Antibodies targeting ITGA2, their antibody-drug conjugates, and applications

Abstract

This invention provides a series of antibodies or antigen-binding fragments thereof that have high specific binding ability to tumor cells expressing the ITGA2 protein. The antibodies or antigen-binding fragments of this invention can achieve excellent killing effects against tumor cells after being conjugated with a drug to form an antibody-drug conjugate.

Description

[Technical Field]

[0001] This invention relates to the field of biopharmaceuticals. Specifically, it relates to antibodies or antigen-binding fragments thereof that target ITGA2, antibody-drug conjugates containing this antibody, and the use of this antibody and / or antibody-drug conjugate in the treatment of related diseases. [Background technology]

[0002] Malignant tumors (cancer) have become the "top killer" threatening the lives and health of people worldwide. More than 14 million people worldwide are diagnosed with tumors each year, and in China alone, there are more than 3 million new tumor cases annually.

[0003] The underlying causes of cancer's high mortality rate are the spread and metastasis of cancer cells, and recurrence and drug resistance in many patients after treatment. Existing clinical treatments such as surgery, radiation therapy, and chemotherapy have little to no effect on cancer cell metastasis, recurrence, and drug resistance, and do not improve patients' long-term survival. Currently, surgical resection is effective in about 10-20% of patients with early-stage cancer, but has little effect on patients with widespread metastasis. Radiation therapy can treat only local lesions and is often used as pre-operative, post-operative adjuvant therapy, and curative treatment for a very limited number of cancer types. Chemotherapy is applicable to patients with widespread metastasis, but its toxic side effects are significant, leading to short-term or long-term drug resistance, and therefore it has a significant short-term therapeutic effect in only about 20-30% of patients. Even with comprehensive treatment combining surgery, radiation therapy, and chemotherapy, the long-term effect, such as the 5-year survival rate, has plateaued at 20-30% for many years, and about 70-80% of patients die within 5 years after treatment due to metastasis, recurrence, or drug resistance. Even in patients with early-stage cancer who show no metastasis at the time of their initial consultation, there are some cases where metastasis and recurrence occur after treatment, leading to death.

[0004] Currently, identifying tumor - related antigens and subsequently preparing drug forms of antibody - drug conjugates to deliver drugs to tumor cells has become an effective method for treating tumors. Such drug forms combine the advantages of the targeting of monoclonal antibodies to tumor cells and the powerful tumor - killing ability of small - molecule cytotoxins, can significantly reduce the toxic side effects of small - molecule toxins, enhance the therapeutic effect of drugs, and have significant therapeutic advantages.

Summary of the Invention

[0005] The inventors have discovered that ITGA2 is a tumor - related antigen that is specifically overexpressed in tumor cells, its expression is up - regulated in many solid tumors, and particularly significant overexpression is observed in cancers such as colorectal cancer, cholangiocarcinoma, pancreatic cancer, and skin cancer. However, currently, the antibody itself that targets ITGA2 alone has limited inhibitory effect on the growth of tumor cells. Therefore, the inventors have developed a series of antibodies with high specific binding ability to cells expressing the ITGA2 protein, and target ITGA2 - positive tumor cells in the form of antibody - drug conjugates to achieve an excellent killing effect on cells.

[0006] In one aspect, 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 comprises a light - chain variable region containing the LCDR1, LCDR2, and LCDR3 sequences, and a heavy - chain variable region containing the HCDR1, HCDR2, and HCDR3 sequences, and wherein the antibody or an antigen - binding fragment thereof has at least one group of light - chain variable region and heavy - chain variable region selected from the following: 1) The light - chain variable region comprises (a) LCDR1 of SEQ ID NO:42, (b) LCDR2 of SEQ ID NO:43, and (c) LCDR3 of SEQ ID NO:44, and the heavy - chain variable region comprises (d) HCDR1 of SEQ ID NO:46, (e) HCDR2 of SEQ ID NO:47, and (f) HCDR3 of SEQ ID NO:48. 2) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 50, (b) LCDR2 with SEQ ID NO: 51, and (c) LCDR3 with SEQ ID NO: 52, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 54, (e) HCDR2 with SEQ ID NO: 55, and (f) HCDR3 with SEQ ID NO: 56. 3) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 58, (b) LCDR2 with SEQ ID NO: 59, and (c) LCDR3 with SEQ ID NO: 60, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 62, (e) HCDR2 with SEQ ID NO: 63, and (f) HCDR3 with SEQ ID NO: 54. 4) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 66, (b) LCDR2 with SEQ ID NO: 67, and (c) LCDR3 with SEQ ID NO: 68, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 70, (e) HCDR2 with SEQ ID NO: 71, and (f) HCDR3 with SEQ ID NO: 72.

[0007] In one embodiment, the present invention provides an isolated antibody or antigen-binding fragment thereof that specifically binds to the ITGA2 protein, wherein the isolated antibody or antigen-binding fragment thereof comprises a light chain variable region containing LCDR1, LCDR2, LCDR3 sequences and a heavy chain variable region containing HCDR1, HCDR2, HCDR3 sequences, wherein the antibody or antigen-binding fragment thereof has at least one group of light chain variable regions and heavy chain variable regions selected from the following: 1) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 74, (b) LCDR2 with SEQ ID NO: 75, and (c) LCDR3 with SEQ ID NO: 76, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 78, (e) HCDR2 with SEQ ID NO: 79, and (f) HCDR3 with SEQ ID NO: 80. 2) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 82, (b) LCDR2 with SEQ ID NO: 83, and (c) LCDR3 with SEQ ID NO: 84, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 86, (e) HCDR2 with SEQ ID NO: 87, and (f) HCDR3 with SEQ ID NO: 88. 3) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 90, (b) LCDR2 with SEQ ID NO: 91, and (c) LCDR3 with SEQ ID NO: 92, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 94, (e) HCDR2 with SEQ ID NO: 95, and (f) HCDR3 with SEQ ID NO: 96. 4) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 98, (b) LCDR2 with SEQ ID NO: 99, and (c) LCDR3 with SEQ ID NO: 100, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 102, (e) HCDR2 with SEQ ID NO: 103, and (f) HCDR3 with SEQ ID NO: 104. 5) The light chain variable region includes (a) LCDR1 of SEQ ID NO: 106, (b) LCDR2 of SEQ ID NO: 107, and (c) LCDR3 of SEQ ID NO: 108, and the heavy chain variable region includes (d) HCDR1 of SEQ ID NO: 110, (e) HCDR2 of SEQ ID NO: 111, and (f) HCDR3 of SEQ ID NO: 112. 6) The light chain variable region includes (a) LCDR1 of SEQ ID NO: 114, (b) LCDR2 of SEQ ID NO: 115, and (c) LCDR3 of SEQ ID NO: 116, and the heavy chain variable region includes (d) HCDR1 of SEQ ID NO: 118, (e) HCDR2 of SEQ ID NO: 119, and (f) HCDR3 of SEQ ID NO: 120. 7) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 122, (b) LCDR2 with SEQ ID NO: 123, and (c) LCDR3 with SEQ ID NO: 124, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 126, (e) HCDR2 with SEQ ID NO: 127, and (f) HCDR3 with SEQ ID NO: 128.

[0008] In one embodiment, the present invention provides an isolated antibody or antigen-binding fragment thereof that specifically binds to the ITGA2 protein, wherein the isolated antibody or antigen-binding fragment thereof comprises a light chain variable region containing LCDR1, LCDR2, LCDR3 sequences and a heavy chain variable region containing HCDR1, HCDR2, HCDR3 sequences, wherein the antibody or antigen-binding fragment thereof has at least one group of light chain variable regions and heavy chain variable regions selected from the following: 1) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 130, (b) LCDR2 with SEQ ID NO: 131, and (c) LCDR3 with SEQ ID NO: 132, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 134, (e) HCDR2 with SEQ ID NO: 135, and (f) HCDR3 with SEQ ID NO: 136. 2) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 138, (b) LCDR2 with SEQ ID NO: 139, and (c) LCDR3 with SEQ ID NO: 140, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 142, (e) HCDR2 with SEQ ID NO: 143, and (f) HCDR3 with SEQ ID NO: 144. 3) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 146, (b) LCDR2 with SEQ ID NO: 147, and (c) LCDR3 with SEQ ID NO: 148, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 150, (e) HCDR2 with SEQ ID NO: 151, and (f) HCDR3 with SEQ ID NO: 152. 4) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 154, (b) LCDR2 with SEQ ID NO: 155, and (c) LCDR3 with SEQ ID NO: 156, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 158, (e) HCDR2 with SEQ ID NO: 159, and (f) HCDR3 with SEQ ID NO: 160.

[0009] In one embodiment, the present invention provides an isolated antibody or antigen-binding fragment thereof that specifically binds to the ITGA2 protein, wherein the isolated antibody or antigen-binding fragment thereof comprises a light chain variable region containing LCDR1, LCDR2, LCDR3 sequences and a heavy chain variable region containing HCDR1, HCDR2, HCDR3 sequences, wherein the antibody or antigen-binding fragment thereof has at least one group of light chain variable regions and heavy chain variable regions selected from the following: 1) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 162, (b) LCDR2 with SEQ ID NO: 163, and (c) LCDR3 with SEQ ID NO: 164, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 166, (e) HCDR2 with SEQ ID NO: 167, and (f) HCDR3 with SEQ ID NO: 168. 2) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 170, (b) LCDR2 with SEQ ID NO: 171, and (c) LCDR3 with SEQ ID NO: 172, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 174, (e) HCDR2 with SEQ ID NO: 175, and (f) HCDR3 with SEQ ID NO: 176. 3) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 178, (b) LCDR2 with SEQ ID NO: 179, and (c) LCDR3 with SEQ ID NO: 180, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 182, (e) HCDR2 with SEQ ID NO: 183, and (f) HCDR3 with SEQ ID NO: 184. 4) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 186, (b) LCDR2 with SEQ ID NO: 187, and (c) LCDR3 with SEQ ID NO: 188, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 190, (e) HCDR2 with SEQ ID NO: 191, and (f) HCDR3 with SEQ ID NO: 192. 5) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 194, (b) LCDR2 with SEQ ID NO: 195, and (c) LCDR3 with SEQ ID NO: 196, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 198, (e) HCDR2 with SEQ ID NO: 199, and (f) HCDR3 with SEQ ID NO: 200.

[0010] In another embodiment, the present invention provides an isolated nucleic acid molecule, a monoclonal antibody of the present invention encoded thereby, or an antigen-binding fragment thereof.

[0011] In another embodiment, the present invention provides an expression vector comprising the nucleic acid molecule of the present invention.

[0012] In another embodiment, the present invention provides a host cell comprising the nucleic acid molecule of the present invention or the expression vector of the present invention.

[0013] In another embodiment, the present invention provides hybridoma cells that express the monoclonal antibody or its antigen-binding fragment portion.

[0014] In another aspect, the present invention provides uses of the monoclonal antibody of the present invention or its antigen-binding fragment or the antibody-drug conjugate of the present invention in the manufacture of a pharmaceutical composition, which optionally uses the pharmaceutical composition to treat a malignant tumor in a patient and to prevent and / or treat the metastasis or recurrence of the malignant tumor.

[0015] In another embodiment, the present invention provides a method for treating a malignant tumor in a patient and for preventing and / or treating the metastasis or recurrence of the malignant tumor, the method comprising administering to the patient an effective amount of the monoclonal antibody of the present invention or its antigen-binding fragment portion, the antibody-drug conjugate of the present invention, or the pharmaceutical composition of the present invention.

[0016] In another embodiment, the present invention provides uses of the monoclonal antibody or its antigen-binding fragment or the antibody-drug conjugate of the present invention in the manufacture of a diagnostic / prognostic composition, optionally for detecting the presence of a malignant tumor in a patient, and optionally for prognosis of recurrence or progression of a malignant tumor in a patient.

[0017] In another aspect, the present invention provides a method for the prognosis of recurrence or progression of malignant tumors in patients, the method being: (a) Isolating a biological sample containing tumor cells from the patient, (b) Contacting a biological sample containing tumor cells with the monoclonal antibody of the present invention or its antigen-binding fragment or the antibody-drug conjugate of the present invention, (c) Identifying the presence of tumor cells that bind to the monoclonal antibody or its antigen-binding fragment, This allows for the assessment of the prognosis regarding the recurrence or progression of malignant tumors in the aforementioned patients.

[0018] In another aspect, the present invention provides a method for detecting / diagnosing the presence of a malignant tumor in a patient, the method being a) Contacting a biological sample obtained from the patient with the monoclonal antibody of the present invention, its antigen-binding fragment, or the antibody-drug conjugate of the present invention, b) detecting the binding of the monoclonal antibody or its antigen-binding fragment to the target antigen in the biological sample, wherein the detection of such binding indicates the presence of a malignant tumor in the patient.

[0019] In another aspect, the present invention provides a method for detecting the presence of tumor cells in a biological sample, the method being a) Contacting the aforementioned biological sample with the monoclonal antibody of the present invention or its antigen-binding fragment or the antibody-drug conjugate of the present invention, b) detecting the binding of the monoclonal antibody or its antigen-binding fragment or the antibody-drug conjugate to the target antigen in the biological sample, Here, the detection of the aforementioned binding indicates the presence of tumor cells in the biological sample.

[0020] In another aspect, the present invention provides a method for isolating tumor cells, the method being (a) To provide a population of cells suspected to contain tumor cells, (b) Identifying a subpopulation of cells that bind to the monoclonal antibody of the present invention or its antigen-binding fragment or the antibody-drug conjugate, (c) Including isolating the subpopulation.

[0021] In another aspect, the present invention provides a method for producing a monoclonal antibody or an antigen-binding fragment thereof that targets human tumor cells expressing ITGA2, the method being: (i) Culturing the host cells of the present invention under conditions suitable for the expression of the nucleic acid molecule or expression vector, (ii) Isolating and purifying the antibody or antigen-binding fragment thereof expressed by the nucleic acid molecule or expression vector.

[0022] The antibody of the present invention has excellent binding affinity to the ITGA2 protein and can exhibit excellent binding to tumor cells expressing ITGA2, particularly colorectal cancer cells, cholangiocarcinoma cells, pancreatic cancer cells, and skin cancer cells. The antibody-drug conjugate of the present invention has excellent killing effects against tumor cells expressing ITGA2, particularly colorectal cancer cells, cholangiocarcinoma cells, pancreatic cancer cells, and skin cancer cells. Sequence description:

[0023] In Table 1 below, the leftmost column represents the sequence number (SEQ ID NO:) in this invention.

[0024] [Table 1] JPEG2026520132000002.jpg225149 JPEG2026520132000003.jpg225149 JPEG2026520132000004.jpg225149 JPEG2026520132000005.jpg225149 JPEG2026520132000006.jpg225149 JPEG2026520132000007.jpg225149 JPEG2026520132000008.jpg225149 JPEG2026520132000009.jpg225149 JPEG2026520132000010.jpg225149 JPEG2026520132000011.jpg225149 JPEG2026520132000012.jpg225149 JPEG2026520132000013.jpg225149 JPEG2026520132000014.jpg205149

[0025] [Table 2] JPEG2026520132000016.jpg225149 JPEG2026520132000017.jpg225149 JPEG2026520132000018.jpg225149 JPEG2026520132000019.jpg225149 JPEG2026520132000020.jpg225149 JPEG2026520132000021.jpg225149

[0026] [Table 3]

[0027] [Table 4] JPEG2026520132000024.jpg225149 JPEG2026520132000025.jpg225149 JPEG2026520132000026.jpg225149 JPEG2026520132000027.jpg128149 [Modes for carrying out the invention]

[0028] (1) General definition In this invention, unless otherwise specified, the scientific and technical terms used herein have meanings that are generally understood by those skilled in the art. Furthermore, the terms and laboratory procedures used herein relating to protein and nucleic acid chemistry, molecular biology, cell and tissue culture, microbiology, and immunology are terms and procedures that are widely used in the corresponding fields. In addition, to better understand this invention, definitions and interpretations of the relevant terms are provided below.

