WO2024001669A1 - 靶向itga2的抗体和包含此抗体的抗体药物缀合物 - Google Patents

靶向itga2的抗体和包含此抗体的抗体药物缀合物 Download PDF

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WO2024001669A1
WO2024001669A1 PCT/CN2023/098076 CN2023098076W WO2024001669A1 WO 2024001669 A1 WO2024001669 A1 WO 2024001669A1 CN 2023098076 W CN2023098076 W CN 2023098076W WO 2024001669 A1 WO2024001669 A1 WO 2024001669A1
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seq
amino acid
acid sequence
light chain
heavy chain
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PCT/CN2023/098076
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English (en)
French (fr)
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黄超兰
黎玮
韩佩
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昱言科技(北京)有限公司
昱谚生物科技（上海）有限公司
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Publication of WO2024001669A1 publication Critical patent/WO2024001669A1/zh

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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
    • C07K16/2839—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 integrin superfamily
    • C07K16/2842—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 integrin superfamily against integrin beta1-subunit-containing molecules, e.g. CD29, CD49
    • 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
    • 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
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/77—Internalization into the cell
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • the invention relates to the field of biomedicine. Specifically, the present invention relates to an ITGA2-targeting antibody or an antigen-binding fragment thereof, an antibody-drug conjugate comprising the antibody, and the use of the antibody and/or antibody-drug conjugate in the treatment of related diseases.
  • Malignant tumors have become the "number one killer” threatening the lives and health of people around the world.
  • Chemotherapy can be used for patients who have spread and metastasized, but due to its severe side effects and the tendency to develop short-term or long-term drug resistance, it can only have a significant short-term effect on about 20-30% of patients. Even if comprehensive treatment measures are combined with surgery, radiotherapy and chemotherapy, the long-term efficacy of 5-year survival has been hovering at 20-30% for many years. About 70-80% of patients suffer from metastasis, recurrence and drug resistance within 5 years after treatment. died within the year. Even among patients with early-stage cancer who have no metastasis at the time of diagnosis, some still develop metastasis and relapse after treatment and die.
  • ITGA2 is a tumor-associated antigen specifically overexpressed by tumor cells, and its expression is up-regulated in most solid tumors, especially in colorectal cancer, cholangiocarcinoma, pancreatic cancer, skin cancer and other cancers. overexpression; however, current antibodies that can target ITGA2 alone have poor inhibitory effects on the growth of tumor cells. Therefore, the inventors developed a series of antibodies with high specific binding ability to tumor cells expressing ITGA2 protein, and targeted ITGA2-positive tumor cells in the form of antibody-drug conjugates to achieve excellent killing effects on cells.
  • the invention provides an isolated antibody or an antigen-binding fragment thereof that specifically binds to the ITGA2 protein, wherein the isolated antibody or an antigen-binding fragment thereof includes a heavy chain containing HCDR1, HCDR2, and HCDR3 sequences. variable region; and a light chain variable region containing LCDR1, LCDR2, LCDR3 sequences, wherein the antibody or antigen-binding fragment portion thereof has a heavy chain variable region and a light chain variable region selected from at least one of the following:
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 112, (b) HCDR2 of SEQ ID NO: 113, and (c) HCDR3 of SEQ ID NO: 114, and the light chain can
  • the variable area includes (d) LCDR1 of SEQ ID NO: 38, (e) LCDR2 of SEQ ID NO: 39, and (f) LCDR3 of SEQ ID NO: 40;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 116, (b) HCDR2 of SEQ ID NO: 117, and (c) HCDR3 of SEQ ID NO: 118, and the light chain can variable region and the light chain variable region includes (d) LCDR1 of SEQ ID NO: 42, (e) LCDR2 of SEQ ID NO: 43, and (f) LCDR3 of SEQ ID NO: 44;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 120, (b) HCDR2 of SEQ ID NO: 121, and (c) HCDR3 of SEQ ID NO: 122, and the light chain can
  • the variable region includes (d) LCDR1 of SEQ ID NO: 46, (e) LCDR2 of SEQ ID NO: 47, and (f) LCDR3 of SEQ ID NO: 48;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 124, (b) HCDR2 of SEQ ID NO: 125, and (c) HCDR3 of SEQ ID NO: 126, and the light chain can
  • the variable area includes (d) LCDR1 of SEQ ID NO: 50, (e) LCDR2 of SEQ ID NO: 51, and (f) LCDR3 of SEQ ID NO: 52;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 128, (b) HCDR2 of SEQ ID NO: 129, and (c) HCDR3 of SEQ ID NO: 130, and the light chain can
  • the variable area includes (d) LCDR1 of SEQ ID NO: 54, (e) LCDR2 of SEQ ID NO: 55, and (f) LCDR3 of SEQ ID NO: 56;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 132, (b) HCDR2 of SEQ ID NO: 133, and (c) HCDR3 of SEQ ID NO: 134, and the light chain can
  • the variable area includes (d) LCDR1 of SEQ ID NO: 58, (e) LCDR2 of SEQ ID NO: 59, and (f) LCDR3 of SEQ ID NO: 60;
  • the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 136, (b) HCDR2 of SEQ ID NO: 137, and (c) HCDR3 of SEQ ID NO: 138, and the light chain may
  • the variable region contains (d) SEQ ID NO: 62 LCDR1, (e) LCDR2 of SEQ ID NO: 63, and (f) LCDR3 of SEQ ID NO: 64;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 140, (b) HCDR2 of SEQ ID NO: 141, and (c) HCDR3 of SEQ ID NO: 142, and the light chain may
  • the variable area includes (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 144, (b) HCDR2 of SEQ ID NO: 145, and (c) HCDR3 of SEQ ID NO: 146, and the light chain may
  • the variable area includes (d) LCDR1 of SEQ ID NO: 70, (e) LCDR2 of SEQ ID NO: 71, and (f) LCDR3 of SEQ ID NO: 72;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 148, (b) HCDR2 of SEQ ID NO: 149, and (c) HCDR3 of SEQ ID NO: 150, and the light chain may
  • the variable region includes (d) LCDR1 of SEQ ID NO: 74, (e) LCDR2 of SEQ ID NO: 75, and (f) LCDR3 of SEQ ID NO: 76;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 152, (b) HCDR2 of SEQ ID NO: 153, and (c) HCDR3 of SEQ ID NO: 154, and the light chain may
  • the variable area includes (d) LCDR1 of SEQ ID NO: 78, (e) LCDR2 of SEQ ID NO: 79, and (f) LCDR3 of SEQ ID NO: 80;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 156, (b) HCDR2 of SEQ ID NO: 157, and (c) HCDR3 of SEQ ID NO: 158, and the light chain may
  • the variable area includes (d) LCDR1 of SEQ ID NO: 82, (e) LCDR2 of SEQ ID NO: 83, and (f) LCDR3 of SEQ ID NO: 84;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 160, (b) HCDR2 of SEQ ID NO: 161, and (c) HCDR3 of SEQ ID NO: 162, and the light chain may
  • the variable area includes (d) LCDR1 of SEQ ID NO: 86, (e) LCDR2 of SEQ ID NO: 87, and (f) LCDR3 of SEQ ID NO: 88;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 164, (b) HCDR2 of SEQ ID NO: 165, and (c) HCDR3 of SEQ ID NO: 166, and the light chain may
  • the variable area includes (d) LCDR1 of SEQ ID NO: 90, (e) LCDR2 of SEQ ID NO: 91, and (f) LCDR3 of SEQ ID NO: 92;
  • the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 168, (b) HCDR2 of SEQ ID NO: 169, and (c) HCDR3 of SEQ ID NO: 170, and the light chain may
  • the variable area includes (d) LCDR1 of SEQ ID NO: 94, (e) LCDR2 of SEQ ID NO: 95, and (f) LCDR3 of SEQ ID NO: 96;
  • the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 172, (b) HCDR2 of SEQ ID NO: 173, and (c) HCDR3 of SEQ ID NO: 174, and the light chain may
  • the variable area includes (d) LCDR1 of SEQ ID NO: 98, (e) LCDR2 of SEQ ID NO: 99, and (f) LCDR3 of SEQ ID NO: 100;
  • the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 176, (b) HCDR2 of SEQ ID NO: 177, and (c) HCDR3 of SEQ ID NO: 178, and the light chain may
  • the variable region contains (d) SEQ ID NO: 102 LCDR1, (e) LCDR2 of SEQ ID NO: 103, and (f) LCDR3 of SEQ ID NO: 104; and
  • the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 180, (b) HCDR2 of SEQ ID NO: 181, and (c) HCDR3 of SEQ ID NO: 182, and the light chain may
  • the variable area includes (d) LCDR1 of SEQ ID NO: 106, (e) LCDR2 of SEQ ID NO: 107, and (f) LCDR3 of SEQ ID NO: 108.
  • the present invention provides an isolated antibody or an antigen-binding fragment portion thereof that specifically binds to ITGA2 protein, wherein the isolated antibody or an antigen-binding fragment portion thereof has a heavy chain selected from at least one of the following groups: and light chain:
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 19, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 19. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 19, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 20, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 20. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 20, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:2, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 21, or contains at least 85%, or at least 90%, of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 21. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 21, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:3, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of SEQ ID NO:
  • the amino acid sequence encoded by the nucleotide sequence of 3 consists of;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 22, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 22. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 22, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:4, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 4;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 23, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 23. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 23, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:5, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 5;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 24, or contains at least 85%, or at least 90%, of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 24. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 24, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 25, or contains at least 85%, or at least 90%, of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 25. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 25, and
  • the light chain includes an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 7, or an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:7.
  • the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 7 has an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, Or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 7;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:8, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 8;
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 9, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 9;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 28, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 28. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 28, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 10, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 10;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:29, or contains at least 85%, at least 90%, of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:29. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or by SEQ.
  • the amino acid sequence encoded by the nucleotide sequence of ID NO: 29 consists of, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 11, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 11;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 12, or has at least 85%, at least 90%, or An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 12;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 13, or has at least 85%, at least 90%, or An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 13;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 32, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 32. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 32, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 14, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 14;
  • the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33, or comprises The amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33 has an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical. , or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 15, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 15;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 16, or has at least 85%, at least 90%, or An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 16;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 17, or has at least 85%, at least 90%, and
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 18, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of SEQ ID NO:
  • the amino acid sequence encoded by the 18 nucleotide sequence consists of.
  • the invention provides an isolated nucleic acid molecule encoding the monoclonal antibody of the invention or an antigen-binding fragment thereof.
  • the invention provides an expression vector comprising the nucleic acid molecule of the invention.
  • the invention provides a host cell comprising the nucleic acid molecule of the invention or the expression vector of the invention.
  • the invention provides a hybridoma cell expressing the monoclonal antibody of the invention or an antigen-binding fragment portion thereof.
  • the invention provides the use of the monoclonal antibody of the invention or the antigen-binding fragment thereof or the antibody-drug conjugate of the invention in the preparation of a pharmaceutical composition; optionally, the pharmaceutical composition is used in patients In the treatment of malignant tumors, prevention and/or treatment of metastasis or recurrence of malignant tumors.
  • the present invention provides a method for treating malignant tumors, preventing and/or treating malignant tumor metastasis or recurrence in a patient, the method comprising administering to the patient an effective amount of the monoclonal antibody of the present invention or its An antigen-binding fragment portion, an antibody-drug conjugate of the invention, or a pharmaceutical composition of the invention.
  • the present invention provides the use of the monoclonal antibody of the present invention or its antigen-binding fragment or the antibody-drug conjugate of the present invention in the preparation of a diagnostic/prognostic composition; optionally, the diagnostic/prognostic composition For detecting the presence of a malignant tumor in a patient; optionally, the diagnostic/prognostic composition is used for prognosticating the recurrence or progression of a malignant tumor in a patient.
  • the present invention provides a method for prognosticating the recurrence or progression of malignant tumors in a patient, the method comprising:
  • the present invention provides a method for detecting/diagnosing the presence of malignant tumors in a patient, comprising:
  • the present invention provides a method for detecting the presence of tumor cells in a biological sample, comprising:
  • detection of said binding represents the presence of tumor cells in said biological sample.
  • the present invention provides a method for isolating tumor cells, the method comprising:
  • the invention provides a method for producing a monoclonal antibody or an antigen-binding fragment thereof targeting human tumor cells expressing ITGA2, comprising:
  • the antibody of the present invention has excellent binding properties to ITGA2 protein and can have excellent binding to tumor cells expressing ITGA2, especially colorectal cancer cells, cholangiocarcinoma cells, pancreatic cancer cells and skin cancer cells.
  • the antibody drug conjugate of the present invention has excellent killing effect on tumor cells expressing ITGA2, especially colorectal cancer cells, cholangiocarcinoma cells, pancreatic cancer and skin cancer cells.
  • Table 1b Amino acid sequences of the variable regions, each CDR and the constant region of the light chain and heavy chain of the antibody of the present invention (SEQ ID NO: 37-183)
  • Table 1c Amino acid sequences of the light and heavy chains of the antibodies of the invention (SEQ ID NO: 184-219).
  • antibody refers to immunoglobulins and immunoglobulin fragments, whether natural or partially or fully synthetic (e.g., recombinant) produced, including full-length immunoglobulins which contain at least a portion of the variable region of the immunoglobulin molecule. Any fragment of a globulin that has the specific ability to bind.
  • an antibody includes any protein having a binding domain that is homologous or substantially homologous to an immunoglobulin antigen-binding domain (antibody binding site).
  • Antibodies include antibody fragments, such as anti-tumor stem cell antibody fragments.
  • antibody therefore includes synthetic antibodies, recombinantly produced antibodies, multispecific antibodies (e.g., bispecific antibodies), human antibodies, non-human antibodies, humanized antibodies, chimeric antibodies, intrabodies, and antibody fragments , such as but not limited to Fab fragment, Fab' fragment, F(ab') 2 fragment, Fv fragment, disulfide-linked Fv (dsFv), Fd fragment, Fd' fragment, single-chain Fv (scFv), single-chain Fab (scFab), diabodies, anti-idiotypic (anti-Id) antibodies, or antigen-binding fragments of any of the above antibodies.
  • multispecific antibodies e.g., bispecific antibodies
  • human antibodies e.g., non-human antibodies, humanized antibodies, chimeric antibodies, intrabodies, and antibody fragments , such as but not limited to Fab fragment, Fab' fragment, F(ab') 2 fragment, Fv fragment, disulfide-linked Fv (dsFv), Fd fragment, F
  • Antibodies provided herein include any immunoglobulin type (e.g., IgG, IgM, IgD, IgE, IgA, and IgY), any class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or subclass (e.g., IgG2a and IgG2b) members.
  • immunoglobulin type e.g., IgG, IgM, IgD, IgE, IgA, and IgY
  • any class e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2
  • subclass e.g., IgG2a and IgG2b
  • an "antibody fragment” or “antigen-binding fragment” of an antibody refers to any portion of a full-length antibody that is less than full length but contains at least a portion of the variable region (e.g., one or more CDRs and/or one or more antibody binding sites) and thus retain binding specificity and at least part of the specificity of the full-length antibody Sexual bonding ability.
  • an antigen-binding fragment refers to an antibody fragment that contains an antigen-binding portion that binds the same antigen as the antibody from which the antibody fragment is derived.
  • Antibody fragments include antibody derivatives produced by enzymatic treatment of full-length antibodies, as well as synthetically produced derivatives, such as recombinantly produced derivatives.
  • Antibodies include antibody fragments.
  • antibody fragments include, but are not limited to, Fab, Fab', F(ab') 2 , single chain Fv (scFv), Fv, dsFv, diabodies, Fd and Fd' fragments, and other fragments, including modified fragments (see, For example, Methods in Molecular Biology, Vol 207: Recombinant Antibodies for Cancer Therapy Methods and Protocols (2003); Chapter 1; p 3-25, Kipriyanov).
  • the fragments may include multiple chains linked together, for example by disulfide bonds and/or by peptide linkers.
  • Antibody fragments generally contain at least or about 50 amino acids, and typically at least or about 200 amino acids.
  • Antigen-binding fragments include any antibody fragment that, when inserted into an antibody framework (e.g., by displacing the corresponding region), results in an antibody that immunospecifically binds (i.e., exhibits a Ka of at least or at least about 10 7 -10 8 M ⁇ 1 ) for the antigen. .
  • monoclonal antibody refers to a population of identical antibodies, meaning that each individual antibody molecule in the population of monoclonal antibodies is identical to every other antibody molecule. This property is in contrast to that of a polyclonal population of antibodies, which contains antibodies with a variety of different sequences.
  • Monoclonal antibodies can be prepared by a number of well-known methods (Smith et al. (2004) J. Clin. Pathol. 57, 912-917; and Nelson et al., J. Clin. Pathol (2000), 53, 111-117).
  • monoclonal antibodies can be produced by immortalizing B cells, such as by fusion with myeloma cells to generate hybridoma cell lines or by infecting B cells with a virus such as EBV.
  • Recombinant techniques can also be used to prepare antibodies in vitro from clonal populations of host cells by transforming the host cells with a plasmid carrying an artificial sequence of nucleotides encoding the antibody.
  • hybridomas refers to a cell or cell line (generally myeloma or lymphoma cells) resulting from the fusion of antibody-producing lymphocytes and non-antibody-producing cancer cells.
  • hybridomas can proliferate and continuously supply specific monoclonal antibodies. Methods for generating hybridomas are known in the art (see, eg, Harlow & Lane, 1988).
  • hybridodoma or “hybridoma cell” is referred to, it also includes subclones and progeny cells of the hybridoma.
  • a "conventional antibody” refers to an antibody that contains two heavy chains (which may be designated H and H') and two light chains (which may be designated L and L') and two antigen-binding sites, where Each heavy chain may be a full-length immunoglobulin heavy chain or any functional region thereof that retains antigen-binding ability (e.g., heavy chains include, but are not limited to, VH chain, VH - CH1 chain, and VH - CH1- CH2 - CH3 chain), and each light chain can be a full-length light chain or any functional region (e.g., light chains include, but are not limited to, VL chains and VL - CL chains). Each heavy chain (H and H') is paired with a light chain (L and L' respectively).
  • a full-length antibody is one that has two full-length heavy chains (e.g., VH- CH1 - CH2 - CH3 or VH - CH1 - CH2 - CH3 - CH4 ) and two full-length light chains (V L -CL ) and hinge regions, e.g. by antibody-secreting B cells Antibodies naturally produced by cells and synthetically produced antibodies with the same domain.
  • dsFv refers to an Fv with engineered intermolecular disulfide bonds that stabilize VH - VL pairs.
  • an F(ab') 2 fragment is an antibody fragment resulting from digestion of an immunoglobulin with pepsin at pH 4.0-4.5, or a fragment of the same structure produced synthetically, such as by recombinant methods.
  • An F(ab') 2 fragment essentially consists of two Fab fragments, where each heavy chain portion contains several additional amino acids, including a cysteine that forms a disulfide bond connecting the two fragments.
  • a scFv fragment refers to an antibody fragment comprising a variable light chain ( VL ) and a variable heavy chain ( VH ) covalently linked in any order by a polypeptide linker.
  • the linker length allows the two variable domains to be bridged with essentially no interference.
  • An exemplary linker is (Gly-Ser) n residues dispersed with some Glu or Lys residues to increase solubility.
  • chimeric antibody refers to an antibody in which the variable region sequences are derived from one species and the constant region sequences are derived from another species, such as where the variable region sequences are derived from a mouse antibody and the constant region sequences are derived from a human antibody of antibodies.
  • Humanized antibodies refer to non-human (e.g., mouse) antibody forms that are chimeric immunoglobulins, immunoglobulin chains, or fragments thereof (e.g., Fv, Fab, Fab', F(ab') 2 or Other antigen-binding subsequences of antibodies) containing minimal sequence derived from non-human immunoglobulins.
  • the humanized antibody is a human immunoglobulin (recipient antibody), wherein the residues of the complementarity determining region (CDR) of the recipient antibody are derived from a non-human species ( Donor antibody) such as mouse, rat or rabbit CDR residue substitution.
  • epitope refers to any antigenic determinant on an antigen to which the paratope of an antibody binds.
  • Epitope determinants typically comprise chemically active surface patterns of molecules, such as amino acids or sugar side chains, and often have specific three-dimensional structural features as well as specific charge characteristics.
  • variable domain or variable region is a specific Ig domain of an antibody heavy or light chain that contains amino acid sequences that vary between different antibodies. Each light chain and each heavy chain have one variable region domain VL and VH respectively. The variable domains provide antigen specificity and are therefore responsible for antigen recognition. Each variable region contains CDRs, which are part of the antigen-binding site domain, and framework regions (FR).
  • antigen-binding domain and "antigen-binding site” are used synonymously to refer to the domain within an antibody that recognizes and physically interacts with a cognate antigen.
  • Natural, conventional full-length antibody molecules have two conventional antigen-binding sites, each containing a heavy chain variable region portion and a light chain variable region portion.
  • Conventional antigen binding sites contain loops connecting antiparallel beta strands within the variable region domain.
  • the antigen binding site may comprise other portions of the variable region domain.
  • Each conventional antigen binding site contains 3 hypervariable regions from the heavy chain and 3 hypervariable regions from the light chain. Hypervariable regions are also called complementarity determining regions (CDRs).
  • variable region domain contains 3 CDRs, named CDR1, CDR2 and CDR3.
  • the light chain variable region domain contains 3 CDRs, named VL CDR1, VL CDR2, and VL CDR3;
  • the heavy chain variable region domain contains 3 CDRs, named VH CDR1, VH CDR2, and VH CDR3.
  • the three CDRs in the variable region are discontinuous along the linear amino acid sequence, but are close in the folded polypeptide.
  • the CDRs are located within loops connecting parallel strands of the ⁇ -sheets of the variable domains.
  • those skilled in the art know and can identify CDRs based on Kabat or Chothia numbering (see, e.g., Kabat, E.A. et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242, and Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917).
  • the abbreviations "VH CDR" and "HCDR” and "VL CDR” and "LCDR” have the same meaning.
  • framework regions are domains located within the antibody variable region domain within the beta sheet; FR regions are relatively more conserved in terms of amino acid sequence than hypervariable regions.
  • a "constant region” domain is a domain in an antibody heavy or light chain that contains an amino acid sequence that is relatively more conserved than the amino acid sequence of the variable region domain.
  • each light chain has a single light chain constant region ( CL ) domain, while each heavy chain contains one or more heavy chain constant region ( CH ) domains, including CH1 , CH 2, CH 3 and CH 4.
  • Full-length IgA, IgD and IgG isotypes contain CH 1 , CH 2 , CH 3 and hinge regions, while IgE and IgM contain CH 1 , CH 2, CH 3 and CH 4.
  • the CH1 and CL domains extend the Fab arms of the antibody molecule and therefore facilitate interaction with the antigen and rotation of the antibody arms.
  • Antibody constant regions may serve effector functions such as, but not limited to, clearance of antigens, pathogens, and toxins to which the antibody specifically binds, such as by interacting with various cells, biomolecules, and groups tissue interaction.
  • a functional region of an antibody is one that includes at least the VH , VL , CH (e.g., CH1 , CH2 , or CH3 ), CL , or hinge region domain of the antibody, or at least a functional region thereof Antibody part.
  • a functional region of a VH domain is at least a portion of an intact VH domain that retains at least part of the binding specificity of the intact VH domain (e.g., by retaining one or more CDRs of the intact VH domain).
  • the functional region of the VH domain thereby binds the antigen alone or in combination with another antibody domain (eg, VL domain) or a region thereof.
  • An exemplary functional region of a VH domain is a region that includes CDR1, CDR2, and/or CDR3 of the VH domain.
  • a functional region of a VL domain is at least a portion of an intact VL domain that retains at least part of the binding specificity of the intact VL domain (e.g., by retaining one or more CDRs of the intact VL domain), The functional region of the VL domain thereby binds the antigen alone or in combination with another antibody domain (eg, VH domain) or a region thereof.
  • An exemplary functional region of the VL domain is the region that includes CDR1, CDR2, and/or CDR3 of the VL domain.
  • telomere binding binds As used herein, “specifically binds” or “immunospecifically binds” with respect to an antibody or antigen-binding fragment thereof are used interchangeably herein and refers to the passage of the antibody or antigen-binding fragment between the antibody-binding site of the antibody and the antigen The ability of non-covalent interactions to form one or more non-covalent bonds with the same antigen.
  • the antigen may be an isolated antigen or present on tumor cells.
  • Kassoc or "Ka” as used herein is intended to represent the rate of association of a specific antibody-antigen interaction
  • Kdis or “Kd” as used herein is intended to represent the dissociation of a specific antibody-antigen interaction rate
  • KD as used herein is intended to mean the dissociation constant, which is derived from the ratio of Kd to Ka (i.e., Kd/Ka) and is expressed as molar concentration (M).
  • M molar concentration
  • the KD value of an antibody can be determined using methods known in the art. Methods for determining the KD of an antibody may be, for example, surface plasmon resonance (SPR) (Rich and Myszka (2000) Curr. Opin.
  • SPR surface plasmon resonance
  • conservative Modifications include amino acid substitutions, additions, and deletions. Modifications can be introduced into the antibodies of the invention by standard techniques well known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis.
  • a “conservative amino acid modification” or “conservative amino acid substitution” is a substitution in which an amino acid residue is replaced with an amino acid residue having similar properties and/or structure. Families of amino acid residues with similar side chains have been defined in the art.
  • amino acids can be divided into aliphatic amino acids, aromatic amino acids, heterocyclic amino acids, sulfur-containing amino acids, and iodine-containing amino acids.
  • Aliphatic amino acids include alanine, valine, leucine, isoleucine, methionine, aspartic acid, glutamic acid, lysine, arginine, glycine, serine, threonine, cysteine Acid, asparagine and glutamine.
  • Aromatic amino acids include: phenylalanine and tyrosine.
  • Heterocyclic amino acids include: histidine and tryptophan.
  • Heterocyclic imino acids include: proline. Classification of amino acids based on chemical properties: Amino acids can be divided into acidic amino acids, basic amino acids, and neutral amino acids. Neutral amino acids include glycine, alanine, leucine, isoleucine, valine, cystine, cysteine, methionine, threonine, serine, phenylalanine, and tyrosine Acid, tryptophan, proline, methionine and hydroxyproline. Acidic amino acids include glutamic acid and aspartic acid. Basic amino acids include lysine, arginine and histidine.
  • amino acids can be classified as follows: having basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains chain (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), non-polar side chain (e.g., alanine, valine, leucine acid, isoleucine, proline, phenylalanine, methionine), ⁇ -branched side chains (e.g. threonine, valine, isoleucine) and aromatic side chains (e.g. tyrosine amino acid, phenylalanine, tryptophan, histidine).
  • basic side chains e.g., lysine, arginine, histidine
  • acidic side chains e.g., aspartic acid, glutamic acid
  • polypeptide refers to two or more amino acids covalently linked.
  • polypeptide and protein are used interchangeably herein.
  • isolated protein means that the protein, polypeptide or antibody (1) is not associated with its naturally related components in its native state and (2) does not contain components from the same species Other proteins that (3) are expressed by cells from different species or (4) do not occur in nature. Therefore, polypeptides that are chemically synthesized or synthesized in a cellular system that is different from the cells from which the polypeptide is naturally derived will be “separated” from its naturally occurring related components.
  • the protein can also be isolated so that it is substantially free of naturally relevant components, ie, using protein purification techniques well known in the art.
  • substitutions of amino acid residues refers to a conservative amino acid modification in a peptide or protein that does not change the function and/or biological activity of the peptide or protein.
  • substitutions of amino acid residues may be conservative amino acid substitutions.
  • Suitable conservative amino acid substitutions are known to those skilled in the art and can generally be performed without altering the biological activity of the resulting molecule.
  • those skilled in the art recognize that a single amino group in a non-essential region of a polypeptide Acid substitution does not substantially alter biological activity (see, eg, Watson et al., Molecular Biology of the Gene, 4th Edition, 1987, The Benjamin/Cummings Pub.co., p. 224).
  • polynucleotide and “nucleic acid molecule” refer to an oligomer or polymer containing at least two linked nucleotides or nucleotide derivatives, including those linked together usually by a phosphodiester bond.
  • DNA deoxyribonucleic acid
  • RNA ribonucleic acid
  • an isolated nucleic acid molecule is a nucleic acid molecule separated from other nucleic acid molecules present in the natural source of the nucleic acid molecule.
  • An "isolated" nucleic acid molecule such as a cDNA molecule, may be substantially free of other cellular material or culture medium when prepared by recombinant techniques, or substantially free of chemical precursors or other chemical components when chemically synthesized.
  • Exemplary isolated nucleic acid molecules provided herein include isolated nucleic acid molecules encoding the provided antibodies or antigen-binding fragments.
  • Sequence "identity” has an art-recognized meaning, and the percentage of sequence identity between two nucleic acid or polypeptide molecules or regions can be calculated using published techniques. Sequence identity can be measured along the entire length of a polynucleotide or polypeptide or along a region of the molecule.
  • identity is well known to those skilled in the art (Carrillo, H. & Lipman, D., SIAM J Applied Math 48:1073 (1988) ).
  • operably linked with respect to a nucleic acid sequence, region, element or domain means that the nucleic acid regions are functionally related to each other.
  • a promoter can be operably linked to a nucleic acid encoding a polypeptide such that the promoter regulates or mediates transcription of the nucleic acid.
  • expression refers to the process of producing a polypeptide through transcription and translation of a polynucleotide.
  • the expression level of a polypeptide can be assessed using any method known in the art, including, for example, methods that determine the amount of polypeptide produced from the host cell. Such methods may include, but are not limited to, quantification of polypeptides in cell lysates by ELISA, gel electrophoresis followed by Coomassie blue staining, Lowry protein assay, and Bradford protein assay.
  • a "host cell” is a cell used to receive, maintain, replicate and amplify a vector. Host cells can also be used to express the polypeptide encoded by the vector. When the host cell divides, the nucleic acid contained in the vector replicates, thereby amplifying the nucleic acid.
  • the host cell can be a eukaryotic cell or a prokaryotic cell. Suitable host cells include, but are not limited to, CHO cells cells, various COS cells, HeLa cells, HEK cells such as HEK 293 cells.
  • a "vector" is a replicable nucleic acid from which one or more heterologous proteins can be expressed when the vector is transformed into an appropriate host cell.
  • References to vectors include those into which nucleic acids encoding polypeptides or fragments thereof can be introduced, usually by restriction digestion and ligation. References to vectors also include those containing a nucleic acid encoding a polypeptide. Vectors are used to introduce nucleic acids encoding polypeptides into host cells, to amplify nucleic acids, or to express/display polypeptides encoded by nucleic acids. Vectors usually remain episomal, but can be designed to integrate the gene or part thereof into the chromosome of the genome. Vectors for artificial chromosomes are also contemplated, such as yeast artificial vectors and mammalian artificial chromosomes. The selection and use of such vehicles is well known to those skilled in the art.
  • expression vector includes a vector capable of expressing DNA operably linked to regulatory sequences, such as a promoter region, that are capable of affecting the expression of such DNA fragments. Such additional segments may include promoter and terminator sequences, and optionally may include one or more origins of replication, one or more selectable markers, enhancers, polyadenylation signals, and the like. Expression vectors are generally derived from plasmid or viral DNA, or may contain elements of both. An expression vector thus refers to a recombinant DNA or RNA construct, such as a plasmid, phage, recombinant virus or other vector, which when introduced into an appropriate host cell results in the expression of cloned DNA. Suitable expression vectors are well known to those skilled in the art and include expression vectors that are replicable in eukaryotic and/or prokaryotic cells as well as expression vectors that remain episomal or are integrated into the genome of the host cell.
  • treating an individual suffering from a disease or disease condition means that the individual's symptoms are partially or completely alleviated, or remain unchanged following treatment. Treatment therefore includes prevention, treatment and/or cure. Prevention means preventing underlying disease and/or preventing symptoms from worsening or disease progression. Treatment also includes any pharmaceutical use of any of the antibodies or antigen-binding fragments thereof provided and the compositions provided herein.
  • therapeutic effect means an effect resulting from treatment of an individual that alters, generally ameliorates, or ameliorates the symptoms of a disease or disease condition, or cures a disease or disease condition.
  • a “therapeutically effective amount” or “therapeutically effective dose” refers to an amount of a substance, compound, material or composition containing a compound that is at least sufficient to produce a therapeutic effect upon administration to a subject. Thus, it is an amount necessary to prevent, cure, ameliorate, block or partially block the symptoms of a disease or condition.
  • a prophylactically effective amount or “prophylactically effective dose” refers to an amount of a substance, compound, material or composition containing a compound that, when administered to a subject, will have a desired prophylactic effect, e.g., prevent or delay a disease or symptom occurrence or recurrence and reduce the possibility of occurrence or recurrence of the disease or symptoms.
  • Complete prevention of an effective dose does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a prophylactically effective amount may be administered in one or more administrations.
  • the term "patient” refers to a mammal, such as a human.
  • ITGA2 Integrin alpha-2.
  • the number of human ITGA2 protein in the Uniprot database is P17301, see https://www.uniprot.org/uniprot/P17301.
  • ITGA2 is a tumor-associated antigen specifically overexpressed by tumor cells, especially overexpressed in cancer patients such as colorectal cancer, cholangiocarcinoma, pancreatic cancer, and skin cancer.
  • the inventors designed a variety of different humanized antibodies targeting the ITGA2 protein target.
  • the antibody of the present invention has excellent binding ability to ITGA2 protein (EC50 ⁇ 1nM), and also has excellent binding ability to HuCCT1 cells with high ITGA2 expression (EC50 ⁇ 5nM).
  • partner molecules such as cytotoxins can be effectively delivered to tumor cells.
  • the invention provides an isolated antibody or an antigen-binding fragment thereof that specifically binds to the ITGA2 protein, wherein the isolated antibody or an antigen-binding fragment thereof includes an HCDR1, HCDR2, or HCDR3 sequence.
  • Heavy chain variable region :
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 112, (b) HCDR2 of SEQ ID NO: 113, and (c) HCDR3 of SEQ ID NO: 114;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 116, (b) HCDR2 of SEQ ID NO: 117, and (c) HCDR3 of SEQ ID NO: 118;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 120, (b) HCDR2 of SEQ ID NO: 121, and (c) HCDR3 of SEQ ID NO: 122;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 124, (b) HCDR2 of SEQ ID NO: 125, and (c) HCDR3 of SEQ ID NO: 126;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 128, (b) HCDR2 of SEQ ID NO: 129, and (c) HCDR3 of SEQ ID NO: 130;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 132, (b) HCDR2 of SEQ ID NO: 133, and (c) HCDR3 of SEQ ID NO: 134;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 136, (b) HCDR2 of SEQ ID NO: 137, and (c) HCDR3 of SEQ ID NO: 138;
  • the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 140, (b) HCDR2 of SEQ ID NO: 141, and (c) HCDR3 of SEQ ID NO: 142;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 144, (b) HCDR2 of SEQ ID NO: 145, and (c) HCDR3 of SEQ ID NO: 146;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 148, (b) HCDR2 of SEQ ID NO: 149, and (c) HCDR3 of SEQ ID NO: 150;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 152, (b) HCDR2 of SEQ ID NO: 153, and (c) HCDR3 of SEQ ID NO: 154;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 156, (b) HCDR2 of SEQ ID NO: 157, and (c) HCDR3 of SEQ ID NO: 158;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 160, (b) HCDR2 of SEQ ID NO: 161, and (c) HCDR3 of SEQ ID NO: 162;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 164, (b) HCDR2 of SEQ ID NO: 165, and (c) HCDR3 of SEQ ID NO: 166;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 168, (b) HCDR2 of SEQ ID NO: 169, and (c) HCDR3 of SEQ ID NO: 170;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 172, (b) HCDR2 of SEQ ID NO: 173, and (c) HCDR3 of SEQ ID NO: 174;
  • the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 176, (b) HCDR2 of SEQ ID NO: 177, and (c) HCDR3 of SEQ ID NO: 178; and
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 180, (b) HCDR2 of SEQ ID NO: 181, and (c) HCDR3 of SEQ ID NO: 182.
  • the present invention provides an isolated antibody or an antigen-binding fragment thereof that specifically binds to the ITGA2 protein, wherein the isolated antibody or an antigen-binding fragment thereof includes a light sequence containing LCDR1, LCDR2, and LCDR3 sequences.
  • Chain variable region :
  • the light chain variable region includes (d) LCDR1 of SEQ ID NO: 38, (e) LCDR2 of SEQ ID NO: 39, and (f) LCDR3 of SEQ ID NO: 40;
  • the light chain variable region and the light chain variable region comprises (d) LCDR1 of SEQ ID NO:42, (e) LCDR2 of SEQ ID NO:43, and (f) LCDR2 of SEQ ID NO:44 LCDR3;
  • the light chain variable region includes (d) LCDR1 of SEQ ID NO: 46, (e) LCDR2 of SEQ ID NO: 47, and (f) LCDR3 of SEQ ID NO: 48;
  • the light chain variable region includes (d) LCDR1 of SEQ ID NO: 50, (e) LCDR2 of SEQ ID NO: 51, and (f) LCDR3 of SEQ ID NO: 52;
  • the light chain variable region includes (d) LCDR1 of SEQ ID NO: 54, (e) LCDR2 of SEQ ID NO: 55, and (f) LCDR3 of SEQ ID NO: 56;
  • the light chain variable region includes (d) LCDR1 of SEQ ID NO: 58, (e) LCDR2 of SEQ ID NO: 59, and (f) LCDR3 of SEQ ID NO: 60;
  • the light chain variable region includes (d) LCDR1 of SEQ ID NO: 62, (e) LCDR2 of SEQ ID NO: 63, and (f) LCDR3 of SEQ ID NO: 64;
  • the light chain variable region includes (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68;
  • the light chain variable region includes (d) LCDR1 of SEQ ID NO:70, (e) LCDR2 of SEQ ID NO:71, and (f) LCDR3 of SEQ ID NO:72;
  • the light chain variable region includes (d) LCDR1 of SEQ ID NO: 74, (e) LCDR2 of SEQ ID NO: 75, and (f) LCDR3 of SEQ ID NO: 76;
  • the light chain variable region includes (d) LCDR1 of SEQ ID NO: 78, (e) LCDR2 of SEQ ID NO: 79, and (f) LCDR3 of SEQ ID NO: 80;
  • the light chain variable region includes (d) LCDR1 of SEQ ID NO: 82, (e) LCDR2 of SEQ ID NO: 83, and (f) LCDR3 of SEQ ID NO: 84;
  • the light chain variable region includes (d) LCDR1 of SEQ ID NO: 86, (e) LCDR2 of SEQ ID NO: 87, and (f) LCDR3 of SEQ ID NO: 88;
  • the light chain variable region includes (d) LCDR1 of SEQ ID NO: 90, (e) LCDR2 of SEQ ID NO: 91, and (f) LCDR3 of SEQ ID NO: 92;
  • the light chain variable region includes (d) LCDR1 of SEQ ID NO: 94, (e) LCDR2 of SEQ ID NO: 95, and (f) LCDR3 of SEQ ID NO: 96;
  • the light chain variable region includes (d) LCDR1 of SEQ ID NO: 98, (e) LCDR2 of SEQ ID NO: 99, and (f) LCDR3 of SEQ ID NO: 100;
  • the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 102, (e) LCDR2 of SEQ ID NO: 103, and (f) LCDR3 of SEQ ID NO: 104; and
  • the light chain variable region includes (d) LCDR1 of SEQ ID NO:106, (e) LCDR2 of SEQ ID NO:107, and (f) LCDR3 of SEQ ID NO:108.
  • the isolated antibody or antigen-binding fragment portion thereof comprises HCDR1, The heavy chain variable region of HCDR2, HCDR3 sequences; and the light chain variable region containing LCDR1, LCDR2, LCDR3 sequences, wherein the antibody or antigen-binding fragment portion thereof has a heavy chain variable region selected from at least one of the following and Light chain variable region:
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 112, (b) HCDR2 of SEQ ID NO: 113, and (c) HCDR3 of SEQ ID NO: 114, and the light chain can
  • the variable area includes (d) LCDR1 of SEQ ID NO: 38, (e) LCDR2 of SEQ ID NO: 39, and (f) LCDR3 of SEQ ID NO: 40;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 116, (b) HCDR2 of SEQ ID NO: 117, and (c) HCDR3 of SEQ ID NO: 118, and the light chain can variable region and the light chain variable region includes (d) LCDR1 of SEQ ID NO: 42, (e) LCDR2 of SEQ ID NO: 43, and (f) LCDR3 of SEQ ID NO: 44;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 120, (b) HCDR2 of SEQ ID NO: 121, and (c) HCDR3 of SEQ ID NO: 122, and the light chain can
  • the variable region includes (d) LCDR1 of SEQ ID NO: 46, (e) LCDR2 of SEQ ID NO: 47, and (f) LCDR3 of SEQ ID NO: 48;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 124, (b) HCDR2 of SEQ ID NO: 125, and (c) HCDR3 of SEQ ID NO: 126, and the light chain can
  • the variable area includes (d) LCDR1 of SEQ ID NO: 50, (e) LCDR2 of SEQ ID NO: 51, and (f) LCDR3 of SEQ ID NO: 52;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 128, (b) HCDR2 of SEQ ID NO: 129, and (c) HCDR3 of SEQ ID NO: 130, and the light chain can
  • the variable area includes (d) LCDR1 of SEQ ID NO: 54, (e) LCDR2 of SEQ ID NO: 55, and (f) LCDR3 of SEQ ID NO: 56;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 132, (b) HCDR2 of SEQ ID NO: 133, and (c) HCDR3 of SEQ ID NO: 134, and the light chain can
  • the variable area includes (d) LCDR1 of SEQ ID NO: 58, (e) LCDR2 of SEQ ID NO: 59, and (f) LCDR3 of SEQ ID NO: 60;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 136, (b) HCDR2 of SEQ ID NO: 137, and (c) HCDR3 of SEQ ID NO: 138, and the light chain may
  • the variable area includes (d) LCDR1 of SEQ ID NO: 62, (e) LCDR2 of SEQ ID NO: 63, and (f) LCDR3 of SEQ ID NO: 64;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 140, (b) HCDR2 of SEQ ID NO: 141, and (c) HCDR3 of SEQ ID NO: 142, and the light chain may
  • the variable area includes (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68;
  • the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 144, (b) HCDR2 of SEQ ID NO: 145, and (c) HCDR3 of SEQ ID NO: 146, and the light chain may
  • the variable region contains (d) SEQ ID NO: 70 LCDR1, (e) LCDR2 of SEQ ID NO: 71, and (f) LCDR3 of SEQ ID NO: 72;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 148, (b) HCDR2 of SEQ ID NO: 149, and (c) HCDR3 of SEQ ID NO: 150, and the light chain may
  • the variable region includes (d) LCDR1 of SEQ ID NO: 74, (e) LCDR2 of SEQ ID NO: 75, and (f) LCDR3 of SEQ ID NO: 76;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 152, (b) HCDR2 of SEQ ID NO: 153, and (c) HCDR3 of SEQ ID NO: 154, and the light chain may
  • the variable area includes (d) LCDR1 of SEQ ID NO: 78, (e) LCDR2 of SEQ ID NO: 79, and (f) LCDR3 of SEQ ID NO: 80;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 156, (b) HCDR2 of SEQ ID NO: 157, and (c) HCDR3 of SEQ ID NO: 158, and the light chain may
  • the variable area includes (d) LCDR1 of SEQ ID NO: 82, (e) LCDR2 of SEQ ID NO: 83, and (f) LCDR3 of SEQ ID NO: 84;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 160, (b) HCDR2 of SEQ ID NO: 161, and (c) HCDR3 of SEQ ID NO: 162, and the light chain may
  • the variable area includes (d) LCDR1 of SEQ ID NO: 86, (e) LCDR2 of SEQ ID NO: 87, and (f) LCDR3 of SEQ ID NO: 88;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 164, (b) HCDR2 of SEQ ID NO: 165, and (c) HCDR3 of SEQ ID NO: 166, and the light chain may
  • the variable area includes (d) LCDR1 of SEQ ID NO: 90, (e) LCDR2 of SEQ ID NO: 91, and (f) LCDR3 of SEQ ID NO: 92;
  • the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 168, (b) HCDR2 of SEQ ID NO: 169, and (c) HCDR3 of SEQ ID NO: 170, and the light chain may
  • the variable area includes (d) LCDR1 of SEQ ID NO: 94, (e) LCDR2 of SEQ ID NO: 95, and (f) LCDR3 of SEQ ID NO: 96;
  • the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 172, (b) HCDR2 of SEQ ID NO: 173, and (c) HCDR3 of SEQ ID NO: 174, and the light chain may
  • the variable area includes (d) LCDR1 of SEQ ID NO: 98, (e) LCDR2 of SEQ ID NO: 99, and (f) LCDR3 of SEQ ID NO: 100;
  • the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 176, (b) HCDR2 of SEQ ID NO: 177, and (c) HCDR3 of SEQ ID NO: 178, and the light chain may
  • the variable region includes (d) LCDR1 of SEQ ID NO: 102, (e) LCDR2 of SEQ ID NO: 103, and (f) LCDR3 of SEQ ID NO: 104; and
  • the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 180, (b) HCDR2 of SEQ ID NO: 181, and (c) HCDR3 of SEQ ID NO: 182, and the light chain may
  • the variable area includes (d) LCDR1 of SEQ ID NO: 106, (e) LCDR2 of SEQ ID NO: 107, and (f) LCDR3 of SEQ ID NO: 108.
  • the isolated antibody or antigen-binding fragment portion thereof comprises a heavy chain variable region having at least one selected from the group consisting of:
  • the heavy chain variable region includes the amino acid sequence of SEQ ID NO: 111 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or identical to the amino acid sequence of SEQ ID NO: 111. Amino acid sequences that are at least 98%, or at least 99% identical;
  • the heavy chain variable region includes the amino acid sequence of SEQ ID NO: 115 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 115. Amino acid sequences that are at least 98%, or at least 99% identical;
  • the heavy chain variable region includes the amino acid sequence of SEQ ID NO: 119 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 119. Amino acid sequences that are at least 98%, or at least 99% identical;
  • the heavy chain variable region includes the amino acid sequence of SEQ ID NO: 123 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, Amino acid sequences that are at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 127 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 127. Amino acid sequences that are at least 98%, or at least 99% identical;
  • the heavy chain variable region includes the amino acid sequence of SEQ ID NO: 131 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, Amino acid sequences that are at least 98%, or at least 99% identical;
