used for the treatment or prevention of BCMA-mediated The application in the medicine of the disease; Preferably, the disease mediated by BCMA is cancer or autoimmune disease.
  16. 一种试剂盒，其包括根据权利要求1-6中任一项所述的抗体或其抗原结合片段或根据权利要求7所述的分离的抗体或其抗原结合片或根据权利要求8所述的多核苷酸分子或根据权利要求9所述的表达载体或根据权利要求10所述的宿主细胞或根据权利要求13所述的药物偶联物或根据权利要求14所述的药物组合物。A kit comprising the antibody or antigen-binding fragment thereof according to any one of claims 1-6 or the isolated antibody or antigen-binding sheet thereof according to claim 7 or the antibody or antigen-binding fragment thereof according to claim 8 The polynucleotide molecule or the expression vector according to claim 9 or the host cell according to claim 10 or the drug conjugate according to claim 13 or the pharmaceutical composition according to claim 14.
  17. 一种使用根据权利要求1-6中任一项所述的抗体或其抗原结合片段，或根据权利要求7所述的分离的抗体或其抗原结合片段检测BCMA的方法，其包括使所述抗体或其抗原结合片段与样品接触，检测所述抗体或其抗原结合片段与BCMA形成的结合物，以及任选地对所述结合物进行定量测定。A method for detecting BCMA using the antibody or antigen-binding fragment thereof according to any one of claims 1-6, or the isolated antibody or antigen-binding fragment thereof according to claim 7, comprising making said antibody Contacting the antibody or antigen-binding fragment thereof with a sample, detecting the conjugate formed by the antibody or antigen-binding fragment thereof and BCMA, and optionally quantifying the conjugate.
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