[0029] As used herein, “antibody” refers to immunoglobulins and immunoglobulin fragments, whether naturally produced or partially or completely synthesized (e.g., recombinant), and includes any fragment that retains the binding specificity of a full-length immunoglobulin, including at least a variable region of a portion of the immunoglobulin molecule. Thus, an antibody includes any protein having a binding domain homologous or substantially homologous to the immunoglobulin antigen-binding domain (antibody binding site). An antibody includes an antibody fragment, for example, an antitumor stem cell antibody fragment. As used herein, the term antibody includes, but is not limited to, synthetic antibodies, recombinant antibodies, multispecific antibodies (e.g., bispecific antibodies), human antibodies, non-human antibodies, humanized antibodies, chimeric antibodies, intracellular antibodies, and antibody fragments, such as Fab fragments, Fab' fragments, F(ab')2 fragments, Fv fragments, Fv(dsFv) linked via disulfide bonds, Fd fragments, Fd' fragments, single-chain Fv(scFv), single-chain Fab(scFab), diabodies, anti-idiotype (anti-Id) antibodies, or antigen-binding fragments of any of the above antibodies. Antibodies as used herein include any immunoglobulin type (e.g., IgG, IgM, IgD, IgE, IgA, and IgY), any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or members of subclasses (e.g., IgG2a and IgG2b).

[0030] As used herein, an “antibody fragment” or “antigen-binding fragment” of an antibody refers to any portion of a full-length antibody that is less than the full length but includes at least some variable regions of the antibody that bind to an antigen (e.g., one or more CDRs and / or one or more antibody-binding sites), and thus retains binding specificity and the ability to specifically bind at least a portion of the full-length antibody. Therefore, an antigen-binding fragment refers to an antibody fragment that includes an antigen-binding portion that binds to the same antigen as the antibody from which the antibody fragment is derived. Antibody fragments include antibody derivatives produced by enzymatic treatment of a full-length antibody, and derivatives produced by synthesis, such as recombinant derivatives. An antibody includes an antibody fragment. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, single-stranded Fv(scFv), Fv, dsFv, diabody, 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 include multiple chains that are linked together, for example, via disulfide bonds and / or 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 the antibody framework (for example, by substituting a corresponding region), bind immunospecifically to the antigen (i.e., at least or at least about 10). 7 -10 8 M -1 Obtain an antibody (showing the Ka value).

[0031] As used herein, “monoclonal antibody” refers to a population of the same antibody, where each individual antibody molecule in the monoclonal antibody population is identical to other antibody molecules. This property is the opposite of the property of a polyclonal population of antibodies, which includes antibodies having multiple different sequences. Monoclonal antibodies can be produced by a variety 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). For example, monoclonal antibodies can be produced, for example, by fusing with myeloma cells to produce a hybridoma cell line or by immortalizing B cells by infecting B cells with a virus such as EBV. Recombinant techniques can further be used to produce antibodies in vitro from a clonal population of host cells by transforming host cells with a plasmid having an artificial sequence of nucleotides encoding the antibody.

[0032] As used herein, the terms “hybridoma” or “hybridoma cell” refer to cells or cell lines produced by the fusion of antibody-producing lymphocytes and non-antibody-producing cancer cells (usually myeloma or lymphoma cells). As is well known to those skilled in the art, hybridomas can proliferate and continuously supply and produce specific monoclonal antibodies. Methods for producing hybridomas are known in the art (see, for example, Harlow & Lane, 1988). When referring to the terms “hybridoma” or “hybridoma cell,” it further includes subclones and progeny cells of hybridomas.

[0033] As used herein, “conventional antibody” means an antibody comprising two heavy chains (which may be denoted as H and H'), two light chains (which may be denoted as 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 (for example, the heavy chain is V H chain, V H -CH 1 chain and V H -C H 1-C H 2-C H including, but not limited to, 3 chains, and each light chain may be a full-length light chain or any functional region (e.g., the light chain may include a V L chain and V L -C L chain, etc.). Each heavy chain (H and H') pairs with one light chain (L and L' respectively).

[0034] As used herein, a full-length antibody is composed of two full-length heavy chains (e.g., V H -C H 1-C H 2-C H 3 or V H -C H 1-C H 2-C H 3-C H 4) and two full-length light chains (V L -C L ) and has a hinge region, for example, an antibody naturally produced by antibody-secreting B cells and an antibody produced synthetically with the same domains.

[0035] As used herein, dsFv refers to an Fv having a stable intermolecular disulfide bond between a V H -V L pair.

[0036] As used herein, a Fab fragment is an antibody fragment obtained by digesting a full-length immunoglobulin with papain, or a fragment having the same structure produced synthetically, for example, by recombinant methods. A Fab fragment includes a light chain (including V L and C L ) and another chain, and the other chain includes the variable domain of the heavy chain (V H ) and one constant region domain of the heavy chain (C H 1).

[0037] As used herein, the F(ab')2 fragment is an antibody fragment formed by digesting immunoglobulin with pepsin at pH 4.0–4.5, or a fragment having the same structure produced by, for example, a recombinant method. The F(ab')2 fragment comprises substantially two Fab fragments, where each heavy chain portion contains several additional amino acids, including cysteine ​​which forms a disulfide bond linking the two fragments.

[0038] As used herein, a Fab' fragment is a fragment containing half of an F(ab')2 fragment (one heavy chain and one light chain).

[0039] As used herein, scFv fragments are variable light chains (V) covalently linked via polypeptide linkers in any order. L ) and variable heavy chain (V H This refers to an antibody fragment containing a linker. The linker is of a length such that the two variable domains are cross-linked with virtually no interference. An exemplary linker is one in which several Glu or Lys residues are dispersed to improve solubility (Gly-Ser). n It is a residue.

[0040] The term "chimeric antibody" refers to an antibody in which the variable region sequence originates from one species and the constant region sequence originates from another species; for example, the variable region sequence originates from a mouse antibody and the constant region sequence originates from a human antibody.

[0041] A “humanized” antibody refers to a non-human (e.g., mouse) antibody form, which is a chimeric immunoglobulin, immunoglobulin chain, or fragment thereof (e.g., Fv, Fab, Fab', F(ab')2, or other antigen-binding subsequences of the antibody) and contains the smallest sequence from the non-human immunoglobulin. Preferably, the humanized antibody is a human immunoglobulin (recipient antibody), where residues in the complementary determinant region (CDR) of the recipient antibody are replaced with CDR residues from a non-human species (donor antibody) having the desired specificity, affinity, and ability, e.g., mouse, rat, or rabbit.

[0042] Furthermore, in humanization, it is possible to introduce mutations to amino acid residues within the CDR1, CDR2, and / or CDR3 regions of VH and / or VL, thereby improving the binding properties (e.g., affinity) of one or more antibodies. For example, mutations can be introduced by PCR-mediated mutation, and their effect on antibody binding or other functional properties can be evaluated by in vitro or in vivo tests as described herein. Typically, conservative mutations are introduced. Such mutations may be amino acid substitutions, additions, or deletions. Also, the number of mutations within the CDR is usually one or two or less. Therefore, the humanized antibodies described in the present invention include antibodies that further contain one or two amino acid mutations within the CDR.

[0043] As used herein, a variable domain or variable region is a specific Ig domain of an antibody heavy chain or light chain, which contains an amino acid sequence that varies between different antibodies. Each light chain and each heavy chain each has one variable region domain V. L and V H It has the following characteristics. The variable domain provides antigen specificity and thereby facilitates antigen recognition. Each variable region includes a CDR and a framework region (FR), the CDR being part of the antigen-binding site domain.

[0044] As used herein, the terms “antigen-binding domain” and “antigen-binding site” are used synonymously to refer to a domain within an antibody that recognizes a cognate antigen and physically interacts with it. A natural, conventional full-length antibody molecule has two conventional antigen-binding sites, each site containing a heavy chain variable region and a light chain variable region. The conventional antigen-binding site contains a loop linking antiparallel β-chains within the variable region domain. The antigen-binding site may also contain other parts of the variable region domain. Each conventional antigen-binding site contains three hypervariable regions from the heavy chain and three hypervariable regions from the light chain. The hypervariable regions are also called complementarity-determining regions (CDRs).

[0045] As used herein, “hypervariable region,” “HV,” “complementarity-determining region,” “CDR,” and “antibody CDR” are used interchangeably to refer to one of several parts within each variable region that jointly form the antigen-binding site of the antibody. Each variable region domain contains three CDRs designated as CDR1, CDR2, and CDR3. For example, the light chain variable region domain contains three CDRs designated as VL CDR1, VL CDR2, and VL CDR3, and the heavy chain variable region domain contains three CDRs designated as VH CDR1, VH CDR2, and VH CDR3. The three CDRs in the variable region are not contiguous along the linear amino acid sequence but are in close proximity in the folded polypeptide. The CDRs are located within a loop that links the parallel chains of the β-fold of the variable domain. As described herein, those skilled in the art will know the Kabat or Chothia number and can identify the CDR based thereon (see, for example, Kabat, EA et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USD Department of Health and Human Services, NIH Publication No. 91-3242, and Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917). In this invention, abbreviations such as "VH CDR" and "HCDR" and "VL CDR" and "LCDR" have the same meaning.

[0046] As used herein, the framework region (FR) is a domain located within the antibody variable region domain in the β-fold, and in terms of amino acid sequence, the FR region is more conserved than the hypervariable region.

[0047] As used herein, the “constant region” domain is a domain in the antibody heavy or light chain that contains an amino acid sequence that is more conserved than the amino acid sequence of the variable region domain. In conventional full-length antibody molecules, each light chain has a single light chain constant region (C L) has a domain, and each heavy chain has one or more heavy chain constant regions (C H ) including the domain, it is C H 1. C H 2, C H 3 and C H Includes 4. Full-length IgA, IgD, and IgG isotypes are C H 1. C H 2, C H 3 and the hinge region are included, and IgE and IgM are C H 1. C H 2, C H 3 and C H Includes 4. C H 1 and C L The domain extends the Fab arm of the antibody molecule, thereby facilitating interaction with antigens and rotation of the antibody arm. The antibody constant region can serve effector functions, such as the clearance of antigens, pathogens, and toxins to which the antibody specifically binds, through interactions with various cells, biomolecules, and tissues, but is not limited to these.

[0048] As used herein, the functional region of an antibody is at least V of the antibody. H , V L , C H (For example, C H 1. C H 2 or C H 3), C L Alternatively, it is an antibody portion that includes a hinge region domain or at least its functional region.

[0049] As used herein, V H The functional area of ​​the domain is complete V H It retains binding specificity for at least some of the domains (e.g., complete V H (By holding one or more CDRs of a domain) Complete V H It is at least a part of the domain, thereby the V H The functional region of the domain can function alone or with another antibody domain (e.g., V L It binds to the antigen by combining the domain (or its region). An example is V HThe functional area of ​​the domain is V H This is the region containing the domain's CDR1, CDR2, and / or CDR3.

[0050] As used herein, V L The functional area of ​​the domain is complete V L It retains binding specificity for at least some of the domains (e.g., complete V L (By holding one or more CDRs of a domain) Complete V L It is at least a part of the domain, thereby the V L The functional region of the domain can function alone or with another antibody domain (e.g., V H It binds to the antigen by combining the domain (or its region). An example is V L The functional area of ​​the domain is V L This is the region containing the domain's CDR1, CDR2, and / or CDR3.

[0051] As used herein, “specifically bind” or “immunologically bind” with respect to an antibody or its antigen-binding fragment is used interchangeably herein and refers to the ability of the antibody or antigen-binding fragment to form one or more non-covalent bonds with a cognitive antigen through non-covalent interactions between the antibody-binding site of the antibody and the antigen. The antigen may be an isolated antigen or may be present in tumor cells.

[0052] As used herein, the terms "Kassoc" or "Ka" are intended to represent the binding rate of a particular antibody-antigen interaction, and the terms "Kdis" or "Kd" are intended to represent the dissociation rate of a particular antibody-antigen interaction. As used herein, the term "KD" is intended to represent the dissociation constant, which is obtained from the ratio of Kd to Ka (i.e., Kd / Ka) and expressed as molar concentration (M). The KD value of an antibody can be measured by methods known in the art. Methods for determining the KD of an antibody may include, for example, surface plasmon resonance (SPR) (Rich and Myszka (2000) Curr. Opin. Biotechnol 11:54; Englebienne (1998) Analyst. 123:1599), isothermal titration calorimetry (ITC), or other kinetic interaction assays known in the art (see, for example, Paul, ed., Fundamental Immunology, 2nd ed., Raven Press, New York, pages 332-336 (1989), and U.S. Patent No. 7,229,619, which describes exemplary SPR and ITC methods for calculating antibody binding affinity). Instruments and methods for detecting and monitoring binding rates in real time are known and commercially available (see BiaCore 2000, Biacore AB, Upsala, Sweden and GE Healthcare Life Sciences, and Malmqvist (2000) Biochem. Soc. Trans. 27:335).

[0053] "Isolated protein," "isolated polypeptide," or "isolated antibody" means that the protein, polypeptide, or antibody (1) is not associated with any naturally occurring related components that are present in its natural state, (2) does not contain proteins from the same species, (3) is expressed by cells from a different species, or (4) does not exist in nature. Therefore, a chemically synthesized polypeptide or a polypeptide synthesized in a cell line different from the cells from which the polypeptide is naturally derived is "isolated" from its naturally occurring related components. Furthermore, isolation can be used to ensure that the protein is substantially free of naturally occurring related components, i.e., by using protein purification techniques well known in this art.

[0054] The "substitution," "deletion," or "addition" of amino acid residues refers to making amino acid modifications in peptides or proteins that are conserved and do not alter the function and / or biological activity of the peptide or protein. For example, amino acid substitutions may be conservative substitutions, and appropriate conservative substitutions are known to those skilled in the art and can generally be made without altering the biological activity of the resulting molecule. Those skilled in the art usually recognize that a single amino acid substitution in a non-essential region of a polypeptide substantially alters its biological activity (see, for example, Watson et al., Molecular Biology of the Gene, 4th Edition, 1987, The Benjamin / Cummings Pub.co., p.224).

[0055] As used herein, the terms “polynucleotide” and “nucleic acid molecule” refer to oligomers or polymers comprising at least two linked nucleotides or nucleotide derivatives, including deoxyribose nucleic acids (DNA) and levos nucleic acids (RNA), which are typically linked via phosphodiester bonds.

[0056] As used herein, an isolated nucleic acid molecule is a nucleic acid molecule isolated from other nucleic acid molecules present in a natural source of nucleic acid molecules. For example, an "isolated" nucleic acid molecule of a cDNA molecule may substantially contain no other cellular material or culture medium when produced by recombinant technology, or substantially contain no chemical precursors or other chemical components when chemically synthesized. Exemplary isolated nucleic acid molecules provided herein include isolated nucleic acid molecules encoding an antibody or antigen-binding fragment provided.

[0057] Sequence "identity" has the meaning recognized in this art, and the percentage of sequence identity between two nucleic acid or polypeptide molecules or regions can be calculated using the disclosed techniques. Sequence identity can be measured along the full length of a polynucleotide or polypeptide or along a region of the molecule. (See, for example, Computational Molecular Biology, Lesk, AM, ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, DW, ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part I, Griffin, AM, and Griffin, HG, 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). There are many methods for determining the identity between two polynucleotides or polypeptides, but the term "identity" is well known to those skilled in the art (Carrillo, H. & Lipman, D., SIAM J Applied Math 48:1073 (1988)).

[0058] As used herein, “operably linked” with respect to nucleic acid sequences, regions, elements, or domains means that the nucleic acid regions are functionally related to one another. For example, a promoter can be operably linked to a nucleic acid encoding a polypeptide, thereby controlling or mediating the transcription of the nucleic acid.