  • the heavy chain variable region includes the amino acid sequence of SEQ ID NO: 135 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, Amino acid sequences that are at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 139 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 139. Amino acid sequences that are at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 143 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, Amino acid sequences that are at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 147 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, the same as the amino acid sequence of SEQ ID NO: 147. Amino acid sequences that are at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 151 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 151. Amino acid sequences that are at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 155 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 155. Amino acid sequences that are at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 159 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 159. Amino acid sequences that are at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 163 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 163. Amino acid sequences that are at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 167 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 167. Amino acid sequences that are at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 171 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 171. Amino acid sequences that are at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 175 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 175. Amino acid sequences that are at least 98%, or at least 99% identical; and
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 179 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 179. Amino acid sequences that are at least 98%, or at least 99% identical.
  • the isolated antibody or antigen-binding fragment portion thereof comprises a light chain variable region having at least one selected from the group consisting of:
  • the light chain variable region includes the amino acid sequence of SEQ ID NO: 37 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, Amino acid sequences that are at least 98%, or at least 99% identical;
  • the light chain variable region comprises the amino acid sequence of SEQ ID NO: 41 or is the same as SEQ ID NO: 41 An amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical;
  • the light chain variable region comprises the amino acid sequence of SEQ ID NO: 45 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 45. Amino acid sequences that are at least 98%, or at least 99% identical;
  • the light chain variable region comprises the amino acid sequence of SEQ ID NO: 49 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 49. Amino acid sequences that are at least 98%, or at least 99% identical;
  • the light chain variable region comprises the amino acid sequence of SEQ ID NO: 53 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, Amino acid sequences that are at least 98%, or at least 99% identical;
  • the light chain variable region comprises the amino acid sequence of SEQ ID NO: 57 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, Amino acid sequences that are at least 98%, or at least 99% identical;
  • the light chain variable region includes the amino acid sequence of SEQ ID NO: 61 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 61. Amino acid sequences that are at least 98%, or at least 99% identical;
  • the light chain variable region comprises the amino acid sequence of SEQ ID NO: 65 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 65. Amino acid sequences that are at least 98%, or at least 99% identical;
  • the light chain variable region comprises the amino acid sequence of SEQ ID NO: 69 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 69. Amino acid sequences that are at least 98%, or at least 99% identical;
  • the light chain variable region comprises the amino acid sequence of SEQ ID NO: 73 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 73. Amino acid sequences that are at least 98%, or at least 99% identical;
  • the light chain variable region comprises the amino acid sequence of SEQ ID NO: 77 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 77. Amino acid sequences that are at least 98%, or at least 99% identical;
  • the light chain variable region which comprises the amino acid sequence of SEQ ID NO: 81 or is the same as SEQ ID NO: 81
  • An amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical;
  • the light chain variable region comprises the amino acid sequence of SEQ ID NO: 85 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 85. Amino acid sequences that are at least 98%, or at least 99% identical;
  • the light chain variable region comprises the amino acid sequence of SEQ ID NO: 89 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 89. Amino acid sequences that are at least 98%, or at least 99% identical;
  • the light chain variable region comprises the amino acid sequence of SEQ ID NO: 93 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 93. Amino acid sequences that are at least 98%, or at least 99% identical;
  • the light chain variable region comprises the amino acid sequence of SEQ ID NO: 97 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 97. Amino acid sequences that are at least 98%, or at least 99% identical;
  • the light chain variable region comprises the amino acid sequence of SEQ ID NO: 101 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 101. Amino acid sequences that are at least 98%, or at least 99% identical; and
  • the light chain variable region comprises the amino acid sequence of SEQ ID NO: 105 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 105. Amino acid sequences that are at least 98%, or at least 99% identical.
  • the isolated antibody or antigen-binding fragment portion thereof comprises a heavy chain variable region and a light chain variable region selected from at least the group consisting of:
  • the heavy chain variable region includes the amino acid sequence of SEQ ID NO: 111 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or identical to the amino acid sequence of SEQ ID NO: 111. Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which includes the amino acid sequence of SEQ ID NO: 37 or is at least 85% or at least 90% identical to the amino acid sequence of SEQ ID NO: 37 , an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 115 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, the same as the amino acid sequence of SEQ ID NO: 115.
  • the heavy chain variable region includes the amino acid sequence of SEQ ID NO: 119 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 119. Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which comprises the amino acid sequence of SEQ ID NO: 45 or is at least 85%, or at least 90% identical to the amino acid sequence of SEQ ID NO: 45 , an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain variable region includes the amino acid sequence of SEQ ID NO: 123 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which includes the amino acid sequence of SEQ ID NO: 49 or is at least 85% or at least 90% identical to the amino acid sequence of SEQ ID NO: 49 , an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 127 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 127.
  • the heavy chain variable region includes the amino acid sequence of SEQ ID NO: 131 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which comprises the amino acid sequence of SEQ ID NO: 57 or is at least 85%, at least 90% identical to the amino acid sequence of SEQ ID NO: 57 , an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain variable region includes the amino acid sequence of SEQ ID NO: 135 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which includes the amino acid sequence of SEQ ID NO: 61 or is at least 85% or at least 90% identical to the amino acid sequence of SEQ ID NO: 61 , an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 139 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, the same as the amino acid sequence of SEQ ID NO: 139.
  • Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which includes the amino group of SEQ ID NO: 65 An acid sequence or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 65;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 143 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which comprises the amino acid sequence of SEQ ID NO: 69 or is at least 85%, at least 90% identical to the amino acid sequence of SEQ ID NO: 69 , an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 147 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 147. Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which includes the amino acid sequence of SEQ ID NO: 73 or is at least 85% or at least 90% identical to the amino acid sequence of SEQ ID NO: 73 , an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 151 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 151. Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which includes the amino acid sequence of SEQ ID NO: 77 or is at least 85%, at least 90% identical to the amino acid sequence of SEQ ID NO: 77 , an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 155 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 155. Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which includes the amino acid sequence of SEQ ID NO: 81 or is at least 85% or at least 90% identical to the amino acid sequence of SEQ ID NO: 81 , an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 159 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 159. Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which includes the amino acid sequence of SEQ ID NO: 85 or is at least 85%, or at least 90% identical to the amino acid sequence of SEQ ID NO: 85 , an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 163 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, the same as the amino acid sequence of SEQ ID NO: 163. Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which includes the amino group of SEQ ID NO: 89 An acid sequence or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 89;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 167 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 167. Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which includes the amino acid sequence of SEQ ID NO: 93 or is at least 85% or at least 90% identical to the amino acid sequence of SEQ ID NO: 93 , an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 171 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 171. Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which includes the amino acid sequence of SEQ ID NO: 97 or is at least 85% or at least 90% identical to the amino acid sequence of SEQ ID NO: 97 , an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 175 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 175. Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which includes the amino acid sequence of SEQ ID NO: 101 or is at least 85% or at least 90% identical to the amino acid sequence of SEQ ID NO: 101 , an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical; and
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 179 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 179. Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which includes the amino acid sequence of SEQ ID NO: 105 or is at least 85% or at least 90% identical to the amino acid sequence of SEQ ID NO: 105 , an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical.
  • the amino acid sequence of the heavy chain variable region of the antibody of the invention (SEQ ID NOs: 111, 115, 119, 123, 127, 131, 135, 139, 143, 147, 151, 155, 159, 163, 167, 171, 175, 179) and/or the amino acid sequence of the light chain variable region (SEQ ID NOs: 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 97, 101, 105)
  • the antibodies have the same or similar biological function and/or activity.
  • the amino acid sequence of the heavy chain variable region of the antibody of the invention (SEQ ID NOs: 111, 115, 119, 123, 127, 131, 135, 139, 143, 147, 151, 155, 159, 163, 167, 171, 175, 179) and/or the amino acid sequence of the light chain variable region (SEQ ID NOs: 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 97, 101, 105)
  • Antibodies having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity are also capable of specifically binding ITGA2 protein.
  • the amino acid sequence of the heavy chain variable region of the antibody of the invention (SEQ ID NOs: 111, 115, 119, 123, 127, 131, 135, 139, 143, 147, 151, 155, 159, 163, 167, 171, 175, 179) and/or the amino acid sequence of the light chain variable region (SEQ ID NOs: 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 97, 101, 105)
  • the invention is resistant to the same heavy chain and/or light chain variable region CDR, and only has conservative amino acid substitutions in other positions of the heavy chain and/or light chain variable region other than the CDR (for example, the framework region), and the conservative amino acid substitutions are sexual amino acid substitutions do not change
  • the aforementioned amino acid sequence of the heavy chain variable region of the antibody of the present invention (SEQ ID NOs: 111, 115, 119, 123, 127, 131, 135, 139, 143, 147, 151, 155, 159 , 163, 167, 171, 175, 179) and/or the amino acid sequence of the light chain variable region (SEQ ID NOs: 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81 , 85, 89, 93, 97, 101, 105)
  • Antibodies having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity are also capable of specificity Binds to ITGA2 protein.
  • the amino acid sequence of the heavy chain variable region of the antibody of the invention (SEQ ID NOs: 111, 115, 119, 123, 127, 131, 135, 139, 143, 147, 151, 155, 159, 163, 167, 171, 175, 179) and/or the amino acid sequence of the light chain variable region (SEQ ID NOs: 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 97, 101, 105)
  • the invention is resistant to the same heavy chain and/or light chain variable region CDR, and only has conservative amino acid substitutions in the framework region in the heavy chain variable region and/or light chain variable region. The conservative amino acid substitutions do not change the corresponding The biological function and/or activity of the antibody, and the
  • the isolated antibody or antigen-binding fragment portion thereof further comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 183 or the same as the amino acid sequence of SEQ ID NO: 183 Amino acid sequences that are at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% homologous.
  • the isolated antibody or antigen-binding fragment portion thereof further comprises a light chain constant region comprising the amino acid sequence of SEQ ID NO: 109 or an amino acid sequence consistent with SEQ ID NO: 109 An amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% homologous; or the light chain constant region comprises SEQ ID NO: 110 or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% homologous to the amino acid sequence of SEQ ID NO: 110.
  • the isolated antibody or antigen-binding fragment portion thereof further comprises a heavy chain constant region and/or a light chain constant region,
  • the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 183 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or identical to the amino acid sequence of SEQ ID NO: 183.
  • the light chain constant region comprises the amino acid sequence of SEQ ID NO: 109 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or identical to the amino acid sequence of SEQ ID NO: 109.
  • the isolated antibody or antigen-binding fragment portion thereof comprises a heavy chain selected from at least one group consisting of:
  • the heavy chain which contains the amino acid sequence of SEQ ID NO: 202 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 202 , or an amino acid sequence that is at least 99% identical;
  • the heavy chain which contains the amino acid sequence of SEQ ID NO: 203 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 203 , or an amino acid sequence that is at least 99% identical;
  • the heavy chain which contains the amino acid sequence of SEQ ID NO: 204 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 204 , or an amino acid sequence that is at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 205 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 205 , or an amino acid sequence that is at least 99% identical;
  • the heavy chain which contains the amino acid sequence of SEQ ID NO: 206 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 206 , or an amino acid sequence that is at least 99% identical;
  • the heavy chain which contains the amino acid sequence of SEQ ID NO: 207 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 207 , or an amino acid sequence that is at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 208 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 208 , or an amino acid sequence that is at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 209 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 209 , or an amino acid sequence that is at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 210 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 210 , or an amino acid sequence that is at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 211 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 211 , or an amino acid sequence that is at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 212 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 212 , or an amino acid sequence that is at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 213 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 213 , or an amino acid sequence that is at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 214 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 214 , or an amino acid sequence that is at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 215 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 215 , or an amino acid sequence that is at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 216 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 216 , or an amino acid sequence that is at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 217 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 217 , or an amino acid sequence that is at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 218 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 218 , or an amino acid sequence that is at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 219 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 219 , or an amino acid sequence that is at least 99% identical.
  • the isolated antibody or antigen-binding fragment portion thereof comprises a light chain selected from at least one group consisting of:
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 184 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 184 , or an amino acid sequence that is at least 99% identical;
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 185 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 185 , or an amino acid sequence that is at least 99% identical;
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 186 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 186 , or an amino acid sequence that is at least 99% identical;
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 187 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 187 , or an amino acid sequence that is at least 99% identical;
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 188 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 188 , or an amino acid sequence that is at least 99% identical;
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 189 or is identical to the amino acid sequence of SEQ ID NO: 189
  • An amino acid sequence whose acid sequence is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical;
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 190 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 190 , or an amino acid sequence that is at least 99% identical;
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 191 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 191 , or an amino acid sequence that is at least 99% identical;
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 192 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 192 , or an amino acid sequence that is at least 99% identical;
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 193 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 193 , or an amino acid sequence that is at least 99% identical;
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 194 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 194 , or an amino acid sequence that is at least 99% identical;
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 195 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 195 , or an amino acid sequence that is at least 99% identical;
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 196 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 196 , or an amino acid sequence that is at least 99% identical;
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 197 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 197 , or an amino acid sequence that is at least 99% identical;
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 198 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 198 , or an amino acid sequence that is at least 99% identical;
  • the light chain comprising the amino acid sequence of SEQ ID NO: 199 or the amino acid sequence of SEQ ID NO: 199 An amino acid sequence with at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity;
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 200 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 200 , or an amino acid sequence that is at least 99% identical;
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 201 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 201 , or an amino acid sequence that is at least 99% identical.
  • the isolated antibody or antigen-binding fragment portion thereof comprises a heavy chain and a light chain selected from at least one group consisting of:
  • the heavy chain which contains the amino acid sequence of SEQ ID NO: 202 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 202 , or an amino acid sequence that is at least 99% identical
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 184 or is at least 85%, at least 90%, at least 95%, or at least the same as the amino acid sequence of SEQ ID NO: 184 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which contains the amino acid sequence of SEQ ID NO: 203 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 203 , or an amino acid sequence that is at least 99% identical
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 185 or is at least 85%, at least 90%, at least 95%, or at least identical to the amino acid sequence of SEQ ID NO: 185 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which contains the amino acid sequence of SEQ ID NO: 204 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 204 , or an amino acid sequence that is at least 99% identical
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 186 or is at least 85%, at least 90%, at least 95%, or at least the same as the amino acid sequence of SEQ ID NO: 186 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 205 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 205 , or an amino acid sequence that is at least 99% identical, and the light chain comprising the amino acid sequence of SEQ ID NO: 187 or at least 85%, at least 90%, at least 95%, or at least the amino acid sequence of SEQ ID NO: 187 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which contains the amino acid sequence of SEQ ID NO: 206 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 206 , or an amino acid sequence that is at least 99% identical
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 188 or is at least 85%, at least 90%, at least 95%, or at least identical to the amino acid sequence of SEQ ID NO: 188 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which contains the amino acid sequence of SEQ ID NO: 207 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 207 , or an amino acid sequence that is at least 99% identical
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 189 or is at least 85%, at least 90%, at least 95%, or at least identical to the amino acid sequence of SEQ ID NO: 189 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 208 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 208 , or an amino acid sequence that is at least 99% identical
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 190 or is at least 85%, at least 90%, at least 95%, or at least identical to the amino acid sequence of SEQ ID NO: 190 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 209 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 209 , or an amino acid sequence that is at least 99% identical
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 191 or is at least 85%, at least 90%, at least 95%, or at least the same as the amino acid sequence of SEQ ID NO: 191 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 210 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 210 , or an amino acid sequence that is at least 99% identical
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 192 or is at least 85%, at least 90%, at least 95%, or at least identical to the amino acid sequence of SEQ ID NO: 192 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 211 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 211 , or an amino acid sequence that is at least 99% identical, and the light chain comprising the amino acid sequence of SEQ ID NO: 193 or at least 85%, at least 90%, at least 95%, or at least the amino acid sequence of SEQ ID NO: 193 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 212 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 212 , or an amino acid sequence that is at least 99% identical
  • the light chain which includes the amino acid sequence of SEQ ID NO: 194 or is at least 85%, at least 90%, at least 95%, or at least the same as the amino acid sequence of SEQ ID NO: 194 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 213 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 213 , or an amino acid sequence that is at least 99% identical
  • the light chain which includes the amino acid sequence of SEQ ID NO: 195 or is at least 85%, at least 90%, at least 95%, or at least identical to the amino acid sequence of SEQ ID NO: 195 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 214 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 214 , or an amino acid sequence that is at least 99% identical
  • the light chain which includes the amino acid sequence of SEQ ID NO: 196 or is at least 85%, at least 90%, at least 95%, or at least the same as the amino acid sequence of SEQ ID NO: 196 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 215 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 215 , or an amino acid sequence that is at least 99% identical
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 197 or is at least 85%, at least 90%, at least 95%, or at least the same as the amino acid sequence of SEQ ID NO: 197 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 216 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 216 , or an amino acid sequence that is at least 99% identical, and the light chain comprising the amino acid sequence of SEQ ID NO: 198 or at least 85%, at least 90%, at least 95%, or at least the amino acid sequence of SEQ ID NO: 198 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 217 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 217 , or an amino acid sequence that is at least 99% identical, and the light chain comprising the amino acid sequence of SEQ ID NO: 199 or at least 85%, at least 90%, at least 95%, or at least the amino acid sequence of SEQ ID NO: 199 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 218 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 218 , or an amino acid sequence that is at least 99% identical
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 200 or is at least 85%, at least 90%, at least 95%, or at least identical to the amino acid sequence of SEQ ID NO: 200 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 219 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 219 , or an amino acid sequence that is at least 99% identical
  • the light chain which includes the amino acid sequence of SEQ ID NO: 201 or is at least 85%, at least 90%, at least 95%, or at least the same as the amino acid sequence of SEQ ID NO: 201 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical.
  • the amino acid sequence of the heavy chain (SEQ ID NOs: 202-219) and/or the light chain of the antibody of the invention is at least 85%, at least An antibody that is 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical has the same or similar biological function and/or activity as an antibody of the invention.
  • the amino acid sequence of the heavy chain (SEQ ID NOs: 202-219) and/or the light chain of the antibody of the invention is at least 85%, at least Antibodies that are 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical are also able to specifically bind the ITGA2 protein.
  • the amino acid sequence of the heavy chain (SEQ ID NOs: 202-219) and/or the light chain of the antibody of the invention is at least 85%, at least An antibody that is 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical has the same heavy chain and/or light chain variable region as the antibody of the invention, except for the heavy chain and/or other positions of the heavy chain and/or light chain outside of the variable region of the light chain (e.g., the constant regions of the heavy chain and/or light chain) have conservative amino acid substitutions that do not alter the corresponding antibody biological functions and/or activities;
  • the aforementioned amino acid sequence has at least 85% or at least 90% similarity with the amino acid sequence of the heavy chain (SEQ ID NOs: 202-219) and/or the amino acid sequence of the light chain (SEQ ID NOs: 184-201) of the antibody of the present invention. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical antibodies are also able to specifically bind to the ITGA2 protein.
  • the amino acid sequence of the heavy chain (SEQ ID NOs: 202-219) and/or the light chain of the antibody of the invention is at least 85%, at least 90%, at least 95%
  • An antibody that is at least 96%, at least 97%, at least 98%, or at least 99% identical has the same heavy chain and/or light chain variable region as the antibody of the invention, only in the heavy chain and/or light chain constant region
  • conservative amino acid substitutions the conservative amino acid substitutions do not change the biological function and/or activity of the corresponding antibody, and the aforementioned antibody can also specifically bind to ITGA2 protein.
  • the isolated antibody or antigen-binding fragment portion thereof consists of a heavy chain and a light chain selected from at least the group consisting of:
  • the heavy chain which consists of the amino acid sequence of SEQ ID NO: 213, and the light chain, which consists of the amino acid sequence of SEQ ID NO: 195;
  • the heavy chain which consists of the amino acid sequence of SEQ ID NO: 215, and the light chain, which consists of the amino acid sequence of SEQ ID NO: 197;
  • the heavy chain which consists of the amino acid sequence of SEQ ID NO: 216
  • the light chain which consists of the amino acid sequence of SEQ ID NO: 198;
  • the heavy chain which consists of the amino acid sequence of SEQ ID NO: 218, and the light chain, which consists of the amino acid sequence of SEQ ID NO: 200;
  • the heavy chain which consists of the amino acid sequence of SEQ ID NO: 219
  • the light chain which consists of the amino acid sequence of SEQ ID NO: 201.
  • the isolated antibody or antigen-binding fragment portion thereof consists of a heavy chain selected from at least one of the following:
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 19, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 19. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 19;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 20, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 20. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 20;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 21, or contains at least 85%, or at least 90%, of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 21. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 21;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 22, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 22. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 22;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 23, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 23. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 23;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 24, or contains at least 85%, or at least 90%, of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 24. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 24;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 25, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 25. %,At least An amino acid sequence that is 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 25;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 27, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 27. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 27;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 28, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 28. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 28;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 29, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 29. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 29;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:32, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:32. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 32;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35; and
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36.
  • the isolated antibody or antigen-binding fragment portion thereof consists of a light chain selected from at least one of the following:
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1 %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1;
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:2, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:2. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2;
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:3, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:3. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 3;
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:4, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:4. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 4;
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:5, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:5. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 5;
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6;
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:7, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:7. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 7;
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 8, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 8. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 8;
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 9, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 9. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 9;
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 10, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 10. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 10;
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 11, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 11. %,to An amino acid sequence that is less than 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 11;
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 12, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 12. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 12;
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 13, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 13. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 13;
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 14, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 14. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 14;
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 15, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 15. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 15;
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 16, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 16. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 16;
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 17, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 17. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 17; and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 18, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 18. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 18.
  • the isolated antibody or antigen-binding fragment portion thereof consists of a heavy chain and a light chain selected from at least the group consisting of:
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 19, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 19. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 19, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 20, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 20. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 20, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:2, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 21, or contains at least 85%, or at least 90%, of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 21. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 21, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:3, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 3;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 22, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 22. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 22, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:4, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 4;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 23, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 23. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 23, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:5, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 5;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 24, or contains at least 85%, or at least 90%, of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 24. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 24, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 25, or contains at least 85%, or at least 90%, of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 25. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 25, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:7, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 7;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26. %,At least an amino acid sequence that is 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:8, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 8;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 27, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 27. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 27, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 9, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 9;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 28, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 28. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 28, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 10, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 10;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 29, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 29. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 29, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 11, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 11;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 12, or has at least 85%, at least 90%, or An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 12;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 13, or has at least 85%, at least 90%, or An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 13;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 32, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 32. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 32, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 14, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 14;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 15, or has at least 85%, at least 90%, At least 95%, An amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 15;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 16, or has at least 85%, at least 90%, or An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 16;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 17, or has at least 85%, at least 90%, and
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 18, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 18.
  • amino acid sequence of the heavy chain of the antibody of the present invention encoded by the aforementioned nucleotide sequence of the present invention (SEQ ID NOs: 19-36) and/or is consistent with the aforementioned nucleotide sequence of the present invention (SEQ ID NOs: 19-36)
  • the amino acid sequences of the light chains of the antibodies of the invention encoded by ID NOs: 1-18) have at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity.
  • the antibody is the same or similar to the antibody of the present invention physical function and/or activity.
  • the amino acid sequence of the heavy chain of the antibody of the present invention encoded by the aforementioned nucleotide sequence of the present invention (SEQ ID NOs: 19-36) and/or is consistent with the aforementioned nucleotide sequence of the present invention (SEQ ID NOs: 19-36)
  • the amino acid sequence of the light chain of the antibody of the invention encoded by ID NOs: 1-18) has at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity.
  • the antibody can also specifically bind to ITGA2 protein.
  • amino acid sequence of the heavy chain of the antibody of the present invention encoded by the aforementioned nucleotide sequence of the present invention (SEQ ID NOs: 19-36) and/or is consistent with the aforementioned nucleotide sequence of the present invention (SEQ ID NOs: 19-36)
  • the amino acid sequence of the light chain of the antibody of the invention encoded by ID NOs: 1-18) has at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity.
  • the antibody has the same heavy chain and/or light chain variable region as the antibody of the invention, only in other positions of the heavy chain and/or light chain other than the heavy chain and/or light chain variable region (e.g., heavy chain and/or the constant region of the light chain) with conservative amino acid substitutions that do not change the biological function and/or activity of the corresponding antibody;
  • the amino acid sequence of the heavy chain of the antibody of the present invention encoded by the aforementioned nucleotide sequence of the present invention (SEQ ID NOs: 19-36) and/or the amino acid sequence of the heavy chain of the antibody of the present invention encoded by the aforementioned nucleotide sequence of the present invention (SEQ ID NOs) :1-18)
  • Antibodies whose light chain amino acid sequences of the encoded antibodies of the present invention have at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity It can also specifically bind ITGA2 protein.
  • amino acid sequence of the heavy chain of the antibody of the present invention encoded by the aforementioned nucleotide sequence of the present invention (SEQ ID NOs: 19-36) and/or is consistent with the aforementioned nucleotide sequence of the present invention (SEQ ID NOs: 19-36)
  • the amino acid sequence of the light chain of the antibody of the invention encoded by ID NOs: 1-18) has at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity.
  • the antibody has the same heavy chain and/or light chain variable region as the antibody of the present invention, and only has conservative amino acid substitutions in the constant region of the heavy chain and/or light chain, and the conservative amino acid substitutions do not change the biology of the corresponding antibody.
  • biological function and/or activity, and the aforementioned antibody can also specifically bind to ITGA2 protein.
  • the antibody or antigen-binding fragment portion is capable of binding ITGA2 protein in vitro with an EC50 of less than 1 nM.
  • the antibody or antigen-binding fragment portion is capable of binding ITGA2 protein on the surface of HuCCT1 cells with an EC50 of less than 5 nM.
  • the antibody is a monoclonal antibody, a polyclonal antibody, a chimeric antibody, or a humanized antibody.
  • the invention provides isolated nucleic acid molecules encoding the aforementioned antibodies of the invention or antigen-binding fragments thereof.
  • the nucleic acid molecule of the invention encodes the heavy chain and/or light chain variable region of the aforementioned antibody of the invention, each CDR in the heavy chain and/or light chain variable region, and the heavy chain and/or Light chain constant region.
  • the nucleotide sequence of the nucleic acid molecule is codon-optimized for the host cell used for expression.
  • the nucleic acid molecules of the invention are operably linked to expression control sequences.
  • the invention also provides an isolated nucleic acid molecule encoding and capable of inventing an antibody or an antigen-binding fragment portion thereof.
  • the nucleic acid molecule includes or consists of a nucleotide sequence selected from any one of the following: SEQ ID NOs: 1-18, and/or the nucleic acid molecule includes a selected nucleotide sequence. From or consisting of any of the nucleotide sequences shown below: SEQ ID NOs: 19-36.
  • the nucleic acid molecule includes or consists of a nucleotide sequence selected from any combination of the following: SEQ ID NO: 1 and SEQ ID NO: 19, SEQ ID NO: 2 and SEQ ID NO:20, SEQ ID NO:3 and SEQ ID NO:21, SEQ ID NO:4 and SEQ ID NO:22, SEQ ID NO:5 and SEQ ID NO:23, SEQ ID NO:6 and SEQ ID NO:24, SEQ ID NO:7 and SEQ ID NO:25, SEQ ID NO:8 and SEQ ID NO:26, SEQ ID NO:9 and SEQ ID NO:27, SEQ ID NO:10 and SEQ ID NO:28, SEQ ID NO:11 and SEQ ID NO:29, SEQ ID NO:12 and SEQ ID NO:30, SEQ ID NO:13 and SEQ ID NO:31, SEQ ID NO:14 and SEQ ID NO: 32.
  • the nucleic acid molecule is operably linked to an expression control sequence.
  • the invention also provides expression vectors comprising at least one nucleic acid molecule of the invention as described above.
  • the invention also provides host cells transformed with at least one of the aforementioned nucleic acid molecules or expression vectors of the invention.
  • the present invention also provides hybridoma cells expressing at least one of the aforementioned antibodies of the present invention or antigen-binding fragment portion thereof.
  • the invention also provides a method for producing the antibody or antigen-binding fragment thereof of the invention, comprising:
  • the nucleotide sequence of the nucleic acid molecule is codon-optimized for the host cell used for expression. In some embodiments, the nucleic acid molecule is operably linked to expression control sequences.
  • the invention also provides a method for producing the antibody or antigen-binding fragment thereof of the invention, comprising:
  • the invention provides antibody-drug conjugates (ADCs) prepared from the antibodies of the invention or antigen-binding fragments thereof.
  • ADCs antibody-drug conjugates
  • the present invention provides an antibody drug conjugate of the following formula, Ab-LD, wherein:
  • L represents the linker connecting the antibody portion to the partner molecule
  • an ADC is prepared by linking a partner molecule to an antibody or antigen-binding fragment thereof via a linker.
  • the antibody serves a targeting function: by binding to the target tissue or cell in which its antigen is found, the antibody directs the conjugate to the target tissue or cell.
  • the linker is, for example, cleaved, releasing the partner molecule to carry out its desired biological function.
  • Partner molecules can be drug payloads or labeling molecules.
  • the drug payload may be a therapeutic agent, for example, the therapeutic agent may be, for example, a cytotoxic agent, a chemotherapeutic agent, a cytostatic agent, an immunomodulatory agent, or the like.
  • the therapeutic agent is a cytotoxic agent, i.e., a cytotoxin.
  • cytotoxic agent and “cytotoxic” are used interchangeably.
  • the label molecule can be any label that produces a detectable signal, such as a radioactive label, a fluorescent label, or an enzyme that catalyzes a detectable modification of a substrate.
  • ADC Antibody-drug conjugate encompasses conjugates formed by connecting the antibody of the present invention or its antigen-binding fragment to a drug payload, as well as conjugates formed by connecting the antibody of the present invention or its antigen-binding fragment to a labeling molecule. The conjugate formed.
  • the proportion of partner molecules linked to the antibody can vary depending on factors such as the amount of partner molecules used during the conjugation reaction and experimental conditions.
  • the ratio of partner molecules to antibodies may be 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1 to 1.5.
  • the present invention also provides an antibody drug conjugate of the following formula, Ab-(L-D)p, wherein:
  • L represents the linker connecting the antibody portion to the partner molecule
  • linker/partner molecules preferably drug payloads conjugated to the aforementioned monoclonal antibody of the present invention or its antigen-binding fragment portion.
  • p is selected from the following values: 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, and 8.0.
  • the linker of the invention is selected from the group consisting of: vc, mc-GGFG, AcLysvc, mc, MalPeg6, m(H20)c, and m(H20)cvc; and/or the linker is Cut. In some embodiments, the linker of the invention is vc.
  • the partner molecule of the present invention is a drug load, and the drug load is a therapeutic molecule; optionally, the drug load is selected from the following: cytotoxic agents, cell inhibitors, Immunomodulators and chemotherapeutic agents; optionally, the drug load is selected from the following: MMAE, MMAF, DM1, DM4, Dxd, SN-38, Topotecan and its derivatives, Exatecan and its derivatives, Belotecan and its derivatives, Camptothecin, Calicheamicin and PBD.
  • the drug load is selected from the following: cytotoxic agents, cell inhibitors, Immunomodulators and chemotherapeutic agents
  • the drug load is selected from the following: MMAE, MMAF, DM1, DM4, Dxd, SN-38, Topotecan and its derivatives, Exatecan and its derivatives, Belotecan and its derivatives, Camptothecin, Calicheamicin and PBD.
  • the drug payload is MMAE.
  • MMAE refers to monomethyl auristatin E, as shown in the figure below, where the wavy line represents the covalent attachment to the linker (L) of the antibody drug conjugate:
  • the drug payload is MMAF.
  • MMAF refers to monomethyl auristatin F, where the wavy line indicates covalent attachment to the linker (L) of the antibody drug conjugate (US2005/0238649):
  • the linker-partner molecule is vcMMAE.
  • vcMMAE drug linker moieties and conjugation methods are disclosed in WO2004010957, US7659241, US7829531, US7851437, and US 11/833,028 (Seattle Genetics, Inc.), which are incorporated herein by reference.
  • the vcMMAE drug linker moiety is conjugated to the antibodies of the invention using methods similar to those disclosed in the above literature.
  • the drug payload may further be a radioisotope, thereby producing a cytotoxic radiopharmaceutical (also known as an antibody radioisotope conjugate).
  • Radioactive compounds that kill tumor cells include, but are not limited to, iodine-131, indium-111, yttrium-90, and lutetium-177. Methods of preparing antibody radioisotope conjugates are known in the art.
  • the partner molecule of the invention is a label molecule; optionally, the label molecule is selected from one of the following: radioactive labels, fluorescent labels, and detectably modified enzymes.
  • the radiolabel is a radioactive isotope, such as iodine-131, indium-111, yttrium-90, and lutetium-177.
  • ITGA2 protein can serve as an effective target for antibody-drug conjugates.
  • the antibody-drug conjugate obtained by coupling an antibody to a small molecule toxin in the present invention can produce excellent killing effect on tumors expressing ITGA2 protein.
  • the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the aforementioned monoclonal antibodies or antigen-binding fragments thereof of the present invention or at least one of the aforementioned antibody-drug conjugates of the present invention, and the therapeutic uses of the pharmaceutical compositions and treatment method.
  • the antibody-drug conjugate of the invention the antibody of the invention is conjugated to a drug payload.
  • the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the aforementioned monoclonal antibodies of the present invention or an antigen-binding fragment portion thereof, or at least one of the aforementioned antibody-drug conjugates of the present invention.
  • the pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier.