[0059] As used herein, “expression” refers to the process of producing polypeptides through the transcription and translation of polynucleotides. Polypeptide expression levels can be assessed using any method known in the art, including, for example, a method for measuring the amount of polypeptide produced from host cells. Such methods may include, but are not limited to, quantitative determination of polypeptides in cell lysates by ELISA, Coomassie blue staining after gel electrophoresis, Lowry protein assays, and Bradford protein assays.

[0060] As used herein, “host cell” is a cell that receives, maintains, replicates, and amplifies a vector. The host cell can also be used to express the polypeptide encoded by the vector. When the host cell divides, the nucleic acids contained in the vector are replicated and thereby amplified. The host cell may be a eukaryotic or prokaryotic cell. Suitable host cells include, but are not limited to, CHO cells, various COS cells, HeLa cells, HEK cells, e.g., HEK 293 cells.

[0061] As used herein, “vector” is a replicable nucleic acid that, when transformed into a suitable host cell, can express one or more heterologous proteins. Vectors include vectors into which nucleic acids encoding polypeptides or fragments thereof can be introduced, usually by restriction enzyme digestion and ligation. Vectors further include vectors containing nucleic acids encoding polypeptides. Vectors are used to introduce nucleic acids encoding polypeptides into host cells to amplify the nucleic acid or to express / present the polypeptide encoded by the nucleic acid. Vectors are usually left free, but may be designed to integrate a gene or a portion thereof into a chromosome of a genome. Furthermore, vectors of artificial chromosomes, e.g., yeast artificial vectors and mammalian artificial chromosomes, are also considered. The selection and use of such media are well known to those skilled in the art.

[0062] As used herein, “expression vector” includes a vector capable of expressing DNA, wherein the DNA is manipulably ligated to a regulatory sequence, for example, a promoter region, which can influence the expression of such DNA fragment. Such additional fragments may include a promoter and a terminator sequence, and optionally include one or more replication origins, one or more selective markers, enhancers, adenylation signals, etc. Expression vectors generally derive from elements that may include plasmid or viral DNA, or both. Thus, an expression vector refers to a recombinant DNA or RNA construct, such as a plasmid, phage, recombinant virus, or other vector, which, when introduced into a suitable host cell, results in the expression of clonal DNA. Suitable expression vectors are well known to those skilled in the art and include expression vectors that can replicate in eukaryotic and / or prokaryotic cells, expression vectors that remain free, or expression vectors that are integrated into the host cell genome.

[0063] As used herein, “treating” an individual having a disease or disease state means that the individual’s symptoms are partially or completely relieved or remain unchanged after treatment. Therefore, treatment includes prevention, cure, and / or remission. Prevention refers to the prevention of a potential disease and / or the prevention of the worsening of symptoms or the progression of the disease. Treatment further includes any pharmaceutically acceptable use of any antibody or its antigen-binding fragment provided and any composition thereof.

[0064] As used herein, “therapeutic effect” refers to the effect obtained by the treatment of an individual, which transforms, usually improves or alleviates, the symptoms of a disease or disease state, or cures the disease or disease state.

[0065] As used herein, “therapeutic dose” or “therapeutic amount” refers to the amount of a substance, compound, material, or composition containing a compound that, after being administered to a subject, is sufficient to produce at least a therapeutic effect. Therefore, it is the amount necessary to prevent, cure, improve, inhibit, or partially inhibit the symptoms of a disease or disorder.

[0066] As used herein, “preventive effective dose” or “preventive effective dose” refers to the amount of a substance, compound, material, or composition containing a compound that, when administered to a subject, has a desired preventive effect, such as preventing or delaying the onset or recurrence of a disease or disorder, or reducing the likelihood of the onset or recurrence of a disease or disorder. The complete preventive effective dose does not have to be achieved in a single dose, but may only be achieved after a series of doses have been administered. Therefore, the preventive effective dose may be administered in one or more doses.

[0067] As used herein, the term “patient” refers to a mammal, such as a human. (ii) Antibodies that target the ITGA2 protein

[0068] ITGA2 is an abbreviation for Integrin alpha-2, where the Uniprot database number for the human ITGA2 protein is P17301; see https: / / www.uniprot.org / uniprot / P17301.

[0069] The inventors discovered that ITGA2 is a tumor-associated antigen that is specifically overexpressed in tumor cells, particularly in cancer patients with colorectal cancer, cholangiocarcinoma, pancreatic cancer, and skin cancer. Furthermore, the inventors designed various different humanized antibodies targeting the ITGA2 protein. Experiments in the examples demonstrated that the antibodies of the present invention have excellent binding affinity to the ITGA2 protein (EC50 < 1 nM) and also to ITGA2-highly expressing HuCCT1 cells (EC50 < 5 nM). By utilizing the excellent binding affinity of the monoclonal antibodies of the present invention, partner molecules, such as cytotoxins, can be effectively delivered to tumor cells.

[0070] Therefore, in one embodiment, the present invention provides an isolated antibody or antigen-binding fragment thereof that specifically binds to the ITGA2 protein, wherein the isolated antibody or antigen-binding fragment thereof comprises a light chain variable region containing LCDR1, LCDR2, LCDR3 sequences and a heavy chain variable region containing HCDR1, HCDR2, HCDR3 sequences, wherein the antibody or antigen-binding fragment thereof has at least one group of light chain variable regions and heavy chain variable regions selected from the following: 1) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 42, (b) LCDR2 with SEQ ID NO: 43, and (c) LCDR3 with SEQ ID NO: 44, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 46, (e) HCDR2 with SEQ ID NO: 47, and (f) HCDR3 with SEQ ID NO: 48. 2) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 50, (b) LCDR2 with SEQ ID NO: 51, and (c) LCDR3 with SEQ ID NO: 52, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 54, (e) HCDR2 with SEQ ID NO: 55, and (f) HCDR3 with SEQ ID NO: 56. 3) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 58, (b) LCDR2 with SEQ ID NO: 59, and (c) LCDR3 with SEQ ID NO: 60, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 62, (e) HCDR2 with SEQ ID NO: 63, and (f) HCDR3 with SEQ ID NO: 54. 4) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 66, (b) LCDR2 with SEQ ID NO: 67, and (c) LCDR3 with SEQ ID NO: 68, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 70, (e) HCDR2 with SEQ ID NO: 71, and (f) HCDR3 with SEQ ID NO: 72.

[0071] In some embodiments, the isolated antibody or its antigen-binding fragment portion includes a light chain variable region and a heavy chain variable region having at least one group selected from the following, i.e. 1) The light chain variable region comprising the amino acid sequence of SEQ ID NO:41 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:41, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:45 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:45, 2) The light chain variable region comprising the amino acid sequence of SEQ ID NO:49 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:49, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:53 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:53, 3) The light chain variable region comprising the amino acid sequence of SEQ ID NO: 57 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO: 57, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 61 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO: 61, and 4) The light chain variable region includes the amino acid sequence of SEQ ID NO:65 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:65, and the heavy chain variable region includes the amino acid sequence of SEQ ID NO:69 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:69.

[0072] In some embodiments, an antibody having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of the light chain variable region (SEQ ID NOs: 41, 49, 57, and 65) and the amino acid sequence of the heavy chain variable region (SEQ ID NOs: 45, 53, 61, and 69) of the antibody according to the present invention has the same or similar biological function and / or activity as the antibody of the present invention.

[0073] In some embodiments, 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 with the amino acid sequence of the light chain variable region (SEQ ID NOs: 41, 49, 57-65) and the amino acid sequence of the heavy chain variable region (SEQ ID NOs: 45, 53, 61, and 69) of the antibody according to the present invention can also specifically bind to the ITGA2 protein.

[0074] In some embodiments, an antibody having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of the light chain variable region (SEQ ID NOs: 41, 49, 57, and 65) and the amino acid sequence of the heavy chain variable region (SEQ ID NOs: 45, 53, 61, and 69) of the antibody according to the present invention has the same heavy chain and / or light chain variable region CDR as the antibody of the present invention, and has conserved amino acid substitutions only at other positions in the heavy chain and / or light chain variable region other than the CDR (e.g., the framework region), and such conserved amino acid substitutions do not alter the biological function and / or activity of the corresponding antibody and can, for example, specifically bind to the ITGA2 protein.

[0075] In some embodiments, the isolated antibody or its antigen-binding fragment portion further comprises a light chain constant region and a heavy chain constant region. The light chain constant region includes the amino acid sequence of SEQ ID NO:201 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:201. The heavy chain constant region includes the amino acid sequence of SEQ ID NO:202 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:202.

[0076] In some embodiments, the isolated antibody or its antigen-binding fragment portion comprises a light chain and a heavy chain having at least one group selected from the following, i.e. 1) The light chain comprising the amino acid sequence of SEQ ID NO:203 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:203, and the heavy chain comprising the amino acid sequence of SEQ ID NO:204 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:204, 2) The light chain comprising the amino acid sequence of SEQ ID NO:205 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:205, and the heavy chain comprising the amino acid sequence of SEQ ID NO:206 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:206, 3) The light chain comprising the amino acid sequence of SEQ ID NO:207 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:207, and the heavy chain comprising the amino acid sequence of SEQ ID NO:208 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:208, and 4) The light chain comprises the amino acid sequence of SEQ ID NO:209 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:209, and the heavy chain comprises the amino acid sequence of SEQ ID NO:210 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:210.

[0077] In some embodiments, an antibody having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the light chain amino acid sequence (SEQ ID NOs: 203, 205, 207, and 209) and heavy chain amino acid sequence (SEQ ID NOs: 204, 206, 208, and 210) of the antibody according to the present invention has the same or similar biological function and / or activity as the antibody of the present invention.

[0078] In some embodiments, 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 with the amino acid sequences of the light chain (SEQ ID NOs: 203, 205, 207, and 209) and heavy chain (SEQ ID NOs: 204, 206, 208, and 210) of the antibody according to the present invention can also specifically bind to the ITGA2 protein.

[0079] In some embodiments, an antibody having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequences of the light chain (SEQ ID NOs: 203, 205, 207, and 209) and heavy chain (SEQ ID NOs: 204, 206, 208, and 210) of the antibody according to the present invention has the same heavy chain and / or light chain variable region CDR as the antibody of the present invention, and has conserved amino acid substitutions only at other positions in the heavy chain and / or light chain variable region other than the CDR (e.g., the framework region), wherein the conserved amino acid substitutions do not alter the biological function and / or activity of the corresponding antibody and can, for example, specifically bind to the ITGA2 protein.

[0080] In some embodiments, the isolated antibody or its antigen-binding fragment portion consists of at least one group of light and heavy chains selected from the following: 1) A light chain consisting of the amino acid sequence of SEQ ID NO:203, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:204, 2) A light chain consisting of the amino acid sequence of SEQ ID NO:205, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:206, 3) A light chain consisting of the amino acid sequence of SEQ ID NO:207, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:208, and 4) A light chain consisting of the amino acid sequence of SEQ ID NO:209, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:210.

[0081] In a second aspect, the present invention provides an isolated antibody or antigen-binding fragment thereof that specifically binds to the ITGA2 protein, wherein the isolated antibody or antigen-binding fragment thereof comprises a light chain variable region containing LCDR1, LCDR2, LCDR3 sequences and a heavy chain variable region containing HCDR1, HCDR2, HCDR3 sequences, wherein the antibody or antigen-binding fragment thereof has at least one group of light chain variable regions and heavy chain variable regions selected from the following: 1) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 74, (b) LCDR2 with SEQ ID NO: 75, and (c) LCDR3 with SEQ ID NO: 76, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 78, (e) HCDR2 with SEQ ID NO: 79, and (f) HCDR3 with SEQ ID NO: 80. 2) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 82, (b) LCDR2 with SEQ ID NO: 83, and (c) LCDR3 with SEQ ID NO: 84, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 86, (e) HCDR2 with SEQ ID NO: 87, and (f) HCDR3 with SEQ ID NO: 88. 3) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 90, (b) LCDR2 with SEQ ID NO: 91, and (c) LCDR3 with SEQ ID NO: 92, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 94, (e) HCDR2 with SEQ ID NO: 95, and (f) HCDR3 with SEQ ID NO: 96. 4) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 98, (b) LCDR2 with SEQ ID NO: 99, and (c) LCDR3 with SEQ ID NO: 100, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 102, (e) HCDR2 with SEQ ID NO: 103, and (f) HCDR3 with SEQ ID NO: 104. 5) The light chain variable region includes (a) LCDR1 of SEQ ID NO: 106, (b) LCDR2 of SEQ ID NO: 107, and (c) LCDR3 of SEQ ID NO: 108, and the heavy chain variable region includes (d) HCDR1 of SEQ ID NO: 110, (e) HCDR2 of SEQ ID NO: 111, and (f) HCDR3 of SEQ ID NO: 112. 6) The light chain variable region includes (a) LCDR1 of SEQ ID NO: 114, (b) LCDR2 of SEQ ID NO: 115, and (c) LCDR3 of SEQ ID NO: 116, and the heavy chain variable region includes (d) HCDR1 of SEQ ID NO: 118, (e) HCDR2 of SEQ ID NO: 119, and (f) HCDR3 of SEQ ID NO: 120. 7) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 122, (b) LCDR2 with SEQ ID NO: 123, and (c) LCDR3 with SEQ ID NO: 124, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 126, (e) HCDR2 with SEQ ID NO: 127, and (f) HCDR3 with SEQ ID NO: 128.

[0082] In some embodiments, the isolated antibody or its antigen-binding fragment portion includes a light chain variable region and a heavy chain variable region having at least one group selected from the following, i.e. 1) The light chain variable region comprising the amino acid sequence of SEQ ID NO:73 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:73, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:77 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:77, 2) The light chain variable region comprising the amino acid sequence of SEQ ID NO:81 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:81, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:85 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:85, 3) The light chain variable region comprising the amino acid sequence of SEQ ID NO:89 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:89, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:93 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:93, 4) The light chain variable region comprising the amino acid sequence of SEQ ID NO:97 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:97, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:101 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:101, 5) The light chain variable region comprising the amino acid sequence of SEQ ID NO:105 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:105, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:109 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:109, 6) The light chain variable region comprising the amino acid sequence of SEQ ID NO:113 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:113, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:117 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:117, and 7) The light chain variable region includes the amino acid sequence of SEQ ID NO:121 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:121, and the heavy chain variable region includes the amino acid sequence of SEQ ID NO:125 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:125.

[0083] In some embodiments, an antibody having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of the light chain variable region (SEQ ID NOs: 73, 81, 89, 97, 105, 113, and 121) and the amino acid sequence of the heavy chain variable region (SEQ ID NOs: 77, 85, 93, 101, 109, 117, and 125) of the antibody according to the present invention has the same or similar biological function and / or activity as the antibody of the present invention.

[0084] In some embodiments, 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 with the amino acid sequences of the light chain variable region (SEQ ID NOs: 73, 81, 89, 97, 105, 113, and 121) and the heavy chain variable region (SEQ ID NOs: 77, 85, 93, 101, 109, 117, and 125) of the antibody according to the present invention can also specifically bind to the ITGA2 protein.

[0085] In some embodiments, an antibody having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of the light chain variable region (SEQ ID NOs: 73, 81, 89, 97, 105, 113, and 121) and the amino acid sequence of the heavy chain variable region (SEQ ID NOs: 77, 85, 93, 101, 109, 117, and 125) of the antibody according to the present invention has the same heavy chain and / or light chain variable region CDR as the antibody of the present invention, and has conserved amino acid substitutions only at other positions in the heavy chain and / or light chain variable region other than the CDR (e.g., the framework region), wherein the conserved amino acid substitutions do not alter the biological function and / or activity of the corresponding antibody and can, for example, specifically bind to the ITGA2 protein.