  • a "therapeutically effective amount" of at least one of the aforementioned monoclonal antibodies or antigen-binding fragment portions thereof of the present invention or at least one of the aforementioned antibody-drug conjugates of the present invention preferably results in a reduction in the severity of disease symptoms and in the asymptomatic phase of the disease. Increase in frequency and duration, or prevent impairment or disability caused by suffering from disease.
  • a "therapeutically effective amount" of at least one of the aforementioned monoclonal antibodies or antigen-binding fragment portions thereof of the present invention or at least one of the aforementioned antibody-drug conjugates of the present invention relative to a subject who does not receive treatment cell growth or tumor growth is inhibited by at least about 10%, preferably at least about 20%, more preferably at least about 30%, more preferably at least about 40%, more preferably at least about 50%, more preferably at least about 60%, even more preferably At least about 70%, more preferably at least about 80%.
  • the ability to inhibit tumor growth can be evaluated in animal model systems that predict efficacy against human tumors.
  • an effective amount of an antibody or antigen-binding fragment thereof of the invention is capable of reducing tumor size or otherwise alleviating symptoms in a subject such as preventing and/or treating metastasis or recurrence.
  • One skilled in the art can determine this amount based on factors such as the size of the subject, the severity of the subject's symptoms, and the particular composition or route of administration chosen.
  • the present invention provides at least one of the aforementioned monoclonal antibodies of the present invention or antigen-binding fragment portion thereof or or the use of at least one of the aforementioned antibody-drug conjugates of the present invention in the preparation of pharmaceutical compositions.
  • the pharmaceutical composition is used to treat malignant tumors, prevent and/or treat malignant tumor metastasis or recurrence in patients.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one of the aforementioned monoclonal antibodies or antigen-binding fragment portions thereof of the present invention or at least one of the aforementioned antibody-drug conjugates of the present invention, said composition being used in patients Methods for treating malignant tumors, preventing and/or treating metastasis or recurrence of malignant tumors.
  • the present invention provides a method for treating malignant tumors, preventing and/or treating malignant tumor metastasis or recurrence in a patient, the method comprising administering to the patient an effective amount of at least one of the aforementioned monoclonal compounds of the present invention.
  • the malignant tumor is a tumor expressing ITGA2 protein.
  • the malignant tumor is selected from the group consisting of: breast cancer, colorectal cancer, large intestine cancer, skin cancer, pancreatic cancer, prostate cancer, liver cancer, lung cancer, gastric cancer, leukemia, cholangiocarcinoma, cervical cancer, endometrial cancer, esophageal cancer cancer, head and neck cancer, lymphoma, medullary thyroid cancer, non-Hodgkin's lymphoma, ovarian cancer, glioma, melanoma, and bladder cancer.
  • the malignant tumor is selected from the group consisting of colorectal cancer, cholangiocarcinoma, pancreatic cancer, and skin cancer.
  • the malignancy is colorectal cancer.
  • the malignant tumor is cholangiocarcinoma.
  • the malignant tumor is pancreatic cancer.
  • the malignancy is skin cancer.
  • ITGA2 is a tumor-associated antigen that is specifically overexpressed by tumor cells, especially in cancer patients such as colorectal cancer, cholangiocarcinoma, pancreatic cancer, and skin cancer, and is expressed on the surface of tumor cells.
  • the present invention provides a diagnostic/prognostic composition
  • a diagnostic/prognostic composition comprising at least one of the aforementioned monoclonal antibodies or antigen-binding fragments thereof of the present invention or at least one of the aforementioned antibody-drug conjugates of the present invention, the diagnostic/prognostic uses of this composition and its diagnostic /prognosis method.
  • the antibodies of the invention are conjugated to a label molecule.
  • the aforementioned antibody-drug conjugate of the present invention refers to a conjugate formed by connecting the antibody of the present invention or its antigen-binding fragment and a labeling molecule.
  • the present invention provides the use of at least one of the aforementioned monoclonal antibodies or antigen-binding fragment portions thereof of the present invention or at least one of the aforementioned antibody-drug conjugates of the present invention in the preparation of diagnostic/prognostic compositions.
  • the diagnostic composition is used to detect the presence of malignant tumors in a patient.
  • the prognostic composition is used to prognose the recurrence or progression of malignant tumors in a patient.
  • the present invention provides a method for detecting/diagnosing the presence of malignant tumors in a patient, said method comprising administering to said patient an effective amount of at least one monoclonal antibody or antigen-binding fragment thereof of the aforementioned invention. part, at least one of the aforementioned antibody-drug conjugates of the present invention, and/or at least one of the aforementioned diagnostic/prognostic compositions of the present invention.
  • the invention provides a method of detecting/diagnosing the presence of malignancy in a patient, comprising:
  • the present invention provides a method for prognosticating the recurrence or progression of malignant tumors in a patient, the method comprising administering to the patient an effective amount of at least one of the aforementioned monoclonal antibodies of the present invention or an antigen-binding fragment thereof. , at least one aforementioned antibody-drug conjugate of the present invention, and/or at least one aforementioned diagnostic/prognostic composition of the present invention.
  • the present invention provides a method for prognosticating the recurrence or progression of malignant tumors in a patient, the method comprising:
  • the progression of the malignant tumor comprises metastasis of the malignant tumor in the patient.
  • binding to at least one of the aforementioned monoclonal antibodies or antigen-binding fragment portions thereof of the present invention, at least one of the aforementioned antibody-drug conjugates of the present invention, and/or at least one of the aforementioned diagnostics of the present invention is identified.
  • the presence of tumor cells in the prognostic composition indicates a high risk of recurrence or progression of malignant tumor in said patient.
  • the partner molecule of the present invention is a label molecule; optionally, the label molecule is selected from one of the following: radioactive labels (such as isotopes), fluorescent labels (such as fluorescent dyes), chemical substances, and Detection of modified enzymes and tags.
  • the biological sample is selected from one of the following: blood sample, tissue sample, and lymph sample.
  • kits for use in the method of the present invention which kit includes at least one of the aforementioned monoclonal antibodies or antigen-binding fragments thereof of the present invention, at least one of the aforementioned antibody-drug conjugates of the present invention, At least one of the aforementioned pharmaceutical compositions of the present invention, or one of the aforementioned diagnostic/prognostic compositions of the present invention, and instructions for use.
  • the kit may further include at least one additional detection reagent for detecting at least one of the aforementioned monoclonal antibodies or antigen-binding fragments thereof of the present invention, and at least one of the aforementioned antibody drugs of the present invention.
  • Kits generally include labels indicating the intended use and/or method of use of the contents of the kit. The term label includes any written or recorded material on or provided with the kit or otherwise provided with the kit.
  • Example 1-ITGA2 protein is specifically overexpressed on the surface of various cancer cells
  • HuCC-T1 human cholangiocarcinoma cell; Mason cell: CTCC-003-0103
  • HCCC-9810 human cholangiocarcinoma cell; Wuhan Punosai: CL-0095
  • AsPC-1 human metastatic pancreatic cancer cell; Wuhan Pronoce: CL-0027
  • BxPC-3 human orthotopic pancreatic adenocarcinoma cell; Mason cell: CTCC-001-0360
  • A431 human epidermal cancer cell; Wuhan Pronoce: CL-0015)
  • HT- 29 human colorectal adenocarcinoma cell line; Wuhan Prose: CL-0118
  • CHO hamster ovary cells; Wuhan Prose: CL-0061
  • the design, vector construction, expression, purification and identification of the ITGA2 antibody sequence of the present invention were all entrusted to Sanyou Biopharmaceutical (Shanghai) Co., Ltd.
  • the construction process mainly includes constructing the ITGA2 antibody sequence on the pcDNA3.4 vector, and obtaining the plasmid after PCR, enzyme digestion, ligation, transformation, identification, sequencing, comparison, and extraction.
  • the vector containing the light chain and heavy chain sequences of the ITGA2 antibody of the present invention is shown in Table 4 below:
  • the 16 plasmids in the light chain are Kappa type and 2 plasmids are Lambda type; the 18 plasmids in the heavy chain are IgG1 type.
  • Humanized antibody light chain coding sequence FS002-A1-LC (Kappa) (SEQ ID NO: 1), which is used to express humanized light chain variable region + human light chain constant region
  • Humanized antibody light chain coding sequence FS002-A5-LC (Kappa) (SEQ ID NO: 2), which is used to express humanized light chain variable region + human light chain constant region
  • Humanized antibody light chain coding sequence FS002-A15-LC (Kappa) (SEQ ID NO: 3), which is used to express humanized light chain variable region + human light chain constant region
  • Humanized antibody light chain coding sequence FS002-A36-LC (Kappa) (SEQ ID NO: 4), which is used to express humanized light chain variable region + human light chain constant region
  • Humanized antibody light chain coding sequence FS002-A66-LC (Kappa) (SEQ ID NO: 5), which is used to express humanized light chain variable region + human light chain constant region
  • Humanized antibody light chain coding sequence FS002-A10-LC (Kappa-2) (SEQ ID NO: 6), which is used to express humanized light chain variable region + human light chain constant region
  • Humanized antibody light chain coding sequence FS002-C9-LC (Kappa-2) (SEQ ID NO: 7), which is used for expression Humanized light chain variable region + human light chain constant region
  • Humanized antibody light chain coding sequence FS002-C11-LC (Kappa-2) (SEQ ID NO: 8), which is used to express humanized light chain variable region + human light chain constant region
  • Humanized antibody light chain coding sequence FS002-C216-LC (Kappa-2) (SEQ ID NO: 9), which is used to express humanized light chain variable region + human light chain constant region
  • Humanized antibody light chain coding sequence FS002-C375-LC (Kappa-2) (SEQ ID NO: 10), which is used to express humanized light chain variable region + human light chain constant region
  • Humanized antibody light chain coding sequence FS002-C417-LC (Kappa-2) (SEQ ID NO: 11), which is used to express humanized light chain variable region + human light chain constant region
  • Humanized antibody light chain coding sequence FS002-B27-LC (Kappa-2) (SEQ ID NO: 12), which is used to express humanized light chain variable region + human light chain constant region
  • Humanized antibody light chain coding sequence FS002-C330-LC (Kappa-2) (SEQ ID NO: 13), which is used to express humanized light chain variable region + human light chain constant region
  • Humanized antibody light chain coding sequence FS002-C153-LC(LambdaC2)-2 (SEQ ID NO: 14), which is used to express humanized light chain variable region + human light chain constant region
  • Humanized antibody light chain coding sequence FS002-C241-LC(LambdaC2)-2 (SEQ ID NO: 15), which is used to express humanized light chain variable region + human light chain constant region
  • Humanized antibody light chain coding sequence FS002-C15-LC (Kappa-2) (SEQ ID NO: 16), which is used to express humanized light chain variable region + human light chain constant region
  • Humanized antibody light chain coding sequence FS002-C58-LC (Kappa-2) (SEQ ID NO: 17), which is used to express humanized light chain variable region + human light chain constant region
  • Humanized antibody light chain coding sequence FS002-A72-LC (Kappa-2) (SEQ ID NO: 18), which is used to express humanized light chain variable region + human light chain constant region
  • Humanized antibody heavy chain coding sequence FS002-A1-HC (IgG1) (SEQ ID NO: 19), which is used to express humanized heavy chain variable region + human heavy chain constant region
  • Humanized antibody heavy chain coding sequence FS002-A5-HC (IgG1) (SEQ ID NO: 20), which is used to express humanized heavy chain variable region + human heavy chain constant region
  • Humanized antibody heavy chain coding sequence FS002-A15-HC (IgG1) (SEQ ID NO: 21), which is used to express humanized heavy chain variable region + human heavy chain constant region
  • Humanized antibody heavy chain coding sequence FS002-36-HC (IgG1) (SEQ ID NO: 22), which is used to express humanized heavy chain variable region + human heavy chain constant region
  • Humanized antibody heavy chain coding sequence FS002-A66-HC (IgG1) (SEQ ID NO: 23), which is used for expression Humanized heavy chain variable region + human heavy chain constant region
  • Humanized antibody heavy chain coding sequence FS002-A10-HC (IgG1) (SEQ ID NO: 24), which is used to express humanized heavy chain variable region + human heavy chain constant region
  • Humanized antibody heavy chain coding sequence FS002-C9-HC (IgG1) (SEQ ID NO: 25), which is used to express humanized heavy chain variable region + human heavy chain constant region
  • Humanized antibody heavy chain coding sequence FS002-C11-HC (IgG1) (SEQ ID NO: 26), which is used to express humanized heavy chain variable region + human heavy chain constant region
  • Humanized antibody heavy chain coding sequence FS002-C216-HC (IgG1) (SEQ ID NO: 27), which is used to express humanized heavy chain variable region + human heavy chain constant region
  • Humanized antibody heavy chain coding sequence FS002-C375-HC (IgG1) (SEQ ID NO: 28), which is used to express humanized heavy chain variable region + human heavy chain constant region
  • Humanized antibody heavy chain coding sequence FS002-C417-HC (IgG1) (SEQ ID NO: 29), which is used to express humanized heavy chain variable region + human heavy chain constant region
  • Humanized antibody heavy chain coding sequence FS002-B27-HC (IgG1) (SEQ ID NO: 30), which is used to express humanized heavy chain variable region + human heavy chain constant region
  • Humanized antibody heavy chain coding sequence FS002-C330-HC (IgG1) (SEQ ID NO: 31), which is used to express humanized heavy chain variable region + human heavy chain constant region
  • Humanized antibody heavy chain coding sequence FS002-C153-HC (IgG1) (SEQ ID NO: 32), which is used to express humanized heavy chain variable region + human heavy chain constant region
  • Humanized antibody heavy chain coding sequence FS002-C241-HC (IgG1) (SEQ ID NO: 33), which is used to express humanized heavy chain variable region + human heavy chain constant region
  • Humanized antibody heavy chain coding sequence FS002-C15-HC (IgG1) (SEQ ID NO: 34), which is used to express humanized heavy chain variable region + human heavy chain constant region
  • Humanized antibody heavy chain coding sequence FS002-C58-HC (IgG1) (SEQ ID NO: 35), which is used to express humanized heavy chain variable region + human heavy chain constant region
  • Humanized antibody heavy chain coding sequence FS002-A72-HC (IgG1) (SEQ ID NO: 36), which is used to express humanized heavy chain variable region + human heavy chain constant region
  • amino acid sequences of the light chain variable region and heavy chain variable region in the antibody expressed by the above vector are as follows:
  • VL-CDR1 SEQ ID NO:38:
  • VL-CDR2 SEQ ID NO:39:
  • VL-CDR3 SEQ ID NO:40:
  • VL-CDR1 SEQ ID NO:42:
  • VL-CDR2 SEQ ID NO:43:
  • VL-CDR3 SEQ ID NO:44:
  • VL-CDR1 SEQ ID NO:46:
  • VL-CDR2 SEQ ID NO:47:
  • VL-CDR3 SEQ ID NO:48:
  • VL-CDR1 SEQ ID NO:50:
  • VL-CDR2 SEQ ID NO:51:
  • VL-CDR3 SEQ ID NO:52:
  • VL-CDR1 SEQ ID NO:54:
  • VL-CDR2 SEQ ID NO:55:
  • VL-CDR3 SEQ ID NO:56:
  • VL-CDR1 SEQ ID NO:58:
  • VL-CDR2 SEQ ID NO:59:
  • VL-CDR3 SEQ ID NO:60:
  • VL-CDR1 SEQ ID NO:62:
  • VL-CDR2 SEQ ID NO:63:
  • VL-CDR3 SEQ ID NO:64:
  • VL-CDR1 SEQ ID NO:66:
  • VL-CDR2 SEQ ID NO:67:
  • VL-CDR3 SEQ ID NO:68:
  • VL-CDR1 SEQ ID NO:70:
  • VL-CDR2 SEQ ID NO:71:
  • VL-CDR3 SEQ ID NO:72:
  • VL-CDR1 SEQ ID NO:74:
  • VL-CDR2 SEQ ID NO:75:
  • VL-CDR3 SEQ ID NO:76: ).
  • VL-CDR1 SEQ ID NO:78:
  • VL-CDR2 SEQ ID NO:79:
  • VL-CDR3 SEQ ID NO80:
  • VL-CDR1 SEQ ID NO:82:
  • VL-CDR2 SEQ ID NO:83:
  • VL-CDR3 SEQ ID NO:84:
  • VL-CDR1 SEQ ID NO:86:
  • VL-CDR2 SEQ ID NO:87:
  • VL-CDR3 SEQ ID NO:88: ).
  • VL-CDR1 SEQ ID NO:90:
  • VL-CDR2 SEQ ID NO:91:
  • VL-CDR3 SEQ ID NO:92:
  • VL-CDR1 SEQ ID NO:94:
  • VL-CDR2 SEQ ID NO:95:
  • VL-CDR3 SEQ ID NO:96: ).
  • VL-CDR1 SEQ ID NO:98:
  • VL-CDR2 SEQ ID NO:99:
  • VL-CDR3 SEQ ID NO:100: ).
  • VL-CDR1 SEQ ID NO:102:
  • VL-CDR2 SEQ ID NO:103:
  • VL-CDR3 SEQ ID NO:104:
  • VL-CDR1 SEQ ID NO:106:
  • VL-CDR2 SEQ ID NO:107:
  • VL-CDR3 SEQ ID NO:108:
  • FS002-A1-HC (IgG1) heavy chain variable region (SEQ ID NO:111)
  • VH-CDR1 SEQ ID NO:112:
  • VH-CDR2 SEQ ID NO:113:
  • VH-CDR3 SEQ ID NO:114:
  • FS002-A5-HC (IgG1) heavy chain variable region (SEQ ID NO:115)
  • VH-CDR1 SEQ ID NO:116:
  • VH-CDR2 SEQ ID NO:117:
  • VH-CDR3 SEQ ID NO:118:
  • FS002-A15-HC (IgG1) heavy chain variable region (SEQ ID NO: 119)
  • VH-CDR1 SEQ ID NO:120:
  • VH-CDR2 SEQ ID NO:121:
  • VH-CDR3 SEQ ID NO:122:
  • FS002-A36-HC (IgG1) heavy chain variable region (SEQ ID NO: 123)
  • VH-CDR1 SEQ ID NO:124:
  • VH-CDR2 SEQ ID NO:125:
  • VH-CDR3 SEQ ID NO:126:
  • FS002-A66-HC (IgG1) heavy chain variable region (SEQ ID NO: 127)
  • VH-CDR1 SEQ ID NO:128:
  • VH-CDR2 SEQ ID NO:129:
  • VH-CDR3 SEQ ID NO:130: ).
  • FS002-A10-HC (IgG1) heavy chain variable region (SEQ ID NO:131)
  • VH-CDR1 SEQ ID NO:132:
  • VH-CDR2 SEQ ID NO:133:
  • VH-CDR3 SEQ ID NO:134:
  • FS002-C9-HC (IgG1) heavy chain variable region (SEQ ID NO:135)
  • VH-CDR1 SEQ ID NO:136:
  • VH-CDR2 SEQ ID NO:137:
  • VH-CDR3 SEQ ID NO:138:
  • FS002-C11-HC (IgG1) heavy chain variable region (SEQ ID NO: 139)
  • VH-CDR1 SEQ ID NO:140:
  • VH-CDR2 SEQ ID NO:141:
  • VH-CDR3 SEQ ID NO:142:
  • VH-CDR1 SEQ ID NO:144:
  • VH-CDR2 SEQ ID NO:145:
  • VH-CDR3 SEQ ID NO:146:
  • VH-CDR1 SEQ ID NO:148:
  • VH-CDR2 SEQ ID NO:149:
  • VH-CDR3 SEQ ID NO:150: ).
  • VH-CDR1 SEQ ID NO:152:
  • VH-CDR2 SEQ ID NO:153:
  • VH-CDR3 SEQ ID NO:154:
  • VH-CDR1 SEQ ID NO:156:
  • VH-CDR2 SEQ ID NO:157:
  • VH-CDR3 SEQ ID NO:158:
  • FS002-C330-HC (IgG1) heavy chain variable region (SEQ ID NO:159)
  • VH-CDR1 SEQ ID NO:160:
  • VH-CDR2 SEQ ID NO:161:
  • VH-CDR3 SEQ ID NO:162:
  • FS002-C153-HC (IgG1) heavy chain variable region (SEQ ID NO:163)
  • VH-CDR1 SEQ ID NO:164:
  • VH-CDR2 SEQ ID NO:165:
  • VH-CDR3 SEQ ID NO:166:
  • FS002-C241-HC (IgG1) heavy chain variable region (SEQ ID NO:167)
  • VH-CDR1 SEQ ID NO:168:
  • VH-CDR2 SEQ ID NO:169:
  • VH-CDR3 SEQ ID NO:170: .
  • FS002-C15-HC (IgG1) heavy chain variable region (SEQ ID NO:171)
  • VH-CDR1 SEQ ID NO:172:
  • VH-CDR2 SEQ ID NO:173:
  • VH-CDR3 SEQ ID NO:174:
  • FS002-C58-HC (IgG1) heavy chain variable region (SEQ ID NO:175)
  • VH-CDR1 SEQ ID NO:176:
  • VH-CDR2 SEQ ID NO:177:
  • VH-CDR3 SEQ ID NO:178:
  • VH-CDR1 SEQ ID NO:180:
  • VH-CDR2 SEQ ID NO:181:
  • VH-CDR3 SEQ ID NO:182:
  • IgG1 type heavy chain constant region SEQ ID NO:183
  • the full-length amino acid sequence of the light chain of the antibody is as follows (the shaded part corresponds to the constant region sequence):
  • the full-length amino acid sequence of the heavy chain of the antibody is as follows (the shaded part corresponds to the constant region sequence):
  • Table 5 The heavy chain, light chain, constant region, and variable region of the aforementioned antibodies.
  • the sequence numbers of each CDR are summarized as follows (SEQ ID NO:)
  • the above plasmid was expressed in CHO cells for 7 days as required, and on the 6th day of expression, the antibody was purified using Protein A affinity chromatography.
  • the purity of the resulting antibodies was tested by SDS-PAGE.
  • SDS-PAGE use ImageJ to calculate the purity of the reduced band according to the peak area normalization method, or the purity of the reduced heavy chain plus light chain; the molecular weight of the reference product IPI non-reduced band is about 150kDa, and the purity is greater than 90%; the reduced heavy chain The molecular weight is about 55kDa, the molecular weight of the light chain is about 25kDa, and the purity of the heavy chain plus light chain is greater than 90%.
  • the following method was used to determine the affinity of ITGA2 antibody to ITGA2 protein at the protein level, including coating an ELISA plate with 2ug/mL ITGA2-His. Wash the plate 3 times with PBST and block with 5% PBS-Milk for 2 hours at room temperature. Wash the plate 3 times with PBST, then add the diluted antibody to the ELISA plate, 30 ⁇ L per well, and leave it at room temperature for 60 minutes. Wash the plate three times with PBST, then add anti-human IgG-Fc-HRP (abcam; ab97225) to the ELISA plate and leave it at room temperature for 60 minutes. Add TMB and stop the reaction with 2M stop solution and read the OD450. Finally, the EC50 was used to compare the binding ability of each antibody to ITGA2-his. The antibody Vatelizumab (purchased from Baiying Biotechnology) was used as a positive control. The resulting data from the assay are shown in Table 6 below.
  • HuCCT1 cells Human cholangiocarcinoma cells
  • HuCCT1 cells were plated into a 96-well plate with 50,000 cells in each well, and then washed twice with PBS by blowing evenly, and the PBS was aspirated.
  • the ITGA2 antibody to be detected is used as the primary antibody.
  • Use 1% FBS/PBS solution to prepare a working concentration of 30nM, and dilute it 3 times in sequence, with a total of 5 specific concentration points.
  • Use the prepared antibody diluent to add relative Incubate in a 96-well plate at 4°C for 30 minutes. Then wash twice with 1% FBS/PBS solution, discard the PBS, centrifuge, and discard the antibody supernatant.
  • the results of the EC50 determination are shown in Table 7.
  • the results are shown in Table 7: among these 18 antibodies, 14 antibodies have an EC50 of less than 5nM and can bind ITGA2-positive cells HuCCT1 well.
  • Antibody-drug conjugates were prepared using the following method
  • Coupling buffer 25mM Na 2 B 4 O 7 , 25mM NaCl, 1mM DPTA, pH 7.4
  • Dialysis buffer 1 ⁇ PBS, pH 7.4
  • Antibody reducing concentration 5mg/mL
  • Payload 10mM linker-payload, dimethyl sulfoxide (DMSO)
  • the antibodies FS002-A1, FS002-A15, and FS002-A36 of the present invention were prepared in this example. and antibody-drug conjugates of the positive control antibody Vatelizumab.
  • This example tests the biological activity of the antibody of the present invention in killing cancer cells after conjugating the toxin into an ADC.
  • the human cholangiocarcinoma cell HuCC-T1 from Zhejiang Meisen and the human epidermal cancer cell A431 from Wuhan Punosai Chinese hamster ovary cells CHO derived from ATCC and negative control were plated into a 96-well plate at 2500 cells/well. Place in a 37 °C 5% CO2 incubator and incubate overnight. The next day, half of the culture medium from the cell plate was removed.
  • ITGA2 antibodies alone cannot be used to kill tumor cells in vitro, but surprisingly, it was found that ITGA2 protein can be used as a target for effective antibody-drug conjugates.
  • the antibody-drug conjugate obtained by coupling an antibody to a small molecule toxin in the present invention can produce excellent killing effect on tumors expressing ITGA2 protein.
  • An isolated antibody or an antigen-binding fragment thereof that specifically binds to the ITGA2 protein wherein the isolated antibody or an antigen-binding fragment thereof includes a heavy chain variable region containing HCDR1, HCDR2, and HCDR3 sequences; and A light chain variable region containing LCDR1, LCDR2, and LCDR3 sequences, wherein the antibody or antigen-binding fragment portion thereof has a heavy chain variable region and a light chain variable region selected from at least one of the following:
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 112, (b) HCDR2 of SEQ ID NO: 113, and (c) HCDR3 of SEQ ID NO: 114, and the light chain can
  • the variable area includes (d) LCDR1 of SEQ ID NO: 38, (e) LCDR2 of SEQ ID NO: 39, and (f) LCDR3 of SEQ ID NO: 40;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 116, (b) HCDR2 of SEQ ID NO: 117, and (c) HCDR3 of SEQ ID NO: 118, and the light chain can variable region and the light chain variable region includes (d) LCDR1 of SEQ ID NO: 42, (e) LCDR2 of SEQ ID NO: 43, and (f) LCDR3 of SEQ ID NO: 44;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 120, (b) HCDR2 of SEQ ID NO: 121, and (c) HCDR3 of SEQ ID NO: 122, and the light chain can
  • the variable region includes (d) LCDR1 of SEQ ID NO: 46, (e) LCDR2 of SEQ ID NO: 47, and (f) LCDR3 of SEQ ID NO: 48;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 124, (b) HCDR2 of SEQ ID NO: 125, and (c) HCDR3 of SEQ ID NO: 126, and the light chain can
  • the variable area includes (d) LCDR1 of SEQ ID NO: 50, (e) LCDR2 of SEQ ID NO: 51, and (f) LCDR3 of SEQ ID NO: 52;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 128, (b) HCDR2 of SEQ ID NO: 129, and (c) HCDR3 of SEQ ID NO: 130, and the light chain can
  • the variable area includes (d) LCDR1 of SEQ ID NO: 54, (e) LCDR2 of SEQ ID NO: 55, and (f) LCDR3 of SEQ ID NO: 56;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 132, (b) HCDR2 of SEQ ID NO: 133, and (c) HCDR3 of SEQ ID NO: 134, and the light chain can
  • the variable area includes (d) LCDR1 of SEQ ID NO: 58, (e) LCDR2 of SEQ ID NO: 59, and (f) LCDR3 of SEQ ID NO: 60;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 136, (b) HCDR2 of SEQ ID NO: 137, and (c) HCDR3 of SEQ ID NO: 138, and the light chain may
  • the variable area includes (d) LCDR1 of SEQ ID NO: 62, (e) LCDR2 of SEQ ID NO: 63, and (f) LCDR3 of SEQ ID NO: 64;
  • the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 140, (b) HCDR2 of SEQ ID NO: 141, and (c) HCDR3 of SEQ ID NO: 142, and the light chain may
  • the variable region includes (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 144, (b) HCDR2 of SEQ ID NO: 145, and (c) HCDR3 of SEQ ID NO: 146, and the light chain may
  • the variable area includes (d) LCDR1 of SEQ ID NO: 70, (e) LCDR2 of SEQ ID NO: 71, and (f) LCDR3 of SEQ ID NO: 72;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 148, (b) HCDR2 of SEQ ID NO: 149, and (c) HCDR3 of SEQ ID NO: 150, and the light chain may
  • the variable region includes (d) LCDR1 of SEQ ID NO: 74, (e) LCDR2 of SEQ ID NO: 75, and (f) LCDR3 of SEQ ID NO: 76;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 152, (b) HCDR2 of SEQ ID NO: 153, and (c) HCDR3 of SEQ ID NO: 154, and the light chain may
  • the variable area includes (d) LCDR1 of SEQ ID NO: 78, (e) LCDR2 of SEQ ID NO: 79, and (f) LCDR3 of SEQ ID NO: 80;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 156, (b) HCDR2 of SEQ ID NO: 157, and (c) HCDR3 of SEQ ID NO: 158, and the light chain may
  • the variable area includes (d) LCDR1 of SEQ ID NO: 82, (e) LCDR2 of SEQ ID NO: 83, and (f) LCDR3 of SEQ ID NO: 84;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 160, (b) HCDR2 of SEQ ID NO: 161, and (c) HCDR3 of SEQ ID NO: 162, and the light chain may
  • the variable area includes (d) LCDR1 of SEQ ID NO: 86, (e) LCDR2 of SEQ ID NO: 87, and (f) LCDR3 of SEQ ID NO: 88;
  • the heavy chain variable region includes (a) HCDR1 of SEQ ID NO: 164, (b) HCDR2 of SEQ ID NO: 165, and (c) HCDR3 of SEQ ID NO: 166, and the light chain may
  • the variable area includes (d) LCDR1 of SEQ ID NO: 90, (e) LCDR2 of SEQ ID NO: 91, and (f) LCDR3 of SEQ ID NO: 92;
  • the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 168, (b) HCDR2 of SEQ ID NO: 169, and (c) HCDR3 of SEQ ID NO: 170, and the light chain may
  • the variable area includes (d) LCDR1 of SEQ ID NO: 94, (e) LCDR2 of SEQ ID NO: 95, and (f) LCDR3 of SEQ ID NO: 96;
  • the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 172, (b) HCDR2 of SEQ ID NO: 173, and (c) HCDR3 of SEQ ID NO: 174, and the light chain may
  • the variable area includes (d) LCDR1 of SEQ ID NO: 98, (e) LCDR2 of SEQ ID NO: 99, and (f) LCDR3 of SEQ ID NO: 100;
  • the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 176, (b) HCDR2 of SEQ ID NO: 177, and (c) HCDR3 of SEQ ID NO: 178, and the light chain may
  • the variable region includes (d) LCDR1 of SEQ ID NO: 102, (e) LCDR2 of SEQ ID NO: 103, and (f) LCDR3 of SEQ ID NO: 104; and
  • the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 180, (b) HCDR2 of SEQ ID NO: 181, and (c) HCDR3 of SEQ ID NO: 182, and the light chain may
  • the variable region includes (d) LCDR1 of SEQ ID NO:106, (e) LCDR2 of SEQ ID NO:107, and (f) LCDR3 of SEQ ID NO:108.
  • the heavy chain variable region includes the amino acid sequence of SEQ ID NO: 111 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or identical to the amino acid sequence of SEQ ID NO: 111. Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which includes the amino acid sequence of SEQ ID NO: 37 or is at least 85% or at least 90% identical to the amino acid sequence of SEQ ID NO: 37 , an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain variable region includes the amino acid sequence of SEQ ID NO: 115 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 115. Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which includes the amino acid sequence of SEQ ID NO: 41 or is at least 85% or at least 90% identical to the amino acid sequence of SEQ ID NO: 41 , an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain variable region includes the amino acid sequence of SEQ ID NO: 119 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 119. Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which comprises the amino acid sequence of SEQ ID NO: 45 or is at least 85%, or at least 90% identical to the amino acid sequence of SEQ ID NO: 45 , an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain variable region includes the amino acid sequence of SEQ ID NO: 123 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which includes the amino acid sequence of SEQ ID NO: 49 or is at least 85% or at least 90% identical to the amino acid sequence of SEQ ID NO: 49 , an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 127 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 127.
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 131 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, the same as the amino acid sequence of SEQ ID NO: 131.
  • the heavy chain variable region includes the amino acid sequence of SEQ ID NO: 135 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which includes the amino acid sequence of SEQ ID NO: 61 or is at least 85% or at least 90% identical to the amino acid sequence of SEQ ID NO: 61 , an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 139 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 139.
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 143 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which comprises the amino acid sequence of SEQ ID NO: 69 or is at least 85%, at least 90% identical to the amino acid sequence of SEQ ID NO: 69 , an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 147 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 147. Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which includes the amino acid sequence of SEQ ID NO: 73 or is at least 85% or at least 90% identical to the amino acid sequence of SEQ ID NO: 73 , an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 151 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 151. Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which includes the amino acid sequence of SEQ ID NO: 77 or is at least 85%, at least 90% identical to the amino acid sequence of SEQ ID NO: 77 , an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 155 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, the same as the amino acid sequence of SEQ ID NO: 155. Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which includes the amino acid sequence of SEQ ID NO: 81 An acid sequence or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 81;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 159 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 159. Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which includes the amino acid sequence of SEQ ID NO: 85 or is at least 85%, or at least 90% identical to the amino acid sequence of SEQ ID NO: 85 , an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 163 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 163. Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which includes the amino acid sequence of SEQ ID NO: 89 or is at least 85% or at least 90% identical to the amino acid sequence of SEQ ID NO: 89 , an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 167 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 167. Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which includes the amino acid sequence of SEQ ID NO: 93 or is at least 85% or at least 90% identical to the amino acid sequence of SEQ ID NO: 93 , an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 171 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 171. Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which includes the amino acid sequence of SEQ ID NO: 97 or is at least 85% or at least 90% identical to the amino acid sequence of SEQ ID NO: 97 , an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 175 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or equal to the amino acid sequence of SEQ ID NO: 175. Amino acid sequences that are at least 98%, or at least 99% identical, and the light chain variable region, which includes the amino acid sequence of SEQ ID NO: 101 or is at least 85% or at least 90% identical to the amino acid sequence of SEQ ID NO: 101 , an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical; and
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 179 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, the same as the amino acid sequence of SEQ ID NO: 179.
  • the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 183 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or identical to the amino acid sequence of SEQ ID NO: 183. Amino acid sequences that are at least 99% identical,
  • the light chain constant region comprises the amino acid sequence of SEQ ID NO: 109 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or identical to the amino acid sequence of SEQ ID NO: 109.
  • An amino acid sequence that is at least 99% identical; or the light chain constant region comprises the amino acid sequence of SEQ ID NO: 110 or is at least 85%, at least 90%, at least 95%, or at least 96% identical to the amino acid sequence of SEQ ID NO: 110 , an amino acid sequence that is at least 97%, at least 98%, or at least 99% identical.
  • the heavy chain which contains the amino acid sequence of SEQ ID NO: 202 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 202 , or an amino acid sequence that is at least 99% identical
  • the light chain which includes the amino acid sequence of SEQ ID NO: 184 or is at least 85%, at least 90%, at least 95%, or at least the same as the amino acid sequence of SEQ ID NO: 184 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which contains the amino acid sequence of SEQ ID NO: 203 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 203 , or an amino acid sequence that is at least 99% identical
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 185 or is at least 85%, at least 90%, at least 95%, or at least identical to the amino acid sequence of SEQ ID NO: 185 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which contains the amino acid sequence of SEQ ID NO: 204 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 204 , or an amino acid sequence that is at least 99% identical
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 186 or is at least 85%, at least 90%, at least 95%, or at least the same as the amino acid sequence of SEQ ID NO: 186 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 205 or the amino acid sequence of SEQ ID NO: 205 An amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, and the light chain comprising SEQ ID NO: 187 or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 187;
  • the heavy chain which contains the amino acid sequence of SEQ ID NO: 206 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 206 , or an amino acid sequence that is at least 99% identical
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 188 or is at least 85%, at least 90%, at least 95%, or at least identical to the amino acid sequence of SEQ ID NO: 188 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which contains the amino acid sequence of SEQ ID NO: 207 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 207 , or an amino acid sequence that is at least 99% identical
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 189 or is at least 85%, at least 90%, at least 95%, or at least identical to the amino acid sequence of SEQ ID NO: 189 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 208 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 208 , or an amino acid sequence that is at least 99% identical
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 190 or is at least 85%, at least 90%, at least 95%, or at least identical to the amino acid sequence of SEQ ID NO: 190 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 209 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 209 , or an amino acid sequence that is at least 99% identical
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 191 or is at least 85%, at least 90%, at least 95%, or at least the same as the amino acid sequence of SEQ ID NO: 191 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 210 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 210 , or an amino acid sequence that is at least 99% identical
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 192 or is at least 85%, at least 90%, at least 95%, or at least identical to the amino acid sequence of SEQ ID NO: 192 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 211 or the amino acid sequence of SEQ ID NO: 211 An amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, and the light chain comprising SEQ ID NO: 193 or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 193;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 212 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 212 , or an amino acid sequence that is at least 99% identical
  • the light chain which includes the amino acid sequence of SEQ ID NO: 194 or is at least 85%, at least 90%, at least 95%, or at least the same as the amino acid sequence of SEQ ID NO: 194 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 213 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 213 , or an amino acid sequence that is at least 99% identical
  • the light chain which includes the amino acid sequence of SEQ ID NO: 195 or is at least 85%, at least 90%, at least 95%, or at least identical to the amino acid sequence of SEQ ID NO: 195 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 214 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 214 , or an amino acid sequence that is at least 99% identical
  • the light chain which includes the amino acid sequence of SEQ ID NO: 196 or is at least 85%, at least 90%, at least 95%, or at least the same as the amino acid sequence of SEQ ID NO: 196 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 215 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 215 , or an amino acid sequence that is at least 99% identical
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 197 or is at least 85%, at least 90%, at least 95%, or at least the same as the amino acid sequence of SEQ ID NO: 197 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 216 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 216 , or an amino acid sequence that is at least 99% identical, and the light chain comprising the amino acid sequence of SEQ ID NO: 198 or at least 85%, at least 90%, at least 95%, or at least the amino acid sequence of SEQ ID NO: 198 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain comprising the amino acid sequence of SEQ ID NO: 217 or the amino acid sequence of SEQ ID NO: 217 An amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, and the light chain comprising SEQ ID NO: 199 or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 199;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 218 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 218 , or an amino acid sequence that is at least 99% identical
  • the light chain which comprises the amino acid sequence of SEQ ID NO: 200 or is at least 85%, at least 90%, at least 95%, or at least identical to the amino acid sequence of SEQ ID NO: 200 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical;
  • the heavy chain which comprises the amino acid sequence of SEQ ID NO: 219 or is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% identical to the amino acid sequence of SEQ ID NO: 219 , or an amino acid sequence that is at least 99% identical
  • the light chain which includes the amino acid sequence of SEQ ID NO: 201 or is at least 85%, at least 90%, at least 95%, or at least the same as the amino acid sequence of SEQ ID NO: 201 Amino acid sequences that are 96%, at least 97%, at least 98%, or at least 99% identical.
  • the heavy chain which consists of the amino acid sequence of SEQ ID NO: 213, and the light chain, which consists of the amino acid sequence of SEQ ID NO: 195;
  • the heavy chain which consists of the amino acid sequence of SEQ ID NO: 215, and the light chain, which consists of the amino acid sequence of SEQ ID NO: 197;
  • the heavy chain which consists of the amino acid sequence of SEQ ID NO: 216
  • the light chain which consists of the amino acid sequence of SEQ ID NO: 198;
  • the heavy chain which consists of the amino acid sequence of SEQ ID NO: 218, and the light chain, which consists of the amino acid sequence of SEQ ID NO: 200;
  • the heavy chain which consists of the amino acid sequence of SEQ ID NO: 219
  • the light chain which consists of the amino acid sequence of SEQ ID NO: 201.
  • An isolated antibody or an antigen-binding fragment portion thereof that specifically binds to ITGA2 protein wherein the isolated antibody or an antigen-binding fragment portion thereof has a heavy chain and a light chain selected from at least one of the following groups:
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 19, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 19. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 19, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1, or has at least 85%, at least 90%, At least 95%, An amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 20, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 20. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 20, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:2, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 21, or contains at least 85%, or at least 90%, of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 21. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 21, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:3, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 3;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 22, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 22. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 22, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:4, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 4;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 23, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 23. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 23, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:5, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 5;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 24, or contains at least 85%, or at least 90%, of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 24. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 24, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 25, or contains at least 85%, or at least 90%, of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 25. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 25, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:7, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 7;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:8, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 8;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 27, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 27. %,At least an amino acid sequence that is 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 27, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 9, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 9;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 28, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 28. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 28, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 10, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 10;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 29, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 29. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 29, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 11, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 11;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequence, or consisting of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 12, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 12;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 13, or has at least 85%, at least 90%, or An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 13;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 32, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 32. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 32, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 14, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 14;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 15, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 15;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 16, or has at least 85%, at least 90%, At least 95%, An amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 16;
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35, or has at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 17, or has at least 85%, at least 90%, and
  • the heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36, or contains at least 85% or at least 90% similarity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36. %, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical amino acid sequences, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36, and
  • the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 18, or has at least 85%, at least 90%, An amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 18.
  • the antibody is capable of binding ITGA2 protein in vitro with an EC50 of less than 1 nM;
  • the antibody can bind to ITGA2 protein on the surface of HuCCT1 cells with an EC50 of less than 5nM;
  • the antibody is a monoclonal antibody, a polyclonal antibody, a chimeric antibody, or a humanized antibody.
  • the nucleic acid molecule includes or consists of a nucleotide sequence selected from any of the following: SEQ ID NOs: 1-18, and/or the nucleic acid molecule includes a nucleotide sequence selected from any of the following. or consists of the nucleotide sequence shown: SEQ ID NOs: 19-36; or
  • the nucleic acid molecule includes or consists of a nucleotide sequence selected from any of the following combinations: SEQ ID NO: 1 and SEQ ID NO: 19, SEQ ID NO: 2 and SEQ ID NO: 20.
  • nucleic acid molecule of technical solution 8 which nucleic acid molecule is operably linked to an expression control sequence.
  • An expression vector comprising the nucleic acid molecule of technical solution 8 or 9.
  • a host cell comprising the nucleic acid molecule of technical solution 8 or 9 or the expression vector of technical solution 10.
  • L represents the linker connecting the antibody portion to the partner molecule
  • L represents the linker connecting the antibody portion to the partner molecule
  • p represents the number of linker/partner molecules (preferably drug payloads) conjugated to the aforementioned antibody of the invention or its antigen-binding fragment part; optionally, p is selected from the following values: 1.0, 1.1, 1.2 ,1.3,1.4,1.5,1.6,1.7,1.8,1.9,2.0,2.1,2.2,2.3,2.4,2.5,2.6,2.7,2.8,2.9,3.0,3.1,3.2,3.3,3.4,3.5,3.6,3.7 ,3.8,3.9,4.0,4.1,4.2,4.3,4.4,4.5,4.6,4.7,4.8,4.9,5.0,5.1,5.2,5.3,5.4,5.5,5.6,5.7,5.8,5.9,6.0,6.1,6.2 , 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, and 8.0.
  • linker is selected from the following one: vc, mc-GGFG, AcLysvc, mc, MalPeg6, m(H20)c and m(H20)cvc; and/ Or the linker is cleavable.
  • the partner molecule is a drug load, and the drug load is a therapeutic molecule; optionally, the drug load is selected from the following: cytotoxic agents, cell inhibitors, immunomodulators, and chemotherapeutic agents.
  • the drug load is selected from the following one: MMAE, MMAF, DM1, DM4, Dxd, SN-38, Topotecan and its derivatives, Exatecan and its derivatives, Belotecan and its derivatives, Camptothecin, Calicheamicin and PBD; or
  • the partner molecule is a label molecule; optionally, the label molecule is selected from one of the following: radioactive labels (eg, isotopes), fluorescent labels (eg, fluorescent dyes), chemicals, and detectably modified enzymes and labels.
  • radioactive labels eg, isotopes
  • fluorescent labels eg, fluorescent dyes
  • composition which contains the antibody or antigen-binding fragment part thereof according to any one of technical solutions 1-7 or the antibody-drug conjugate according to any one of technical solutions 13-15, and optionally pharmaceutically acceptable Carrier.
  • the antibody or antigen-binding fragment portion thereof according to any one of technical solutions 1-7 or the antibody-drug conjugate according to any one of technical solutions 13-15 in the preparation of a pharmaceutical composition; optionally, the The pharmaceutical composition is used to treat malignant tumors, prevent and/or treat malignant tumor metastasis or recurrence in patients; optionally, the pharmaceutical composition is used to detect the presence of malignant tumors in patients; optionally, the pharmaceutical combination Drugs are used to predict the recurrence or progression of malignant tumors in patients.
  • a method for treating malignant tumors, preventing and/or treating malignant tumor metastasis or recurrence in a patient comprising administering to the patient an effective amount of the antibody or antigen thereof of any one of technical solutions 1-7. Binding fragment part, the antibody drug conjugate of any one of technical solutions 13-15, or the pharmaceutical composition of technical solution 16.
  • the malignant tumor is selected from the group consisting of: breast cancer, colorectal cancer, skin cancer, pancreatic cancer, prostate cancer, liver cancer, lung cancer, gastric cancer, leukemia, cholangiocarcinoma, cervical cancer, colon Rectal cancer, endometrial cancer, esophageal cancer, head and neck cancer, lymphoma, medullary thyroid cancer, non-Hodgkin's lymphoma, ovarian cancer, glioma, melanoma, and bladder cancer; preferably, Said malignant tumor is selected from the group consisting of colorectal cancer, cholangiocarcinoma, pancreatic cancer and skin cancer.
  • a method of detecting the presence of tumor cells in a biological sample comprising:
  • detection of said binding represents the presence of tumor cells in said biological sample.
  • a method of detecting the presence of malignancy in a patient comprising:
  • a method for prognosticating the recurrence or progression of malignant tumors in a patient comprising:
  • the malignant tumor is selected from the group consisting of: breast cancer, colorectal cancer, large intestine cancer, skin cancer, pancreatic cancer, prostate cancer, liver cancer, lung cancer, gastric cancer , leukemia, cholangiocarcinoma, cervical cancer, endometrial cancer, esophageal cancer, head and neck cancer, lymphoma, medullary thyroid cancer, non-Hodgkin's lymphoma, ovarian cancer, glioma, melanoma, and bladder Cancer; preferably, the malignant tumor is selected from the group consisting of colorectal cancer, cholangiocarcinoma, pancreatic cancer and skin cancer.