[0086] In some embodiments, the isolated antibody or its antigen-binding fragment portion further comprises a light chain constant region and a heavy chain constant region. The light chain constant region includes the amino acid sequence of SEQ ID NO:201 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:201. The heavy chain constant region includes the amino acid sequence of SEQ ID NO:202 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:202.

[0087] In some embodiments, the isolated antibody or its antigen-binding fragment portion comprises a light chain and a heavy chain having at least one group selected from the following, i.e. 1) The light chain comprising the amino acid sequence of SEQ ID NO:211 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:211, and the heavy chain comprising the amino acid sequence comprising at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:212 or the amino acid sequence of SEQ ID NO:202, 2) The light chain comprising the amino acid sequence of SEQ ID NO:213 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:213, and the heavy chain comprising the amino acid sequence of SEQ ID NO:214 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:214, 3) The light chain comprising the amino acid sequence of SEQ ID NO:215 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:215, and the heavy chain comprising the amino acid sequence of SEQ ID NO:216 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:216, 4) The light chain comprising the amino acid sequence of SEQ ID NO:217 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:217, and the heavy chain comprising the amino acid sequence of SEQ ID NO:218 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:218, 5) The light chain comprising the amino acid sequence of SEQ ID NO:219 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:219, and the heavy chain comprising the amino acid sequence of SEQ ID NO:220 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:220, 6) The light chain comprising the amino acid sequence of SEQ ID NO:221 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:221, and the heavy chain comprising the amino acid sequence of SEQ ID NO:222 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:222, and 7) The light chain comprises the amino acid sequence of SEQ ID NO:223 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:223, and the heavy chain comprises the amino acid sequence of SEQ ID NO:224 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:224.

[0088] In some embodiments, an antibody having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequences of the light chain (SEQ ID NOs: 211, 213, 215, 217, 219, 221, and 223) and heavy chain (SEQ ID NOs: 212, 214, 216, 218, 220, 222, and 224) of the antibody according to the present invention has the same or similar biological function and / or activity as the antibody of the present invention.

[0089] In some embodiments, 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 with the amino acid sequences of the light chain (SEQ ID NOs: 211, 213, 215, 217, 219, 221, and 223) and heavy chain (SEQ ID NOs: 212, 214, 216, 218, 220, 222, and 224) of the antibody according to the present invention can also specifically bind to the ITGA2 protein.

[0090] In some embodiments, an antibody having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of the light chain (SEQ ID NOs: 211, 213, 215, 217, 219, 221, and 223) and the amino acid sequence of the heavy chain (SEQ ID NOs: 212, 214, 216, 218, 220, 222, and 224) of the antibody according to the present invention has the same heavy chain and / or light chain variable region CDR as the antibody of the present invention, and has conserved amino acid substitutions only at other positions in the heavy chain and / or light chain variable region other than the CDR (e.g., the framework region), wherein the conserved amino acid substitutions do not alter the biological function and / or activity of the corresponding antibody and can, for example, specifically bind to the ITGA2 protein.

[0091] In some embodiments, the isolated antibody or its antigen-binding fragment portion consists of at least one group of light and heavy chains selected from the following: 1) A light chain consisting of the amino acid sequence of SEQ ID NO:211, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:212, 2) A light chain consisting of the amino acid sequence of SEQ ID NO:213, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:214, 3) A light chain consisting of the amino acid sequence of SEQ ID NO:215, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:216, 4) A light chain consisting of the amino acid sequence of SEQ ID NO:217, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:218, 5) A light chain consisting of the amino acid sequence of SEQ ID NO:219, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:220, 6) A light chain consisting of the amino acid sequence of SEQ ID NO:221, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:222, and 7) A light chain consisting of the amino acid sequence of SEQ ID NO:223, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:224.

[0092] In a third aspect, the present invention provides an isolated antibody or antigen-binding fragment thereof that specifically binds to the ITGA2 protein, wherein the isolated antibody or antigen-binding fragment thereof comprises a light chain variable region containing LCDR1, LCDR2, LCDR3 sequences and a heavy chain variable region containing HCDR1, HCDR2, HCDR3 sequences, wherein the antibody or antigen-binding fragment thereof has at least one group of light chain variable regions and heavy chain variable regions selected from the following: 1) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 130, (b) LCDR2 with SEQ ID NO: 131, and (c) LCDR3 with SEQ ID NO: 132, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 134, (e) HCDR2 with SEQ ID NO: 135, and (f) HCDR3 with SEQ ID NO: 136. 2) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 138, (b) LCDR2 with SEQ ID NO: 139, and (c) LCDR3 with SEQ ID NO: 140, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 142, (e) HCDR2 with SEQ ID NO: 143, and (f) HCDR3 with SEQ ID NO: 144. 3) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 146, (b) LCDR2 with SEQ ID NO: 147, and (c) LCDR3 with SEQ ID NO: 148, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 150, (e) HCDR2 with SEQ ID NO: 151, and (f) HCDR3 with SEQ ID NO: 152. 4) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 154, (b) LCDR2 with SEQ ID NO: 155, and (c) LCDR3 with SEQ ID NO: 156, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 158, (e) HCDR2 with SEQ ID NO: 159, and (f) HCDR3 with SEQ ID NO: 160.

[0093] In some embodiments, the isolated antibody or its antigen-binding fragment portion includes a light chain variable region and a heavy chain variable region having at least one group selected from the following, i.e. 1) The light chain variable region comprising the amino acid sequence of SEQ ID NO:129 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:129, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:133 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:133, 2) The light chain variable region comprising the amino acid sequence of SEQ ID NO:137 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:137, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:141 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:141, 3) The light chain variable region comprising the amino acid sequence of SEQ ID NO:145 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:145, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:149 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:149, and 4) The light chain variable region includes the amino acid sequence of SEQ ID NO:153 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:153, and the heavy chain variable region includes the amino acid sequence of SEQ ID NO:157 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:157.

[0094] In some embodiments, an antibody having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of the light chain variable region (SEQ ID NOs: 129, 137, 145, and 153) and the amino acid sequence of the heavy chain variable region (SEQ ID NOs: 133, 141, 149, and 157) of the antibody according to the present invention has the same or similar biological function and / or activity as the antibody of the present invention.

[0095] In some embodiments, 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 with the amino acid sequence of the light chain variable region (SEQ ID NOs: 129, 137, 145-153) and the amino acid sequence of the heavy chain variable region (SEQ ID NOs: 133, 141, 149, and 157) of the antibody of the present invention can also specifically bind to the ITGA2 protein.

[0096] In some embodiments, an antibody having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of the light chain variable region (SEQ ID NOs: 129, 137, 145, and 153) and the amino acid sequence of the heavy chain variable region (SEQ ID NOs: 133, 141, 149, and 157) of the antibody according to the present invention has the same heavy chain and / or light chain variable region CDR as the antibody of the present invention, and has conserved amino acid substitutions only at other positions in the heavy chain and / or light chain variable region other than the CDR (e.g., the framework region), wherein the conserved amino acid substitutions do not alter the biological function and / or activity of the corresponding antibody and can, for example, specifically bind to the ITGA2 protein.

[0097] In some embodiments, the isolated antibody or its antigen-binding fragment portion further comprises a light chain constant region and a heavy chain constant region. The light chain constant region includes the amino acid sequence of SEQ ID NO:201 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:201. The heavy chain constant region includes the amino acid sequence of SEQ ID NO:202 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:202.

[0098] In some embodiments, the isolated antibody or its antigen-binding fragment portion comprises a light chain and a heavy chain having at least one group selected from the following, i.e. 1) The light chain comprising the amino acid sequence of SEQ ID NO:225 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:225, and the heavy chain comprising the amino acid sequence of SEQ ID NO:226 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:226, 2) The light chain comprising the amino acid sequence of SEQ ID NO:227 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:227, and the heavy chain comprising the amino acid sequence of SEQ ID NO:228 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:228, 3) The light chain comprising the amino acid sequence of SEQ ID NO:229 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:229, and the heavy chain comprising the amino acid sequence of SEQ ID NO:230 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:230, and 4) The light chain comprises the amino acid sequence of SEQ ID NO:231 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:231, and the heavy chain comprises the amino acid sequence of SEQ ID NO:232 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:232.

[0099] In some embodiments, an antibody having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the light chain amino acid sequence (SEQ ID NOs: 225, 227, 229, and 231) and heavy chain amino acid sequence (SEQ ID NOs: 226, 228, 230, and 232) of the antibody according to the present invention has the same or similar biological function and / or activity as the antibody of the present invention.

[0100] In some embodiments, 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 with the amino acid sequences of the light chain (SEQ ID NOs: 225, 227, 229, and 231) and heavy chain (SEQ ID NOs: 226, 228, 230, and 232) of the antibody according to the present invention can also specifically bind to the ITGA2 protein.

[0101] In some embodiments, an antibody having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of the light chain (SEQ ID NOs: 225, 227, 229, and 231) and the amino acid sequence of the heavy chain (SEQ ID NOs: 226, 228, 230, and 232) of the antibody according to the present invention has the same heavy chain and / or light chain variable region CDR as the antibody of the present invention, and has conserved amino acid substitutions only at other positions in the heavy chain and / or light chain variable region other than the CDR (e.g., the framework region), wherein the conserved amino acid substitutions do not alter the biological function and / or activity of the corresponding antibody and can, for example, specifically bind to the ITGA2 protein.

[0102] In some embodiments, the isolated antibody or its antigen-binding fragment portion consists of at least one group of light and heavy chains selected from the following: 1) A light chain consisting of the amino acid sequence of SEQ ID NO:225, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:226, 2) A light chain consisting of the amino acid sequence of SEQ ID NO:227, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:228, 3) A light chain consisting of the amino acid sequence of SEQ ID NO:229, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:230, and 4) A light chain consisting of the amino acid sequence of SEQ ID NO:231, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:232.

[0103] In a fourth aspect, the present invention provides an isolated antibody or antigen-binding fragment thereof that specifically binds to the ITGA2 protein, wherein the isolated antibody or antigen-binding fragment thereof comprises a light chain variable region containing LCDR1, LCDR2, LCDR3 sequences and a heavy chain variable region containing HCDR1, HCDR2, HCDR3 sequences, wherein the antibody or antigen-binding fragment thereof has at least one group of light chain variable regions and heavy chain variable regions selected from the following: 1) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 162, (b) LCDR2 with SEQ ID NO: 163, and (c) LCDR3 with SEQ ID NO: 164, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 166, (e) HCDR2 with SEQ ID NO: 167, and (f) HCDR3 with SEQ ID NO: 168. 2) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 170, (b) LCDR2 with SEQ ID NO: 171, and (c) LCDR3 with SEQ ID NO: 172, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 174, (e) HCDR2 with SEQ ID NO: 175, and (f) HCDR3 with SEQ ID NO: 176. 3) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 178, (b) LCDR2 with SEQ ID NO: 179, and (c) LCDR3 with SEQ ID NO: 180, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 182, (e) HCDR2 with SEQ ID NO: 183, and (f) HCDR3 with SEQ ID NO: 184. 4) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 186, (b) LCDR2 with SEQ ID NO: 187, and (c) LCDR3 with SEQ ID NO: 188, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 190, (e) HCDR2 with SEQ ID NO: 191, and (f) HCDR3 with SEQ ID NO: 192. 5) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 194, (b) LCDR2 with SEQ ID NO: 195, and (c) LCDR3 with SEQ ID NO: 196, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 198, (e) HCDR2 with SEQ ID NO: 199, and (f) HCDR3 with SEQ ID NO: 200.

[0104] In some embodiments, the isolated antibody or its antigen-binding fragment portion includes a light chain variable region and a heavy chain variable region having at least one group selected from the following, i.e. 1) The light chain variable region comprising the amino acid sequence of SEQ ID NO:161 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:161, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:165 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:165, 2) The light chain variable region comprising the amino acid sequence of SEQ ID NO:169 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:169, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:173 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:173, 3) The light chain variable region comprising the amino acid sequence of SEQ ID NO:177 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:177, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:181 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:181, 4) The light chain variable region comprising the amino acid sequence of SEQ ID NO:185 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:185, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:189 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:189, and 5) The light chain variable region includes the amino acid sequence of SEQ ID NO:193 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:193, and the heavy chain variable region includes the amino acid sequence of SEQ ID NO:197 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:197.

[0105] In some embodiments, an antibody having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of the light chain variable region (SEQ ID NOs: 161, 169, 177, 177, 185, and 193) and the amino acid sequence of the heavy chain variable region (SEQ ID NOs: 165, 173, 181, 189, and 197) of the antibody according to the present invention has the same or similar biological function and / or activity as the antibody of the present invention.

[0106] In some embodiments, 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 with the amino acid sequences of the light chain variable region (SEQ ID NOs: 161, 169, 177, 177, 185, and 193) and the heavy chain variable region (SEQ ID NOs: 165, 173, 181, 189, and 197) of the antibody according to the present invention can also specifically bind to the ITGA2 protein.

[0107] In some embodiments, an antibody having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of the light chain variable region (SEQ ID NOs: 161, 169, 177, 185, and 193) and the amino acid sequence of the heavy chain variable region (SEQ ID NOs: 165, 173, 181, 189, and 197) of the antibody according to the present invention has the same heavy chain and / or light chain variable region CDR as the antibody of the present invention, and has conservative amino acid substitutions only at other positions in the heavy chain and / or light chain variable region other than the CDR (e.g., the framework region), wherein the conservative amino acid substitutions do not alter the biological function and / or activity of the corresponding antibody and can, for example, specifically bind to the ITGA2 protein.

[0108] In some embodiments, the isolated antibody or its antigen-binding fragment portion further comprises a light chain constant region and a heavy chain constant region. The light chain constant region includes the amino acid sequence of SEQ ID NO:201 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:201. The heavy chain constant region includes the amino acid sequence of SEQ ID NO:202 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:202.

[0109] In some embodiments, the isolated antibody or its antigen-binding fragment portion comprises a light chain and a heavy chain having at least one group selected from the following, i.e. 1) The light chain comprising the amino acid sequence of SEQ ID NO:233 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:233, and the heavy chain comprising the amino acid sequence of SEQ ID NO:234 ​​or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:234, 2) The light chain comprising the amino acid sequence of SEQ ID NO:235 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:235, and the heavy chain comprising the amino acid sequence of SEQ ID NO:236 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:236, 3) The light chain comprising the amino acid sequence of SEQ ID NO:237 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:237, and the heavy chain comprising the amino acid sequence of SEQ ID NO:238 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:238, 4) The light chain comprising the amino acid sequence of SEQ ID NO:239 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:239, and the heavy chain comprising the amino acid sequence of SEQ ID NO:240 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:240, and 5) The light chain comprises the amino acid sequence of SEQ ID NO:241 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:241, and the heavy chain comprises the amino acid sequence of SEQ ID NO:242 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:242.

[0110] In some embodiments, an antibody having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequences of the light chain (SEQ ID NOs: 233, 235, 237, 239, and 241) and heavy chain (SEQ ID NOs: 234, 236, 238, 240, and 242) of the antibody according to the present invention has the same or similar biological function and / or activity as the antibody of the present invention.

[0111] In some embodiments, 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 with the amino acid sequences of the light chain (SEQ ID NOs: 233, 235, 237, 239, and 241) and heavy chain (SEQ ID NOs: 234, 236, 238, 240, and 242) of the antibody according to the present invention can also specifically bind to the ITGA2 protein.

[0112] In some embodiments, an antibody having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of the light chain (SEQ ID NOs: 233, 235, 237, 239, and 241) and the amino acid sequence of the heavy chain (SEQ ID NOs: 234, 236, 238, 240, and 242) of the antibody according to the present invention has the same heavy chain and / or light chain variable region CDR as the antibody of the present invention, and has conserved amino acid substitutions only at other positions in the heavy chain and / or light chain variable region other than the CDR (e.g., the framework region), wherein the conserved amino acid substitutions do not alter the biological function and / or activity of the corresponding antibody and can, for example, specifically bind to the ITGA2 protein.

[0113] In some embodiments, the isolated antibody or its antigen-binding fragment portion consists of at least one group of light and heavy chains selected from the following: 1) A light chain consisting of the amino acid sequence of SEQ ID NO:233, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:234, 2) A light chain consisting of the amino acid sequence of SEQ ID NO:235, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:236, 3) A light chain consisting of the amino acid sequence of SEQ ID NO:237, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:238, 4) A light chain consisting of the amino acid sequence of SEQ ID NO:239, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:240, and 5) A light chain consisting of the amino acid sequence of SEQ ID NO:241, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:242.

[0114] In the aforementioned embodiments, the antibody or antigen-binding fragment can be bound in vitro to the ITGA2 protein with an EC50 of less than 1 nM.

[0115] In the aforementioned embodiments, the antibody or antigen-binding fragment can bind to the ITGA2 protein on the surface of HuCCT1 cells with an EC50 of less than 5 nM.

[0116] In the aforementioned embodiments, the antibody is a monoclonal antibody, a polyclonal antibody, a chimeric antibody, or a humanized antibody.

[0117] The amino acid sequence numbers (SEQ ID NO:) for the antibodies of the present invention and their corresponding structures are summarized in Table 2 below.

[0118] [Table 5]

[0119] [Table 6]

[0120] [Table 7]

[0121] [Table 8]

[0122] In another aspect, the present invention provides an isolated antibody or antigen-binding fragment thereof that specifically binds to the ITGA2 protein, wherein the isolated antibody or antigen-binding fragment thereof has at least one group of light chains and heavy chains selected from the following: 1) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:1, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:1, 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:2, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:2, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:2. 2) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:3, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:3, 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:4, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:4, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:4. 3) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:5, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:5, 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:6, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:6, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:6. 4) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:7, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:7, 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:8, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:8, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:8.

[0123] In another aspect, the present invention provides an isolated antibody or antigen-binding fragment thereof that specifically binds to the ITGA2 protein, wherein the isolated antibody or antigen-binding fragment thereof has at least one group of light chains and heavy chains selected from the following: 1) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:9, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:9, 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:10, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:10, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:10. 2) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:11, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:11, 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:12, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:12, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:12. 3) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:13, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:13, 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:14, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:14, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:14. 4) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:15, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:15, 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:16, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:16, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:16. 5) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:17, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:17, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:17. The heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:18, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:18, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:18. 6) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:19, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:19, or consists 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 an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:20, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:20. 7) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:21, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:21, or consists 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 an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:22, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:22.

[0124] In another aspect, the present invention provides an isolated antibody or antigen-binding fragment thereof that specifically binds to the ITGA2 protein, wherein the isolated antibody or antigen-binding fragment thereof has at least one group of light chains and heavy chains selected from the following: 1) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:23, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:23, or consists 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 an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:24, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:24. 2) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:25, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:25, 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 an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:26, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:26. 3) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:27, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:27, or consists 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 an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:28, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:28. 4) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:29, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:29, or consists 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 an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:30, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:30.

[0125] In another aspect, the present invention provides an isolated antibody or antigen-binding fragment thereof that specifically binds to the ITGA2 protein, wherein the isolated antibody or antigen-binding fragment thereof has at least one group of light chains and heavy chains selected from the following: 1) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:31, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:31, or consists 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 an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:32, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:32. 2) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:33, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:33, or consists 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 an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:34, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:34. 3) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:35, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:35, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:35. The heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:36, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:36, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:36. 4) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:37, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:37, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:37. The heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:38, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:38, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:38. 5) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:39, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:39, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:39. The heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:40, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:40, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:40.

[0126] In some embodiments, the antibody or antigen-binding fragment can be conjugated in vitro to the ITGA2 protein with an EC50 of less than 1 nM.

[0127] In some embodiments, the antibody or antigen-binding fragment can bind to the ITGA2 protein on the surface of HuCCT1 cells with an EC50 of less than 5 nM.

[0128] In some embodiments, the antibody is a monoclonal antibody, a polyclonal antibody, a chimeric antibody, or a humanized antibody. (iii) nucleic acids, vectors, host cells, hybridomas, and antibody production methods

[0129] In one embodiment, the present invention provides an isolated nucleic acid molecule that encodes the antibody of the present invention or an antigen-binding fragment thereof. In some embodiments, the nucleic acid molecule of the present invention encodes the heavy chain and / or light chain variable region, each CDR in the heavy chain and / or light chain variable region, and the heavy chain and / or light chain constant region of the antibody of the present invention. In some embodiments, the nucleotide sequence of the nucleic acid molecule is codon-optimized for expression in a host cell. In some embodiments, the nucleic acid molecule of the present invention is operably linked to an expression regulatory sequence.

[0130] The present invention further provides isolated nucleic acid molecules that encode the antibody or antigen-binding fragment portion thereof of the present invention.

[0131] In one embodiment, the present invention further provides an isolated nucleic acid molecule, the nucleic acid molecule is SEQ ID NO:1 and SEQ ID NO:2, SEQ ID NO:3 and SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, and It contains or consists of a nucleotide sequence shown in any one combination selected from SEQ ID NO:7 and SEQ ID NO:8.

[0132] In one embodiment, the present invention further provides an isolated nucleic acid molecule, the nucleic acid molecule is SEQ ID NO:9 and SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:12, SEQ ID NO:13 and SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16, SEQ ID NO:17 and SEQ ID NO:18, SEQ ID NO:19 and SEQ ID NO:20, and It contains or consists of a nucleotide sequence shown in any one combination selected from SEQ ID NO:21 and SEQ ID NO:22.

[0133] In one embodiment, the present invention further provides an isolated nucleic acid molecule, the nucleic acid molecule is SEQ ID NO:23 and SEQ ID NO:24, SEQ ID NO:25 and SEQ ID NO:26, SEQ ID NO:27 and SEQ ID NO:28, and It contains or consists of a nucleotide sequence shown in any one combination selected from SEQ ID NO:29 and SEQ ID NO:30.

[0134] In one embodiment, the present invention further provides an isolated nucleic acid molecule, the nucleic acid molecule is SEQ ID NO:31 and SEQ ID NO:32, SEQ ID NO:33 and SEQ ID NO:34, SEQ ID NO:35 and SEQ ID NO:36, SEQ ID NO:37 and SEQ ID NO:38, and It contains or consists of a nucleotide sequence shown in any one combination selected from SEQ ID NO:39 and SEQ ID NO:40.

[0135] In some embodiments, the nucleic acid molecule is operably linked to an expression regulatory sequence.

[0136] The nucleotide sequence numbers (SEQ ID NO:) for the antibodies of the present invention and their corresponding structures are summarized in Table 3 below.

[0137] [Table 9]

[0138] [Table 10]

[0139] [Table 11]

[0140] [Table 12]

[0141] The present invention further provides an expression vector comprising at least one nucleic acid molecule of the present invention as described above.

[0142] The present invention further provides a host cell which is transformed with at least one of the nucleic acid molecules or expression vectors of the present invention described above.

[0143] The present invention further provides hybridoma cells that express at least one of the antibodies or antigen-binding fragments thereof described above.

[0144] The present invention further provides a method for producing the antibody or antigen-binding fragment thereof, the method being: (i) Culturing the host cells of the present invention under conditions suitable for the expression of the nucleic acid molecule or expression vector, (ii) The process includes isolating and purifying an antibody or antigen-binding fragment thereof expressed by the host cell.

[0145] In some embodiments, the nucleotide sequence of the nucleic acid molecule is codon-optimized for expression in a host cell. In some embodiments, the nucleic acid molecule is operably linked to an expression regulatory sequence.

[0146] The present invention further provides a method for producing the antibody or antigen-binding fragment thereof, the method being: (i) To produce hybridoma cells capable of expressing the monoclonal antibody of the present invention or its antigen-binding fragment portion, (ii) The process includes isolating and purifying an antibody or antigen-binding fragment thereof expressed by the hybridoma cells. (iv) Antibody drug conjugates

[0147] In one embodiment, the present invention provides an antibody-drug conjugate (ADC) produced with the antibody or its antigen-binding fragment.

[0148] Specifically, the present invention provides an antibody-drug conjugate represented by the following formula, which is Ab-LD, where, The symbol "Ab" represents at least one of the monoclonal antibodies of the present invention described above or its antigen-binding fragment portion. The symbol "L" represents a linker that connects the antibody portion and the partner molecule. The symbol "D" represents the partner molecule.

[0149] As used herein, ADCs are produced by linking a partner molecule with an antibody or its antigen-binding fragment via a linker. In the ADC of the present invention, the antibody performs a targeting function, and the antibody leads the conjugate to the target tissue or cell where the antigen expressing it is present by binding to the target tissue or cell. The linker is then cleaved, for example, and the partner molecule is released to exert its desired biological function.

[0150] The partner molecule may be a drug payload or a labeled molecule. The drug payload may be a therapeutic agent, for example, the therapeutic agent may be a cytotoxic agent, a chemotherapeutic agent, a cell inhibitor, an immunomodulator, etc. In some embodiments, the therapeutic agent is a cytotoxic agent, i.e., a cytotoxin. As used herein, “cytotoxic agent” and “cytotoxin” are used interchangeably.

[0151] The labeling molecule may be any label that produces a detectable signal, such as radiolabeling, fluorescent labeling, or an enzyme that catalyzes a detectable modification of the substrate.

[0152] As used herein, the terms “drug,” “payload,” and “drug payload” are interchangeable. As used herein, an antibody-drug conjugate (ADC) includes conjugates formed by linking the antibody of the present invention or its antigen-binding fragment with a drug payload, and conjugates formed by linking the antibody of the present invention or its antigen-binding fragment with a labeled molecule.

[0153] The proportion of partner molecules conjugated to the antibody may vary depending on the following factors, which are, for example, the amount of partner molecules used in the conjugation reaction and the experimental conditions. The ratio of partner molecules to antibody may be 1-6, 1-5, 1-4, 1-3, 1-2, or 1-1.5.

[0154] Therefore, the present invention also provides an antibody-drug conjugate represented by the following formula, Ab-(LD)p, where, The symbol "Ab" represents at least one of the monoclonal antibodies of the present invention described above or its antigen-binding fragment portion. The symbol "L" represents a linker that connects the antibody portion and the partner molecule. The symbol "D" represents a partner molecule. The symbol "p" represents the number of linker / partner molecules (preferably drug payloads) conjugated to the monoclonal antibody or its antigen-binding fragment portion of the present invention described above.

[0155] In some embodiments, p is 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, The value is selected from the following numbers: 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.

[0156] In some embodiments, the linker of the present invention is selected from one of vc, mc-GGFG, AcLysvc, mc, MalPeg6, m(H2O)c, and m(H2O)cvc, and / or the linker is cleavable. In some embodiments, the linker of the present invention is vc.

[0157] In some embodiments, the partner molecule of the present invention is a drug payload, the drug payload is a therapeutic molecule, and optionally the drug payload is selected from one of cytotoxic agents, cell inhibitors, immunomodulators and chemotherapeutic agents, and optionally the drug payload is selected from one of MMAE, MMAF, DM1, DM4, Dxd, SN-38, Topotecan and its derivatives, Exatecan and its derivatives, Belotecan and its derivatives, Camptothecin, Calichemicin and PBD.

[0158] In some embodiments, the drug payload is MMAE. "MMAE" refers to monomethyl auristatin E, and as shown in the following figure, the wavy line indicates covalent linkage with the linker (L) of the antibody-drug conjugate: [ka]

[0159] In some embodiments, the drug payload is MMAF, where MMAF refers to monomethyl auristatin F, and the dashed line indicates that it is covalently linked to the linker (L) of the antibody-drug conjugate (US2005 / 0238649): [ka]

[0160] In some embodiments, the linker-partner molecule is vcMMAE. The vcMMAE drug linker moiety and conjugation methods are disclosed in WO2004010957, US7659241, US7829531, US7851437 and US11 / 833,028 (Seattle Genetics, Inc.), which are incorporated herein by reference. The vcMMAE drug linker moiety is conjugated with the antibody of the present invention using a method similar to that disclosed in the above documents.

[0161] For further information on cytotoxin types, linkers and methods for conjugating therapeutic agents and antibodies, see Saito, G. et al. (2003) Adv. Drug Deliv. Rev. 55:199-215, Trail, PA et al. (2003) Cancer. Immunol. Immunother. 52:328-337, Payne, G. (2003) Cancer Cell 3:207-212, Allen, TM (2002) Nat. Rev. Cancer 2:750-763, Pastan, I. and Kreitman, RJ (2002) Curr. Opin. Investig. Drugs 3:1089-1091, and Senter, PD and Springer, CJ (2001) Adv. Drug Deliv. Rev. 53:247-264, which are incorporated herein by reference.

[0162] In some embodiments, the drug payload may further consist of radioisotopes, thereby generating cytotoxic radiopharmaceuticals (also known as antibody radioisotope conjugates). Examples of radioisotopes that exhibit killing effects against tumor cells include, but are not limited to, iodine-131, indium-111, yttrium-90, and lutetium-177. Methods for producing antibody radioisotope conjugates are known in the art.

[0163] In some embodiments, the partner molecule of the present invention is a labeling molecule, which is optionally selected from among radiolabeling, fluorescent labeling, and a detectably modified enzyme. In some embodiments, the radiolabeling is a radioisotope, such as iodine-131, indium-111, yttrium-90, and lutetium-177.

[0164] Experiments have demonstrated that the ITGA2 protein can be an effective target for antibody-drug conjugates. In this invention, the antibody-drug conjugate obtained by coupling an antibody with a small molecule toxin can exhibit excellent killing effects against tumors expressing the ITGA2 protein. (5) Pharmaceutical compositions, therapeutic uses and methods

[0165] The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of at least one monoclonal antibody of the present invention or its antigen-binding fragment portion or at least one antibody-drug conjugate of the present invention, therapeutic uses of the pharmaceutical composition, and therapeutic methods. In the antibody-drug conjugate of the present invention, the antibody of the present invention is conjugated with a drug payload.

[0166] In one embodiment, the present invention provides a pharmaceutical composition comprising at least one monoclonal antibody of the present invention or its antigen-binding fragment portion or at least one antibody-drug conjugate of the present invention in a therapeutically effective amount. In some embodiments, the pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier.

[0167] At least one of the monoclonal antibodies or their antigen-binding fragments or at least one antibody-drug conjugates of the present invention in a "therapeutic effective dose" preferably results in a reduction in the severity of disease symptoms, an increase in the frequency and duration of asymptomatic periods, or prevention of injury or loss of function resulting from suffering caused by the disease. For example, in the treatment of tumors, at least one of the monoclonal antibodies or their antigen-binding fragments or at least one antibody-drug conjugates of the present invention in a "therapeutic effective dose" preferably inhibits cell proliferation or tumor growth 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%, more preferably at least about 70%, and more preferably at least about 80%. The ability to inhibit tumor growth can be evaluated in animal model systems to predict therapeutic effects on human tumors. Alternatively, it can be evaluated by testing the ability to inhibit cell proliferation, and such inhibition can be measured in vitro by tests well known to those skilled in the art. An effective amount of the antibody of the present invention or its antigen-binding fragment can reduce tumor size or otherwise alleviate the symptoms of the target, for example, prevent and / or treat metastasis or recurrence. Those skilled in the art can determine this amount based on factors such as the size of the target, the severity of the symptoms of the target, and the selected specific composition or route of administration.

[0168] In another embodiment, the present invention provides uses for at least one of the monoclonal antibodies of the present invention or its antigen-binding fragment portion or at least one of the antibody-drug conjugates of the present invention in the manufacture of a pharmaceutical composition. In some embodiments, the pharmaceutical composition is for treating malignant tumors in patients and for preventing and / or treating metastasis or recurrence of malignant tumors.