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Abstract

本发明提供了一系列与表达ITGA2蛋白的肿瘤细胞具有高特异性结合能力的抗体或其抗原结合片段部分。本发明的抗体或其抗原结合片段部分在与药物缀合形成抗体-药物缀合物后，可以对肿瘤细胞实现优异的杀伤效果。

Description

靶向ITGA2的抗体和包含此抗体的抗体药物缀合物
本申请要求2022年06月27日提交的题为“靶向ITGA2的抗体和包含此抗体的抗体药物缀合物”的中国专利申请202210743539.0的优先权，此优先权文本的全部内容援引并入本申请。
技术领域
本发明涉及生物医药领域。具体而言，本发明涉及一种靶向ITGA2的抗体或其抗原结合片段，包含此抗体的抗体药物缀合物、以及此抗体和/或抗体药物缀合物在治疗相关疾病中的用途。
背景技术
恶性肿瘤(癌症)已成为威胁全世界人民生命与健康的“头号杀手”。全世界每年肿瘤的发病人数超过1400万，仅在我国每年新增的肿瘤患者超过300万。
导致癌症高死亡率的根本原因是癌细胞的扩散、转移和治疗后多数患者易复发和耐药。临床上现有的治疗手段，手术、放疗、化疗对癌细胞转移、复发、耐药疗效甚微，或只有近期疗效，并不能改变患者长期的存活情况。目前，手术切除对大约10-20％的早期患者效果好，但对已发生扩散转移的患者几乎无效。放疗只能治疗局部病灶，常作为术前、术后的辅助治疗和少数种类癌症的根治性治疗。化疗可用于已发生扩散转移的患者，但因毒副作用大，容易产生近期或远期的耐药，因而只能对大约20-30％的患者有明显的近期疗效。即使采用手术、放疗和化疗联合应用的综合治疗措施，其生存5年的远期疗效多年一直徘徊在20-30％，约70-80％的患者在治疗后因转移、复发和耐药在5年内死亡。即便是就诊时无转移的早期癌症患者，也还是有一部分在治疗后发生转移复发而死亡。
目前通过鉴定肿瘤相关抗原，随后通过制备抗体-药物缀合物的药物形式将药物递送至肿瘤细胞是一种有效的治疗肿瘤的方法。这种药物形式结合了单抗对肿瘤细胞的靶向性以及小分子细胞毒素的强大肿瘤杀伤的优势，可显著降低小分子毒素的毒副作用，又可提高药物疗效，具有显著的治疗优势。
发明内容
本发明人发现，ITGA2是一种肿瘤细胞特异性过表达的肿瘤相关抗原，在多数实体瘤中均有上调表达，特别在结直肠癌、胆管癌、胰腺癌、和皮肤癌等癌症中存在显著 的过表达；然而目前能够单独靶向ITGA2的抗体本身对肿瘤细胞的生长抑制作用不佳。因此，本发明人开发出一系列与表达ITGA2蛋白的肿瘤细胞具有高特异性结合能力的抗体，通过抗体-药物缀合物的形式靶向ITGA2阳性的肿瘤细胞以实现对细胞的优异杀伤效果。
一方面，本发明提供了一种特异性结合ITGA2蛋白的分离的抗体或其抗原结合片段部分，其中，所述的分离的抗体或其抗原结合片段部分包含含有HCDR1、HCDR2、HCDR3序列的重链可变区；以及含有LCDR1、LCDR2、LCDR3序列的轻链可变区，其中所述抗体或其抗原结合片段部分具有选自以下至少一组的重链可变区和轻链可变区：
1)所述重链可变区包含(a)SEQ ID NO：112的HCDR1，(b)SEQ ID NO：113的HCDR2，和(c)SEQ ID NO：114的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：38的LCDR1，(e)SEQ ID NO：39的LCDR2，和(f)SEQ ID NO：40的LCDR3；
2)所述重链可变区包含(a)SEQ ID NO：116的HCDR1，(b)SEQ ID NO：117的HCDR2，和(c)SEQ ID NO：118的HCDR3，且所述轻链可变区且所述轻链可变区包含(d)SEQ ID NO：42的LCDR1，(e)SEQ ID NO：43的LCDR2，和(f)SEQ ID NO：44的LCDR3；
3)所述重链可变区包含(a)SEQ ID NO：120的HCDR1，(b)SEQ ID NO：121的HCDR2，和(c)SEQ ID NO：122的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：46的LCDR1，(e)SEQ ID NO：47的LCDR2，和(f)SEQ ID NO：48的LCDR3；
4)所述重链可变区包含(a)SEQ ID NO：124的HCDR1，(b)SEQ ID NO：125的HCDR2，和(c)SEQ ID NO：126的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：50的LCDR1，(e)SEQ ID NO：51的LCDR2，和(f)SEQ ID NO：52的LCDR3；
5)所述重链可变区包含(a)SEQ ID NO：128的HCDR1，(b)SEQ ID NO：129的HCDR2，和(c)SEQ ID NO：130的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：54的LCDR1，(e)SEQ ID NO：55的LCDR2，和(f)SEQ ID NO：56的LCDR3；
6)所述重链可变区包含(a)SEQ ID NO：132的HCDR1，(b)SEQ ID NO：133的HCDR2，和(c)SEQ ID NO：134的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：58的LCDR1，(e)SEQ ID NO：59的LCDR2，和(f)SEQ ID NO：60的LCDR3；
7)所述重链可变区包含(a)SEQ ID NO：136的HCDR1，(b)SEQ ID NO：137的HCDR2，和(c)SEQ ID NO：138的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：62 的LCDR1，(e)SEQ ID NO：63的LCDR2，和(f)SEQ ID NO：64的LCDR3；
8)所述重链可变区包含(a)SEQ ID NO：140的HCDR1，(b)SEQ ID NO：141的HCDR2，和(c)SEQ ID NO：142的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：66的LCDR1，(e)SEQ ID NO：67的LCDR2，和(f)SEQ ID NO：68的LCDR3；
9)所述重链可变区包含(a)SEQ ID NO：144的HCDR1，(b)SEQ ID NO：145的HCDR2，和(c)SEQ ID NO：146的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：70的LCDR1，(e)SEQ ID NO：71的LCDR2，和(f)SEQ ID NO：72的LCDR3；
10)所述重链可变区包含(a)SEQ ID NO：148的HCDR1，(b)SEQ ID NO：149的HCDR2，和(c)SEQ ID NO：150的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：74的LCDR1，(e)SEQ ID NO：75的LCDR2，和(f)SEQ ID NO：76的LCDR3；
11)所述重链可变区包含(a)SEQ ID NO：152的HCDR1，(b)SEQ ID NO：153的HCDR2，和(c)SEQ ID NO：154的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：78的LCDR1，(e)SEQ ID NO：79的LCDR2，和(f)SEQ ID NO：80的LCDR3；
12)所述重链可变区包含(a)SEQ ID NO：156的HCDR1，(b)SEQ ID NO：157的HCDR2，和(c)SEQ ID NO：158的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：82的LCDR1，(e)SEQ ID NO：83的LCDR2，和(f)SEQ ID NO：84的LCDR3；
13)所述重链可变区包含(a)SEQ ID NO：160的HCDR1，(b)SEQ ID NO：161的HCDR2，和(c)SEQ ID NO：162的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：86的LCDR1，(e)SEQ ID NO：87的LCDR2，和(f)SEQ ID NO：88的LCDR3；
14)所述重链可变区包含(a)SEQ ID NO：164的HCDR1，(b)SEQ ID NO：165的HCDR2，和(c)SEQ ID NO：166的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：90的LCDR1，(e)SEQ ID NO：91的LCDR2，和(f)SEQ ID NO：92的LCDR3；
15)所述重链可变区包含(a)SEQ ID NO：168的HCDR1，(b)SEQ ID NO：169的HCDR2，和(c)SEQ ID NO：170的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：94的LCDR1，(e)SEQ ID NO：95的LCDR2，和(f)SEQ ID NO：96的LCDR3；
16)所述重链可变区包含(a)SEQ ID NO：172的HCDR1，(b)SEQ ID NO：173的HCDR2，和(c)SEQ ID NO：174的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：98的LCDR1，(e)SEQ ID NO：99的LCDR2，和(f)SEQ ID NO：100的LCDR3；
17)所述重链可变区包含(a)SEQ ID NO：176的HCDR1，(b)SEQ ID NO：177的HCDR2，和(c)SEQ ID NO：178的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：102 的LCDR1，(e)SEQ ID NO：103的LCDR2，和(f)SEQ ID NO：104的LCDR3；和
18)所述重链可变区包含(a)SEQ ID NO：180的HCDR1，(b)SEQ ID NO：181的HCDR2，和(c)SEQ ID NO：182的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：106的LCDR1，(e)SEQ ID NO：107的LCDR2，和(f)SEQ ID NO：108的LCDR3。
另一方面，本发明提供了一种特异性结合ITGA2蛋白的分离的抗体或其抗原结合片段部分，其中，所述的分离的抗体或其抗原结合片段部分具有选自以下至少一组的重链和轻链：
1)所述重链包含由SEQ ID NO：19的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：19的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：19的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：1的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：1的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：1的核苷酸序列所编码的氨基酸序列组成；
2)所述重链包含由SEQ ID NO：20的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：20的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：20的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：2的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：2的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：2的核苷酸序列所编码的氨基酸序列组成；
3)所述重链包含由SEQ ID NO：21的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：21的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：21的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：3的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：3的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO： 3的核苷酸序列所编码的氨基酸序列组成；
4)所述重链包含由SEQ ID NO：22的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：22的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：22的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：4的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：4的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：4的核苷酸序列所编码的氨基酸序列组成；
5)所述重链包含由SEQ ID NO：23的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：23的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：23的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：5的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：5的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：5的核苷酸序列所编码的氨基酸序列组成；
6)所述重链包含由SEQ ID NO：24的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：24的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：24的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：6的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：6的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：6的核苷酸序列所编码的氨基酸序列组成；
7)所述重链包含由SEQ ID NO：25的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：25的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：25的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：7的核苷酸序列所编码的氨基酸序列，或包含与由 SEQ ID NO：7的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：7的核苷酸序列所编码的氨基酸序列组成；
8)所述重链包含由SEQ ID NO：26的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：26的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：26的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：8的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：8的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：8的核苷酸序列所编码的氨基酸序列组成；
9)所述重链包含由SEQ ID NO：27的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：27的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：27的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：9的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：9的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：9的核苷酸序列所编码的氨基酸序列组成；
10)所述重链包含由SEQ ID NO：28的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：28的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：28的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：10的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：10的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：10的核苷酸序列所编码的氨基酸序列组成；
11)所述重链包含由SEQ ID NO：29的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：29的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ  ID NO：29的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：11的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：11的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：11的核苷酸序列所编码的氨基酸序列组成；
12)所述重链包含由SEQ ID NO：30的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：30的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：30的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：12的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：12的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：12的核苷酸序列所编码的氨基酸序列组成；
13)所述重链包含由SEQ ID NO：31的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：31的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：31的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：13的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：13的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：13的核苷酸序列所编码的氨基酸序列组成；
14)所述重链包含由SEQ ID NO：32的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：32的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：32的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：14的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：14的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：14的核苷酸序列所编码的氨基酸序列组成；
15)所述重链包含由SEQ ID NO：33的核苷酸序列所编码的氨基酸序列，或包含与 由SEQ ID NO：33的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：33的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：15的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：15的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：15的核苷酸序列所编码的氨基酸序列组成；
16)所述重链包含由SEQ ID NO：34的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：34的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：34的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：16的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：16的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：16的核苷酸序列所编码的氨基酸序列组成；
17)所述重链包含由SEQ ID NO：35的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：35的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：35的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：17的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：17的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：17的核苷酸序列所编码的氨基酸序列组成；和
18)所述重链包含由SEQ ID NO：36的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：36的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：36的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：18的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：18的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO： 18的核苷酸序列所编码的氨基酸序列组成。
又一方面，本发明提供了一种分离的核酸分子，其编码本发明的的单克隆抗体或其抗原结合片段。
又一方面，本发明提供了一种表达载体，其包含本发明的核酸分子。
又一方面，本发明提供了一种宿主细胞，其包含本发明的核酸分子或本发明的表达载体。
又一方面，本发明提供了一种杂交瘤细胞，其表达本发明的单克隆抗体或其抗原结合片段部分。
又一方面，本发明提供了本发明的单克隆抗体或其抗原结合片段或者本发明的抗体药物缀合物在制备药物组合物中的用途；可选地，所述药物组合物用于在患者中治疗恶性肿瘤、预防和/或治疗恶性肿瘤转移或复发。
又一方面，本发明提供了一种在患者中治疗恶性肿瘤、预防和/或治疗恶性肿瘤转移或复发的方法，所述方法包括给所述患者施用有效量的本发明的单克隆抗体或其抗原结合片段部分、本发明的抗体药物缀合物、或者本发明的药物组合物。
又一方面，本发明提供了本发明的单克隆抗体或其抗原结合片段或者本发明的抗体药物缀合物在制备诊断/预后组合物中的用途；可选地，所述诊断/预后组合物用于检测患者中恶性肿瘤的存在；可选地，所述诊断/预后组合物用于预后患者中恶性肿瘤复发或进展。
又一方面，本发明提供了一种用于预后患者中恶性肿瘤复发或进展的方法，所述方法包括：
(a)从所述患者中分离包含肿瘤细胞的生物学样品；
(b)使所述包含肿瘤细胞的生物学样品与本发明的单克隆抗体或其抗原结合片段或者本发明的抗体药物缀合物接触；和
(c)鉴定结合所述单克隆抗体或其抗原结合片段的肿瘤细胞的存在，
从而预后所述患者中恶性肿瘤的复发或进展。
又一方面，本发明提供了一种用于检测/诊断患者中恶性肿瘤的存在的方法，包括：
a)使获得自所述患者的生物学样品与本发明的单克隆抗体或其抗原结合片段或者本发明的抗体药物缀合物接触；
b)检测所述单克隆抗体或其抗原结合片段与所述生物学样品中的靶抗原的结合，其中检出所述结合代表所述患者中存在恶性肿瘤。
又一方面，本发明提供了一种用于检测生物学样品中肿瘤细胞存在的方法，包括：
a)使所述生物学样品与本发明的单克隆抗体或其抗原结合片段或者本发明的抗体药物缀合物接触；
b)检测所述单克隆抗体或其抗原结合片段或者所述抗体药物缀合物与所述生物学样品中的靶抗原的结合，
其中检出所述结合代表所述生物学样品中存在肿瘤细胞。
又一方面，本发明提供了一种用于分离肿瘤细胞的方法，所述方法包括：
(a)提供疑似包含肿瘤细胞的细胞群；
(b)鉴定所述细胞的亚群，其结合本发明的的单克隆抗体或其抗原结合片段或者所述抗体药物缀合物；和
(c)分离所述亚群。
又一方面，本发明提供了一种生产靶向表达ITGA2的人肿瘤细胞的单克隆抗体或其抗原结合片段的方法，包括：
(i)在适合所述核酸分子或表达载体表达的情况下培养本发明的宿主细胞，和
(ii)分离并纯化由所述核酸分子或表达载体表达的抗体或其抗原结合片段。
本发明的抗体对ITGA2蛋白具有优异的结合性，能够与表达ITGA2的肿瘤细胞，尤其是结直肠癌细胞、胆管癌细胞，胰腺癌细胞和皮肤癌细胞有优异的结合。本发明的抗体药物缀合物对于表达ITGA2的肿瘤细胞，尤其是结直肠癌细胞、胆管癌细胞，胰腺癌和皮肤癌细胞具有优异的杀伤效果。
序列说明：
以下表1中最左栏为本发明中的序列编号(SEQ ID NO：)。
表1a本发明抗体的轻链和重链的核酸编码序列SEQ ID NO:1-36







表1b本发明抗体的轻链和重链的可变区、各个CDR以及恒定区的氨基酸序列(SEQ ID NO:37-183)