[0169] In another embodiment, the present invention provides a pharmaceutical composition comprising at least one monoclonal antibody of the present invention or an antigen-binding fragment thereof or at least one antibody-drug conjugate of the present invention, and a method for treating a malignant tumor in a patient, and for preventing and / or treating the metastasis or recurrence of a malignant tumor.

[0170] In another embodiment, the present invention provides a method for treating a malignant tumor in a patient and for preventing and / or treating the metastasis or recurrence of the malignant tumor, the method comprising administering to the patient an effective amount of at least one monoclonal antibody of the present invention or an antigen-binding fragment thereof, at least one antibody-drug conjugate of the present invention, and / or at least one pharmaceutical composition of the present invention.

[0171] In some embodiments, the malignant tumor is a tumor that expresses the ITGA2 protein. The malignant tumor is selected from the group consisting of breast cancer, colorectal cancer, colon cancer, skin cancer, pancreatic cancer, prostate cancer, liver cancer, lung cancer, gastric cancer, leukemia, bile duct cancer, cervical cancer, endometrial cancer, esophageal cancer, head and neck cancer, lymphoma, medullary thyroid carcinoma, non-Hodgkin lymphoma, ovarian cancer, glioma, melanoma, and bladder cancer. In some embodiments, the malignant tumor is selected from the group consisting of colorectal cancer, bile duct cancer, pancreatic cancer, and skin cancer. In some embodiments, the malignant tumor is colorectal cancer. In some embodiments, the malignant tumor is bile duct cancer. In some embodiments, the malignant tumor is pancreatic cancer. In some embodiments, the malignant tumor is skin cancer. (vi) Diagnostic / prognostic compositions, diagnostic / prognostic uses and methods

[0172] As described herein, ITGA2 is a tumor-associated antigen that is specifically overexpressed in tumor cells, particularly in cancer patients with colorectal cancer, cholangiocarcinoma, pancreatic cancer, and skin cancer, and is expressed on the surface of tumor cells.

[0173] The present invention provides a diagnostic / prognostic composition comprising at least one monoclonal antibody of the present invention or its antigen-binding fragment portion or at least one antibody-drug conjugate of the present invention, a diagnostic / prognostic use of the composition, and a diagnostic / prognostic method. In the diagnostic / prognostic drug conjugate of the present invention, the antibody of the present invention is conjugated with a labeled molecule. With respect to the diagnostic / prognostic composition, diagnostic / prognostic use, and diagnostic / prognostic method, the antibody-drug conjugate of the present invention refers to a conjugate formed by linking the antibody of the present invention or its antigen-binding fragment with a labeled molecule.

[0174] In one embodiment, the present invention provides applications for at least one of the monoclonal antibodies described above, or an antigen-binding fragment thereof, or at least one antibody-drug conjugate described above, in the manufacture of diagnostic / prognostic compositions. In some embodiments, the diagnostic composition is for detecting the presence of a malignant tumor in a patient. In some embodiments, the prognostic composition is used for prognosis of recurrence or progression of a malignant tumor in a patient.

[0175] In another embodiment, the present invention provides a method for detecting / diagnosing the presence of a malignant tumor in a patient, the method comprising administering to the patient an effective amount of at least one monoclonal antibody of the present invention or its antigen-binding fragment portion, at least one antibody-drug conjugate of the present invention, and / or at least one diagnostic / prognostic composition of the present invention.

[0176] In some embodiments, the present invention provides a method for detecting / diagnosing the presence of a malignant tumor in a patient, and the method is a) Contacting a biological sample obtained from the patient with at least one monoclonal antibody of the present invention or its antigen-binding fragment portion, at least one antibody-drug conjugate of the present invention, and / or at least one diagnostic / prognostic composition of the present invention, b) detecting the binding of at least one of the monoclonal antibodies or antigen-binding fragment portions thereof of the present invention, at least one of the antibody-drug conjugates of the present invention, and / or at least one of the diagnostic / prognostic compositions of the present invention to a target antigen in the biological sample, wherein the detection of the binding between the antibody and the target antigen indicates the presence of a malignant tumor in the patient.

[0177] In another aspect, the present invention provides a method for prognosticating recurrence or progression of a malignant tumor in a patient, the method comprising administering to the patient an effective amount of at least one of the monoclonal antibodies or antigen-binding fragment portions thereof of the present invention, at least one of the antibody-drug conjugates of the present invention, and / or at least one of the diagnostic / prognostic compositions of the present invention.

[0178] In some embodiments, the present invention provides a method for prognosticating recurrence or progression of a malignant tumor in a patient, the method comprising (a) separating a biological sample containing tumor cells from the patient; (b) contacting the biological sample containing tumor cells with at least one of the monoclonal antibodies or antigen-binding fragment portions thereof of the present invention, at least one of the antibody-drug conjugates of the present invention, and / or at least one of the diagnostic / prognostic compositions of the present invention; (c) identifying that the binding between the antibody and the tumor cells indicates the presence of the tumor cells; thereby prognosticating recurrence or progression of the malignant tumor in the patient.

[0179] In some embodiments, the progression of the malignant tumor includes metastasis in the patient with the malignant tumor.

[0180] In some embodiments, the identification of tumor cells bound to at least one of the monoclonal antibodies or antigen-binding fragments thereof, at least one antibody-drug conjugate, and / or at least one diagnostic / prognostic composition of the present invention suggests a high risk of recurrence or progression of malignant tumor in the patient.

[0181] In some embodiments, the partner molecule of the present invention is a labeling molecule, which is optionally selected from radiolabeling (e.g., isotopes), fluorescent labeling (e.g., fluorescent dyes), chemical substances, and detectably modified enzymes and tags.

[0182] In some embodiments, the biological sample is selected from one of a blood sample, a tissue sample, and a lymph sample.

[0183] Methods for detecting antibody-antigen binding are well known in this field, such as ELISA. (7), Kit

[0184] Within the scope of the present invention, the kit used in the method of the present invention further includes at least one monoclonal antibody or antigen-binding fragment thereof as described above, at least one antibody-drug conjugate as described above, at least one pharmaceutical composition as described above, or one diagnostic / prognostic composition as described above, and instructions for use.

[0185] In some embodiments, the kit may further include at least one additional detection reagent for detecting the presence of at least one monoclonal antibody or antigen-binding fragment thereof as described above, at least one antibody-drug conjugate as described above, at least one pharmaceutical composition as described above, or one diagnostic / prognostic composition as described above. The kit generally includes a label indicating the intended use and / or method of use of the kit contents. The term "label" includes any written or recorded material that is on the kit, provided with the kit, or otherwise provided with the kit. [Examples]

[0186] The present invention can be further understood by referring to the embodiments for carrying out some of the inventions presented herein, which are merely illustrative and not intended to limit the scope of the invention in any way. Clearly, various modifications and changes can be made to the invention without departing from the essence of the invention, and these modifications and changes are also included within the scope of protection claimed by this application.

[0187] Example 1 - The ITGA2 protein is specifically overexpressed on the surface of various cancer cells. HuCC-T1 (human cholangiocarcinoma cells; Meisen cells: CTCC-003-0103), HCCC-9810 (human cholangiocarcinoma cells; Wuhan Punocai: CL-0095), AsPC-1 (human metastatic pancreatic cancer cells; Wuhan Punocai: CL-0027), BxPC-3 (human in situ pancreatic cancer cells; Meisen cells: CTCC-001-0360), A431 (human epidermal carcinoma cells; Wuhan Punocai: CL-0015), HT-29 (human colorectal cancer cell line; Wuhan Punocai: CL-0118), and CHO (hamster ovary cells; Wuhan Punocai: CL-0061) cells were seeded in 96-deep-well plates. 50,000 cells / 100 μL were seeded into each well, with 3 wells dedicated to each cell type. The cells were then repeatedly pipetted with PBS and washed twice. A PBS solution containing 1% FBS was added to each well at a volume of 100 μL / well and incubated at 4°C for 30 minutes. A FITC-labeled mouse anti-human ITGA2 antibody solution (BD Pharmingen: 555498) was diluted to working concentration at 20 μL / well and incubated at 4°C in a light-shielded refrigerator for 30 minutes. After incubation, the cells were washed twice with 500 μL of 1% FBS and then resuspended in PBS with 250 μL of cells. The blank reference solution was 250 μL of PBS solution containing the reference control solution. Using flow cytometry, the ITGA2 protein copy number of each cell line was collected and analyzed based on the molecules of equivalent soluble fluorescent dyes (MESF). The results are shown in Table 4 below.

[0188] [Table 13]

[0189] As shown in Table 4, under equivalent antibody concentrations and treatment conditions, the ITGA2 protein was highly expressed on the surface of HuCCT1, BxPC-3, HCCC-9810, ASPC-1, and A431 cells (MESF > 150,000), while it was hardly expressed on the surface of negative control cells (CHO) (MESF < 1000, which can be considered a background value at the experimental technique level).

[0190] Example 2 - Production of ITGA2 Antibody 1. Vector Construction The design, vector construction, expression, purification, and identification of the ITGA2 antibody sequence of the present invention were all entrusted to Shanghai Sanyou Biomedicine Co., Ltd. for implementation. The construction process mainly included constructing the sequence of the ITGA2 antibody on the pcDNA3.4 vector. After undergoing PCR, digestion, ligation, transformation, identification, sequencing, alignment, and extraction, the plasmid was obtained.

[0191] The vectors containing the light chain and heavy chain sequences of the ITGA2 antibody of the present invention are as shown in Table 5 below.

[0192] [Table 14] The coding sequences of the light chain and heavy chain in each plasmid vector in the above table are as shown in the sequences of SEQ ID NO: 1 - 40 in Table 1 above (the hatching corresponds to the constant region sequence). The amino acid sequences of the light chain variable region, heavy chain variable region, constant region, and light chain and heavy chain in the antibody expressed by the above vector are as shown in the sequences of SEQ ID NO: 41 - 242 in Tables 2 - 4 above.

[0193] Table 6: The sequence numbers of the heavy chain, light chain, constant region, variable region, and each CDR of the aforementioned antibody are summarized as follows (the numbers in columns 3 - 7 and 9 - 13 in the following table represent the numbers of SEQ ID NO:, for example, the number 1 represents SEQ ID NO: 1)

[0194] [Table 15]

[0195] [Table 16]

[0196] [Table 17]

[0197] [Table 18]

[0198] 2. Antibody expression and purification, and SDS-PAGE identification Using the ExpiCHO-s expression system, the plasmid was expressed in CHO cells for 7 days according to the instructions. On day 6 of expression, the plasmid was purified by Protein A affinity chromatography to obtain the antibody.

[0199] Subsequently, the concentration of the obtained antibody was detected by SDS-PAGE. In SDS-PAGE, the purity of the reduced band, or the total purity of the reduced heavy and light chains, was calculated using ImageJ according to the peak area normalization method. The reference sample IPI had a non-reduced band molecular weight of approximately 150 kDa and a purity of over 90%. Under reducing conditions, the heavy chain molecular weight was approximately 55 kDa, the light chain molecular weight was approximately 25 kDa, and the total purity of the heavy and light chains was over 90%.

[0200] Example 3 - Evaluation of protein-level affinity between anti-ITGA2 antibody and ITGA2 protein by ELISA method The following method was used to measure the protein-level affinity between the ITGA2 antibody and the ITGA2 protein, including coating ELISA plates with 2 ug / mL ITGA2-His. The plates were washed three times with PBST and blocked with 5% PBS-Milk at room temperature for 2 hours. The plates were washed three times with PBST, and diluted antibodies were added to the ELISA plates at 30 μL per well and left at room temperature for 60 minutes. The plates were washed three times with PBST, and anti-human IgG-Fc-HRP (abcam; ab97225) was added to the ELISA plates and left at room temperature for 60 minutes. TMB was added, the reaction was stopped with 2 M stop solution, and the OD450 was read. Finally, the binding ability of each antibody to ITGA2-his was compared by EC50. The positive control antibody Vatelizumab and the negative control antibody hIgG1 were purchased from Hyakuei Seibutsu. The measurement results are shown in Table 7 below.

[0201] [Table 19]

[0202] As shown in the table above, all 20 target antibodies showed good binding activity to ITGA2-His (EC50 < 1 nM).

[0203] Example 4 - Flow cytometry measurement of cellular affinity between anti-ITGA2 antibody and ITGA2 Human cholangiocarcinoma cells (HuCCT1 cells) were seeded in 96-well plates at a rate of 50,000 cells per well. The mixture was repeatedly pipetted with PBS, washed twice, and the PBS was aspirated and discarded. The target antibody, ITGA2, was used as the primary antibody. A 30 nM working concentration was prepared in a 1% FBS / PBS solution and sequentially diluted threefold to establish a total of five specific concentration points. The prepared antibody dilutions were added to the corresponding 96-well plates and incubated at 4°C for 30 minutes. The mixture was then repeatedly pipetted with 1% FBS / PBS solution, washed twice, the PBS was aspirated and discarded, and the antibody supernatant was aspirated and discarded after centrifugation. Goat anti-human secondary antibody IgG(H+L), which had been de-cross-reactive with other species using a PBS solution containing 10% FBS, was mixed at a ratio of 1:300 and added to the 96-well plates. The mixture was incubated at 4°C for 30 minutes. The samples were collected using flow cytometry and analyzed, and finally, the affinity of the antibody to the ITGA2 target was evaluated based on EC50. The antibody vatelizumab (purchased from Hyakuei Seibutsu) was used as a positive control antibody that binds to ITGA2.

[0204] The results of the EC50 measurements are shown in Table 8. As shown in Table 8, all 20 antibodies had an EC50 of less than 1 nM and were able to bind well to ITGA2-positive HuCCT1 cells.

[0205] [Table 20]

[0206] Example 5 - Production of Antibody-Drug Conjugates (ADCs) The antibody-drug conjugate is manufactured using the following method. Materials and methods: Coupling buffer: 25mM Na2B4O7, 25mM NaCl, 1mM DPTA, pH 7.4 Dialysis buffer: 1x PBS, pH7.4 Antibody reduction concentration: 5 mg / mL Tris(2-chloroethyl) phosphate (TCEP): 5 mM, binding buffer TCEP:antibody=2.3:1 Payload: 10 mM linker-payload, dimethyl sulfoxide (DMSO) DMSO in the final reaction: 10% Payload:Antibody = 10:1 Reduction temperature and time: 25°C and 2 hours Coupling temperature and time: 25°C and 4 hours Coupling step: Thaw the antibody and dialyze it at 4°C for >4 hours using coupling buffer. If necessary, concentrate the antibody solution to 2-5 mg / ml. Add TCEP activator, reduce the antibody, and incubate in an ice bath at 25°C. The linker-payload solution is mixed in DMSO (10 mM). Based on the molar concentration, calculate the volume of each conjugated effective linker-payload solution. The antibody is mixed with the linker-payload in the desired molar ratio and incubated in a 25°C water bath. Dialyze the conjugate with ADC storage buffer at 4°C for more than 4 hours, and replace the buffer at least every 4 hours. ADC was extracted and filtered using a 0.22 μm filter, and the sample was subjected to SEC-HPLC and HIC-HPLC analysis.

[0207] Using the method described above, vc-MMAE (mc-vc-PAB-MMAE, C68H105N11O15, provided by Eichi Chemical) was used as a linker-payload to produce antibody-drug conjugates of the 12 antibodies of the present invention and the positive control antibody vatelizumab in this example.

[0208] [Table 21]

[0209] Example 6 - Biological activity of antibody-drug conjugates (ADCs) in killing cancer cells In this example, the antibody of the present invention was conjugated with a toxin to form an ADC, and its biological activity for killing cancer cells was then tested.