注：表中氨基酸序列中用黑体和下划线标出的序列为对应的CDR序列
表1c本发明抗体的轻链和重链的氨基酸序列(SEQ ID NO:184-219)。



注：表中氨基酸序列中用黑体和下划线标出的序列为对应的CDR序列
具体实施方式
(一)、一般性定义
在本发明中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且，本文中所用的蛋白质和核酸化学、分子生物学、细胞和组织培养、微生物学、免疫学相关术语和实验室操作步骤均为相应领域内广泛使用的术语和常规步骤。同时，为了更好地理解本发明，下面提供相关术语的定义和解释。
如本文所用，“抗体”指免疫球蛋白和免疫球蛋白片段，无论天然的或者部分或全部合成(例如重组)产生的，包括其至少包含免疫球蛋白分子的部分可变区的保留全长免疫球蛋白的结合特异性能力的任何片段。因此，抗体包括具有与免疫球蛋白抗原结合结构域(抗体结合位点)同源或基本上同源的结合结构域的任何蛋白。抗体包括抗体片段，例如抗肿瘤干细胞抗体片段。如本文所用，因此术语抗体包括合成抗体、重组产生的抗体、多特异性抗体(例如双特异性抗体)、人抗体、非人抗体、人源化抗体、嵌合抗体、胞内抗体以及抗体片段，例如但不限于Fab片段、Fab'片段、F(ab’)2片段、Fv片段、二硫键连接的Fv(dsFv)、Fd片段、Fd’片段、单链Fv(scFv)、单链Fab(scFab)、双抗体、抗独特型(抗Id)抗体、或者上述任何抗体的抗原结合片段。本文所提供的抗体包括任何免疫球蛋白类型(例如，IgG、IgM、IgD、IgE、IgA和IgY)、任何类别(例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)或亚类(例如，IgG2a和IgG2b)的成员。
如本文所用，抗体的“抗体片段”或“抗原结合片段”指全长抗体的任何部分，其少于全长，但是至少包含结合抗原的所述抗体的部分可变区(例如一个或多个CDR和/或一个或多个抗体结合位点)，并且因此保留结合特异性以及所述全长抗体的至少部分特异 性结合能力。因此，抗原结合片段指包含与衍生抗体片段的抗体结合相同抗原的抗原结合部分的抗体片段。抗体片段包括通过酶促处理全长抗体所产生的抗体衍生物，以及合成产生的衍生物，例如重组产生的衍生物。抗体包括抗体片段。抗体片段的实例包括但不限于Fab、Fab'、F(ab’)2、单链Fv(scFv)、Fv、dsFv、双抗体、Fd和Fd’片段以及其他片段，包括修饰的片段(参见，例如，Methods in Molecular Biology,Vol 207:Recombinant Antibodies for Cancer Therapy Methods and Protocols(2003)；Chapter 1；p 3-25,Kipriyanov)。所述片段可以包括连接在一起的多条链，例如通过二硫键和/或通过肽接头。抗体片段一般包含至少或约50个氨基酸，并且典型至少或约200个氨基酸。抗原结合片段包括任何抗体片段，其在被插入抗体框架(例如通过置换相应区域)时获得免疫特异性地结合(即表现出至少或至少约107-108M-1的Ka)抗原的抗体。
如本文所用，“单克隆抗体”指相同抗体的群体，表示单克隆抗体群体中的每个单独的抗体分子与其他抗体分子相同。这种特性与抗体的多克隆群体的特性相反，所述抗体的多克隆群体包含具有多种不同序列的抗体。单克隆抗体可以通过许多公知的方法来制备(Smith et al.(2004)J.Clin.Pathol.57,912-917；和Nelson et al.,J Clin Pathol(2000),53,111-117)。例如，单克隆抗体可以通过永生化B细胞来制备，例如通过与骨髓瘤细胞融合以产生杂交瘤细胞系或者通过用诸如EBV的病毒感染B细胞。重组技术还可以用来在体外通过用携带编码抗体的核苷酸的人工序列的质粒转化宿主细胞来从宿主细胞的克隆群体制备抗体。
如本文中所用，术语“杂交瘤”或“杂交瘤细胞”指由融合产抗体的淋巴细胞和不产抗体的癌细胞而产生的细胞或细胞系(通常为骨髓瘤或淋巴瘤细胞)。如本领域普通技术人员所知的，杂交瘤可增殖并持续供应产生特定单克隆抗体。用于产生杂交瘤的方法为本领域已知的(见例如，Harlow&Lane，1988)。当提及术语“杂交瘤”或“杂交瘤细胞”时，其还包括杂交瘤的亚克隆和后代细胞。
如本文所用，“常规抗体”指包含两条重链(其可以标示为H和H’)和两条轻链(其可以标示为L和L’)和两个抗原结合位点的抗体，其中每条重链可以是全长免疫球蛋白重链或保留抗原结合能力的其任何功能区(例如重链包括但不限于VH链、VH-CH1链和VH-CH1-CH2-CH3链)，并且每条轻链可以是全长轻链或任何功能区(例如轻链包括但不限于VL链和VL-CL链)。每条重链(H和H’)与一条轻链(分别为L和L’)配对。
如本文所用，全长抗体是具有两条全长重链(例如VH-CH1-CH2-CH3或VH-CH1-CH2-CH3-CH4)和两条全长轻链(VL-CL)和铰链区的抗体，例如通过抗体分泌B细 胞天然产生的抗体以及合成产生的具有相同结构域的抗体。
如本文所用，dsFv指具有稳定VH-VL对的工程化分子间二硫键的Fv。
如本文所用，Fab片段是用木瓜蛋白酶消化全长免疫球蛋白所获得的抗体片段，或者例如通过重组方法合成产生的具有相同结构的片段。Fab片段包含轻链(包含VL和CL)和另一条链，所述另一条链包含重链的可变结构域(VH)和重链的一个恒定区结构域(CH1)。
如本文所用，F(ab’)2片段是在pH 4.0-4.5下用胃蛋白酶消化免疫球蛋白所导致的抗体片段，或者例如通过重组方法合成产生的具有相同结构的片段。F(ab’)2片段基本上包含两个Fab片段，其中每个重链部分包含额外的几个氨基酸，包括形成连接两个片段的二硫键的半胱氨酸。
如本文所用，Fab’片段是包含F(ab’)2片段的一半(一条重链和一条轻链)的片段。
如本文所用，scFv片段指包含通过多肽接头以任何顺序共价连接的可变轻链(VL)和可变重链(VH)的抗体片段。接头长度使得两个可变结构域基本不干扰地桥接。示例性接头是分散有一些Glu或Lys残基以增加溶解性的(Gly-Ser)n残基。
术语“嵌合抗体”是指这样的抗体，其中可变区序列源自一个物种，恒定区序列源自另一物种，如其中可变区序列源自小鼠抗体及恒定区序列源自人抗体的抗体。
“人源化”抗体是指非人(例如小鼠)抗体形式，其是嵌合的免疫球蛋白、免疫球蛋白链或者其片段(如Fv、Fab、Fab'、F(ab')2或者抗体的其它抗原结合亚序列)，含有源自非人免疫球蛋白的最小序列。优选地，人源化抗体是人免疫球蛋白(接受者抗体)，其中接受者抗体的互补决定区(CDR)的残基由来自具有希望的特异性、亲和性和能力的非人物种(供体抗体)如小鼠、大鼠或者兔的CDR残基置换。
此外，在人源化中，还可能对VH和/或VL的CDR1、CDR2和/或CDR3区内的氨基酸残基进行突变，由此改善抗体的一或多种结合特性(例如亲和性)。可进行例如PCR介导的突变引入突变，其对抗体结合或其它功能特性的影响可利用本文所述的体外或体内测试评估。通常，引入保守性突变。此类突变可为氨基酸取代、添加或缺失。另外，CDR内的突变通常不超过一个或两个。因此，本发明所述人源化抗体还涵盖CDR内包含1或2两个氨基酸突变的抗体。
如本文所用，术语“表位”指抗体的互补位结合的抗原上的任何抗原决定簇。表位决定簇通常包含分子的化学活性表面分型，例如氨基酸或糖侧链，并且通常具有特定的三维结构特征以及特定的电荷特征。
如本文所用，可变结构域或可变区是抗体重链或轻链的特定Ig结构域，其包含在不同抗体之间变化的氨基酸序列。每条轻链和每条重链分别具有一个可变区结构域VL和VH。可变结构域提供抗原特异性，并且因此负责抗原识别。每个可变区包含CDR和框架区(FR)，CDR是抗原结合位点结构域的部分。
如本文所用，“抗原结合结构域”和“抗原结合位点(antigen-binding site)”同义地用来指识别并与同种(cognate)抗原物理相互作用的抗体内的结构域。天然的常规全长抗体分子具有两个常规抗原结合位点，每个包含重链可变区部分和轻链可变区部分。常规抗原结合位点包含连接可变区结构域内反向平行的β链的环。抗原结合位点可以包含可变区结构域的其他部分。每个常规抗原结合位点包含3个来自重链的高变区和3个来自轻链的高变区。高变区也称为互补决定区(CDR)。
如本文所用，“高变区”、“HV”、“互补决定区”和“CDR”和“抗体CDR”可交换地用来指一起形成抗体的抗原结合位点的每个可变区内的多个部分中的一个。每个可变区结构域包含3个CDR，命名为CDR1、CDR2和CDR3。例如，轻链可变区结构域包含3个CDR，命名为VL CDR1、VL CDR2和VL CDR3；重链可变区结构域包含3个CDR，命名为VH CDR1、VH CDR2和VH CDR3。可变区中的3个CDR沿线性氨基酸序列是不连续的，但是在折叠的多肽中接近。CDR位于连接可变结构域的β折叠的平行链的环内。如本文所述，本领域技术人员知道并且可以基于Kabat或Chothia编号鉴定CDR(参见例如，Kabat,E.A.et al.(1991)Sequences of Proteins of Immunological Interest,Fifth Edition,U.S.Department of Health and Human Services,NIH Publication No.91-3242,和Chothia,C.et al.(1987)J.Mol.Biol.196:901-917)。在本发明中，缩写“VH CDR”和“HCDR”以及“VL CDR”和“LCDR”具有相同含义。
如本文所用，框架区(FR)是位于β折叠内的抗体可变区结构域内的结构域；在氨基酸序列方面，FR区比高变区相对更保守。
如本文所用，“恒定区”结构域是抗体重链或轻链中的结构域，其包含比可变区结构域的氨基酸序列相对更保守的氨基酸序列。在常规全长抗体分子中，每条轻链具有单个轻链恒定区(CL)结构域，而每条重链包含一个或多个重链恒定区(CH)结构域，包括CH1、CH2、CH3和CH4。全长IgA、IgD和IgG同种型包含CH1、CH2、CH3和铰链区，而IgE和IgM包含CH1、CH2、CH3和CH4。CH1和CL结构域延伸抗体分子的Fab臂，因此有助于与抗原相互作用以及转动抗体臂。抗体恒定区可以服务于效应子功能，例如但不限于清除该抗体特异性结合的抗原、病原体和毒素，例如通过与各种细胞、生物分子和组 织相互作用。
如本文所用，抗体的功能区是包含该抗体的至少VH、VL、CH(例如CH1、CH2或CH3)、CL或铰链区结构域或者至少其功能区的抗体部分。
如本文所用，VH结构域的功能区是保留完整VH结构域的至少部分结合特异性(例如通过保留完整VH结构域的一个或多个CDR)的完整VH结构域的至少一部分，从而所述VH结构域的功能区单独地或者与另一抗体结构域(例如VL结构域)或其区域组合地结合抗原。示例性VH结构域的功能区是包含VH结构域的CDR1、CDR2和/或CDR3的区域。
如本文所用，VL结构域的功能区是保留完整VL结构域的至少部分结合特异性(例如通过保留完整VL结构域的一个或多个CDR)的完整VL结构域的至少一部分，从而所述VL结构域的功能区单独地或者与另一抗体结构域(例如VH结构域)或其区域组合地结合抗原。示例性VL结构域的功能区是包含VL结构域的CDR1、CDR2和/或CDR3的区域。
如本文所用，关于抗体或其抗原结合片段的“特异性结合”或“免疫特异性地结合”在本文中可交换使用，并且指抗体或抗原结合片段通过抗体和抗原的抗体结合位点之间的非共价相互作用与同种抗原形成一个或多个非共价键的能力。所述抗原可以是分离的抗原或存在于肿瘤细胞。
本文使用的术语“Kassoc”或“Ka”旨在表示特定的抗体-抗原相互作用的结合速率，而本文使用的术语“Kdis”或“Kd”旨在表示特定的抗体-抗原相互作用的解离速率。本文使用的术语“KD”旨在表示解离常数，它是由Kd与Ka之比(即Kd/Ka)得到，并被表示为摩尔浓度(M)。抗体的KD值可以使用本领域已知的方法测定。确定抗体的KD的方法可以是例如表面等离子共振(SPR)(Rich and Myszka(2000)Curr.Opin.Biotechnol11:54；Englebienne(1998)Analyst.123:1599)、等温滴定量热法(ITC)或本领域已知的其他动力学相互作用测定(参见，例如，Paul,ed.,Fundamental Immunology,2nd ed.,Raven Press,New York,pages 332-336(1989)；还参见描述用于计算抗体的结合亲和力的示例性SPR和ITC方法的美国专利第7,229,619号)。用于实时检测和监测结合速率的仪器和方法是已知的，并且可商购(参见，BiaCore 2000,Biacore AB,Upsala,Sweden and GE Healthcare Life Sciences；Malmqvist(2000)Biochem.Soc.Trans.27:335)。
本文使用的术语“保守的序列修饰”或“保守的氨基酸修饰”或“保守性氨基酸取代”是指不会显著影响或改变含该氨基酸序列的抗体的结合特性的氨基酸修饰。这样的保守 修饰包括氨基酸替换、添加和缺失。可以通过本领域公知的标准技术，诸如定点诱变和PCR介导的诱变，向本发明抗体中引入修饰。“保守的氨基酸修饰”或“保守性氨基酸取代”是其中将氨基酸残基替换为具有相似性质和/或结构的氨基酸残基的替换。具有相似侧链的氨基酸残基的家族在本领域中已经有定义。
常见的氨基酸有20种，有很多分类方式。例如，根据其结合基团不同的氨基酸分类：可将氨基酸分为脂肪族氨基酸、芳香族氨基酸、杂环氨基酸、含硫氨基酸、含碘氨基酸。脂肪族氨基酸包括丙氨酸、缬氨酸、亮氨酸、异亮氨酸、蛋氨酸、天冬氨酸、谷氨酸、赖氨酸、精氨酸、甘氨酸、丝氨酸、苏氨酸、半胱氨酸、天冬酰胺和谷氨酰胺。芳香族氨基酸包括：苯丙氨酸和酪氨酸。杂环族氨基酸包括：组氨酸和色氨酸。杂环亚氨基酸包括：脯氨酸。根据化学性质分类的氨基酸分类：可将氨基酸分为酸性氨基酸、碱性氨基酸、中性氨基酸。中性氨基酸包括甘氨酸、丙氨酸、亮氨酸、异亮氨酸、缬氨酸、胱氨酸、半胱氨酸、甲硫氨酸、苏氨酸、丝氨酸、苯丙氨酸、酪氨酸、色氨酸、脯氨酸、蛋氨酸和羟脯氨酸。酸性氨基酸包括谷氨酸和天门冬氨酸。碱性氨基酸包括赖氨酸、精氨酸和组氨酸。
此外，氨基酸还可以分类为如下：具有碱性侧链(例如赖氨酸、精氨酸、组氨酸)、酸性侧链(例如天冬氨酸、谷氨酸)、不带电荷极性侧链(例如甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、色氨酸)、非极性侧链(例如丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸)、β-分支侧链(例如苏氨酸、缬氨酸、异亮氨酸)和芳族侧链(例如酪氨酸、苯丙氨酸、色氨酸、组氨酸)的氨基酸。
如本文所用，“多肽”指共价连接的两个或更多个氨基酸。术语“多肽”和“蛋白质”在本文中可交换使用。
"分离的蛋白质"、"分离的多肽"或"分离的抗体"指所述蛋白质、多肽或抗体(1)不与在其天然状态下伴随其天然相关成分关联，(2)不含来自相同物种的其它蛋白质，(3)由来自不同物种的细胞表达，或(4)不在天然中发生。因此，经化学合成的多肽或在不同于多肽的天然来源细胞的细胞系统中合成的多肽将会与其天然相关成分"分离"。还可通过分离以使蛋白质实质上不含天然相关成分，即使用本领域众所周知的蛋白质纯化技术。
氨基酸残基的“取代”、“缺失”或“添加”是指在肽或蛋白中，进行保守的、不改变肽或蛋白质功能和/或生物学活性的氨基酸修饰。例如，氨基酸残基的取代可以是保守的氨基酸取代，合适的保守氨基酸取代是本领域技术人员已知的，并且一般可以进行而不改变所得分子的生物活性。通常，本领域技术人员认识到多肽的非必需区中的单个氨基 酸取代基本上不改变生物活性(参见，例如，Watson et al.,Molecular Biology of the Gene,4th Edition,1987,The Benjamin/Cummings Pub.co.,p.224)。
如本文所用，术语“多核苷酸”和“核酸分子”指包含至少两个连接的核苷酸或核苷酸衍生物的寡聚体或聚合物，包括通常通过磷酸二酯键连接在一起的脱氧核糖核酸(DNA)和核糖核酸(RNA)。
如本文所用，分离的核酸分子是从存在于核酸分子的天然来源中的其他核酸分子分离的核酸分子。诸如cDNA分子的“分离的”核酸分子可以在通过重组技术制备时基本上不含其他细胞物质或培养基，或者在化学合成时基本上不含化学前体或其他化学成分。本文所提供的示例性分离的核酸分子包括编码所提供的抗体或抗原结合片段的分离的核酸分子。
序列“相同性”具有本领域公认的含义，并且可以利用公开的技术计算两个核酸或多肽分子或区域之间序列相同性的百分比。可以沿着多核苷酸或多肽的全长或者沿着该分子的区域测量序列相同性。(参见，例如：Computational Molecular Biology,Lesk,A.M.,ed.,Oxford University Press,New York,1988；Biocomputing:Informatics and Genome Projects,Smith,D.W.,ed.,Academic Press,New York,1993；Computer Analysis of Sequence Data,Part I,Griffin,A.M.,and Griffin,H.G.,eds.,Humana Press,New Jersey,1994；Sequence Analysis in Molecular Biology,von Heinje,G.,Academic Press,1987；and Sequence Analysis Primer,Gribskov,M.and Devereux,J.,eds.,M Stockton Press,New York,1991)。虽然存在许多测量两个多核苷酸或多肽之间的相同性的方法，但是术语“相同性”是技术人员公知的(Carrillo,H.&Lipman,D.,SIAM J Applied Math 48:1073(1988))。
如本文所用，关于核酸序列、区域、元件或结构域的“可操作地连接”表示核酸区域互相功能相关。例如，启动子可以可操作地连接至编码多肽的核酸，从而所述启动子调控或介导所述核酸的转录。
如本文所用，“表达”指通过多核苷酸的转录和翻译产生多肽的过程。多肽的表达水平可以利用本领域已知的任何方法来评价，包括例如测定从宿主细胞产生的多肽的量的方法。这类方法可以包括但不限于通过ELISA定量细胞裂解物中的多肽，凝胶电泳之后考马斯蓝染色，Lowry蛋白测定以及Bradford蛋白测定。
如本文所用，“宿主细胞”是用于接受、保持、复制和扩增载体的细胞。宿主细胞还可以用来表达载体所编码的多肽。当宿主细胞分裂时，载体中所含的核酸复制，从而扩增核酸。宿主细胞可以是真核细胞或原核细胞。合适的宿主细胞包括但不限于CHO细 胞、各种COS细胞、HeLa细胞、HEK细胞例如HEK 293细胞。
如本文所用，“载体”是可复制的核酸，当载体转化入适当的宿主细胞时，可以从该载体表达一种或多种异源蛋白。关于载体包括那些通常通过限制酶切消化和连接可以将编码多肽或其片段的核酸引入其中的载体。关于载体还包括那些包含编码多肽的核酸的载体。载体用来将编码多肽的核酸引入宿主细胞，用于扩增核酸或者用于表达/展示核酸所编码的多肽。载体通常保持游离，但是可以设计为使基因或其部分整合入基因组的染色体。还考虑人工染色体的载体，例如酵母人工载体和哺乳动物人工染色体。这类媒介物的选择和用途是本领域技术人员公知的。
如本文所用，“表达载体”包括能够表达DNA的载体，所述DNA与诸如启动子区的能够影响这类DNA片段表达的调控序列可操作地连接。这类额外的片段可以包括启动子和终止子序列，并且任选地可以包括一个或多个复制起点、一个或多个选择标记、增强子、多腺苷酸化信号等。表达载体一般来源于质粒或病毒DNA，或者可以包含这两者的元件。因此，表达载体指重组DNA或RNA构建体，例如质粒、噬菌体、重组病毒或其他载体，当引入适当的宿主细胞时，导致克隆DNA的表达。适当的表达载体是本领域技术人员公知的，并且包括在真核细胞和/或原核细胞中可复制的表达载体以及保持游离的表达载体或者整合入宿主细胞基因组的表达载体。
如本文所用，“治疗”患有疾病或疾病状况的个体表示所述个体的症状部分或全部缓解，或者在治疗后保持不变。因此，治疗包括预防、治疗和/或治愈。预防指防止潜在疾病和/或防止症状恶化或疾病发展。治疗还包括所提供的任何抗体或其抗原结合片段以及本文所提供的组合物的任何药学用途。
如本文所用，“疗效”表示由个体的治疗所导致的效果，其改变、通常改良或改善疾病或疾病状况的症状，或者治愈疾病或疾病状况。
如本文所用，“治疗有效量”或“治疗有效剂量”指施用于对象之后至少足以产生疗效的物质、化合物、材料或包含化合物的组合物的量。因此，其为防止、治愈、改善、阻滞或部分阻滞疾病或病症的症状所必需的量。
如本文所用，“预防有效量”或“预防有效剂量”指在施用于对象时会具有预期的预防效果的物质、化合物、材料或包含化合物的组合物的量，例如，防止或延迟疾病或症状的发生或复发，减少疾病或症状发生或复发的可能性。完全预防有效剂量不必通过施用一个剂量发生，并且可以仅在施用一系列剂量之后发生。因此，预防有效量可以在一次或多次施用中施用。
如本文中所使用的，术语“患者”是指哺乳动物，例如人。
(二)、靶向ITGA2蛋白的抗体
ITGA2全称为整合素α2(Integrin alpha-2)，其中人ITGA2蛋白在Uniprot数据库中的编号为P17301，参见https://www.uniprot.org/uniprot/P17301。
本发明人发现ITGA2是一种肿瘤细胞特异性过表达的肿瘤相关抗原，尤其是在结直肠癌，胆管癌，胰腺癌和皮肤癌等癌症病人过表达。在此基础上，本发明人针对ITGA2蛋白质这个靶点，设计出多种不同的人源化抗体。实施例的实验证明，本发明的抗体对于ITGA2蛋白具有优异的结合能力(EC50＜1nM)，同时对ITGA2高表达的HuCCT1细胞也有优异的结合能力(EC50＜5nM)。利用本发明单克隆抗体的优异结合能力，可以有效地将配偶体分子例如细胞毒素递送至肿瘤细胞。
因此，一方面，本发明提供了一种特异性结合ITGA2蛋白的分离的抗体或其抗原结合片段部分，其中，所述的分离的抗体或其抗原结合片段部分包含含有HCDR1、HCDR2、HCDR3序列的重链可变区：
1)所述重链可变区包含(a)SEQ ID NO：112的HCDR1，(b)SEQ ID NO：113的HCDR2，和(c)SEQ ID NO：114的HCDR3；
2)所述重链可变区包含(a)SEQ ID NO：116的HCDR1，(b)SEQ ID NO：117的HCDR2，和(c)SEQ ID NO：118的HCDR3；
3)所述重链可变区包含(a)SEQ ID NO：120的HCDR1，(b)SEQ ID NO：121的HCDR2，和(c)SEQ ID NO：122的HCDR3；
4)所述重链可变区包含(a)SEQ ID NO：124的HCDR1，(b)SEQ ID NO：125的HCDR2，和(c)SEQ ID NO：126的HCDR3；
5)所述重链可变区包含(a)SEQ ID NO：128的HCDR1，(b)SEQ ID NO：129的HCDR2，和(c)SEQ ID NO：130的HCDR3；
6)所述重链可变区包含(a)SEQ ID NO：132的HCDR1，(b)SEQ ID NO：133的HCDR2，和(c)SEQ ID NO：134的HCDR3；
7)所述重链可变区包含(a)SEQ ID NO：136的HCDR1，(b)SEQ ID NO：137的HCDR2，和(c)SEQ ID NO：138的HCDR3；
8)所述重链可变区包含(a)SEQ ID NO：140的HCDR1，(b)SEQ ID NO：141的HCDR2，和(c)SEQ ID NO：142的HCDR3；
9)所述重链可变区包含(a)SEQ ID NO：144的HCDR1，(b)SEQ ID NO：145的HCDR2，和(c)SEQ ID NO：146的HCDR3；
10)所述重链可变区包含(a)SEQ ID NO：148的HCDR1，(b)SEQ ID NO：149的HCDR2，和(c)SEQ ID NO：150的HCDR3；
11)所述重链可变区包含(a)SEQ ID NO：152的HCDR1，(b)SEQ ID NO：153的HCDR2，和(c)SEQ ID NO：154的HCDR3；
12)所述重链可变区包含(a)SEQ ID NO：156的HCDR1，(b)SEQ ID NO：157的HCDR2，和(c)SEQ ID NO：158的HCDR3；
13)所述重链可变区包含(a)SEQ ID NO：160的HCDR1，(b)SEQ ID NO：161的HCDR2，和(c)SEQ ID NO：162的HCDR3；
14)所述重链可变区包含(a)SEQ ID NO：164的HCDR1，(b)SEQ ID NO：165的HCDR2，和(c)SEQ ID NO：166的HCDR3；
15)所述重链可变区包含(a)SEQ ID NO：168的HCDR1，(b)SEQ ID NO：169的HCDR2，和(c)SEQ ID NO：170的HCDR3；
16)所述重链可变区包含(a)SEQ ID NO：172的HCDR1，(b)SEQ ID NO：173的HCDR2，和(c)SEQ ID NO：174的HCDR3；
17)所述重链可变区包含(a)SEQ ID NO：176的HCDR1，(b)SEQ ID NO：177的HCDR2，和(c)SEQ ID NO：178的HCDR3；和
18)所述重链可变区包含(a)SEQ ID NO：180的HCDR1，(b)SEQ ID NO：181的HCDR2，和(c)SEQ ID NO：182的HCDR3。
另一方面，本发明提供了一种特异性结合ITGA2蛋白的分离的抗体或其抗原结合片段部分，其中，所述的分离的抗体或其抗原结合片段部分包含含有LCDR1、LCDR2、LCDR3序列的轻链可变区：
1)所述轻链可变区包含(d)SEQ ID NO：38的LCDR1，(e)SEQ ID NO：39的LCDR2，和(f)SEQ ID NO：40的LCDR3；
2)所述轻链可变区且所述轻链可变区包含(d)SEQ ID NO：42的LCDR1，(e)SEQ ID NO：43的LCDR2，和(f)SEQ ID NO：44的LCDR3；
3)所述轻链可变区包含(d)SEQ ID NO：46的LCDR1，(e)SEQ ID NO：47的LCDR2，和(f)SEQ ID NO：48的LCDR3；
4)所述轻链可变区包含(d)SEQ ID NO：50的LCDR1，(e)SEQ ID NO：51的LCDR2， 和(f)SEQ ID NO：52的LCDR3；
5)所述轻链可变区包含(d)SEQ ID NO：54的LCDR1，(e)SEQ ID NO：55的LCDR2，和(f)SEQ ID NO：56的LCDR3；
6)所述轻链可变区包含(d)SEQ ID NO：58的LCDR1，(e)SEQ ID NO：59的LCDR2，和(f)SEQ ID NO：60的LCDR3；
7)所述轻链可变区包含(d)SEQ ID NO：62的LCDR1，(e)SEQ ID NO：63的LCDR2，和(f)SEQ ID NO：64的LCDR3；
8)所述轻链可变区包含(d)SEQ ID NO：66的LCDR1，(e)SEQ ID NO：67的LCDR2，和(f)SEQ ID NO：68的LCDR3；
9)所述轻链可变区包含(d)SEQ ID NO：70的LCDR1，(e)SEQ ID NO：71的LCDR2，和(f)SEQ ID NO：72的LCDR3；
10)所述轻链可变区包含(d)SEQ ID NO：74的LCDR1，(e)SEQ ID NO：75的LCDR2，和(f)SEQ ID NO：76的LCDR3；
11)所述轻链可变区包含(d)SEQ ID NO：78的LCDR1，(e)SEQ ID NO：79的LCDR2，和(f)SEQ ID NO：80的LCDR3；
12)所述轻链可变区包含(d)SEQ ID NO：82的LCDR1，(e)SEQ ID NO：83的LCDR2，和(f)SEQ ID NO：84的LCDR3；
13)所述轻链可变区包含(d)SEQ ID NO：86的LCDR1，(e)SEQ ID NO：87的LCDR2，和(f)SEQ ID NO：88的LCDR3；
14)所述轻链可变区包含(d)SEQ ID NO：90的LCDR1，(e)SEQ ID NO：91的LCDR2，和(f)SEQ ID NO：92的LCDR3；
15)所述轻链可变区包含(d)SEQ ID NO：94的LCDR1，(e)SEQ ID NO：95的LCDR2，和(f)SEQ ID NO：96的LCDR3；
16)所述轻链可变区包含(d)SEQ ID NO：98的LCDR1，(e)SEQ ID NO：99的LCDR2，和(f)SEQ ID NO：100的LCDR3；
17)所述轻链可变区包含(d)SEQ ID NO：102的LCDR1，(e)SEQ ID NO：103的LCDR2，和(f)SEQ ID NO：104的LCDR3；和
18)所述轻链可变区包含(d)SEQ ID NO：106的LCDR1，(e)SEQ ID NO：107的LCDR2，和(f)SEQ ID NO：108的LCDR3。
在一些实施方式中，所述的分离的抗体或其抗原结合片段部分包含含有HCDR1、 HCDR2、HCDR3序列的重链可变区；以及含有LCDR1、LCDR2、LCDR3序列的轻链可变区，其中所述抗体或其抗原结合片段部分具有选自以下至少一组的重链可变区和轻链可变区：
1)所述重链可变区包含(a)SEQ ID NO：112的HCDR1，(b)SEQ ID NO：113的HCDR2，和(c)SEQ ID NO：114的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：38的LCDR1，(e)SEQ ID NO：39的LCDR2，和(f)SEQ ID NO：40的LCDR3；
2)所述重链可变区包含(a)SEQ ID NO：116的HCDR1，(b)SEQ ID NO：117的HCDR2，和(c)SEQ ID NO：118的HCDR3，且所述轻链可变区且所述轻链可变区包含(d)SEQ ID NO：42的LCDR1，(e)SEQ ID NO：43的LCDR2，和(f)SEQ ID NO：44的LCDR3；
3)所述重链可变区包含(a)SEQ ID NO：120的HCDR1，(b)SEQ ID NO：121的HCDR2，和(c)SEQ ID NO：122的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：46的LCDR1，(e)SEQ ID NO：47的LCDR2，和(f)SEQ ID NO：48的LCDR3；
4)所述重链可变区包含(a)SEQ ID NO：124的HCDR1，(b)SEQ ID NO：125的HCDR2，和(c)SEQ ID NO：126的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：50的LCDR1，(e)SEQ ID NO：51的LCDR2，和(f)SEQ ID NO：52的LCDR3；
5)所述重链可变区包含(a)SEQ ID NO：128的HCDR1，(b)SEQ ID NO：129的HCDR2，和(c)SEQ ID NO：130的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：54的LCDR1，(e)SEQ ID NO：55的LCDR2，和(f)SEQ ID NO：56的LCDR3；
6)所述重链可变区包含(a)SEQ ID NO：132的HCDR1，(b)SEQ ID NO：133的HCDR2，和(c)SEQ ID NO：134的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：58的LCDR1，(e)SEQ ID NO：59的LCDR2，和(f)SEQ ID NO：60的LCDR3；
7)所述重链可变区包含(a)SEQ ID NO：136的HCDR1，(b)SEQ ID NO：137的HCDR2，和(c)SEQ ID NO：138的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：62的LCDR1，(e)SEQ ID NO：63的LCDR2，和(f)SEQ ID NO：64的LCDR3；
8)所述重链可变区包含(a)SEQ ID NO：140的HCDR1，(b)SEQ ID NO：141的HCDR2，和(c)SEQ ID NO：142的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：66的LCDR1，(e)SEQ ID NO：67的LCDR2，和(f)SEQ ID NO：68的LCDR3；
9)所述重链可变区包含(a)SEQ ID NO：144的HCDR1，(b)SEQ ID NO：145的HCDR2，和(c)SEQ ID NO：146的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：70 的LCDR1，(e)SEQ ID NO：71的LCDR2，和(f)SEQ ID NO：72的LCDR3；
10)所述重链可变区包含(a)SEQ ID NO：148的HCDR1，(b)SEQ ID NO：149的HCDR2，和(c)SEQ ID NO：150的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：74的LCDR1，(e)SEQ ID NO：75的LCDR2，和(f)SEQ ID NO：76的LCDR3；
11)所述重链可变区包含(a)SEQ ID NO：152的HCDR1，(b)SEQ ID NO：153的HCDR2，和(c)SEQ ID NO：154的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：78的LCDR1，(e)SEQ ID NO：79的LCDR2，和(f)SEQ ID NO：80的LCDR3；
12)所述重链可变区包含(a)SEQ ID NO：156的HCDR1，(b)SEQ ID NO：157的HCDR2，和(c)SEQ ID NO：158的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：82的LCDR1，(e)SEQ ID NO：83的LCDR2，和(f)SEQ ID NO：84的LCDR3；
13)所述重链可变区包含(a)SEQ ID NO：160的HCDR1，(b)SEQ ID NO：161的HCDR2，和(c)SEQ ID NO：162的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：86的LCDR1，(e)SEQ ID NO：87的LCDR2，和(f)SEQ ID NO：88的LCDR3；
14)所述重链可变区包含(a)SEQ ID NO：164的HCDR1，(b)SEQ ID NO：165的HCDR2，和(c)SEQ ID NO：166的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：90的LCDR1，(e)SEQ ID NO：91的LCDR2，和(f)SEQ ID NO：92的LCDR3；
15)所述重链可变区包含(a)SEQ ID NO：168的HCDR1，(b)SEQ ID NO：169的HCDR2，和(c)SEQ ID NO：170的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：94的LCDR1，(e)SEQ ID NO：95的LCDR2，和(f)SEQ ID NO：96的LCDR3；
16)所述重链可变区包含(a)SEQ ID NO：172的HCDR1，(b)SEQ ID NO：173的HCDR2，和(c)SEQ ID NO：174的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：98的LCDR1，(e)SEQ ID NO：99的LCDR2，和(f)SEQ ID NO：100的LCDR3；
17)所述重链可变区包含(a)SEQ ID NO：176的HCDR1，(b)SEQ ID NO：177的HCDR2，和(c)SEQ ID NO：178的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：102的LCDR1，(e)SEQ ID NO：103的LCDR2，和(f)SEQ ID NO：104的LCDR3；和
18)所述重链可变区包含(a)SEQ ID NO：180的HCDR1，(b)SEQ ID NO：181的HCDR2，和(c)SEQ ID NO：182的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：106的LCDR1，(e)SEQ ID NO：107的LCDR2，和(f)SEQ ID NO：108的LCDR3。
在一些实施方式中，所述的分离的抗体或其抗原结合片段部分包含具有选自以下至少一组的重链可变区：
1)所述重链可变区，其包含SEQ ID NO：111的氨基酸序列或与SEQ ID NO：111的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
2)所述重链可变区，其包含SEQ ID NO：115的氨基酸序列或与SEQ ID NO：115的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
3)所述重链可变区，其包含SEQ ID NO：119的氨基酸序列或与SEQ ID NO：119的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
4)所述重链可变区，其包含SEQ ID NO：123的氨基酸序列或与SEQ ID NO：123的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
5)所述重链可变区，其包含SEQ ID NO：127的氨基酸序列或与SEQ ID NO：127的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
6)所述重链可变区，其包含SEQ ID NO：131的氨基酸序列或与SEQ ID NO：131的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
7)所述重链可变区，其包含SEQ ID NO：135的氨基酸序列或与SEQ ID NO：135的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
8)所述重链可变区，其包含SEQ ID NO：139的氨基酸序列或与SEQ ID NO：139的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
9)所述重链可变区，其包含SEQ ID NO：143的氨基酸序列或与SEQ ID NO：143的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
10)所述重链可变区，其包含SEQ ID NO：147的氨基酸序列或与SEQ ID NO：147的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
11)所述重链可变区，其包含SEQ ID NO：151的氨基酸序列或与SEQ ID NO：151的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
12)所述重链可变区，其包含SEQ ID NO：155的氨基酸序列或与SEQ ID NO：155的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
13)所述重链可变区，其包含SEQ ID NO：159的氨基酸序列或与SEQ ID NO：159的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
14)所述重链可变区，其包含SEQ ID NO：163的氨基酸序列或与SEQ ID NO：163的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
15)所述重链可变区，其包含SEQ ID NO：167的氨基酸序列或与SEQ ID NO：167的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
16)所述重链可变区，其包含SEQ ID NO：171的氨基酸序列或与SEQ ID NO：171的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
17)所述重链可变区，其包含SEQ ID NO：175的氨基酸序列或与SEQ ID NO：175的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；和
18)所述重链可变区，其包含SEQ ID NO：179的氨基酸序列或与SEQ ID NO：179的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列。
在一些实施方式中，所述的分离的抗体或其抗原结合片段部分包含具有选自以下至少一组的轻链可变区：
1)所述轻链可变区，其包含SEQ ID NO：37的氨基酸序列或与SEQ ID NO：37的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
2)所述轻链可变区，其包含SEQ ID NO：41的氨基酸序列或与SEQ ID NO：41 的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
3)所述轻链可变区，其包含SEQ ID NO：45的氨基酸序列或与SEQ ID NO：45的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
4)所述轻链可变区，其包含SEQ ID NO：49的氨基酸序列或与SEQ ID NO：49的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
5)所述轻链可变区，其包含SEQ ID NO：53的氨基酸序列或与SEQ ID NO：53的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
6)所述轻链可变区，其包含SEQ ID NO：57的氨基酸序列或与SEQ ID NO：57的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
7)所述轻链可变区，其包含SEQ ID NO：61的氨基酸序列或与SEQ ID NO：61的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
8)所述轻链可变区，其包含SEQ ID NO：65的氨基酸序列或与SEQ ID NO：65的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
9)所述轻链可变区，其包含SEQ ID NO：69的氨基酸序列或与SEQ ID NO：69的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
10)所述轻链可变区，其包含SEQ ID NO：73的氨基酸序列或与SEQ ID NO：73的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
11)所述轻链可变区，其包含SEQ ID NO：77的氨基酸序列或与SEQ ID NO：77的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
12)所述轻链可变区，其包含SEQ ID NO：81的氨基酸序列或与SEQ ID NO：81 的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
13)所述轻链可变区，其包含SEQ ID NO：85的氨基酸序列或与SEQ ID NO：85的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
14)所述轻链可变区，其包含SEQ ID NO：89的氨基酸序列或与SEQ ID NO：89的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
15)所述轻链可变区，其包含SEQ ID NO：93的氨基酸序列或与SEQ ID NO：93的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
16)所述轻链可变区，其包含SEQ ID NO：97的氨基酸序列或与SEQ ID NO：97的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
17)所述轻链可变区，其包含SEQ ID NO：101的氨基酸序列或与SEQ ID NO：101的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；和
18)所述轻链可变区，其包含SEQ ID NO：105的氨基酸序列或与SEQ ID NO：105的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列。
在一些实施方式中，所述的分离的抗体或其抗原结合片段部分包含具有选自以下至少一组的重链可变区和轻链可变区：
1)所述重链可变区，其包含SEQ ID NO：111的氨基酸序列或与SEQ ID NO：111的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：37的氨基酸序列或与SEQ ID NO：37的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
2)所述重链可变区，其包含SEQ ID NO：115的氨基酸序列或与SEQ ID NO：115的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：41的氨基 酸序列或与SEQ ID NO：41的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
3)所述重链可变区，其包含SEQ ID NO：119的氨基酸序列或与SEQ ID NO：119的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：45的氨基酸序列或与SEQ ID NO：45的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
4)所述重链可变区，其包含SEQ ID NO：123的氨基酸序列或与SEQ ID NO：123的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：49的氨基酸序列或与SEQ ID NO：49的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
5)所述重链可变区，其包含SEQ ID NO：127的氨基酸序列或与SEQ ID NO：127的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：53的氨基酸序列或与SEQ ID NO：53的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
6)所述重链可变区，其包含SEQ ID NO：131的氨基酸序列或与SEQ ID NO：131的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：57的氨基酸序列或与SEQ ID NO：57的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
7)所述重链可变区，其包含SEQ ID NO：135的氨基酸序列或与SEQ ID NO：135的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：61的氨基酸序列或与SEQ ID NO：61的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
8)所述重链可变区，其包含SEQ ID NO：139的氨基酸序列或与SEQ ID NO：139的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：65的氨基 酸序列或与SEQ ID NO：65的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
9)所述重链可变区，其包含SEQ ID NO：143的氨基酸序列或与SEQ ID NO：143的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：69的氨基酸序列或与SEQ ID NO：69的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
10)所述重链可变区，其包含SEQ ID NO：147的氨基酸序列或与SEQ ID NO：147的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：73的氨基酸序列或与SEQ ID NO：73的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
11)所述重链可变区，其包含SEQ ID NO：151的氨基酸序列或与SEQ ID NO：151的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：77的氨基酸序列或与SEQ ID NO：77的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
12)所述重链可变区，其包含SEQ ID NO：155的氨基酸序列或与SEQ ID NO：155的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：81的氨基酸序列或与SEQ ID NO：81的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
13)所述重链可变区，其包含SEQ ID NO：159的氨基酸序列或与SEQ ID NO：159的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：85的氨基酸序列或与SEQ ID NO：85的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
14)所述重链可变区，其包含SEQ ID NO：163的氨基酸序列或与SEQ ID NO：163的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：89的氨基 酸序列或与SEQ ID NO：89的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
15)所述重链可变区，其包含SEQ ID NO：167的氨基酸序列或与SEQ ID NO：167的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：93的氨基酸序列或与SEQ ID NO：93的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
16)所述重链可变区，其包含SEQ ID NO：171的氨基酸序列或与SEQ ID NO：171的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：97的氨基酸序列或与SEQ ID NO：97的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
17)所述重链可变区，其包含SEQ ID NO：175的氨基酸序列或与SEQ ID NO：175的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：101的氨基酸序列或与SEQ ID NO：101的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；和
18)所述重链可变区，其包含SEQ ID NO：179的氨基酸序列或与SEQ ID NO：179的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：105的氨基酸序列或与SEQ ID NO：105的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列。
在一些实施方式中，与所述本发明抗体的重链可变区的氨基酸序列(SEQ ID NOs:111、115、119、123、127、131、135、139、143、147、151、155、159、163、167、171、175、179)和/或轻链可变区的氨基酸序列(SEQ ID NOs:37、41、45、49、53、57、61、65、69、73、77、81、85、89、93、97、101、105)具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的抗体与本发明的抗体相同或相似的生物学功能和/或活性。
在一些实施方式中，与所述本发明抗体的重链可变区的氨基酸序列(SEQ ID NOs:111、115、119、123、127、131、135、139、143、147、151、155、159、163、167、 171、175、179)和/或轻链可变区的氨基酸序列(SEQ ID NOs:37、41、45、49、53、57、61、65、69、73、77、81、85、89、93、97、101、105)具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的抗体也能够特异性结合ITGA2蛋白。
在一些实施方式中，与所述本发明抗体的重链可变区的氨基酸序列(SEQ ID NOs:111、115、119、123、127、131、135、139、143、147、151、155、159、163、167、171、175、179)和/或轻链可变区的氨基酸序列(SEQ ID NOs:37、41、45、49、53、57、61、65、69、73、77、81、85、89、93、97、101、105)具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的抗体具有与本发明抗相同的重链和/或轻链可变区CDR，仅在除CDR之外的重链和/或轻链可变区的其他位置(例如框架区)具有保守性氨基酸取代，所述保守性氨基酸取代不改变相应抗体的生物学功能和/或活性；
可选地，前述与所述本发明抗体的重链可变区的氨基酸序列(SEQ ID NOs:111、115、119、123、127、131、135、139、143、147、151、155、159、163、167、171、175、179)和/或轻链可变区的氨基酸序列(SEQ ID NOs:37、41、45、49、53、57、61、65、69、73、77、81、85、89、93、97、101、105)具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的抗体也能够特异性结合ITGA2蛋白。
在一些实施方式中，与所述本发明抗体的重链可变区的氨基酸序列(SEQ ID NOs:111、115、119、123、127、131、135、139、143、147、151、155、159、163、167、171、175、179)和/或轻链可变区的氨基酸序列(SEQ ID NOs:37、41、45、49、53、57、61、65、69、73、77、81、85、89、93、97、101、105)具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的抗体具有与本发明抗相同的重链和/或轻链可变区CDR，仅在重链可变区和/或轻链可变区中的框架区具有保守性氨基酸取代，所述保守性氨基酸取代不改变相应抗体的生物学功能和/或活性，且前述抗体也能够特异性结合ITGA2蛋白。
在一些实施方式中，所述的分离的抗体或其抗原结合片段部分进一步包含重链恒定区，所述重链恒定区包含SEQ ID NO：183的氨基酸序列或与SEQ ID NO：183的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％同源性相同性的氨基酸序列。
在一些实施方式中，所述的分离的抗体或其抗原结合片段部分进一步包含轻链恒定区，所述轻链恒定区包含SEQ ID NO：109的氨基酸序列或与SEQ ID NO：109的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％同源性相同性的氨基酸序列；或者所述轻链恒定区包含SEQ ID NO：110的氨基酸序列或与SEQ ID NO：110的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％同源性相同性的氨基酸序列。
在一些实施方式中，所述的分离的抗体或其抗原结合片段部分进一步包含重链恒定区和/或轻链恒定区，
所述重链恒定区包含SEQ ID NO：183的氨基酸序列或与SEQ ID NO：183的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％同源性相同性的氨基酸序列，
所述轻链恒定区包含SEQ ID NO：109的氨基酸序列或与SEQ ID NO：109的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％同源性相同性的氨基酸序列；或者所述轻链恒定区包含SEQ ID NO：110的氨基酸序列或与SEQ ID NO：110的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％同源性相同性的氨基酸序列。
在一些实施方式中，所述的分离的抗体或其抗原结合片段部分包含具有选自以下至少一组的重链：
1)所述重链，其包含SEQ ID NO：202的氨基酸序列或与SEQ ID NO：202的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
2)所述重链，其包含SEQ ID NO：203的氨基酸序列或与SEQ ID NO：203的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
3)所述重链，其包含SEQ ID NO：204的氨基酸序列或与SEQ ID NO：204的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
4)所述重链，其包含SEQ ID NO：205的氨基酸序列或与SEQ ID NO：205的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
5)所述重链，其包含SEQ ID NO：206的氨基酸序列或与SEQ ID NO：206的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
6)所述重链，其包含SEQ ID NO：207的氨基酸序列或与SEQ ID NO：207的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
7)所述重链，其包含SEQ ID NO：208的氨基酸序列或与SEQ ID NO：208的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
8)所述重链，其包含SEQ ID NO：209的氨基酸序列或与SEQ ID NO：209的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
9)所述重链，其包含SEQ ID NO：210的氨基酸序列或与SEQ ID NO：210的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
10)所述重链，其包含SEQ ID NO：211的氨基酸序列或与SEQ ID NO：211的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
11)所述重链，其包含SEQ ID NO：212的氨基酸序列或与SEQ ID NO：212的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
12)所述重链，其包含SEQ ID NO：213的氨基酸序列或与SEQ ID NO：213的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
13)所述重链，其包含SEQ ID NO：214的氨基酸序列或与SEQ ID NO：214的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
14)所述重链，其包含SEQ ID NO：215的氨基酸序列或与SEQ ID NO：215的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
15)所述重链，其包含SEQ ID NO：216的氨基酸序列或与SEQ ID NO：216的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
16)所述重链，其包含SEQ ID NO：217的氨基酸序列或与SEQ ID NO：217的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
17)所述重链，其包含SEQ ID NO：218的氨基酸序列或与SEQ ID NO：218的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；和
18)所述重链，其包含SEQ ID NO：219的氨基酸序列或与SEQ ID NO：219的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列。
在一些实施方式中，所述的分离的抗体或其抗原结合片段部分包含具有选自以下至少一组的轻链：
1)所述轻链，其包含SEQ ID NO：184的氨基酸序列或与SEQ ID NO：184的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
2)所述轻链，其包含SEQ ID NO：185的氨基酸序列或与SEQ ID NO：185的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
3)所述轻链，其包含SEQ ID NO：186的氨基酸序列或与SEQ ID NO：186的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
4)所述轻链，其包含SEQ ID NO：187的氨基酸序列或与SEQ ID NO：187的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
5)所述轻链，其包含SEQ ID NO：188的氨基酸序列或与SEQ ID NO：188的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
6)所述轻链，其包含SEQ ID NO：189的氨基酸序列或与SEQ ID NO：189的氨基 酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
7)所述轻链，其包含SEQ ID NO：190的氨基酸序列或与SEQ ID NO：190的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
8)所述轻链，其包含SEQ ID NO：191的氨基酸序列或与SEQ ID NO：191的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
9)所述轻链，其包含SEQ ID NO：192的氨基酸序列或与SEQ ID NO：192的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
10)所述轻链，其包含SEQ ID NO：193的氨基酸序列或与SEQ ID NO：193的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
11)所述轻链，其包含SEQ ID NO：194的氨基酸序列或与SEQ ID NO：194的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
12)所述轻链，其包含SEQ ID NO：195的氨基酸序列或与SEQ ID NO：195的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
13)所述轻链，其包含SEQ ID NO：196的氨基酸序列或与SEQ ID NO：196的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
14)所述轻链，其包含SEQ ID NO：197的氨基酸序列或与SEQ ID NO：197的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
15)所述轻链，其包含SEQ ID NO：198的氨基酸序列或与SEQ ID NO：198的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
16)所述轻链，其包含SEQ ID NO：199的氨基酸序列或与SEQ ID NO：199的氨 基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
17)所述轻链，其包含SEQ ID NO：200的氨基酸序列或与SEQ ID NO：200的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；和
18)所述轻链，其包含SEQ ID NO：201的氨基酸序列或与SEQ ID NO：201的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列。
在一些实施方式中，所述的分离的抗体或其抗原结合片段部分包含具有选自以下至少一组的重链和轻链：
1)所述重链，其包含SEQ ID NO：202的氨基酸序列或与SEQ ID NO：202的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：184的氨基酸序列或与SEQ ID NO：184的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
2)所述重链，其包含SEQ ID NO：203的氨基酸序列或与SEQ ID NO：203的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：185的氨基酸序列或与SEQ ID NO：185的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
3)所述重链，其包含SEQ ID NO：204的氨基酸序列或与SEQ ID NO：204的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：186的氨基酸序列或与SEQ ID NO：186的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
4)所述重链，其包含SEQ ID NO：205的氨基酸序列或与SEQ ID NO：205的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：187的氨基酸序列或与SEQ ID NO：187的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
5)所述重链，其包含SEQ ID NO：206的氨基酸序列或与SEQ ID NO：206的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：188的氨基酸序列或与SEQ ID NO：188的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
6)所述重链，其包含SEQ ID NO：207的氨基酸序列或与SEQ ID NO：207的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：189的氨基酸序列或与SEQ ID NO：189的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
7)所述重链，其包含SEQ ID NO：208的氨基酸序列或与SEQ ID NO：208的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：190的氨基酸序列或与SEQ ID NO：190的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
8)所述重链，其包含SEQ ID NO：209的氨基酸序列或与SEQ ID NO：209的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：191的氨基酸序列或与SEQ ID NO：191的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
9)所述重链，其包含SEQ ID NO：210的氨基酸序列或与SEQ ID NO：210的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：192的氨基酸序列或与SEQ ID NO：192的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
10)所述重链，其包含SEQ ID NO：211的氨基酸序列或与SEQ ID NO：211的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：193的氨基酸序列或与SEQ ID NO：193的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
11)所述重链，其包含SEQ ID NO：212的氨基酸序列或与SEQ ID NO：212的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：194的氨基酸序列或与SEQ ID NO：194的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
12)所述重链，其包含SEQ ID NO：213的氨基酸序列或与SEQ ID NO：213的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：195的氨基酸序列或与SEQ ID NO：195的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
13)所述重链，其包含SEQ ID NO：214的氨基酸序列或与SEQ ID NO：214的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：196的氨基酸序列或与SEQ ID NO：196的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
14)所述重链，其包含SEQ ID NO：215的氨基酸序列或与SEQ ID NO：215的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：197的氨基酸序列或与SEQ ID NO：197的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
15)所述重链，其包含SEQ ID NO：216的氨基酸序列或与SEQ ID NO：216的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：198的氨基酸序列或与SEQ ID NO：198的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
16)所述重链，其包含SEQ ID NO：217的氨基酸序列或与SEQ ID NO：217的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：199的氨基酸序列或与SEQ ID NO：199的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
17)所述重链，其包含SEQ ID NO：218的氨基酸序列或与SEQ ID NO：218的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：200的氨基酸序列或与SEQ ID NO：200的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；和
18)所述重链，其包含SEQ ID NO：219的氨基酸序列或与SEQ ID NO：219的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：201的氨基酸序列或与SEQ ID NO：201的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列。
在一些实施方式中，与所述本发明抗体的重链的氨基酸序列(SEQ ID NOs:202-219)和/或轻链的氨基酸序列(SEQ ID NOs:184-201)具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的抗体与本发明的抗体相同或相似的生物学功能和/或活性。
在一些实施方式中，与所述本发明抗体的重链的氨基酸序列(SEQ ID NOs:202-219)和/或轻链的氨基酸序列(SEQ ID NOs:184-201)具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的抗体也能够特异性结合ITGA2蛋白。
在一些实施方式中，与所述本发明抗体的重链的氨基酸序列(SEQ ID NOs:202-219)和/或轻链的氨基酸序列(SEQ ID NOs:184-201)具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的抗体具有与本发明抗相同的重链和/或轻链可变区，仅在除重链和/或轻链可变区之外的重链和/或轻链的其他位置(例如重链和/或轻链的恒定区)具有保守性氨基酸取代，所述保守性氨基酸取代不改变相应抗体的生物学功能和/或活性；
可选地，前述与所述本发明抗体的重链的氨基酸序列(SEQ ID NOs:202-219)和/或轻链的氨基酸序列(SEQ ID NOs:184-201)具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的抗体也能够特异性结合ITGA2蛋白。
在一些实施方式中，与所述本发明抗体的重链的氨基酸序列(SEQ ID NOs:202-219)和/或轻链的氨基酸序列(SEQ ID NOs:184-201)具有至少85％、至少90％、至少95％、 至少96％、至少97％、至少98％、或至少99％相同性的抗体具有与本发明抗体相同的重链和/或轻链可变区，仅在重链和/或轻链的恒定区具有保守性氨基酸取代，所述保守性氨基酸取代不改变相应抗体的生物学功能和/或活性，且前述抗体也能够特异性结合ITGA2蛋白。
在一些实施方式中，所述的分离的抗体或其抗原结合片段部分由选自以下至少一组的重链和轻链组成：
1)所述重链，其由SEQ ID NO：202的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：184的氨基酸序列组成；
2)所述重链，其由SEQ ID NO：203的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：185的氨基酸序列组成；
3)所述重链，其由SEQ ID NO：204的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：186的氨基酸序列组成；
4)所述重链，其由SEQ ID NO：205的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：187的氨基酸序列组成；
5)所述重链，其由SEQ ID NO：206的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：188的氨基酸序列组成；
6)所述重链，其由SEQ ID NO：207的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：189的氨基酸序列组成；
7)所述重链，其由SEQ ID NO：208的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：190的氨基酸序列组成；
8)所述重链，其由SEQ ID NO：209的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：191的氨基酸序列组成；
9)所述重链，其由SEQ ID NO：210的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：192的氨基酸序列组成；
10)所述重链，其由SEQ ID NO：211的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：193的氨基酸序列组成；
11)所述重链，其由SEQ ID NO：212的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：194的氨基酸序列组成；
12)所述重链，其由SEQ ID NO：213的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：195的氨基酸序列组成；
13)所述重链，其由SEQ ID NO：214的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：196的氨基酸序列组成；
14)所述重链，其由SEQ ID NO：215的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：197的氨基酸序列组成；
15)所述重链，其由SEQ ID NO：216的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：198的氨基酸序列组成；
16)所述重链，其由SEQ ID NO：217的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：199的氨基酸序列组成；
17)所述重链，其由SEQ ID NO：218的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：200的氨基酸序列组成；和
18)所述重链，其由SEQ ID NO：219的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：201的氨基酸序列组成。
本发明的抗体及其相应结构中的氨基酸序列编号(SEQ ID NO：)总结如下表2中：