[0210] Human epidermal carcinoma cells A431 from Wuhan Punusai were seeded at 2500 cells / well in 96-well plates. The plates were incubated overnight in a 37°C 5% CO2 incubator. The following day, half of the culture medium was removed from the cell plates. In complete medium, 2x hIgG1-vcMMAE (negative control ADC, supplied by Ruizhi Chemical), a control antibody, and the ADC molecules prepared in the above example were mixed. A 3-fold gradient dilution was then performed to establish a total of 11 specific concentration points. Serial dilutions of the above molecules were added to appropriate wells and incubated in a 37°C 5% CO2 incubator for 5 days. After incubation, 100 μL of Cell-Titer-Glo 2.0 reagent was added to the 96-well plates, mixed with a plate shaker for 2 minutes, and finally equilibrated at room temperature for 10 minutes. The readings were obtained using a microplate reader. Finally, the biological activity of the ADCs against each cell line was compared by IC50.

[0211] The results are shown in Table 10. As shown in Table 10, the ADC molecules produced with the 12 antibodies in this invention and the positive control molecule Vatelizumab-vc-MMAE all showed good killing effects against ITGA2-positive cells A431 (IC50 < 0.1 nM). The ITGA2 antibody Vatelizumab not coupled with vc-MMAE, or the negative control hIgG1-vc-MMAE, were not able to effectively kill A431 cells.

[0212] [Table 22]

[0213] The above results suggest that the ITGA2 antibody cannot be used alone to kill tumor cells in vitro. However, surprisingly, we discovered that the ITGA2 protein can function as a target for effective antibody-drug conjugates. In this invention, the antibody-drug conjugate obtained by coupling the antibody with a small molecule toxin can exhibit excellent killing effects against tumors expressing the ITGA2 protein.

[0214] Summary of technical proposals: Summary of Technical Proposals A 1. An isolated antibody or antigen-binding fragment thereof that specifically binds to the ITGA2 protein, wherein the isolated antibody or antigen-binding fragment thereof comprises a light chain variable region containing LCDR1, LCDR2, LCDR3 sequences and a heavy chain variable region containing HCDR1, HCDR2, HCDR3 sequences, wherein the antibody or antigen-binding fragment thereof has at least one group of light chain variable regions and heavy chain variable regions selected from the following: 1) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 42, (b) LCDR2 with SEQ ID NO: 43, and (c) LCDR3 with SEQ ID NO: 44, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 46, (e) HCDR2 with SEQ ID NO: 47, and (f) HCDR3 with SEQ ID NO: 48. 2) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 50, (b) LCDR2 with SEQ ID NO: 51, and (c) LCDR3 with SEQ ID NO: 52, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 54, (e) HCDR2 with SEQ ID NO: 55, and (f) HCDR3 with SEQ ID NO: 56. 3) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 58, (b) LCDR2 with SEQ ID NO: 59, and (c) LCDR3 with SEQ ID NO: 60, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 62, (e) HCDR2 with SEQ ID NO: 63, and (f) HCDR3 with SEQ ID NO: 54. 4) An isolated antibody or its antigen-binding fragment portion, wherein the light chain variable region includes (a) LCDR1 with SEQ ID NO: 66, (b) LCDR2 with SEQ ID NO: 67, and (c) LCDR3 with SEQ ID NO: 68, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 70, (e) HCDR2 with SEQ ID NO: 71, and (f) HCDR3 with SEQ ID NO: 72.

[0215] 2. The isolated antibody or its antigen-binding fragment portion comprises a light chain variable region and a heavy chain variable region having at least one group selected from the following, i.e. 1) The light chain variable region comprising the amino acid sequence of SEQ ID NO:41 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:41, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:45 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:45, 2) The light chain variable region comprising the amino acid sequence of SEQ ID NO:49 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:49, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:53 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:53, 3) The light chain variable region comprising the amino acid sequence of SEQ ID NO: 57 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO: 57, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 61 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO: 61, and 4) The isolated antibody or antigen-binding fragment portion thereof according to Technical Proposal 1, comprising the light chain variable region containing the amino acid sequence of SEQ ID NO:65 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:65, and the heavy chain variable region containing the amino acid sequence of SEQ ID NO:69 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:69.

[0216] 3. The isolated antibody or its antigen-binding fragment portion further comprises a light chain constant region and a heavy chain constant region, The light chain constant region includes the amino acid sequence of SEQ ID NO:201 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:201. The heavy chain constant region comprises the amino acid sequence of SEQ ID NO:202 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:202, as described in Technical Proposal 1 or 2, an isolated antibody or its antigen-binding fragment portion.

[0217] 4. The isolated antibody or its antigen-binding fragment portion comprises a light chain and a heavy chain having at least one group selected from the following, i.e. 1) The light chain comprising the amino acid sequence of SEQ ID NO:203 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:203, and the heavy chain comprising the amino acid sequence of SEQ ID NO:204 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:204, 2) The light chain comprising the amino acid sequence of SEQ ID NO:205 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:205, and the heavy chain comprising the amino acid sequence of SEQ ID NO:206 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:206, 3) The light chain comprising the amino acid sequence of SEQ ID NO:207 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:207, and the heavy chain comprising the amino acid sequence of SEQ ID NO:208 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:208, and 4) The isolated antibody or antigen-binding fragment portion thereof according to any one of Technical Proposals 1 to 3, comprising the light chain containing the amino acid sequence of SEQ ID NO:209 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:209, and the heavy chain containing the amino acid sequence of SEQ ID NO:210 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:210.

[0218] 5. The isolated antibody or its antigen-binding fragment portion consists of at least one group of light and heavy chains selected from the following: 1) A light chain consisting of the amino acid sequence of SEQ ID NO:203, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:204, 2) A light chain consisting of the amino acid sequence of SEQ ID NO:205, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:206, 3) A light chain consisting of the amino acid sequence of SEQ ID NO:207, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:208, and 4) An isolated antibody or antigen-binding fragment thereof according to any one of Technical Proposals 1 to 4, comprising a light chain consisting of the amino acid sequence of SEQ ID NO: 209 and the heavy chain consisting of the amino acid sequence of SEQ ID NO: 210.

[0219] 6. An isolated antibody or antigen-binding fragment thereof that specifically binds to the ITGA2 protein, wherein the isolated antibody or antigen-binding fragment thereof has at least one group of light chains and heavy chains selected from the following: 1) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:1, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:1, 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:2, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:2, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:2. 2) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:3, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:3, 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:4, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:4, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:4. 3) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:5, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:5, 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:6, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:6, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:6. 4) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:7, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:7, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:7. The heavy chain comprises an isolated antibody or its antigen-binding fragment portion, which includes an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:8, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:8, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:8.

[0220] 7. The antibody can bind to the ITGA2 protein in vitro with an EC50 of less than 1 nM, and / or The aforementioned antibody can bind to the ITGA2 protein on the surface of HuCCT1 cells with an EC50 of less than 5 nM. and / or, the antibody is a monoclonal antibody, a polyclonal antibody, a chimeric antibody, or a humanized antibody, as described in any one of the Technical Claims 1 to 6, an isolated antibody or its antigen-binding fragment portion.

[0221] 8. An isolated nucleic acid molecule that encodes an antibody or antigen-binding fragment thereof as described in any one of the technical proposals 1 to 7, or The nucleic acid molecule is SEQ ID NO:1 and SEQ ID NO:2, SEQ ID NO:3 and SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, and An isolated nucleic acid molecule containing or consisting of a nucleotide sequence shown in any one combination selected from SEQ ID NO:7 and SEQ ID NO:8.

[0222] 9. The nucleic acid molecule is an isolated nucleic acid molecule according to Technical Proposal 8, wherein the nucleic acid molecule is operably linked to an expression regulatory sequence.

[0223] 10. An expression vector containing a nucleic acid molecule as described in Technical Proposal 8 or 9.

[0224] 11. A host cell containing a nucleic acid molecule described in Technical Proposal 8 or 9, or an expression vector described in Technical Proposal 10.

[0225] 12. Hybridoma cells expressing an antibody or its antigen-binding fragment portion as described in any one of Technical Proposals 1 to 7.

[0226] 13. An antibody-drug conjugate shown in the following formula, Ab-LD, and here, The symbol "Ab" represents at least one of the antibodies of the present invention described above or its antigen-binding fragment portion, The symbol "L" represents a linker that connects the antibody portion and the partner molecule. The symbol "D" represents a partner molecule. or Ab-(LD)p, where The symbol "Ab" represents at least one of the antibodies of the present invention described above or its antigen-binding fragment portion, The symbol "L" represents a linker that connects the antibody portion and the partner molecule. The symbol "D" represents a partner molecule. The symbol "p" represents the number of linker / partner molecules (preferably drug payloads) conjugated to the antibody or antigen-binding fragment portion of the present invention as described above. Optionally, p can be 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. An antibody-drug conjugate selected from the following values: 0.8, 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.

[0227] 14. The antibody-drug conjugate according to proposal 13, wherein the linker is selected from one of vc, mc-GGFG, AcLysvc, mc, MalPeg6, m(H2O)c, and m(H2O)cvc, and / or the linker is cleavable.

[0228] 15. The partner molecule is a drug payload, the drug payload is a therapeutic molecule, and optionally the drug payload is selected from one of cytotoxic agents, cell inhibitors, immunomodulators and chemotherapeutic agents, and optionally the drug payload is selected from one of 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 antibody-drug conjugate according to proposal 13 or 14, wherein the partner molecule is a labeling molecule, and optionally, the labeling molecule is selected from one of the following: radiolabeling (e.g., isotope), fluorescent labeling (e.g., fluorescent dye), chemical substance, and a detectably modified enzyme and tag.

[0229] 16. A pharmaceutical composition comprising an antibody or an antigen-binding fragment thereof as described in any one of Technical Proposals 1 to 7, or an antibody-drug conjugate as described in any one of Technical Proposals 13 to 15, and optionally, a pharmaceutically acceptable carrier.

[0230] 17. Uses in the manufacture of a pharmaceutical composition of an antibody or antigen-binding fragment thereof as described in any one of Technical Proposals 1 to 7, or an antibody-drug conjugate as described in any one of Technical Proposals 13 to 15, wherein the pharmaceutical composition is optionally used to treat a malignant tumor in a patient, prevent and / or treat the metastasis or recurrence of the malignant tumor, optionally used to detect the presence of a malignant tumor in a patient, and optionally used for the prognosis of the recurrence or progression of a malignant tumor in a patient.

[0231] 18. A method for preventing and / or treating metastasis or recurrence of a malignant tumor in a patient, the method comprising administering to the patient an effective amount of an antibody or antigen-binding fragment thereof described in any one of Technical Proposals 1 to 7, an antibody-drug conjugate described in any one of Technical Proposals 13 to 15, or a pharmaceutical composition described in Technical Proposal 16.

[0232] 19. The method according to Technical Proposal 18, wherein the malignant tumor is selected from the group consisting of breast cancer, colorectal cancer, skin cancer, pancreatic cancer, prostate cancer, liver cancer, lung cancer, stomach cancer, leukemia, bile duct cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, head and neck cancer, lymphoma, medullary thyroid carcinoma, non-Hodgkin lymphoma, ovarian cancer, glioma, melanoma, and bladder cancer, and preferably the malignant tumor is selected from the group consisting of colorectal cancer, bile duct cancer, pancreatic cancer, and skin cancer.

[0233] 20. The method according to proposal 18 or 19, further comprising administering to the patient other antitumor treatment means, for example, a chemotherapeutic agent, an antibody targeting another tumor-specific antigen, or radiotherapy.

[0234] 21. A method for detecting the presence of tumor cells in a biological sample, a) Contacting the biological sample with an antibody or its antigen-binding fragment portion described in any one of Technical Proposals 1 to 7, b) The process includes detecting the binding of the antibody or its antigen-binding fragment to the target antigen in the biological sample, Here, the detection of the binding indicates the presence of tumor cells in the biological sample.

[0235] 22. A method for detecting the presence of a malignant tumor in a patient, a) Contacting the biological sample obtained from the patient with an antibody or its antigen-binding fragment described in any one of Technical Proposals 1 to 7, b) A method comprising detecting the binding of the antibody or its antigen-binding fragment portion to a target antigen in the biological sample, wherein the detection of the binding indicates the presence of a malignant tumor in the patient.

[0236] 23. A method for determining the prognosis of recurrence or progression of malignant tumors in patients, wherein the method is: (a) Isolating a biological sample containing tumor cells from the patient, (b) Contacting the biological sample containing the tumor cells with an antibody or its antigen-binding fragment described in any one of the technical proposals 1 to 7, (c) Identifying the presence of tumor cells that bind to the antibody or its antigen-binding fragment portion, A method for determining the prognosis of recurrence or progression of a malignant tumor in the aforementioned patient.

[0237] 24. The method according to the proposal 23, wherein the progression of the malignant tumor includes metastasis in the patient with the malignant tumor.

[0238] 25. The method according to Technical Proposal 23 or 24, wherein the biological sample is selected from one of a blood sample, a tissue sample, and a lymph sample.

[0239] 26. The method according to any one of Technical Claims 23 to 25, wherein the malignant tumor is selected from the group consisting of breast cancer, colorectal cancer, colon cancer, skin cancer, pancreatic cancer, prostate cancer, liver cancer, lung cancer, stomach cancer, leukemia, bile duct cancer, cervical cancer, endometrial cancer, esophageal cancer, head and neck cancer, lymphoma, medullary thyroid carcinoma, non-Hodgkin lymphoma, ovarian cancer, glioma, melanoma, and bladder cancer, and preferably the malignant tumor is selected from the group consisting of colorectal cancer, bile duct cancer, pancreatic cancer, and skin cancer.

[0240] 27. A method for producing an antibody or an antigen-binding fragment thereof that targets human tumor cells expressing ITGA2, (i) Culturing the host cells of the technical proposal 11 under conditions suitable for the expression of the nucleic acid molecule or expression vector, (ii) A method comprising isolating and purifying an antibody or an antigen-binding fragment thereof expressed by the nucleic acid molecule or expression vector.

[0241] Summary of Technical Proposals B 1. An isolated antibody or antigen-binding fragment thereof that specifically binds to the ITGA2 protein, wherein the isolated antibody or antigen-binding fragment thereof comprises a light chain variable region containing LCDR1, LCDR2, LCDR3 sequences and a heavy chain variable region containing HCDR1, HCDR2, HCDR3 sequences, wherein the antibody or antigen-binding fragment thereof has at least one group of light chain variable regions and heavy chain variable regions selected from the following: 1) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 74, (b) LCDR2 with SEQ ID NO: 75, and (c) LCDR3 with SEQ ID NO: 76, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 78, (e) HCDR2 with SEQ ID NO: 79, and (f) HCDR3 with SEQ ID NO: 80. 2) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 82, (b) LCDR2 with SEQ ID NO: 83, and (c) LCDR3 with SEQ ID NO: 84, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 86, (e) HCDR2 with SEQ ID NO: 87, and (f) HCDR3 with SEQ ID NO: 88. 3) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 90, (b) LCDR2 with SEQ ID NO: 91, and (c) LCDR3 with SEQ ID NO: 92, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 94, (e) HCDR2 with SEQ ID NO: 95, and (f) HCDR3 with SEQ ID NO: 96. 4) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 98, (b) LCDR2 with SEQ ID NO: 99, and (c) LCDR3 with SEQ ID NO: 100, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 102, (e) HCDR2 with SEQ ID NO: 103, and (f) HCDR3 with SEQ ID NO: 104. 5) The light chain variable region includes (a) LCDR1 of SEQ ID NO: 106, (b) LCDR2 of SEQ ID NO: 107, and (c) LCDR3 of SEQ ID NO: 108, and the heavy chain variable region includes (d) HCDR1 of SEQ ID NO: 110, (e) HCDR2 of SEQ ID NO: 111, and (f) HCDR3 of SEQ ID NO: 112. 6) The light chain variable region includes (a) LCDR1 of SEQ ID NO: 114, (b) LCDR2 of SEQ ID NO: 115, and (c) LCDR3 of SEQ ID NO: 116, and the heavy chain variable region includes (d) HCDR1 of SEQ ID NO: 118, (e) HCDR2 of SEQ ID NO: 119, and (f) HCDR3 of SEQ ID NO: 120. 7) An isolated antibody or antigen-binding fragment thereof, wherein the light chain variable region includes (a) LCDR1 of SEQ ID NO: 122, (b) LCDR2 of SEQ ID NO: 123, and (c) LCDR3 of SEQ ID NO: 124, and the heavy chain variable region includes (d) HCDR1 of SEQ ID NO: 126, (e) HCDR2 of SEQ ID NO: 127, and (f) HCDR3 of SEQ ID NO: 128.