在一些实施方式中，所述的分离的抗体或其抗原结合片段部分由选自以下至少一组的重链组成：
1)所述重链包含由SEQ ID NO：19的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：19的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：19的核苷酸序列所编码的氨基酸序列组成；
2)所述重链包含由SEQ ID NO：20的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：20的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：20的核苷酸序列所编码的氨基酸序列组成；
3)所述重链包含由SEQ ID NO：21的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：21的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：21的核苷酸序列所编码的氨基酸序列组成；
4)所述重链包含由SEQ ID NO：22的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：22的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：22的核苷酸序列所编码的氨基酸序列组成；
5)所述重链包含由SEQ ID NO：23的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：23的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：23的核苷酸序列所编码的氨基酸序列组成；
6)所述重链包含由SEQ ID NO：24的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：24的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：24的核苷酸序列所编码的氨基酸序列组成；
7)所述重链包含由SEQ ID NO：25的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：25的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少 95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：25的核苷酸序列所编码的氨基酸序列组成；
8)所述重链包含由SEQ ID NO：26的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：26的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：26的核苷酸序列所编码的氨基酸序列组成；
9)所述重链包含由SEQ ID NO：27的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：27的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：27的核苷酸序列所编码的氨基酸序列组成；
10)所述重链包含由SEQ ID NO：28的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：28的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：28的核苷酸序列所编码的氨基酸序列组成；
11)所述重链包含由SEQ ID NO：29的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：29的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：29的核苷酸序列所编码的氨基酸序列组成；
12)所述重链包含由SEQ ID NO：30的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：30的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：30的核苷酸序列所编码的氨基酸序列组成；
13)所述重链包含由SEQ ID NO：31的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：31的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：31的核苷酸序列所编码的氨基酸序列组成；
14)所述重链包含由SEQ ID NO：32的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：32的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：32的核苷酸序列所编码的氨基酸序列组成；
15)所述重链包含由SEQ ID NO：33的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：33的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：33的核苷酸序列所编码的氨基酸序列组成；
16)所述重链包含由SEQ ID NO：34的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：34的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：34的核苷酸序列所编码的氨基酸序列组成；
17)所述重链包含由SEQ ID NO：35的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：35的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：35的核苷酸序列所编码的氨基酸序列组成；和
18)所述重链包含由SEQ ID NO：36的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：36的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：36的核苷酸序列所编码的氨基酸序列组成。
在一些实施方式中，所述的分离的抗体或其抗原结合片段部分由选自以下至少一组的轻链组成：
1)所述轻链包含由SEQ ID NO：1的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：1的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：1的核苷酸序列所编码的氨基酸序列组成；
2)所述轻链包含由SEQ ID NO：2的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：2的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：2的核苷酸序列所编码的氨基酸序列组成；
3)所述轻链包含由SEQ ID NO：3的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：3的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：3的核苷酸序列所编码的氨基酸序列组成；
4)所述轻链包含由SEQ ID NO：4的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：4的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：4的核苷酸序列所编码的氨基酸序列组成；
5)所述轻链包含由SEQ ID NO：5的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：5的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：5的核苷酸序列所编码的氨基酸序列组成；
6)所述轻链包含由SEQ ID NO：6的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：6的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：6的核苷酸序列所编码的氨基酸序列组成；
7)所述轻链包含由SEQ ID NO：7的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：7的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：7的核苷酸序列所编码的氨基酸序列组成；
8)所述轻链包含由SEQ ID NO：8的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：8的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：8的核苷酸序列所编码的氨基酸序列组成；
9)所述轻链包含由SEQ ID NO：9的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：9的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：9的核苷酸序列所编码的氨基酸序列组成；
10)所述轻链包含由SEQ ID NO：10的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：10的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：10的核苷酸序列所编码的氨基酸序列组成；
11)所述轻链包含由SEQ ID NO：11的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：11的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至 少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：11的核苷酸序列所编码的氨基酸序列组成；
12)所述轻链包含由SEQ ID NO：12的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：12的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：12的核苷酸序列所编码的氨基酸序列组成；
13)所述轻链包含由SEQ ID NO：13的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：13的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：13的核苷酸序列所编码的氨基酸序列组成；
14)所述轻链包含由SEQ ID NO：14的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：14的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：14的核苷酸序列所编码的氨基酸序列组成；
15)所述轻链包含由SEQ ID NO：15的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：15的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：15的核苷酸序列所编码的氨基酸序列组成；
16)所述轻链包含由SEQ ID NO：16的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：16的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：16的核苷酸序列所编码的氨基酸序列组成；
17)所述轻链包含由SEQ ID NO：17的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：17的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：17的核苷酸序列所编码的氨基酸序列组成；和
18)所述轻链包含由SEQ ID NO：18的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：18的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：18的核苷酸序列所编码的氨基酸序列组成。
在一些实施方式中，所述的分离的抗体或其抗原结合片段部分由选自以下至少一组的重链和轻链组成：
1)所述重链包含由SEQ ID NO：19的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：19的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：19的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：1的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：1的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：1的核苷酸序列所编码的氨基酸序列组成；
2)所述重链包含由SEQ ID NO：20的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：20的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：20的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：2的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：2的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：2的核苷酸序列所编码的氨基酸序列组成；
3)所述重链包含由SEQ ID NO：21的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：21的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：21的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：3的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：3的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：3的核苷酸序列所编码的氨基酸序列组成；
4)所述重链包含由SEQ ID NO：22的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：22的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：22的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：4的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：4的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：4的核苷酸序列所编码的氨基酸序列组成；
5)所述重链包含由SEQ ID NO：23的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：23的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：23的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：5的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：5的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：5的核苷酸序列所编码的氨基酸序列组成；
6)所述重链包含由SEQ ID NO：24的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：24的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：24的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：6的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：6的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：6的核苷酸序列所编码的氨基酸序列组成；
7)所述重链包含由SEQ ID NO：25的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：25的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：25的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：7的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：7的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：7的核苷酸序列所编码的氨基酸序列组成；
8)所述重链包含由SEQ ID NO：26的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：26的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少 95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：26的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：8的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：8的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：8的核苷酸序列所编码的氨基酸序列组成；
9)所述重链包含由SEQ ID NO：27的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：27的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：27的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：9的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：9的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：9的核苷酸序列所编码的氨基酸序列组成；
10)所述重链包含由SEQ ID NO：28的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：28的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：28的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：10的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：10的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：10的核苷酸序列所编码的氨基酸序列组成；
11)所述重链包含由SEQ ID NO：29的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：29的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：29的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：11的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：11的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：11的核苷酸序列所编码的氨基酸序列组成；
12)所述重链包含由SEQ ID NO：30的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：30的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：30的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：12的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：12的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：12的核苷酸序列所编码的氨基酸序列组成；
13)所述重链包含由SEQ ID NO：31的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：31的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：31的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：13的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：13的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：13的核苷酸序列所编码的氨基酸序列组成；
14)所述重链包含由SEQ ID NO：32的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：32的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：32的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：14的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：14的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：14的核苷酸序列所编码的氨基酸序列组成；
15)所述重链包含由SEQ ID NO：33的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：33的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：33的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：15的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：15的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、 至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：15的核苷酸序列所编码的氨基酸序列组成；
16)所述重链包含由SEQ ID NO：34的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：34的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：34的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：16的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：16的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：16的核苷酸序列所编码的氨基酸序列组成；
17)所述重链包含由SEQ ID NO：35的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：35的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：35的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：17的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：17的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：17的核苷酸序列所编码的氨基酸序列组成；和
18)所述重链包含由SEQ ID NO：36的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：36的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：36的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：18的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：18的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：18的核苷酸序列所编码的氨基酸序列组成。
在一些实施方式中，与前述本发明的核苷酸序列(SEQ ID NOs:19-36)所编码的本发明抗体的重链的氨基酸序列和/或与前述本发明的核苷酸序列(SEQ ID NOs:1-18)所编码的本发明抗体的轻链的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的抗体与本发明的抗体相同或相似的生 物学功能和/或活性。
在一些实施方式中，与前述本发明的核苷酸序列(SEQ ID NOs:19-36)所编码的本发明抗体的重链的氨基酸序列和/或与前述本发明的核苷酸序列(SEQ ID NOs:1-18)所编码的本发明抗体的轻链的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的抗体也能够特异性结合ITGA2蛋白。
在一些实施方式中，与前述本发明的核苷酸序列(SEQ ID NOs:19-36)所编码的本发明抗体的重链的氨基酸序列和/或与前述本发明的核苷酸序列(SEQ ID NOs:1-18)所编码的本发明抗体的轻链的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的抗体具有与本发明抗相同的重链和/或轻链可变区，仅在除重链和/或轻链可变区之外的重链和/或轻链的其他位置(例如重链和/或轻链的恒定区)具有保守性氨基酸取代，所述保守性氨基酸取代不改变相应抗体的生物学功能和/或活性；
可选地，与前述本发明的核苷酸序列(SEQ ID NOs:19-36)所编码的本发明抗体的重链的氨基酸序列和/或与前述本发明的核苷酸序列(SEQ ID NOs:1-18)所编码的本发明抗体的轻链的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的抗体也能够特异性结合ITGA2蛋白。
在一些实施方式中，与前述本发明的核苷酸序列(SEQ ID NOs:19-36)所编码的本发明抗体的重链的氨基酸序列和/或与前述本发明的核苷酸序列(SEQ ID NOs:1-18)所编码的本发明抗体的轻链的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的抗体具有与本发明抗体相同的重链和/或轻链可变区，仅在重链和/或轻链的恒定区具有保守性氨基酸取代，所述保守性氨基酸取代不改变相应抗体的生物学功能和/或活性，且前述抗体也能够特异性结合ITGA2蛋白。
在一些实施方式中，所述抗体或抗原结合片段部分能够以小于1nM的EC50在体外结合ITGA2蛋白。
在一些实施方式中，所述抗体或抗原结合片段部分能够以小于5nM的EC50结合HuCCT1细胞表面的ITGA2蛋白。
在一些实施方式中，所述抗体是单克隆抗体、多克隆抗体、嵌合抗体、或人源化抗体。
(三)、核酸、载体、宿主细胞、杂交瘤和抗体产生方法
一方面，本发明提供分离的核酸分子，其编码前述本发明的抗体或其抗原结合片段。在一些实施方式中，本发明的核酸分子编码前述本发明的抗体的重链和/或轻链可变区、重链和/或轻链可变区中的各个CDR，以及重链和/或轻链恒定区。在一些实施方式中，所述核酸分子的核苷酸序列针对用于表达的宿主细胞进行密码子优化。在一些实施方式中，本发明的核酸分子与表达调控序列可操作地连接。
本发明还提供了一种分离的核酸分子，其编码并且能发明的的抗体或其抗原结合片段部分。
在一些实施方式中，所述核酸分子包括选自以下任意一种所示的核苷酸序列或由此核苷酸序列组成：SEQ ID NOs:1-18，和/或所述核酸分子包括选自以下任意一种所示的核苷酸序列或由此核苷酸序列组成：SEQ ID NOs:19-36。
在一些实施方式中，所述核酸分子包括选自以下任意一种组合所示的核苷酸序列或由此核苷酸序列组成：SEQ ID NO:1和SEQ ID NO:19、SEQ ID NO:2和SEQ ID NO:20、SEQ ID NO:3和SEQ ID NO:21、SEQ ID NO:4和SEQ ID NO:22、SEQ ID NO:5和SEQ ID NO:23、SEQ ID NO:6和SEQ ID NO:24、SEQ ID NO:7和SEQ ID NO:25、SEQ ID NO:8和SEQ ID NO:26、SEQ ID NO:9和SEQ ID NO:27、SEQ ID NO:10和SEQ ID NO:28、SEQ ID NO:11和SEQ ID NO:29、SEQ ID NO:12和SEQ ID NO:30、SEQ ID NO:13和SEQ ID NO:31、SEQ ID NO:14和SEQ ID NO:32、SEQ ID NO:15和SEQ ID NO:33、SEQ ID NO:16和SEQ ID NO:34、SEQ ID NO:17和SEQ ID NO:35、以及SEQ ID NO:18和SEQ ID NO:36。
在一些实施方式中，所述核酸分子，所述核酸分子与表达调控序列可操作地连接。
本发明的抗体及其相应结构中的核苷酸序列编号(SEQ ID NO：)总结如下表3中

本发明还提供表达载体，其包含至少一种前述本发明的核酸分子。
本发明还提供宿主细胞，其由至少一种前述本发明的核酸分子或表达载体转化。
本发明还提供杂交瘤细胞，其表达至少一种前述本发明的抗体或其抗原结合片段部分。
本发明还提供一种生产本发明的抗体或其抗原结合片段的方法，包括：
(i)在适合所述核酸分子或表达载体表达的情况下培养本发明的宿主细胞，和
(ii)分离并纯化由所述宿主细胞表达的抗体或其抗原结合片段。
在一些实施方式中，所述核酸分子的核苷酸序列针对用于表达的宿主细胞进行密码子优化。在一些实施方式中，所述核酸分子与表达调控序列可操作地连接。
本发明还提供一种生产本发明的抗体或其抗原结合片段的方法，包括：
(i)制备能够表达本发明的单克隆抗体或其抗原结合片段部分的杂交瘤细胞，和
(ii)分离并纯化由所述杂交瘤细胞表达的抗体或其抗原结合片段。
(四)、抗体药物缀合物
一方面，本发明提供由本发明的抗体或其抗原结合片段制备的抗体药物缀合物(Antibody-drug conjugate,ADC)。
具体地，本发明提供一种如下式的抗体药物缀合物，Ab-L-D，其中：
符号“Ab”代表至少一种前述本发明的单克隆抗体或其抗原结合片段部分；
符号“L”代表连接抗体部分和配偶体分子的连接子；和
符号“D”代表配偶体分子。
如本文所用，ADC是通过连接子将配偶体分子与抗体或其抗原结合片段连接制备的。在本发明的ADC中，抗体发挥靶向功能：通过结合至其中发现它的抗原的靶组织或细胞，抗体将缀合物引向该靶组织或细胞。在那里，接头被例如切割，释放配偶体分子以行使其期望的生物功能。
配偶体分子可以是药物载荷物或标记分子。药物载荷物可以为治疗剂，例如所述治疗剂可以是例如细胞毒性剂、化学治疗剂、细胞抑制剂、免疫调节剂等。在一些实施方式中，治疗剂是细胞毒性剂，即细胞毒素。如本文所用，术语“细胞毒性剂”和“细胞毒素”可交换地使用。
标记分子可以是产生可检测信号的任何标记，诸如放射性标记、荧光标记或催化底物的可检测修饰的酶。
如本文所用，术语“药物(drug)”、“载荷物(payload)”和“药物载荷物(drug payload)”可交换地使用。如本文所用，抗体药物缀合物(Antibody-drug conjugate,ADC)涵盖由本发明抗体或其抗原结合片段与药物载荷物连接形成的缀合物，以及由本发明抗体或其抗原结合片段与标记分子连接形成的缀合物。
与抗体连接的配偶体分子的比例可以依据以下因素而不同，其中所述因素诸如在缀合反应期间使用的配偶体分子的量以及实验条件。配偶体分子与抗体的比可以为1至6、1至5、1至4、1至3、1至2或1至1.5。
因此，本发明也提供一种如下式的抗体药物缀合物，Ab-(L-D)p，其中：
符号“Ab”代表至少一种前述本发明的单克隆抗体或其抗原结合片段部分；
符号“L”代表连接抗体部分和配偶体分子的连接子；
符号“D”代表配偶体分子；和
符号“p”代表缀合至前述本发明的单克隆抗体或其抗原结合片段部分的连接子/配偶体分子(优选药物载荷物)的数量。
在一些实施方式中，p选自以下数值：1.0、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、4.1、4.2、4.3、4.4、4.5、4.6、4.7、4.8、4.9、5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、 7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、和8.0。
在一些实施方式中，本发明的连接子选自以下一种：vc、mc-GGFG、AcLysvc、mc、MalPeg6、m(H20)c及m(H20)cvc；和/或所述连接子是可切割的。在一些实施方式中，本发明的连接子为vc。
在一些实施方式中，本发明的配偶体分子为药物载荷物，所述药物载荷物为治疗性分子；可选地，所述药物载荷物选自以下一种：细胞毒性剂、细胞抑制剂、免疫调节剂和化学治疗剂；可选地，所述药物载荷物选自以下一种：MMAE、MMAF、DM1、DM4、Dxd、SN-38、Topotecan及其衍生物、Exatecan及其衍生物、Belotecan及其衍生物、Camptothecin、Calicheamicin和PBD。
在一些实施方式中，药物载荷物是MMAE。“MMAE”是指单甲基auristatin E，如下图所示，其中波浪线表示与抗体药物缀合物的接头(L)共价连接：
在一些实施方式中，药物载荷物是MMAF。MMAF是指单甲基auristatin F，其中波浪线表示与抗体药物缀合物的接头(L)共价连接(US2005/0238649)：
在一些实施方式中，连接子-配偶体分子为vcMMAE。vcMMAE药物接头部分和缀合方法公开于WO2004010957、US7659241、US7829531、US7851437和US 11/833,028(SeattleGenetics,Inc.)，其通过引用结合到本文中。使用与上述文献中所公开的方法类似的方法，vcMMAE药物接头部分与本发明的抗体缀合。
关于细胞毒素的类型、用于缀合治疗剂与抗体的接头和方法的进一步讨论，可以进一步参见Saito，G.等(2003)Adv.Drug Deliv.Rev.55：199-215；Trail，P.A.等(2003)Cancer.Immunol.Immunother.52：328-337；Payne，G.(2003)Cancer Cell 3：207-212；Allen，T.M.(2002)Nat.Rev.Cancer 2：750-763；Pastan，I.和Kreitman，R.J.(2002)Curr.Opin.Investig.Drugs 3：1089-1091；Senter，P.D.和Springer，C.J.(2001)Adv.Drug Deliv.Rev.53：247-264，这些文献通过引用合并入本文。
在一些实施方式中，药物载荷物可进一步为放射性同位素，由此产生具有细胞毒性的放射性药物(也被称作抗体放射性同位素缀合物)。对肿瘤细胞具有杀伤的放射性同 位素的示例括但不限于碘131、铟111、钇90和镥177。制备抗体放射性同位素缀合物的方法是本领域已知的。
在一些实施方式中，本发明的配偶体分子为标记分子；可选地，所述标记分子选自以下一种：放射性标记、荧光标记和可检测修饰的酶。在一些实施方式中，放射性标记为放射性同位素，例如碘131、铟111、钇90和镥177。
实验证明，ITGA2蛋白可作为有效的抗体药物缀合物的靶点。本发明对抗体进行小分子毒素偶联而得到的抗体药物缀合物可以对表达ITGA2蛋白的肿瘤产生优异的杀伤效果。
(五)、药物组合物、治疗用途和方法
本发明提供包含治疗有效量的至少一种前述本发明的单克隆抗体或其抗原结合片段部分或者至少一种前述本发明的抗体药物缀合物的药物组合物，此药物组合物的治疗用途及治疗方法。在本发明的抗体药物缀合物中，本发明的抗体与药物载荷物缀合。
一方面，本发明提供包含治疗有效量的至少一种前述本发明的单克隆抗体或其抗原结合片段部分或者至少一种前述本发明的抗体药物缀合物的药物组合物。在一些实施方式中，本发明的药物组合物可以进一步包括药学上可接受的载体。
“治疗有效量”的至少一种前述本发明的单克隆抗体或其抗原结合片段部分或者至少一种前述本发明的抗体药物缀合物优选地导致疾病症状的严重性降低，疾病无症状期的频率和持续时间增加，或者防止因疾病痛苦而引起的损伤或失能。例如，对于肿瘤的治疗，相对于未接受治疗的对象，“治疗有效量”的至少一种前述本发明的单克隆抗体或其抗原结合片段部分或者至少一种前述本发明的抗体药物缀合物优选地将细胞生长或肿瘤生长抑制至少约10％，优选至少约20％，更优选至少约30％，更优选至少约40％，更优选至少约50％，更优选至少约60％，更优选至少约70％，更优选至少约80％。抑制肿瘤生长的能力可以在预测对人类肿瘤的疗效的动物模型系统中评价。或者，也可以通过检查抑制细胞生长的能力来评价，这种抑制可以通过本领域技术人员公知的试验在体外测定。有效量的本发明的抗体或其抗原结合片段能够减小肿瘤大小，或者以其他方式缓解对象的症状如预防和/或治疗转移或复发。本领域技术人员可以根据如下因素确定这种量，如对象的大小、对象症状的严重性和选择的特定组合物或给药途径。
另一方面，本发明提供至少一种前述本发明的单克隆抗体或其抗原结合片段部分或 者至少一种前述本发明的抗体药物缀合物在制备药物组合物中的用途。在一些实施方式中，所述药物组合物用于在患者中治疗恶性肿瘤、预防和/或治疗恶性肿瘤转移或复发。
另一方面，本发明提供包含至少一种前述本发明的单克隆抗体或其抗原结合片段部分或者至少一种前述本发明的抗体药物缀合物的药物组合物，所述组合物用于在患者中治疗恶性肿瘤、预防和/或治疗恶性肿瘤转移或复发的方法。
另一方面，本发明提供一种在患者中治疗恶性肿瘤、预防和/或治疗恶性肿瘤转移或复发的方法，所述方法包括给所述患者施用有效量的至少一种前述本发明的单克隆抗体或其抗原结合片段部分、至少一种前述本发明的抗体药物缀合物、和/或至少一种前述本发明的药物组合物。
在一些实施方式中，所述恶性肿瘤为表达ITGA2蛋白的肿瘤。所述恶性肿瘤选自以下组成的组：乳腺癌、结直肠癌、大肠癌、皮肤癌、胰腺癌、前列腺癌、肝癌、肺癌、胃癌、白血病、胆管癌、宫颈癌、子宫内膜癌、食管癌、头颈部癌、淋巴瘤、甲状腺髓质癌、非霍金奇淋巴瘤、卵巢癌、神经胶质瘤、黑素瘤、和膀胱癌。在一些实施方式中，所述恶性肿瘤选自以下组成的组：结直肠癌、胆管癌，胰腺癌和皮肤癌。在一些实施方式中，所述恶性肿瘤为结直肠癌。在一些实施方式中，所述恶性肿瘤为胆管癌。在一些实施方式中，所述恶性肿瘤为胰腺癌。在一些实施方式中，所述恶性肿瘤为皮肤癌。
(六)、诊断/预后组合物、诊断/预后用途和方法
如本文所述，ITGA2是一种肿瘤细胞特异性过表达的肿瘤相关抗原，尤其是在结直肠癌、胆管癌，胰腺癌和皮肤癌等癌症病人过表达，并表达在肿瘤细胞的表面。
本发明提供包含至少一种前述本发明的单克隆抗体或其抗原结合片段部分或者至少一种前述本发明的抗体药物缀合物的诊断/预后组合物，此组合物的诊断/预后用途及诊断/预后方法。在本发明的诊断/预后药物缀合物中，本发明的抗体与标记分子缀合。对于诊断/预后组合物，诊断/预后用途及诊断/预后方法而言，前述本发明的抗体药物缀合物是指由本发明抗体或其抗原结合片段与标记分子连接形成的缀合物。
一方面，本发明提供至少一种前述本发明的单克隆抗体或其抗原结合片段部分或者至少一种前述本发明的抗体药物缀合物在制备诊断/预后组合物中的用途。在一些实施方式中，所述诊断组合物用于检测患者中恶性肿瘤的存在。在一些实施方式中，所述预后组合物用于预后患者中恶性肿瘤复发或进展。
另一方面，本发明提供一种用于检测/诊断患者中恶性肿瘤的存在的方法，所述方法包括给所述患者施用有效量的至少一种前述本发明的单克隆抗体或其抗原结合片段部分、至少一种前述本发明的抗体药物缀合物、和/或至少一种前述本发明的诊断/预后组合物。
在一些实施方式中，本发明提供了一种检测/诊断患者中恶性肿瘤的存在的方法，包括：
a)使获得自所述患者的生物学样品与至少一种前述本发明的单克隆抗体或其抗原结合片段部分、至少一种前述本发明的抗体药物缀合物、和/或至少一种前述本发明的诊断/预后组合物接触；
b)检测至少一种前述本发明的单克隆抗体或其抗原结合片段部分、至少一种前述本发明的抗体药物缀合物、和/或至少一种前述本发明的诊断/预后组合物与所述生物学样品中的靶抗原的结合，其中检测到抗体与靶抗原的结合代表所述患者中存在恶性肿瘤。
另一方面，本发明提供一种用于预后患者中恶性肿瘤复发或进展的方法，所述方法包括给所述患者施用有效量的至少一种前述本发明的单克隆抗体或其抗原结合片段部分、至少一种前述本发明的抗体药物缀合物、和/或至少一种前述本发明的诊断/预后组合物。
在一些实施方式中，本发明提供了一种用于预后患者中恶性肿瘤复发或进展的方法，所述方法包括：
(a)从所述患者中分离包含肿瘤细胞的生物学样品；
(b)使所述包含肿瘤细胞的生物学样品与至少一种前述本发明的单克隆抗体或其抗原结合片段部分、至少一种前述本发明的抗体药物缀合物、和/或至少一种前述本发明的诊断/预后组合物接触；和
(c)鉴定抗体与肿瘤细胞的结合代表肿瘤细胞的存在，
从而预后所述患者中恶性肿瘤的复发或进展。
在一些实施方案中，所述恶性肿瘤的进展包含所述恶性肿瘤在患者中的转移。
在一些实施方案中，鉴定到结合至少一种前述本发明的单克隆抗体或其抗原结合片段部分、至少一种前述本发明的抗体药物缀合物、和/或至少一种前述本发明的诊断/预后组合物的肿瘤细胞的存在提示所述患者中恶性肿瘤复发或进展的高风险。
在一些实施方式中，本发明的配偶体分子为标记分子；可选地，所述标记分子选自以下一种：放射性标记(例如同位素)、荧光标记(例如荧光染料)、化学物质、和可检测修饰的酶和标签。
在一些实施方案中，所述生物学样品选自以下一种：血液样品、组织样品、和淋巴样品。
用于检测抗体-抗原结合的方法是本领域已知的，例如ELISA等。
(七)、试剂盒
本发明的范围内还包括用于本发明的方法的试剂盒，该试剂盒包括至少一种前述本发明的单克隆抗体或其抗原结合片段、至少一种前述本发明的抗体药物缀合物、至少一种前述本发明的药物组合物、或者一种前述本发明的诊断/预后组合物，以及使用说明。
在一些实施方案中，所述试剂盒可以进一步包括至少一种另外的检测试剂，其用于检测至少一种前述本发明的单克隆抗体或其抗原结合片段、至少一种前述本发明的抗体药物缀合物、至少一种前述本发明的药物组合物、或者一种前述本发明的诊断/预后组合物的存在。试剂盒一般包括表明试剂盒内容物的预期用途和/或使用方法的标签。术语标签包括在试剂盒上或与试剂盒一起提供的或以其他方式随试剂盒提供的任何书面的或记录的材料。
实施例
通过参考在此给出的一些具体实施例可获得对本发明的进一步的理解，这些实施例仅用于说明本发明，其无意于对本发明的范围做出任何限制。显然，可以对本发明作出多种改动和变化而不脱离本发明的实质，因此，这些改动和变化同样在本申请要求保护的范围内。
实施例1-ITGA2蛋白在多种癌细胞表面存在特异性过表达
将HuCC-T1(人胆管癌细胞；美森细胞：CTCC-003-0103)、HCCC-9810(人胆管癌细胞；武汉普诺赛：CL-0095)、AsPC-1(人转移胰腺癌细胞；武汉普诺赛：CL-0027)、BxPC-3(人原位胰腺腺癌细胞；美森细胞：CTCC-001-0360)、A431(人表皮癌细胞；武汉普诺赛：CL-0015)、HT-29(人结直肠腺癌细胞系；武汉普诺赛：CL-0118)、和CHO(仓鼠卵巢细胞；武汉普诺赛：CL-0061)细胞铺入96深孔板。每个孔铺入50000/100μL，每种细胞需要铺3个孔。然后用PBS重复吹匀，洗涤两次。每孔添加含1％FBS的PBS溶液，添加量为100μL/孔，4℃冰箱中孵育30分钟。将FITC标记的小鼠抗人ITGA2抗体溶液(BD Pharmingen:555498)稀释到工作浓度，20μL/孔，在4℃冰箱中避光孵育30分钟。孵育后，用500ul 1％FBS洗涤细胞两次，然后加入250ul PBS 重悬细胞。空白参考溶液为包含参考对照液的250μL PBS溶液。采用流式细胞仪收集并分析各个细胞系的ITGA2蛋白拷贝数值，以等效可溶性荧光色素分子计(Molecules of Equivalent Soluble Fluorochrome，MESF)。结果如下表3所示。
表3
如表3所示，同等抗体浓度及处理条件下，HuCCT1,BxPC-3,HCCC-9810，ASPC-1，和A431细胞表面ITGA2蛋白表达较高(MESF＞150,000)，在阴性对照细胞CHO表面几乎无表达(MESF＜1000，可视为实验技术层面的本底值)。
实施例2-ITGA2抗体的制备
1.载体构建
本发明的ITGA2抗体序列的设计、载体构建、表达、纯化和鉴定等均委托三优生物医药(上海)有限公司完成。构建过程主要包括将ITGA2抗体的序列构建在pcDNA3.4载体上，经PCR、酶切、连接、转化、鉴定、测序、比对、抽提后得到质粒。
包含本发明ITGA2抗体的轻链和重链序列的载体如下表4所示：

轻链16个质粒为Kappa类,2个质粒为Lambda类；重链18个质粒为IgG1型。
上表中各个质粒载体中轻链和重链的编码序列如下(阴影部分对应恒定区序列)：
轻链：
人源化抗体轻链编码序列：FS002-A1-LC(Kappa)(SEQ ID NO:1)，其用于表达人源化轻链可变区+人轻链恒定区
人源化抗体轻链编码序列：FS002-A5-LC(Kappa)(SEQ ID NO:2)，其用于表达人源化轻链可变区+人轻链恒定区
人源化抗体轻链编码序列：FS002-A15-LC(Kappa)(SEQ ID NO:3)，其用于表达人源化轻链可变区+人轻链恒定区

人源化抗体轻链编码序列：FS002-A36-LC(Kappa)(SEQ ID NO:4)，其用于表达人源化轻链可变区+人轻链恒定区
人源化抗体轻链编码序列：FS002-A66-LC(Kappa)(SEQ ID NO:5)，其用于表达人源化轻链可变区+人轻链恒定区
人源化抗体轻链编码序列：FS002-A10-LC(Kappa-2)(SEQ ID NO:6)，其用于表达人源化轻链可变区+人轻链恒定区
人源化抗体轻链编码序列：FS002-C9-LC(Kappa-2)(SEQ ID NO:7)，其用于表达 人源化轻链可变区+人轻链恒定区
人源化抗体轻链编码序列：FS002-C11-LC(Kappa-2)(SEQ ID NO:8)，其用于表达人源化轻链可变区+人轻链恒定区
人源化抗体轻链编码序列：FS002-C216-LC(Kappa-2)(SEQ ID NO:9)，其用于表达人源化轻链可变区+人轻链恒定区
人源化抗体轻链编码序列：FS002-C375-LC(Kappa-2)(SEQ ID NO:10)，其用于表达人源化轻链可变区+人轻链恒定区

人源化抗体轻链编码序列：FS002-C417-LC(Kappa-2)(SEQ ID NO:11)，其用于表达人源化轻链可变区+人轻链恒定区
人源化抗体轻链编码序列：FS002-B27-LC(Kappa-2)(SEQ ID NO:12)，其用于表达人源化轻链可变区+人轻链恒定区
人源化抗体轻链编码序列：FS002-C330-LC(Kappa-2)(SEQ ID NO:13)，其用于表达人源化轻链可变区+人轻链恒定区
人源化抗体轻链编码序列：FS002-C153-LC(LambdaC2)-2(SEQ ID NO:14)，其用于表达人源化轻链可变区+人轻链恒定区

人源化抗体轻链编码序列：FS002-C241-LC(LambdaC2)-2(SEQ ID NO:15)，其用于表达人源化轻链可变区+人轻链恒定区
人源化抗体轻链编码序列：FS002-C15-LC(Kappa-2)(SEQ ID NO:16)，其用于表达人源化轻链可变区+人轻链恒定区
人源化抗体轻链编码序列：FS002-C58-LC(Kappa-2)(SEQ ID NO:17)，其用于表达人源化轻链可变区+人轻链恒定区
人源化抗体轻链编码序列：FS002-A72-LC(Kappa-2)(SEQ ID NO:18)，其用于表达人源化轻链可变区+人轻链恒定区

重链：
人源化抗体重链编码序列：FS002-A1-HC(IgG1)(SEQ ID NO:19)，其用于表达人源化重链可变区+人重链恒定区
人源化抗体重链编码序列：FS002-A5-HC(IgG1)(SEQ ID NO:20)，其用于表达人源化重链可变区+人重链恒定区

人源化抗体重链编码序列：FS002-A15-HC(IgG1)(SEQ ID NO:21)，其用于表达人源化重链可变区+人重链恒定区
人源化抗体重链编码序列：FS002-36-HC(IgG1)(SEQ ID NO:22)，其用于表达人源化重链可变区+人重链恒定区
人源化抗体重链编码序列：FS002-A66-HC(IgG1)(SEQ ID NO:23)，其用于表达 人源化重链可变区+人重链恒定区
人源化抗体重链编码序列：FS002-A10-HC(IgG1)(SEQ ID NO:24)，其用于表达人源化重链可变区+人重链恒定区
人源化抗体重链编码序列：FS002-C9-HC(IgG1)(SEQ ID NO:25)，其用于表达人源化重链可变区+人重链恒定区

人源化抗体重链编码序列：FS002-C11-HC(IgG1)(SEQ ID NO:26)，其用于表达人源化重链可变区+人重链恒定区
人源化抗体重链编码序列：FS002-C216-HC(IgG1)(SEQ ID NO:27)，其用于表达人源化重链可变区+人重链恒定区

人源化抗体重链编码序列：FS002-C375-HC(IgG1)(SEQ ID NO:28)，其用于表达人源化重链可变区+人重链恒定区
人源化抗体重链编码序列：FS002-C417-HC(IgG1)(SEQ ID NO:29)，其用于表达人源化重链可变区+人重链恒定区

人源化抗体重链编码序列：FS002-B27-HC(IgG1)(SEQ ID NO:30)，其用于表达人源化重链可变区+人重链恒定区
人源化抗体重链编码序列：FS002-C330-HC(IgG1)(SEQ ID NO:31)，其用于表达人源化重链可变区+人重链恒定区

人源化抗体重链编码序列：FS002-C153-HC(IgG1)(SEQ ID NO:32)，其用于表达人源化重链可变区+人重链恒定区
人源化抗体重链编码序列：FS002-C241-HC(IgG1)(SEQ ID NO:33)，其用于表达人源化重链可变区+人重链恒定区
人源化抗体重链编码序列：FS002-C15-HC(IgG1)(SEQ ID NO:34)，其用于表达人源化重链可变区+人重链恒定区
人源化抗体重链编码序列：FS002-C58-HC(IgG1)(SEQ ID NO:35)，其用于表达人源化重链可变区+人重链恒定区
人源化抗体重链编码序列：FS002-A72-HC(IgG1)(SEQ ID NO:36)，其用于表达人源化重链可变区+人重链恒定区

上述载体表达出的抗体中的轻链可变区和重链可变区的氨基酸序列如下：
轻链可变区(氨基酸序列)：
FS002-A1-LC(Kappa)轻链可变区(SEQ ID NO:37)
下划线斜体部分分别依次标示VL-CDR1(SEQ ID NO:38：)、VL-CDR2(SEQ ID NO:39：)、VL-CDR3(SEQ ID NO:40：)。
FS002-A5-LC(Kappa)轻链可变区(SEQ ID NO:41)
下划线斜体部分分别依次标示VL-CDR1(SEQ ID NO:42：)、VL-CDR2(SEQ ID NO:43：)、VL-CDR3(SEQ ID NO:44：)。
FS002-A15-LC(Kappa)轻链可变区(SEQ ID NO:45)
下划线斜体部分分别依次标示VL-CDR1(SEQ ID NO:46：)、VL-CDR2(SEQ ID NO:47：)、VL-CDR3(SEQ ID NO:48：)。
FS002-A36-LC(Kappa)轻链可变区(SEQ ID NO:49)
下划线斜体部分分别依次标示VL-CDR1(SEQ ID NO:50：)、VL-CDR2(SEQ ID NO:51：)、VL-CDR3(SEQ ID NO:52：)。
FS002-A66-LC(Kappa)轻链可变区(SEQ ID NO:53)
下划线斜体部分分别依次标示VL-CDR1(SEQ ID NO:54：)、VL-CDR2(SEQ ID NO:55：)、VL-CDR3(SEQ ID NO:56：)。
FS002-A10-LC(Kappa-2)轻链可变区(SEQ ID NO:57)
下划线斜体部分分别依次标示VL-CDR1(SEQ ID NO:58：)、VL-CDR2(SEQ ID NO:59：)、VL-CDR3(SEQ ID NO:60：)。
FS002-C9-LC(Kappa-2)轻链可变区(SEQ ID NO:61)
下划线斜体部分分别依次标示VL-CDR1(SEQ ID NO:62：)、VL-CDR2(SEQ ID NO:63：)、VL-CDR3(SEQ ID NO:64：)。
FS002-C11-LC(Kappa-2)轻链可变区(SEQ ID NO:65)
下划线斜体部分分别依次标示VL-CDR1(SEQ ID NO:66：)、VL-CDR2(SEQ ID NO:67：)、VL-CDR3(SEQ ID NO:68：)。
FS002-C216-LC(Kappa-2)轻链可变区(SEQ ID NO:69)
下划线斜体部分分别依次标示VL-CDR1(SEQ ID NO:70：)、VL-CDR2(SEQ ID NO:71：)、VL-CDR3(SEQ ID NO:72：)。
FS002-C375-LC(Kappa-2)轻链可变区(SEQ ID NO:73)
下划线斜体部分分别依次标示VL-CDR1(SEQ ID NO:74：)、VL-CDR2(SEQ ID NO:75：)、VL-CDR3(SEQ ID NO:76：)。
FS002-C417-LC(Kappa-2)轻链可变区(SEQ ID NO:77)
下划线斜体部分分别依次标示VL-CDR1(SEQ ID NO:78：)、VL-CDR2(SEQ ID NO:79：)、VL-CDR3(SEQ ID NO80：)。
FS002-B27-LC(Kappa-2)轻链可变区(SEQ ID NO:81)
下划线斜体部分分别依次标示VL-CDR1(SEQ ID NO:82：)、VL-CDR2(SEQ ID NO:83：)、VL-CDR3(SEQ ID NO:84：)。
FS002-C330-LC(Kappa-2)轻链可变区(SEQ ID NO:85)
下划线斜体部分分别依次标示VL-CDR1(SEQ ID NO:86：)、VL-CDR2(SEQ ID NO:87：)、VL-CDR3(SEQ ID NO:88：)。
FS002-C153-LC(LambdaC2)-2轻链可变区(SEQ ID NO:89)
下划线斜体部分分别依次标示VL-CDR1(SEQ ID NO:90：)、VL-CDR2(SEQ ID NO:91：)、VL-CDR3(SEQ ID NO:92：)。
FS002-C241-LC(LambdaC2)-2轻链可变区(SEQ ID NO:93)
下划线斜体部分分别依次标示VL-CDR1(SEQ ID NO:94：)、VL-CDR2(SEQ ID NO:95：)、VL-CDR3(SEQ ID NO:96：)。
FS002-C15-LC(Kappa-2)轻链可变区(SEQ ID NO:97)
下划线斜体部分分别依次标示VL-CDR1(SEQ ID NO:98：)、VL-CDR2(SEQ ID NO:99：)、VL-CDR3(SEQ ID NO:100：)。
FS002-C58-LC(Kappa-2)轻链可变区(SEQ ID NO:101)
下划线斜体部分分别依次标示VL-CDR1(SEQ ID NO:102：)、VL-CDR2(SEQ ID NO:103：)、VL-CDR3(SEQ ID NO:104：)。
FS002-A72-LC(Kappa-2)轻链可变区(SEQ ID NO:105)
下划线斜体部分分别依次标示VL-CDR1(SEQ ID NO:106：)、VL-CDR2(SEQ ID NO:107：)、VL-CDR3(SEQ ID NO:108：)。
轻链恒定区(氨基酸序列)：
Kappa型轻链恒定区序列(SEQ ID NO:109)
Lambda型轻链恒定区序列(SEQ ID NO:110)
重链可变区(氨基酸序列)：
FS002-A1-HC(IgG1)重链可变区(SEQ ID NO:111)
下划线斜体部分分别依次标示VH-CDR1(SEQ ID NO:112：)、VH-CDR2(SEQ ID NO:113：)、VH-CDR3(SEQ ID NO:114：)。
FS002-A5-HC(IgG1)重链可变区(SEQ ID NO:115)
下划线斜体部分分别依次标示VH-CDR1(SEQ ID NO:116：)、VH-CDR2(SEQ ID NO:117：)、VH-CDR3(SEQ ID NO:118：)。
FS002-A15-HC(IgG1)重链可变区(SEQ ID NO:119)
下划线斜体部分分别依次标示VH-CDR1(SEQ ID NO:120：)、VH-CDR2(SEQ ID NO:121：)、VH-CDR3(SEQ ID NO:122：)。
FS002-A36-HC(IgG1)重链可变区(SEQ ID NO:123)
下划线斜体部分分别依次标示VH-CDR1(SEQ ID NO:124：)、VH-CDR2(SEQ ID NO:125：)、VH-CDR3(SEQ ID NO:126：)。
FS002-A66-HC(IgG1)重链可变区(SEQ ID NO:127)
下划线斜体部分分别依次标示VH-CDR1(SEQ ID NO:128：)、VH-CDR2(SEQ ID NO:129：)、VH-CDR3(SEQ ID NO:130：)。
FS002-A10-HC(IgG1)重链可变区(SEQ ID NO:131)
下划线斜体部分分别依次标示VH-CDR1(SEQ ID NO:132：)、VH-CDR2(SEQ ID NO:133：)、VH-CDR3(SEQ ID NO:134：)。
FS002-C9-HC(IgG1)重链可变区(SEQ ID NO:135)
下划线斜体部分分别依次标示VH-CDR1(SEQ ID NO:136：)、VH-CDR2(SEQ ID NO:137：)、VH-CDR3(SEQ ID NO:138：)。
FS002-C11-HC(IgG1)重链可变区(SEQ ID NO:139)
下划线斜体部分分别依次标示VH-CDR1(SEQ ID NO:140：)、VH-CDR2(SEQ ID NO:141：)、VH-CDR3(SEQ ID NO:142：)。
FS002-C216-HC(IgG1)重链可变区(SEQ ID NO:143)
下划线斜体部分分别依次标示VH-CDR1(SEQ ID NO:144：)、VH-CDR2(SEQ ID NO:145：)、VH-CDR3(SEQ ID NO:146：)。
FS002-C375-HC(IgG1)重链可变区(SEQ ID NO:147)
下划线斜体部分分别依次标示VH-CDR1(SEQ ID NO:148：)、VH-CDR2(SEQ ID NO:149：)、VH-CDR3(SEQ ID NO:150：)。
FS002-C417-HC(IgG1)重链可变区(SEQ ID NO:151)
下划线斜体部分分别依次标示VH-CDR1(SEQ ID NO:152：)、VH-CDR2(SEQ ID NO:153：)、VH-CDR3(SEQ ID NO:154：)。
FS002-B27-HC(IgG1)重链可变区(SEQ ID NO:155)
下划线斜体部分分别依次标示VH-CDR1(SEQ ID NO:156：)、VH-CDR2(SEQ ID NO:157：)、VH-CDR3(SEQ ID NO:158：)。
FS002-C330-HC(IgG1)重链可变区(SEQ ID NO:159)
下划线斜体部分分别依次标示VH-CDR1(SEQ ID NO:160：)、VH-CDR2(SEQ ID NO:161：)、VH-CDR3(SEQ ID NO:162：)。
FS002-C153-HC(IgG1)重链可变区(SEQ ID NO:163)
下划线斜体部分分别依次标示VH-CDR1(SEQ ID NO:164：)、VH-CDR2(SEQ ID NO:165：)、VH-CDR3(SEQ ID NO:166：)。
FS002-C241-HC(IgG1)重链可变区(SEQ ID NO:167)
下划线斜体部分分别依次标示VH-CDR1(SEQ ID NO:168：)、VH-CDR2(SEQ ID NO:169：)、VH-CDR3(SEQ ID NO:170：。
FS002-C15-HC(IgG1)重链可变区(SEQ ID NO:171)
下划线斜体部分分别依次标示VH-CDR1(SEQ ID NO:172：)、VH-CDR2(SEQ ID NO:173：)、VH-CDR3(SEQ ID NO:174：)。
FS002-C58-HC(IgG1)重链可变区(SEQ ID NO:175)
下划线斜体部分分别依次标示VH-CDR1(SEQ ID NO:176：)、VH-CDR2(SEQ ID NO:177：)、VH-CDR3(SEQ ID NO:178：)。
FS002-A72-HC(IgG1)重链可变区(SEQ ID NO:179)
下划线斜体部分分别依次标示VH-CDR1(SEQ ID NO:180：)、VH-CDR2(SEQ ID NO:181：)、VH-CDR3(SEQ ID NO:182：)。
IgG1型重链恒定区(SEQ ID NO:183)
抗体的轻链的全长氨基酸序列如下(阴影部分对应恒定区序列)：
FS002-A1-LC(Kappa)轻链(SEQ ID NO:184)
FS002-A5-LC(Kappa)轻链(SEQ ID NO:185)
FS002-A15-LC(Kappa)轻链(SEQ ID NO:186)
FS002-A36-LC(Kappa)轻链(SEQ ID NO:187)
FS002-A66-LC(Kappa)轻链(SEQ ID NO:188)
FS002-A10-LC(Kappa-2)轻链(SEQ ID NO:189)
FS002-C9-LC(Kappa-2)轻链(SEQ ID NO:190)
FS002-C11-LC(Kappa-2)轻链(SEQ ID NO:191)
FS002-C216-LC(Kappa-2)轻链(SEQ ID NO:192)
FS002-C375-LC(Kappa-2)轻链(SEQ ID NO:193)
FS002-C417-LC(Kappa-2)轻链(SEQ ID NO:194)
FS002-B27-LC(Kappa-2)轻链(SEQ ID NO:195)
FS002-C330-LC(Kappa-2)轻链(SEQ ID NO:196)
FS002-C153-LC(LambdaC2)-2轻链(SEQ ID NO:197)
FS002-C241-LC(LambdaC2)-2轻链(SEQ ID NO:198)
FS002-C15-LC(Kappa-2)轻链(SEQ ID NO:199)
FS002-C58-LC(Kappa-2)轻链(SEQ ID NO:200)
FS002-A72-LC(Kappa-2)轻链(SEQ ID NO:201)
抗体的重链的全长氨基酸序列如下(阴影部分对应恒定区序列)：
FS002-A1-HC(IgG1)重链(SEQ ID NO:202)
FS002-A5-HC(IgG1)重链(SEQ ID NO:203)
FS002-A15-HC(IgG1)重链(SEQ ID NO:204)
FS002-A36-HC(IgG1)重链(SEQ ID NO:205)
FS002-A66-HC(IgG1)重链(SEQ ID NO:206)
FS002-A10-HC(IgG1)重链(SEQ ID NO:207)
FS002-C9-HC(IgG1)重链(SEQ ID NO:208)
FS002-C11-HC(IgG1)重链(SEQ ID NO:209)
FS002-C216-HC(IgG1)重链(SEQ ID NO:210)
FS002-C375-HC(IgG1)重链(SEQ ID NO:211)
FS002-C417-HC(IgG1)重链(SEQ ID NO:212)
FS002-B27-HC(IgG1)重链(SEQ ID NO:213)
FS002-C330-HC(IgG1)重链(SEQ ID NO:214)
FS002-C153-HC(IgG1)重链(SEQ ID NO:215)
FS002-C241-HC(IgG1)重链(SEQ ID NO:216)
FS002-C15-HC(IgG1)重链(SEQ ID NO:217)
FS002-C58-HC(IgG1)重链(SEQ ID NO:218)
FS002-A72-HC(IgG1)重链(SEQ ID NO:219)
表5：前述抗体的重链、轻链、恒定区、可变区，各个CDR的序列编号总结如下(SEQ ID NO:)
2.抗体的表达和纯化、以及SDS-PAGE鉴定
运用ExpiCHO-s表达系统，将上述质粒按照要求进行在CHO细胞中为期7天的表达，并在表达第6天，使用Protein A亲和层析纯化得到抗体。
随后，通过SDS-PAGE检测所得抗体的纯度。在SDS-PAGE中，用ImageJ按照峰面积归一法计算还原条带纯度，或者还原重链加轻链和的纯度；参照品IPI非还原条带分子量150kDa左右，纯度大于90％；还原重链分子量55kDa左右，轻链分子量25kDa左右，重链加轻链纯度大于90％。
实施例3-通过ELISA方法评估抗ITGA2抗体在蛋白水平上与ITGA2蛋白的亲和 力
采用以下方法测定ITGA2抗体在蛋白水平上与ITGA2蛋白的亲和力，包括用2ug/mL ITGA2-His包被ELISA板。用PBST清洗板3次，并在室温下用5％PBS-Milk封闭板2小时。用PBST清洗板3次，然后在ELISA板中加入稀释的抗体，每孔30μL，在室温下放置60分钟。用PBST清洗板3次，然后在ELISA板中加入抗人IgG-Fc-HRP(abcam；ab97225)，在室温下放置60分钟。加入TMB并用2M终止液终止反应并读取OD450。最终通过EC50来比较各个抗体对ITGA2-his的结合能力。抗体Vatelizumab(购买于百英生物)作为阳性对照。测定的结果数据显示在下表6中。
表6
如上表所示的结果，18个待检测抗体中有17个抗体与ITGA2-His均有较好的结合活性(EC50＜1nM)。
实施例4-通过流式细胞术测定抗ITGA2抗体在细胞学水平上与ITGA2的亲和力
将人胆管癌细胞HuCCT1细胞铺入96孔板，每孔50000细胞，然后用PBS重复吹匀洗涤两次，吸弃PBS。待检测ITGA2抗体作为一抗，用1％FBS/PBS溶液配制工作浓度为30nM，依次3倍稀释，共5个特异性浓度点。用配制完成的抗体稀释液加入相对 应的96孔板中，4℃孵育30分钟。然后用1％FBS/PBS溶液重复吹匀洗涤两次，吸弃PBS离心后吸弃抗体上清。用10％FBS含量的PBS溶液按照1：300配制去除其他物种交叉识别能力的山羊抗人二抗IgG(H+L)，加入96孔板中，4℃孵育30分钟。采用流式细胞仪收集并分析，最终通过EC50来评价抗体对于ITGA2靶点的亲和力大小。抗体Vatelizumab(购买于百英生物)作为结合ITGA2的阳性对照抗体。
EC50的测定的结果显示在表7中。如表7中所示结果：在这18个抗体中，有14个抗体的EC50小于5nM，可以很好地结合ITGA2阳性细胞HuCCT1。
表7
实施例5-抗体-药物缀合物(ADC)的制备
采用以下方法制备抗体-药物缀合物
材料和方法：
偶联缓冲液：25mM Na2B4O7、25mM NaCl、1mM DPTA、pH 7.4
透析缓冲液：1×PBS，pH 7.4
抗体还原浓度：5mg/mL
磷酸三(2-氯乙基)酯(TCEP)：5mM，结合缓冲液
TCEP:抗体＝2.3:1
有效载荷：10mM接头-有效载荷，二甲基亚砜(DMSO)
最终反应中的DMSO：10％
有效载荷:抗体＝10:1
还原温度和时间：25℃和2小时
偶联温度和时间：25℃和4小时
偶联步骤：
解冻并使用偶联缓冲液在4℃下透析抗体，>4小时；
如果需要，将抗体溶液浓缩至2-5mg/ml；
加入TCEP工作液还原抗体，25℃水浴孵育；
在DMSO(10mM)中制备接头-载荷溶液；
根据摩尔浓度计算每个缀合的有效接头-载荷溶液的体积；
以所需的摩尔比将抗体与接头-载荷混合，并在25℃水浴中孵育；
在4℃下使用ADC储存缓冲液透析缀合物大于4小时，至少每隔4小时更换一次缓冲液；和
使用0.22μm过滤器提取和过滤ADC，并提交样品供SEC-HPLC和HIC-HPLC分析。
通过上述方法，使用vc-MMAE(mc-vc-PAB-MMAE，C68H105N11O15，由睿智化学提供)作为接头-载荷，在本实施例中制备本发明的抗体FS002-A1、FS002-A15、FS002-A36和阳性对照抗体Vatelizumab的抗体-药物缀合物。
表8
实施例6–抗体-药物缀合物(ADC)对癌细胞杀伤的生物学活性
本实施例测试将本发明的抗体缀合毒素成为ADC后，其对于癌细胞杀伤的生物学活性。
将浙江美森来源的人胆管癌细胞HuCC-T1、武汉普诺赛来源的人表皮癌细胞A431 和阴性对照ATCC来源的中国仓鼠卵巢细胞CHO铺入96孔板，2500个/孔。放入37℃5％CO2培养箱过夜孵育。第二天将细胞板的一半培养基去除。用完全培养基配制2x的hIgG1(阴性对照抗体，百英生物提供)、Vatelizumab、FS002-A1-vc-MMAE、FS002-A15-vc-MMAE、FS002-A36-vc-MMAE、Vatelizumab-vc-MMAE、hIgG1-vcMMAE(阴性对照ADC，睿智化学提供)，随后进行3倍梯度稀释，共11个特异性浓度点，向适当孔中加入上述分子的连续稀释物，放入37℃5％CO2培养箱孵育5天。孵育结束后，向96孔板中加入100uL的Cell-Titer-Glo 2.0试剂，在摇板机上混匀2分钟，最后在室温下平衡10分钟。使用酶标仪进行读数。最终通过IC50来比较ADC对各个细胞系的生物学活性。
结果显示在表9中。如表9中所示结果：FS002-A1-vc-MMAE、FS002-A15-vc-MMAE、FS002-A36-vc-MMAE和Vatelizumab-vc-MMAE对于HuCC-T1和A431均具有较好的杀伤效果，但是对阴性对照细胞CHO均无杀伤效果。阴性对照抗体hIgG1、未偶联vc-MMAE的ITGA2抗体Vatelizumab或者阴性对照hIgG1-vc-MMAE均无法有效杀伤HuCC-T1和A431细胞。
表9
上述结果提示，ITGA2抗体在体外是无法单独用于杀伤肿瘤细胞，但是令人惊奇地，发现ITGA2蛋白可作为有效的抗体药物缀合物的靶点。本发明对抗体进行小分子毒素偶联而得到的抗体药物缀合物可以对表达ITGA2蛋白的肿瘤产生优异的杀伤效果。 技术方案集合：
1.一种特异性结合ITGA2蛋白的分离的抗体或其抗原结合片段部分，其中，所述的分离的抗体或其抗原结合片段部分包含含有HCDR1、HCDR2、HCDR3序列的重链可变区；以及含有LCDR1、LCDR2、LCDR3序列的轻链可变区，其中所述抗体或其抗原结合片段部分具有选自以下至少一组的重链可变区和轻链可变区：
1)所述重链可变区包含(a)SEQ ID NO：112的HCDR1，(b)SEQ ID NO：113的HCDR2，和(c)SEQ ID NO：114的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：38的LCDR1，(e)SEQ ID NO：39的LCDR2，和(f)SEQ ID NO：40的LCDR3；
2)所述重链可变区包含(a)SEQ ID NO：116的HCDR1，(b)SEQ ID NO：117的HCDR2，和(c)SEQ ID NO：118的HCDR3，且所述轻链可变区且所述轻链可变区包含(d)SEQ ID NO：42的LCDR1，(e)SEQ ID NO：43的LCDR2，和(f)SEQ ID NO：44的LCDR3；
3)所述重链可变区包含(a)SEQ ID NO：120的HCDR1，(b)SEQ ID NO：121的HCDR2，和(c)SEQ ID NO：122的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：46的LCDR1，(e)SEQ ID NO：47的LCDR2，和(f)SEQ ID NO：48的LCDR3；
4)所述重链可变区包含(a)SEQ ID NO：124的HCDR1，(b)SEQ ID NO：125的HCDR2，和(c)SEQ ID NO：126的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：50的LCDR1，(e)SEQ ID NO：51的LCDR2，和(f)SEQ ID NO：52的LCDR3；
5)所述重链可变区包含(a)SEQ ID NO：128的HCDR1，(b)SEQ ID NO：129的HCDR2，和(c)SEQ ID NO：130的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：54的LCDR1，(e)SEQ ID NO：55的LCDR2，和(f)SEQ ID NO：56的LCDR3；
6)所述重链可变区包含(a)SEQ ID NO：132的HCDR1，(b)SEQ ID NO：133的HCDR2，和(c)SEQ ID NO：134的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：58的LCDR1，(e)SEQ ID NO：59的LCDR2，和(f)SEQ ID NO：60的LCDR3；
7)所述重链可变区包含(a)SEQ ID NO：136的HCDR1，(b)SEQ ID NO：137的HCDR2，和(c)SEQ ID NO：138的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：62的LCDR1，(e)SEQ ID NO：63的LCDR2，和(f)SEQ ID NO：64的LCDR3；
8)所述重链可变区包含(a)SEQ ID NO：140的HCDR1，(b)SEQ ID NO：141的HCDR2，和(c)SEQ ID NO：142的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：66的LCDR1，(e)SEQ ID NO：67的LCDR2，和(f)SEQ ID NO：68的LCDR3；
9)所述重链可变区包含(a)SEQ ID NO：144的HCDR1，(b)SEQ ID NO：145的HCDR2，和(c)SEQ ID NO：146的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：70的LCDR1，(e)SEQ ID NO：71的LCDR2，和(f)SEQ ID NO：72的LCDR3；
10)所述重链可变区包含(a)SEQ ID NO：148的HCDR1，(b)SEQ ID NO：149的HCDR2，和(c)SEQ ID NO：150的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：74的LCDR1，(e)SEQ ID NO：75的LCDR2，和(f)SEQ ID NO：76的LCDR3；
11)所述重链可变区包含(a)SEQ ID NO：152的HCDR1，(b)SEQ ID NO：153的HCDR2，和(c)SEQ ID NO：154的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：78的LCDR1，(e)SEQ ID NO：79的LCDR2，和(f)SEQ ID NO：80的LCDR3；
12)所述重链可变区包含(a)SEQ ID NO：156的HCDR1，(b)SEQ ID NO：157的HCDR2，和(c)SEQ ID NO：158的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：82的LCDR1，(e)SEQ ID NO：83的LCDR2，和(f)SEQ ID NO：84的LCDR3；
13)所述重链可变区包含(a)SEQ ID NO：160的HCDR1，(b)SEQ ID NO：161的HCDR2，和(c)SEQ ID NO：162的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：86的LCDR1，(e)SEQ ID NO：87的LCDR2，和(f)SEQ ID NO：88的LCDR3；
14)所述重链可变区包含(a)SEQ ID NO：164的HCDR1，(b)SEQ ID NO：165的HCDR2，和(c)SEQ ID NO：166的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：90的LCDR1，(e)SEQ ID NO：91的LCDR2，和(f)SEQ ID NO：92的LCDR3；
15)所述重链可变区包含(a)SEQ ID NO：168的HCDR1，(b)SEQ ID NO：169的HCDR2，和(c)SEQ ID NO：170的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：94的LCDR1，(e)SEQ ID NO：95的LCDR2，和(f)SEQ ID NO：96的LCDR3；
16)所述重链可变区包含(a)SEQ ID NO：172的HCDR1，(b)SEQ ID NO：173的HCDR2，和(c)SEQ ID NO：174的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：98的LCDR1，(e)SEQ ID NO：99的LCDR2，和(f)SEQ ID NO：100的LCDR3；
17)所述重链可变区包含(a)SEQ ID NO：176的HCDR1，(b)SEQ ID NO：177的HCDR2，和(c)SEQ ID NO：178的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：102的LCDR1，(e)SEQ ID NO：103的LCDR2，和(f)SEQ ID NO：104的LCDR3；和
18)所述重链可变区包含(a)SEQ ID NO：180的HCDR1，(b)SEQ ID NO：181的HCDR2，和(c)SEQ ID NO：182的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：106的LCDR1，(e)SEQ ID NO：107的LCDR2，和(f)SEQ ID NO：108的LCDR3。
2.根据技术方案1所述的分离的抗体或其抗原结合片段部分，其中，所述的分离的抗体或其抗原结合片段部分包含具有选自以下至少一组的重链可变区和轻链可变区：
1)所述重链可变区，其包含SEQ ID NO：111的氨基酸序列或与SEQ ID NO：111的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：37的氨基酸序列或与SEQ ID NO：37的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
2)所述重链可变区，其包含SEQ ID NO：115的氨基酸序列或与SEQ ID NO：115的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：41的氨基酸序列或与SEQ ID NO：41的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
3)所述重链可变区，其包含SEQ ID NO：119的氨基酸序列或与SEQ ID NO：119的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：45的氨基酸序列或与SEQ ID NO：45的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
4)所述重链可变区，其包含SEQ ID NO：123的氨基酸序列或与SEQ ID NO：123的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：49的氨基酸序列或与SEQ ID NO：49的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
5)所述重链可变区，其包含SEQ ID NO：127的氨基酸序列或与SEQ ID NO：127的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：53的氨基酸序列或与SEQ ID NO：53的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
6)所述重链可变区，其包含SEQ ID NO：131的氨基酸序列或与SEQ ID NO：131的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：57的氨基 酸序列或与SEQ ID NO：57的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
7)所述重链可变区，其包含SEQ ID NO：135的氨基酸序列或与SEQ ID NO：135的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：61的氨基酸序列或与SEQ ID NO：61的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
8)所述重链可变区，其包含SEQ ID NO：139的氨基酸序列或与SEQ ID NO：139的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：65的氨基酸序列或与SEQ ID NO：65的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
9)所述重链可变区，其包含SEQ ID NO：143的氨基酸序列或与SEQ ID NO：143的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：69的氨基酸序列或与SEQ ID NO：69的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
10)所述重链可变区，其包含SEQ ID NO：147的氨基酸序列或与SEQ ID NO：147的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：73的氨基酸序列或与SEQ ID NO：73的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
11)所述重链可变区，其包含SEQ ID NO：151的氨基酸序列或与SEQ ID NO：151的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：77的氨基酸序列或与SEQ ID NO：77的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
12)所述重链可变区，其包含SEQ ID NO：155的氨基酸序列或与SEQ ID NO：155的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：81的氨基 酸序列或与SEQ ID NO：81的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
13)所述重链可变区，其包含SEQ ID NO：159的氨基酸序列或与SEQ ID NO：159的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：85的氨基酸序列或与SEQ ID NO：85的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
14)所述重链可变区，其包含SEQ ID NO：163的氨基酸序列或与SEQ ID NO：163的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：89的氨基酸序列或与SEQ ID NO：89的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
15)所述重链可变区，其包含SEQ ID NO：167的氨基酸序列或与SEQ ID NO：167的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：93的氨基酸序列或与SEQ ID NO：93的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
16)所述重链可变区，其包含SEQ ID NO：171的氨基酸序列或与SEQ ID NO：171的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：97的氨基酸序列或与SEQ ID NO：97的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
17)所述重链可变区，其包含SEQ ID NO：175的氨基酸序列或与SEQ ID NO：175的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：101的氨基酸序列或与SEQ ID NO：101的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；和
18)所述重链可变区，其包含SEQ ID NO：179的氨基酸序列或与SEQ ID NO：179的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：105的氨基 酸序列或与SEQ ID NO：105的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列。
3.根据技术方案1或2所述的分离的抗体或其抗原结合片段部分，其中，所述的分离的抗体或其抗原结合片段部分进一步包含重链恒定区和/或轻链恒定区，
所述重链恒定区包含SEQ ID NO：183的氨基酸序列或与SEQ ID NO：183的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，
所述轻链恒定区包含SEQ ID NO：109的氨基酸序列或与SEQ ID NO：109的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；或者所述轻链恒定区包含SEQ ID NO：110的氨基酸序列或与SEQ ID NO：110的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列。
4.根据技术方案1-3中任一项所述的分离的抗体或其抗原结合片段部分，其中，所述的分离的抗体或其抗原结合片段部分包含具有选自以下至少一组的重链和轻链：
1)所述重链，其包含SEQ ID NO：202的氨基酸序列或与SEQ ID NO：202的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：184的氨基酸序列或与SEQ ID NO：184的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
2)所述重链，其包含SEQ ID NO：203的氨基酸序列或与SEQ ID NO：203的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：185的氨基酸序列或与SEQ ID NO：185的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
3)所述重链，其包含SEQ ID NO：204的氨基酸序列或与SEQ ID NO：204的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：186的氨基酸序列或与SEQ ID NO：186的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
4)所述重链，其包含SEQ ID NO：205的氨基酸序列或与SEQ ID NO：205的氨 基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：187的氨基酸序列或与SEQ ID NO：187的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
5)所述重链，其包含SEQ ID NO：206的氨基酸序列或与SEQ ID NO：206的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：188的氨基酸序列或与SEQ ID NO：188的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
6)所述重链，其包含SEQ ID NO：207的氨基酸序列或与SEQ ID NO：207的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：189的氨基酸序列或与SEQ ID NO：189的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
7)所述重链，其包含SEQ ID NO：208的氨基酸序列或与SEQ ID NO：208的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：190的氨基酸序列或与SEQ ID NO：190的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
8)所述重链，其包含SEQ ID NO：209的氨基酸序列或与SEQ ID NO：209的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：191的氨基酸序列或与SEQ ID NO：191的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
9)所述重链，其包含SEQ ID NO：210的氨基酸序列或与SEQ ID NO：210的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：192的氨基酸序列或与SEQ ID NO：192的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
10)所述重链，其包含SEQ ID NO：211的氨基酸序列或与SEQ ID NO：211的氨 基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：193的氨基酸序列或与SEQ ID NO：193的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
11)所述重链，其包含SEQ ID NO：212的氨基酸序列或与SEQ ID NO：212的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：194的氨基酸序列或与SEQ ID NO：194的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
12)所述重链，其包含SEQ ID NO：213的氨基酸序列或与SEQ ID NO：213的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：195的氨基酸序列或与SEQ ID NO：195的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
13)所述重链，其包含SEQ ID NO：214的氨基酸序列或与SEQ ID NO：214的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：196的氨基酸序列或与SEQ ID NO：196的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
14)所述重链，其包含SEQ ID NO：215的氨基酸序列或与SEQ ID NO：215的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：197的氨基酸序列或与SEQ ID NO：197的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
15)所述重链，其包含SEQ ID NO：216的氨基酸序列或与SEQ ID NO：216的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：198的氨基酸序列或与SEQ ID NO：198的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
16)所述重链，其包含SEQ ID NO：217的氨基酸序列或与SEQ ID NO：217的氨 基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：199的氨基酸序列或与SEQ ID NO：199的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
17)所述重链，其包含SEQ ID NO：218的氨基酸序列或与SEQ ID NO：218的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：200的氨基酸序列或与SEQ ID NO：200的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；和
18)所述重链，其包含SEQ ID NO：219的氨基酸序列或与SEQ ID NO：219的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：201的氨基酸序列或与SEQ ID NO：201的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列。
5.根据技术方案1-4中任一项所述的分离的抗体或其抗原结合片段部分，其中，所述的分离的抗体或其抗原结合片段部分由选自以下至少一组的重链和轻链组成：
1)所述重链，其由SEQ ID NO：202的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：184的氨基酸序列组成；
2)所述重链，其由SEQ ID NO：203的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：185的氨基酸序列组成；
3)所述重链，其由SEQ ID NO：204的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：186的氨基酸序列组成；
4)所述重链，其由SEQ ID NO：205的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：187的氨基酸序列组成；
5)所述重链，其由SEQ ID NO：206的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：188的氨基酸序列组成；
6)所述重链，其由SEQ ID NO：207的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：189的氨基酸序列组成；
7)所述重链，其由SEQ ID NO：208的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：190的氨基酸序列组成；
8)所述重链，其由SEQ ID NO：209的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：191的氨基酸序列组成；
9)所述重链，其由SEQ ID NO：210的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：192的氨基酸序列组成；
10)所述重链，其由SEQ ID NO：211的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：193的氨基酸序列组成；
11)所述重链，其由SEQ ID NO：212的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：194的氨基酸序列组成；
12)所述重链，其由SEQ ID NO：213的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：195的氨基酸序列组成；
13)所述重链，其由SEQ ID NO：214的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：196的氨基酸序列组成；
14)所述重链，其由SEQ ID NO：215的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：197的氨基酸序列组成；
15)所述重链，其由SEQ ID NO：216的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：198的氨基酸序列组成；
16)所述重链，其由SEQ ID NO：217的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：199的氨基酸序列组成；
17)所述重链，其由SEQ ID NO：218的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：200的氨基酸序列组成；和
18)所述重链，其由SEQ ID NO：219的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：201的氨基酸序列组成。
6.一种特异性结合ITGA2蛋白的分离的抗体或其抗原结合片段部分，其中，所述的分离的抗体或其抗原结合片段部分具有选自以下至少一组的重链和轻链：
1)所述重链包含由SEQ ID NO：19的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：19的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：19的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：1的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：1的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、 至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：1的核苷酸序列所编码的氨基酸序列组成；
2)所述重链包含由SEQ ID NO：20的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：20的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：20的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：2的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：2的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：2的核苷酸序列所编码的氨基酸序列组成；
3)所述重链包含由SEQ ID NO：21的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：21的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：21的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：3的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：3的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：3的核苷酸序列所编码的氨基酸序列组成；
4)所述重链包含由SEQ ID NO：22的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：22的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：22的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：4的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：4的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：4的核苷酸序列所编码的氨基酸序列组成；
5)所述重链包含由SEQ ID NO：23的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：23的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：23的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：5的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：5的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：5的核苷酸序列所编码的氨基酸序列组成；
6)所述重链包含由SEQ ID NO：24的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：24的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：24的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：6的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：6的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：6的核苷酸序列所编码的氨基酸序列组成；
7)所述重链包含由SEQ ID NO：25的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：25的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：25的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：7的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：7的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：7的核苷酸序列所编码的氨基酸序列组成；
8)所述重链包含由SEQ ID NO：26的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：26的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：26的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：8的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：8的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：8的核苷酸序列所编码的氨基酸序列组成；
9)所述重链包含由SEQ ID NO：27的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：27的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少 95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：27的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：9的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：9的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：9的核苷酸序列所编码的氨基酸序列组成；
10)所述重链包含由SEQ ID NO：28的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：28的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：28的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：10的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：10的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：10的核苷酸序列所编码的氨基酸序列组成；
11)所述重链包含由SEQ ID NO：29的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：29的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：29的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：11的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：11的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：11的核苷酸序列所编码的氨基酸序列组成；
12)所述重链包含由SEQ ID NO：30的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：30的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：30的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：12的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：12的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：12的核苷酸序列所编码的氨基酸序列组成；
13)所述重链包含由SEQ ID NO：31的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：31的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：31的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：13的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：13的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：13的核苷酸序列所编码的氨基酸序列组成；
14)所述重链包含由SEQ ID NO：32的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：32的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：32的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：14的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：14的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：14的核苷酸序列所编码的氨基酸序列组成；
15)所述重链包含由SEQ ID NO：33的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：33的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：33的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：15的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：15的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：15的核苷酸序列所编码的氨基酸序列组成；
16)所述重链包含由SEQ ID NO：34的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：34的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：34的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：16的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：16的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、 至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：16的核苷酸序列所编码的氨基酸序列组成；
17)所述重链包含由SEQ ID NO：35的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：35的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：35的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：17的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：17的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：17的核苷酸序列所编码的氨基酸序列组成；和
18)所述重链包含由SEQ ID NO：36的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：36的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：36的核苷酸序列所编码的氨基酸序列组成，且
所述轻链包含由SEQ ID NO：18的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：18的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：18的核苷酸序列所编码的氨基酸序列组成。
7.技术方案1-6中任一项所述的分离的抗体或其抗原结合片段部分，
其中所述抗体能够以小于1nM的EC50在体外结合ITGA2蛋白；和/或
其中所述抗体能够以小于5nM的EC50结合HuCCT1细胞表面的ITGA2蛋白；
和/或其中所述抗体是单克隆抗体、多克隆抗体、嵌合抗体、或人源化抗体。
8.一种分离的核酸分子，其编码技术方案1-7中任一项的抗体或其抗原结合片段部分；或者
所述核酸分子包括选自以下任意一种所示的核苷酸序列或由此核苷酸序列组成：SEQ ID NOs:1-18，和/或所述核酸分子包括选自以下任意一种所示的核苷酸序列或由此核苷酸序列组成：SEQ ID NOs:19-36；或者
所述核酸分子包括选自以下任意一种组合所示的核苷酸序列或由此核苷酸序列组成：SEQ ID NO:1和SEQ ID NO:19、SEQ ID NO:2和SEQ ID NO:20、SEQ ID NO:3和SEQ ID NO:21、SEQ ID NO:4和SEQ ID NO:22、SEQ ID NO:5和SEQ ID NO:23、 SEQ ID NO:6和SEQ ID NO:24、SEQ ID NO:7和SEQ ID NO:25、SEQ ID NO:8和SEQ ID NO:26、SEQ ID NO:9和SEQ ID NO:27、SEQ ID NO:10和SEQ ID NO:28、SEQ ID NO:11和SEQ ID NO:29、SEQ ID NO:12和SEQ ID NO:30、SEQ ID NO:13和SEQ ID NO:31、SEQ ID NO:14和SEQ ID NO:32、SEQ ID NO:15和SEQ ID NO:33、SEQ ID NO:16和SEQ ID NO:34、SEQ ID NO:17和SEQ ID NO:35、以及SEQ ID NO:18和SEQ ID NO:36。
9.技术方案8的分离的核酸分子，所述核酸分子与表达调控序列可操作地连接。
10.一种表达载体，其包含技术方案8或9的核酸分子。
11.一种宿主细胞，其包含技术方案8或9的核酸分子或技术方案10的表达载体。
12.一种杂交瘤细胞，其表达技术方案1-7中任一项的抗体或其抗原结合片段部分。
13.一种如下式的抗体药物缀合物：
Ab-L-D，其中：
符号“Ab”代表至少一种前述本发明的抗体或其抗原结合片段部分；
符号“L”代表连接抗体部分和配偶体分子的连接子；和
符号“D”代表配偶体分子；
或者
Ab-(L-D)p，其中：
符号“Ab”代表至少一种前述本发明的抗体或其抗原结合片段部分；
符号“L”代表连接抗体部分和配偶体分子的连接子；
符号“D”代表配偶体分子；和
符号“p”代表缀合至前述本发明的抗体或其抗原结合片段部分的连接子/配偶体分子(优选药物载荷物)的数量；可选地，p选自以下数值：1.0、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、4.1、4.2、4.3、4.4、4.5、4.6、4.7、4.8、4.9、5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、和8.0。
14.如技术方案13的抗体药物缀合物，其中所述连接子选自以下一种：vc、mc-GGFG、AcLysvc、mc、MalPeg6、m(H20)c及m(H20)cvc；和/或所述连接子是可切割的。
15.如技术方案13或14的抗体药物缀合物，其中
所述配偶体分子为药物载荷物，所述药物载荷物为治疗性分子；可选地，所述药物载荷物选自以下一种：细胞毒性剂、细胞抑制剂、免疫调节剂和化学治疗剂；可选地，所述药物载荷物选自以下一种：MMAE、MMAF、DM1、DM4、Dxd、SN-38、Topotecan及其衍生物、Exatecan及其衍生物、Belotecan及其衍生物、Camptothecin、Calicheamicin和PBD；或者
所述配偶体分子为标记分子；可选地，所述标记分子选自以下一种：放射性标记(例如同位素)、荧光标记(例如荧光染料)、化学物质、和可检测修饰的酶和标签。
16.药物组合物，其包含技术方案1-7中任一项的抗体或其抗原结合片段部分或者技术方案13-15中任一项的抗体药物缀合物、以及可选地药学上可接受的载体。
17.技术方案1-7中任一项的抗体或其抗原结合片段部分或者技术方案13-15中任一项的抗体药物缀合物在制备药物组合物中的用途；可选地，所述药物组合物用于在患者中治疗恶性肿瘤、预防和/或治疗恶性肿瘤转移或复发；可选地，所述药物组合物用于检测患者中恶性肿瘤的存在；可选地，所述药物组合物用于预后患者中恶性肿瘤复发或进展。
18.一种在患者中治疗恶性肿瘤、预防和/或治疗恶性肿瘤转移或复发的方法，所述方法包括给所述患者施用有效量的技术方案1-7中任一项的抗体或其抗原结合片段部分、技术方案13-15中任一项的抗体药物缀合物、或者技术方案16的药物组合物。
19.技术方案18的方法，其中所述恶性肿瘤选自以下组成的组：乳腺癌、大肠癌、皮肤癌、胰腺癌、前列腺癌、肝癌、肺癌、胃癌、白血病、胆管癌、宫颈癌、结肠直肠癌、子宫内膜癌、食管癌、头颈部癌、淋巴瘤、甲状腺髓质癌、非霍金奇淋巴瘤、卵巢癌、神经胶质瘤、黑素瘤、和膀胱癌；优选地，所述恶性肿瘤选自以下组成的组：结直肠癌、胆管癌，胰腺癌和皮肤癌。
20.技术方案18或19的方法，还包括给所述患者施用其它抗肿瘤治疗手段，例如施用化疗剂、靶向其它肿瘤特异性抗原的抗体或放疗。
21.一种检测生物学样品中肿瘤细胞存在的方法，包括：
a)使所述生物学样品与技术方案1-7中任一项的抗体或其抗原结合片段部分接触；
b)检测所述抗体或其抗原结合片段部分与所述生物学样品中的靶抗原的结合，
其中检出所述结合代表所述生物学样品中存在肿瘤细胞。
22.一种检测患者中恶性肿瘤的存在的方法，包括：
a)使获得自所述患者的生物学样品与技术方案1-7中任一项的抗体或其抗原结合 片段部分接触；
b)检测所述抗体或其抗原结合片段部分与所述生物学样品中的靶抗原的结合，其中检出所述结合代表所述患者中存在恶性肿瘤。
23.一种用于预后患者中恶性肿瘤复发或进展的方法，所述方法包括：
(a)从所述患者中分离包含肿瘤细胞的生物学样品；
(b)使所述包含肿瘤细胞的生物学样品与技术方案1-7中任一项的抗体或其抗原结合片段部分接触；和
(c)鉴定结合所述抗体或其抗原结合片段部分的肿瘤细胞的存在，
从而预后所述患者中恶性肿瘤的复发或进展。
24.技术方案23的方法，其中所述恶性肿瘤的进展包含所述恶性肿瘤在患者中的转移。
25.技术方案23或24的方法，其中所述生物学样品选自以下一种：血液样品、组织样品、和淋巴样品。
26.技术方案23-25中任一项的方法，其中所述恶性肿瘤选自以下组成的组：乳腺癌、结直肠癌、大肠癌、皮肤癌、胰腺癌、前列腺癌、肝癌、肺癌、胃癌、白血病、胆管癌、宫颈癌、子宫内膜癌、食管癌、头颈部癌、淋巴瘤、甲状腺髓质癌、非霍金奇淋巴瘤、卵巢癌、神经胶质瘤、黑素瘤、和膀胱癌；优选地，所述恶性肿瘤选自以下组成的组：结直肠癌、胆管癌，胰腺癌和皮肤癌。
27.一种生产靶向表达ITGA2的人肿瘤细胞的抗体或其抗原结合片段部分的方法，包括：
(i)在适合所述核酸分子或表达载体表达的情况下培养技术方案11的宿主细胞，和
(ii)分离并纯化由所述核酸分子或表达载体表达的抗体或其抗原结合片段部分。

Claims (16)

  1. 一种特异性结合ITGA2蛋白的分离的抗体或其抗原结合片段部分，其中，所述的分离的抗体或其抗原结合片段部分包含含有HCDR1、HCDR2、HCDR3序列的重链可变区；以及含有LCDR1、LCDR2、LCDR3序列的轻链可变区，其中所述抗体或其抗原结合片段部分具有选自以下至少一组的重链可变区和轻链可变区：
    1)所述重链可变区包含(a)SEQ ID NO：112的HCDR1，(b)SEQ ID NO：113的HCDR2，和(c)SEQ ID NO：114的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：38的LCDR1，(e)SEQ ID NO：39的LCDR2，和(f)SEQ ID NO：40的LCDR3；
    2)所述重链可变区包含(a)SEQ ID NO：116的HCDR1，(b)SEQ ID NO：117的HCDR2，和(c)SEQ ID NO：118的HCDR3，且所述轻链可变区且所述轻链可变区包含(d)SEQ ID NO：42的LCDR1，(e)SEQ ID NO：43的LCDR2，和(f)SEQ ID NO：44的LCDR3；
    3)所述重链可变区包含(a)SEQ ID NO：120的HCDR1，(b)SEQ ID NO：121的HCDR2，和(c)SEQ ID NO：122的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：46的LCDR1，(e)SEQ ID NO：47的LCDR2，和(f)SEQ ID NO：48的LCDR3；
    4)所述重链可变区包含(a)SEQ ID NO：124的HCDR1，(b)SEQ ID NO：125的HCDR2，和(c)SEQ ID NO：126的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：50的LCDR1，(e)SEQ ID NO：51的LCDR2，和(f)SEQ ID NO：52的LCDR3；
    5)所述重链可变区包含(a)SEQ ID NO：128的HCDR1，(b)SEQ ID NO：129的HCDR2，和(c)SEQ ID NO：130的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：54的LCDR1，(e)SEQ ID NO：55的LCDR2，和(f)SEQ ID NO：56的LCDR3；
    6)所述重链可变区包含(a)SEQ ID NO：132的HCDR1，(b)SEQ ID NO：133的HCDR2，和(c)SEQ ID NO：134的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：58的LCDR1，(e)SEQ ID NO：59的LCDR2，和(f)SEQ ID NO：60的LCDR3；
    7)所述重链可变区包含(a)SEQ ID NO：136的HCDR1，(b)SEQ ID NO：137的HCDR2，和(c)SEQ ID NO：138的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：62的LCDR1，(e)SEQ ID NO：63的LCDR2，和(f)SEQ ID NO：64的LCDR3；
    8)所述重链可变区包含(a)SEQ ID NO：140的HCDR1，(b)SEQ ID NO：141的HCDR2，和(c)SEQ ID NO：142的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：66 的LCDR1，(e)SEQ ID NO：67的LCDR2，和(f)SEQ ID NO：68的LCDR3；
    9)所述重链可变区包含(a)SEQ ID NO：144的HCDR1，(b)SEQ ID NO：145的HCDR2，和(c)SEQ ID NO：146的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：70的LCDR1，(e)SEQ ID NO：71的LCDR2，和(f)SEQ ID NO：72的LCDR3；
    10)所述重链可变区包含(a)SEQ ID NO：148的HCDR1，(b)SEQ ID NO：149的HCDR2，和(c)SEQ ID NO：150的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：74的LCDR1，(e)SEQ ID NO：75的LCDR2，和(f)SEQ ID NO：76的LCDR3；
    11)所述重链可变区包含(a)SEQ ID NO：152的HCDR1，(b)SEQ ID NO：153的HCDR2，和(c)SEQ ID NO：154的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：78的LCDR1，(e)SEQ ID NO：79的LCDR2，和(f)SEQ ID NO：80的LCDR3；
    12)所述重链可变区包含(a)SEQ ID NO：156的HCDR1，(b)SEQ ID NO：157的HCDR2，和(c)SEQ ID NO：158的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：82的LCDR1，(e)SEQ ID NO：83的LCDR2，和(f)SEQ ID NO：84的LCDR3；
    13)所述重链可变区包含(a)SEQ ID NO：160的HCDR1，(b)SEQ ID NO：161的HCDR2，和(c)SEQ ID NO：162的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：86的LCDR1，(e)SEQ ID NO：87的LCDR2，和(f)SEQ ID NO：88的LCDR3；
    14)所述重链可变区包含(a)SEQ ID NO：164的HCDR1，(b)SEQ ID NO：165的HCDR2，和(c)SEQ ID NO：166的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：90的LCDR1，(e)SEQ ID NO：91的LCDR2，和(f)SEQ ID NO：92的LCDR3；
    15)所述重链可变区包含(a)SEQ ID NO：168的HCDR1，(b)SEQ ID NO：169的HCDR2，和(c)SEQ ID NO：170的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：94的LCDR1，(e)SEQ ID NO：95的LCDR2，和(f)SEQ ID NO：96的LCDR3；
    16)所述重链可变区包含(a)SEQ ID NO：172的HCDR1，(b)SEQ ID NO：173的HCDR2，和(c)SEQ ID NO：174的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：98的LCDR1，(e)SEQ ID NO：99的LCDR2，和(f)SEQ ID NO：100的LCDR3；
    17)所述重链可变区包含(a)SEQ ID NO：176的HCDR1，(b)SEQ ID NO：177的HCDR2，和(c)SEQ ID NO：178的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：102的LCDR1，(e)SEQ ID NO：103的LCDR2，和(f)SEQ ID NO：104的LCDR3；和
    18)所述重链可变区包含(a)SEQ ID NO：180的HCDR1，(b)SEQ ID NO：181的HCDR2，和(c)SEQ ID NO：182的HCDR3，且所述轻链可变区包含(d)SEQ ID NO：106的LCDR1，(e)SEQ ID NO：107的LCDR2，和(f)SEQ ID NO：108的LCDR3。
  2. 根据权利要求1所述的分离的抗体或其抗原结合片段部分，其中，所述的分离的抗体或其抗原结合片段部分包含具有选自以下至少一组的重链可变区和轻链可变区：
    1)所述重链可变区，其包含SEQ ID NO：111的氨基酸序列或与SEQ ID NO：111的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：37的氨基酸序列或与SEQ ID NO：37的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    2)所述重链可变区，其包含SEQ ID NO：115的氨基酸序列或与SEQ ID NO：115的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：41的氨基酸序列或与SEQ ID NO：41的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    3)所述重链可变区，其包含SEQ ID NO：119的氨基酸序列或与SEQ ID NO：119的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：45的氨基酸序列或与SEQ ID NO：45的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    4)所述重链可变区，其包含SEQ ID NO：123的氨基酸序列或与SEQ ID NO：123的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：49的氨基酸序列或与SEQ ID NO：49的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    5)所述重链可变区，其包含SEQ ID NO：127的氨基酸序列或与SEQ ID NO：127的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：53的氨基酸序列或与SEQ ID NO：53的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    6)所述重链可变区，其包含SEQ ID NO：131的氨基酸序列或与SEQ ID NO：131的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：57的氨基 酸序列或与SEQ ID NO：57的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    7)所述重链可变区，其包含SEQ ID NO：135的氨基酸序列或与SEQ ID NO：135的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：61的氨基酸序列或与SEQ ID NO：61的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    8)所述重链可变区，其包含SEQ ID NO：139的氨基酸序列或与SEQ ID NO：139的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：65的氨基酸序列或与SEQ ID NO：65的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    9)所述重链可变区，其包含SEQ ID NO：143的氨基酸序列或与SEQ ID NO：143的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：69的氨基酸序列或与SEQ ID NO：69的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    10)所述重链可变区，其包含SEQ ID NO：147的氨基酸序列或与SEQ ID NO：147的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：73的氨基酸序列或与SEQ ID NO：73的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    11)所述重链可变区，其包含SEQ ID NO：151的氨基酸序列或与SEQ ID NO：151的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：77的氨基酸序列或与SEQ ID NO：77的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    12)所述重链可变区，其包含SEQ ID NO：155的氨基酸序列或与SEQ ID NO：155的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：81的氨基 酸序列或与SEQ ID NO：81的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    13)所述重链可变区，其包含SEQ ID NO：159的氨基酸序列或与SEQ ID NO：159的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：85的氨基酸序列或与SEQ ID NO：85的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    14)所述重链可变区，其包含SEQ ID NO：163的氨基酸序列或与SEQ ID NO：163的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：89的氨基酸序列或与SEQ ID NO：89的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    15)所述重链可变区，其包含SEQ ID NO：167的氨基酸序列或与SEQ ID NO：167的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：93的氨基酸序列或与SEQ ID NO：93的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    16)所述重链可变区，其包含SEQ ID NO：171的氨基酸序列或与SEQ ID NO：171的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：97的氨基酸序列或与SEQ ID NO：97的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    17)所述重链可变区，其包含SEQ ID NO：175的氨基酸序列或与SEQ ID NO：175的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：101的氨基酸序列或与SEQ ID NO：101的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；和
    18)所述重链可变区，其包含SEQ ID NO：179的氨基酸序列或与SEQ ID NO：179的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链可变区，其包含SEQ ID NO：105的氨基 酸序列或与SEQ ID NO：105的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列。
  3. 根据权利要求1或2所述的分离的抗体或其抗原结合片段部分，其中，所述的分离的抗体或其抗原结合片段部分进一步包含重链恒定区和/或轻链恒定区，
    所述重链恒定区包含SEQ ID NO：183的氨基酸序列或与SEQ ID NO：183的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，
    所述轻链恒定区包含SEQ ID NO：109的氨基酸序列或与SEQ ID NO：109的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；或者所述轻链恒定区包含SEQ ID NO：110的氨基酸序列或与SEQ ID NO：110的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列。
  4. 根据权利要求3所述的分离的抗体或其抗原结合片段部分，其中，所述的分离的抗体或其抗原结合片段部分包含具有选自以下至少一组的重链和轻链：
    1)所述重链，其包含SEQ ID NO：202的氨基酸序列或与SEQ ID NO：202的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：184的氨基酸序列或与SEQ ID NO：184的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    2)所述重链，其包含SEQ ID NO：203的氨基酸序列或与SEQ ID NO：203的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：185的氨基酸序列或与SEQ ID NO：185的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    3)所述重链，其包含SEQ ID NO：204的氨基酸序列或与SEQ ID NO：204的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：186的氨基酸序列或与SEQ ID NO：186的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    4)所述重链，其包含SEQ ID NO：205的氨基酸序列或与SEQ ID NO：205的氨 基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：187的氨基酸序列或与SEQ ID NO：187的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    5)所述重链，其包含SEQ ID NO：206的氨基酸序列或与SEQ ID NO：206的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：188的氨基酸序列或与SEQ ID NO：188的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    6)所述重链，其包含SEQ ID NO：207的氨基酸序列或与SEQ ID NO：207的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：189的氨基酸序列或与SEQ ID NO：189的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    7)所述重链，其包含SEQ ID NO：208的氨基酸序列或与SEQ ID NO：208的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：190的氨基酸序列或与SEQ ID NO：190的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    8)所述重链，其包含SEQ ID NO：209的氨基酸序列或与SEQ ID NO：209的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：191的氨基酸序列或与SEQ ID NO：191的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    9)所述重链，其包含SEQ ID NO：210的氨基酸序列或与SEQ ID NO：210的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：192的氨基酸序列或与SEQ ID NO：192的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    10)所述重链，其包含SEQ ID NO：211的氨基酸序列或与SEQ ID NO：211的氨 基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：193的氨基酸序列或与SEQ ID NO：193的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    11)所述重链，其包含SEQ ID NO：212的氨基酸序列或与SEQ ID NO：212的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：194的氨基酸序列或与SEQ ID NO：194的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    12)所述重链，其包含SEQ ID NO：213的氨基酸序列或与SEQ ID NO：213的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：195的氨基酸序列或与SEQ ID NO：195的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    13)所述重链，其包含SEQ ID NO：214的氨基酸序列或与SEQ ID NO：214的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：196的氨基酸序列或与SEQ ID NO：196的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    14)所述重链，其包含SEQ ID NO：215的氨基酸序列或与SEQ ID NO：215的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：197的氨基酸序列或与SEQ ID NO：197的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    15)所述重链，其包含SEQ ID NO：216的氨基酸序列或与SEQ ID NO：216的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：198的氨基酸序列或与SEQ ID NO：198的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    16)所述重链，其包含SEQ ID NO：217的氨基酸序列或与SEQ ID NO：217的氨 基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：199的氨基酸序列或与SEQ ID NO：199的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；
    17)所述重链，其包含SEQ ID NO：218的氨基酸序列或与SEQ ID NO：218的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：200的氨基酸序列或与SEQ ID NO：200的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列；和
    18)所述重链，其包含SEQ ID NO：219的氨基酸序列或与SEQ ID NO：219的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，以及所述轻链，其包含SEQ ID NO：201的氨基酸序列或与SEQ ID NO：201的氨基酸序列至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列。
  5. 根据权利要求4所述的分离的抗体或其抗原结合片段部分，其中，所述的分离的抗体或其抗原结合片段部分由选自以下至少一组的重链和轻链组成：
    1)所述重链，其由SEQ ID NO：202的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：184的氨基酸序列组成；
    2)所述重链，其由SEQ ID NO：203的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：185的氨基酸序列组成；
    3)所述重链，其由SEQ ID NO：204的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：186的氨基酸序列组成；
    4)所述重链，其由SEQ ID NO：205的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：187的氨基酸序列组成；
    5)所述重链，其由SEQ ID NO：206的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：188的氨基酸序列组成；
    6)所述重链，其由SEQ ID NO：207的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：189的氨基酸序列组成；
    7)所述重链，其由SEQ ID NO：208的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：190的氨基酸序列组成；
    8)所述重链，其由SEQ ID NO：209的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：191的氨基酸序列组成；
    9)所述重链，其由SEQ ID NO：210的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：192的氨基酸序列组成；
    10)所述重链，其由SEQ ID NO：211的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：193的氨基酸序列组成；
    11)所述重链，其由SEQ ID NO：212的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：194的氨基酸序列组成；
    12)所述重链，其由SEQ ID NO：213的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：195的氨基酸序列组成；
    13)所述重链，其由SEQ ID NO：214的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：196的氨基酸序列组成；
    14)所述重链，其由SEQ ID NO：215的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：197的氨基酸序列组成；
    15)所述重链，其由SEQ ID NO：216的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：198的氨基酸序列组成；
    16)所述重链，其由SEQ ID NO：217的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：199的氨基酸序列组成；
    17)所述重链，其由SEQ ID NO：218的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：200的氨基酸序列组成；和
    18)所述重链，其由SEQ ID NO：219的氨基酸序列组成，以及所述轻链，其由SEQ ID NO：201的氨基酸序列组成。
  6. 一种特异性结合ITGA2蛋白的分离的抗体或其抗原结合片段部分，其中，所述的分离的抗体或其抗原结合片段部分具有选自以下至少一组的重链和轻链：
    1)所述重链包含由SEQ ID NO：19的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：19的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：19的核苷酸序列所编码的氨基酸序列组成，且
    所述轻链包含由SEQ ID NO：1的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：1的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、 至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：1的核苷酸序列所编码的氨基酸序列组成；
    2)所述重链包含由SEQ ID NO：20的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：20的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：20的核苷酸序列所编码的氨基酸序列组成，且
    所述轻链包含由SEQ ID NO：2的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：2的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：2的核苷酸序列所编码的氨基酸序列组成；
    3)所述重链包含由SEQ ID NO：21的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：21的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：21的核苷酸序列所编码的氨基酸序列组成，且
    所述轻链包含由SEQ ID NO：3的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：3的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：3的核苷酸序列所编码的氨基酸序列组成；
    4)所述重链包含由SEQ ID NO：22的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：22的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：22的核苷酸序列所编码的氨基酸序列组成，且
    所述轻链包含由SEQ ID NO：4的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：4的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：4的核苷酸序列所编码的氨基酸序列组成；
    5)所述重链包含由SEQ ID NO：23的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：23的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：23的核苷酸序列所编码的氨基酸序列组成，且
    所述轻链包含由SEQ ID NO：5的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：5的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：5的核苷酸序列所编码的氨基酸序列组成；
    6)所述重链包含由SEQ ID NO：24的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：24的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：24的核苷酸序列所编码的氨基酸序列组成，且
    所述轻链包含由SEQ ID NO：6的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：6的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：6的核苷酸序列所编码的氨基酸序列组成；
    7)所述重链包含由SEQ ID NO：25的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：25的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：25的核苷酸序列所编码的氨基酸序列组成，且
    所述轻链包含由SEQ ID NO：7的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：7的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：7的核苷酸序列所编码的氨基酸序列组成；
    8)所述重链包含由SEQ ID NO：26的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：26的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：26的核苷酸序列所编码的氨基酸序列组成，且
    所述轻链包含由SEQ ID NO：8的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：8的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：8的核苷酸序列所编码的氨基酸序列组成；
    9)所述重链包含由SEQ ID NO：27的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：27的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少 95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：27的核苷酸序列所编码的氨基酸序列组成，且
    所述轻链包含由SEQ ID NO：9的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：9的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：9的核苷酸序列所编码的氨基酸序列组成；
    10)所述重链包含由SEQ ID NO：28的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：28的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：28的核苷酸序列所编码的氨基酸序列组成，且
    所述轻链包含由SEQ ID NO：10的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：10的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：10的核苷酸序列所编码的氨基酸序列组成；
    11)所述重链包含由SEQ ID NO：29的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：29的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：29的核苷酸序列所编码的氨基酸序列组成，且
    所述轻链包含由SEQ ID NO：11的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：11的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：11的核苷酸序列所编码的氨基酸序列组成；
    12)所述重链包含由SEQ ID NO：30的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：30的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：30的核苷酸序列所编码的氨基酸序列组成，且
    所述轻链包含由SEQ ID NO：12的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：12的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：12的核苷酸序列所编码的氨基酸序列组成；
    13)所述重链包含由SEQ ID NO：31的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：31的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：31的核苷酸序列所编码的氨基酸序列组成，且
    所述轻链包含由SEQ ID NO：13的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：13的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：13的核苷酸序列所编码的氨基酸序列组成；
    14)所述重链包含由SEQ ID NO：32的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：32的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：32的核苷酸序列所编码的氨基酸序列组成，且
    所述轻链包含由SEQ ID NO：14的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：14的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：14的核苷酸序列所编码的氨基酸序列组成；
    15)所述重链包含由SEQ ID NO：33的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：33的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：33的核苷酸序列所编码的氨基酸序列组成，且
    所述轻链包含由SEQ ID NO：15的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：15的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：15的核苷酸序列所编码的氨基酸序列组成；
    16)所述重链包含由SEQ ID NO：34的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：34的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：34的核苷酸序列所编码的氨基酸序列组成，且
    所述轻链包含由SEQ ID NO：16的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：16的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、 至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：16的核苷酸序列所编码的氨基酸序列组成；
    17)所述重链包含由SEQ ID NO：35的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：35的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：35的核苷酸序列所编码的氨基酸序列组成，且
    所述轻链包含由SEQ ID NO：17的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：17的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：17的核苷酸序列所编码的氨基酸序列组成；和
    18)所述重链包含由SEQ ID NO：36的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：36的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：36的核苷酸序列所编码的氨基酸序列组成，且
    所述轻链包含由SEQ ID NO：18的核苷酸序列所编码的氨基酸序列，或包含与由SEQ ID NO：18的核苷酸序列所编码的氨基酸序列具有至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、或至少99％相同性的氨基酸序列，或者由SEQ ID NO：18的核苷酸序列所编码的氨基酸序列组成。
  7. 权利要求1-6中任一项所述的分离的抗体或其抗原结合片段部分，
    其中所述抗体能够以小于1nM的EC50在体外结合ITGA2蛋白；和/或
    其中所述抗体能够以小于5nM的EC50结合HuCCT1细胞表面的ITGA2蛋白；
    和/或其中所述抗体是单克隆抗体、多克隆抗体、嵌合抗体、或人源化抗体。
  8. 一种分离的核酸分子，其编码权利要求1-7中任一项的抗体或其抗原结合片段部分；或者
    所述核酸分子包括选自以下任意一种所示的核苷酸序列或由此核苷酸序列组成：SEQ ID NOs:1-18，和/或所述核酸分子包括选自以下任意一种所示的核苷酸序列或由此核苷酸序列组成：SEQ ID NOs:19-36；或者
    所述核酸分子包括选自以下任意一种组合所示的核苷酸序列或由此核苷酸序列组成：SEQ ID NO:1和SEQ ID NO:19、SEQ ID NO:2和SEQ ID NO:20、SEQ ID NO:3和SEQ ID NO:21、SEQ ID NO:4和SEQ ID NO:22、SEQ ID NO:5和SEQ ID NO:23、 SEQ ID NO:6和SEQ ID NO:24、SEQ ID NO:7和SEQ ID NO:25、SEQ ID NO:8和SEQ ID NO:26、SEQ ID NO:9和SEQ ID NO:27、SEQ ID NO:10和SEQ ID NO:28、SEQ ID NO:11和SEQ ID NO:29、SEQ ID NO:12和SEQ ID NO:30、SEQ ID NO:13和SEQ ID NO:31、SEQ ID NO:14和SEQ ID NO:32、SEQ ID NO:15和SEQ ID NO:33、SEQ ID NO:16和SEQ ID NO:34、SEQ ID NO:17和SEQ ID NO:35、以及SEQ ID NO:18和SEQ ID NO:36。
  9. 一种如下式的抗体药物缀合物：
    Ab-L-D，其中：
    符号“Ab”代表至少一种前述本发明的抗体或其抗原结合片段部分；
    符号“L”代表连接抗体部分和配偶体分子的连接子；和
    符号“D”代表配偶体分子；
    或者
    Ab-(L-D)p，其中：
    符号“Ab”代表至少一种前述本发明的抗体或其抗原结合片段部分；
    符号“L”代表连接抗体部分和配偶体分子的连接子；
    符号“D”代表配偶体分子；和
    符号“p”代表缀合至前述本发明的抗体或其抗原结合片段部分的连接子/配偶体分子(优选药物载荷物)的数量；可选地，p选自以下数值：1.0、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、4.1、4.2、4.3、4.4、4.5、4.6、4.7、4.8、4.9、5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、和8.0。
  10. 如权利要求9的抗体药物缀合物，其中所述连接子选自以下一种：vc、mc-GGFG、AcLysvc、mc、MalPeg6、m(H20)c及m(H20)cvc；和/或所述连接子是可切割的。
  11. 如权利要求9或10的抗体药物缀合物，其中
    所述配偶体分子为药物载荷物，所述药物载荷物为治疗性分子；可选地，所述药物载荷物选自以下一种：细胞毒性剂、细胞抑制剂、免疫调节剂和化学治疗剂；可选地，所述药物载荷物选自以下一种：MMAE、MMAF、DM1、DM4、Dxd、SN-38、Topotecan及其衍生物、Exatecan及其衍生物、Belotecan及其衍生物、Camptothecin、Calicheamicin和PBD；或者
    所述配偶体分子为标记分子；可选地，所述标记分子选自以下一种：放射性标记(例如同位素)、荧光标记(例如荧光染料)、化学物质、和可检测修饰的酶和标签。
  12. 药物组合物，其包含权利要求1-7中任一项的抗体或其抗原结合片段部分或者权利要求9-11中任一项的抗体药物缀合物、以及可选地药学上可接受的载体。
  13. 权利要求1-7中任一项的抗体或其抗原结合片段部分或者权利要求9-11中任一项的抗体药物缀合物在制备药物组合物中的用途；可选地，所述药物组合物用于在患者中治疗恶性肿瘤、预防和/或治疗恶性肿瘤转移或复发；可选地，所述药物组合物用于检测患者中恶性肿瘤的存在；可选地，所述药物组合物用于预后患者中恶性肿瘤复发或进展。
  14. 一种在患者中治疗恶性肿瘤、预防和/或治疗恶性肿瘤转移或复发的方法，所述方法包括给所述患者施用有效量的权利要求1-7中任一项的抗体或其抗原结合片段部分、权利要求9-11中任一项的抗体药物缀合物、或者权利要求16的药物组合物。
  15. 权利要求14的方法，其中所述恶性肿瘤选自以下组成的组：乳腺癌、大肠癌、皮肤癌、胰腺癌、前列腺癌、肝癌、肺癌、胃癌、白血病、胆管癌、宫颈癌、结肠直肠癌、子宫内膜癌、食管癌、头颈部癌、淋巴瘤、甲状腺髓质癌、非霍金奇淋巴瘤、卵巢癌、神经胶质瘤、黑素瘤、和膀胱癌；优选地，所述恶性肿瘤选自以下组成的组：结直肠癌、胆管癌，胰腺癌和皮肤癌。
  16. 权利要求14或15的方法，还包括给所述患者施用其它抗肿瘤治疗手段，例如施用化疗剂、靶向其它肿瘤特异性抗原的抗体或放疗。
PCT/CN2023/098076 2022-06-27 2023-06-02 靶向itga2的抗体和包含此抗体的抗体药物缀合物 WO2024001669A1 (zh)

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