[0242] 2. The isolated antibody or its antigen-binding fragment portion comprises a light chain variable region and a heavy chain variable region having at least one group selected from the following, i.e. 1) The light chain variable region comprising the amino acid sequence of SEQ ID NO:73 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:73, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:77 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:77, 2) The light chain variable region comprising the amino acid sequence of SEQ ID NO:81 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:81, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:85 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:85, 3) The light chain variable region comprising the amino acid sequence of SEQ ID NO:89 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:89, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:93 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:93, 4) The light chain variable region comprising the amino acid sequence of SEQ ID NO:97 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:97, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:101 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:101, 5) The light chain variable region comprising the amino acid sequence of SEQ ID NO:105 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:105, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:109 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:109, 6) The light chain variable region comprising the amino acid sequence of SEQ ID NO:113 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:113, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:117 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:117, and 7) The isolated antibody or antigen-binding fragment portion thereof according to Technical Proposal 1, comprising the light chain variable region containing the amino acid sequence of SEQ ID NO:121 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:121, and the heavy chain variable region containing the amino acid sequence of SEQ ID NO:125 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:125.

[0243] 3. The isolated antibody or its antigen-binding fragment portion further comprises a light chain constant region and a heavy chain constant region, The light chain constant region includes the amino acid sequence of SEQ ID NO:201 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:201. The heavy chain constant region comprises the amino acid sequence of SEQ ID NO:202 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:202, as described in Technical Proposal 1 or 2, an isolated antibody or its antigen-binding fragment portion.

[0244] 4. The isolated antibody or its antigen-binding fragment portion comprises a light chain and a heavy chain having at least one group selected from the following, i.e. 1) The light chain comprising the amino acid sequence of SEQ ID NO:211 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:211, and the heavy chain comprising the amino acid sequence comprising at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:212 or the amino acid sequence of SEQ ID NO:202, 2) The light chain comprising the amino acid sequence of SEQ ID NO:213 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:213, and the heavy chain comprising the amino acid sequence of SEQ ID NO:214 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:214, 3) The light chain comprising the amino acid sequence of SEQ ID NO:215 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:215, and the heavy chain comprising the amino acid sequence of SEQ ID NO:216 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:216, 4) The light chain comprising the amino acid sequence of SEQ ID NO:217 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:217, and the heavy chain comprising the amino acid sequence of SEQ ID NO:218 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:218, 5) The light chain comprising the amino acid sequence of SEQ ID NO:219 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:219, and the heavy chain comprising the amino acid sequence of SEQ ID NO:220 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:220, 6) The light chain comprising the amino acid sequence of SEQ ID NO:221 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:221, and the heavy chain comprising the amino acid sequence of SEQ ID NO:222 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:222, and 7) The isolated antibody or antigen-binding fragment portion thereof according to any one of Technical Proposals 1 to 3, comprising the light chain containing the amino acid sequence of SEQ ID NO:223 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:223, and the heavy chain containing the amino acid sequence of SEQ ID NO:224 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:224.

[0245] 5. The isolated antibody or its antigen-binding fragment portion consists of at least one group of light and heavy chains selected from the following: 1) A light chain consisting of the amino acid sequence of SEQ ID NO:211, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:212, 2) A light chain consisting of the amino acid sequence of SEQ ID NO:213, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:214, 3) A light chain consisting of the amino acid sequence of SEQ ID NO:215, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:216, 4) A light chain consisting of the amino acid sequence of SEQ ID NO:217, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:218, 5) A light chain consisting of the amino acid sequence of SEQ ID NO:219, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:220, 6) A light chain consisting of the amino acid sequence of SEQ ID NO:221, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:222, and 7) An isolated antibody or antigen-binding fragment thereof according to any one of Technical Proposals 1 to 4, comprising a light chain consisting of the amino acid sequence of SEQ ID NO:223 and the heavy chain consisting of the amino acid sequence of SEQ ID NO:224.

[0246] 6. An isolated antibody or antigen-binding fragment thereof that specifically binds to the ITGA2 protein, wherein the isolated antibody or antigen-binding fragment thereof has at least one group of light chains and heavy chains selected from the following: 1) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:9, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:9, 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:10, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:10, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:10. 2) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:11, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:11, 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:12, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:12, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:12. 3) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:13, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:13, 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:14, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:14, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:14. 4) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:15, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:15, 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:16, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:16, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:16. 5) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:17, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:17, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:17. The heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:18, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:18, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:18. 6) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:19, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:19, or consists 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 an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:20, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:20. 7) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:21, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:21, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:21. The heavy chain comprises an isolated antibody or its antigen-binding fragment portion, which includes an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:22, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:22, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:22.

[0247] 7. The antibody can bind to the ITGA2 protein in vitro with an EC50 of less than 1 nM, and / or The aforementioned antibody can bind to the ITGA2 protein on the surface of HuCCT1 cells with an EC50 of less than 5 nM. and / or, the antibody is a monoclonal antibody, a polyclonal antibody, a chimeric antibody, or a humanized antibody, as described in any one of the Technical Claims 1 to 6, an isolated antibody or its antigen-binding fragment portion.

[0248] 8. An isolated nucleic acid molecule that encodes an antibody or antigen-binding fragment thereof as described in any one of the technical proposals 1 to 7, or The nucleic acid molecule is SEQ ID NO:9 and SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:12, SEQ ID NO:13 and SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16, SEQ ID NO:17 and SEQ ID NO:18, SEQ ID NO:19 and SEQ ID NO:20, and An isolated nucleic acid molecule containing or consisting of a nucleotide sequence shown in any one combination selected from SEQ ID NO:21 and SEQ ID NO:22.

[0249] 9. The nucleic acid molecule is an isolated nucleic acid molecule according to Technical Proposal 8, wherein the nucleic acid molecule is operably linked to an expression regulatory sequence.

[0250] 10. An expression vector containing a nucleic acid molecule as described in Technical Proposal 8 or 9.

[0251] 11. A host cell containing a nucleic acid molecule described in Technical Proposal 8 or 9, or an expression vector described in Technical Proposal 10.

[0252] 12. Hybridoma cells expressing an antibody or its antigen-binding fragment portion as described in any one of Technical Proposals 1 to 7.

[0253] 13. An antibody-drug conjugate shown in the following formula, Ab-LD, and here, The symbol "Ab" represents at least one of the antibodies of the present invention described above or its antigen-binding fragment portion, The symbol "L" represents a linker that connects the antibody portion and the partner molecule. The symbol "D" represents a partner molecule. or Ab-(LD)p, where The symbol "Ab" represents at least one of the antibodies of the present invention described above or its antigen-binding fragment portion, The symbol "L" represents a linker that connects the antibody portion and the partner molecule. The symbol "D" represents a partner molecule. The symbol "p" represents the number of linker / partner molecules (preferably drug payloads) conjugated to the antibody or antigen-binding fragment portion of the present invention as described above. Optionally, p can be 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. An antibody-drug conjugate selected from the following values: 0.8, 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.

[0254] 14. The antibody-drug conjugate according to proposal 13, wherein the linker is selected from one of vc, mc-GGFG, AcLysvc, mc, MalPeg6, m(H2O)c, and m(H2O)cvc, and / or the linker is cleavable.

[0255] 15. The partner molecule is a drug payload, the drug payload is a therapeutic molecule, and optionally the drug payload is selected from one of cytotoxic agents, cell inhibitors, immunomodulators and chemotherapeutic agents, and optionally the drug payload is selected from one of 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 antibody-drug conjugate according to proposal 13 or 14, wherein the partner molecule is a labeling molecule, and optionally, the labeling molecule is selected from one of the following: radiolabeling (e.g., isotope), fluorescent labeling (e.g., fluorescent dye), chemical substance, and a detectably modified enzyme and tag.

[0256] 16. A pharmaceutical composition comprising an antibody or an antigen-binding fragment thereof as described in any one of Technical Proposals 1 to 7, or an antibody-drug conjugate as described in any one of Technical Proposals 13 to 15, and optionally, a pharmaceutically acceptable carrier.

[0257] 17. Uses in the manufacture of a pharmaceutical composition of an antibody or antigen-binding fragment thereof as described in any one of Technical Proposals 1 to 7, or an antibody-drug conjugate as described in any one of Technical Proposals 13 to 15, wherein the pharmaceutical composition is optionally used to treat a malignant tumor in a patient, prevent and / or treat the metastasis or recurrence of the malignant tumor, optionally used to detect the presence of a malignant tumor in a patient, and optionally used for the prognosis of the recurrence or progression of a malignant tumor in a patient.

[0258] 18. A method for preventing and / or treating metastasis or recurrence of a malignant tumor in a patient, the method comprising administering to the patient an effective amount of an antibody or antigen-binding fragment thereof described in any one of Technical Proposals 1 to 7, an antibody-drug conjugate described in any one of Technical Proposals 13 to 15, or a pharmaceutical composition described in Technical Proposal 16.

[0259] 19. The method according to Technical Proposal 18, wherein the malignant tumor is selected from the group consisting of breast cancer, colorectal cancer, skin cancer, pancreatic cancer, prostate cancer, liver cancer, lung cancer, stomach cancer, leukemia, bile duct cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, head and neck cancer, lymphoma, medullary thyroid carcinoma, non-Hodgkin lymphoma, ovarian cancer, glioma, melanoma, and bladder cancer, and preferably the malignant tumor is selected from the group consisting of colorectal cancer, bile duct cancer, pancreatic cancer, and skin cancer.

[0260] 20. The method according to proposal 18 or 19, further comprising administering to the patient other antitumor treatment means, for example, a chemotherapeutic agent, an antibody targeting another tumor-specific antigen, or radiotherapy.

[0261] 21. A method for detecting the presence of tumor cells in a biological sample, a) Contacting the biological sample with an antibody or its antigen-binding fragment portion described in any one of Technical Proposals 1 to 7, b) The process includes detecting the binding of the antibody or its antigen-binding fragment to the target antigen in the biological sample, Here, the detection of the binding indicates the presence of tumor cells in the biological sample.

[0262] 22. A method for detecting the presence of a malignant tumor in a patient, a) Contacting the biological sample obtained from the patient with an antibody or its antigen-binding fragment described in any one of Technical Proposals 1 to 7, b) A method comprising detecting the binding of the antibody or its antigen-binding fragment portion to a target antigen in the biological sample, wherein the detection of the binding indicates the presence of a malignant tumor in the patient.

[0263] 23. A method for determining the prognosis of recurrence or progression of malignant tumors in patients, wherein the method is: (a) Isolating a biological sample containing tumor cells from the patient, (b) Contacting the biological sample containing the tumor cells with an antibody or its antigen-binding fragment described in any one of the technical proposals 1 to 7, (c) Identifying the presence of tumor cells that bind to the antibody or its antigen-binding fragment portion, A method for determining the prognosis of recurrence or progression of a malignant tumor in the aforementioned patient.

[0264] 24. The method according to the proposal 23, wherein the progression of the malignant tumor includes metastasis in the patient with the malignant tumor.

[0265] 25. The method according to Technical Proposal 23 or 24, wherein the biological sample is selected from one of a blood sample, a tissue sample, and a lymph sample.

[0266] 26. The method according to any one of Technical Claims 23 to 25, wherein the malignant tumor is selected from the group consisting of breast cancer, colorectal cancer, colon cancer, skin cancer, pancreatic cancer, prostate cancer, liver cancer, lung cancer, stomach cancer, leukemia, bile duct cancer, cervical cancer, endometrial cancer, esophageal cancer, head and neck cancer, lymphoma, medullary thyroid carcinoma, non-Hodgkin lymphoma, ovarian cancer, glioma, melanoma, and bladder cancer, and preferably the malignant tumor is selected from the group consisting of colorectal cancer, bile duct cancer, pancreatic cancer, and skin cancer.

[0267] 27. A method for producing an antibody or an antigen-binding fragment thereof that targets human tumor cells expressing ITGA2, (i) Culturing the host cells of the technical proposal 11 under conditions suitable for the expression of the nucleic acid molecule or expression vector, (ii) A method comprising isolating and purifying an antibody or an antigen-binding fragment thereof expressed by the nucleic acid molecule or expression vector.

[0268] Summary of Technical Proposals C 1. An isolated antibody or antigen-binding fragment thereof that specifically binds to the ITGA2 protein, wherein the isolated antibody or antigen-binding fragment thereof comprises a light chain variable region containing LCDR1, LCDR2, LCDR3 sequences and a heavy chain variable region containing HCDR1, HCDR2, HCDR3 sequences, wherein the antibody or antigen-binding fragment thereof has at least one group of light chain variable regions and heavy chain variable regions selected from the following: 1) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 130, (b) LCDR2 with SEQ ID NO: 131, and (c) LCDR3 with SEQ ID NO: 132, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 134, (e) HCDR2 with SEQ ID NO: 135, and (f) HCDR3 with SEQ ID NO: 136. 2) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 138, (b) LCDR2 with SEQ ID NO: 139, and (c) LCDR3 with SEQ ID NO: 140, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 142, (e) HCDR2 with SEQ ID NO: 143, and (f) HCDR3 with SEQ ID NO: 144. 3) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 146, (b) LCDR2 with SEQ ID NO: 147, and (c) LCDR3 with SEQ ID NO: 148, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 150, (e) HCDR2 with SEQ ID NO: 151, and (f) HCDR3 with SEQ ID NO: 152. 4) An isolated antibody or antigen-binding fragment thereof, wherein the light chain variable region includes (a) LCDR1 of SEQ ID NO: 154, (b) LCDR2 of SEQ ID NO: 155, and (c) LCDR3 of SEQ ID NO: 156, and the heavy chain variable region includes (d) HCDR1 of SEQ ID NO: 158, (e) HCDR2 of SEQ ID NO: 159, and (f) HCDR3 of SEQ ID NO: 160.

[0269] 2. The isolated antibody or its antigen-binding fragment portion comprises a light chain variable region and a heavy chain variable region having at least one group selected from the following, i.e. 1) The light chain variable region comprising the amino acid sequence of SEQ ID NO:129 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:129, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:133 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:133, 2) The light chain variable region comprising the amino acid sequence of SEQ ID NO:137 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:137, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:141 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:141, 3) The light chain variable region comprising the amino acid sequence of SEQ ID NO:145 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:145, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:149 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:149, and 4) The isolated antibody or antigen-binding fragment portion thereof according to Technical Proposal 1, comprising the light chain variable region containing the amino acid sequence of SEQ ID NO:153 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:153, and the heavy chain variable region containing the amino acid sequence of SEQ ID NO:157 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:157.

[0270] 3. The isolated antibody or its antigen-binding fragment portion further comprises a light chain constant region and a heavy chain constant region, The light chain constant region includes the amino acid sequence of SEQ ID NO:201 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:201. The heavy chain constant region comprises the amino acid sequence of SEQ ID NO:202 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:202, as described in Technical Proposal 1 or 2, an isolated antibody or its antigen-binding fragment portion.

[0271] 4. The isolated antibody or its antigen-binding fragment portion comprises a light chain and a heavy chain having at least one group selected from the following, i.e. 1) The light chain comprising the amino acid sequence of SEQ ID NO:225 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:225, and the heavy chain comprising the amino acid sequence of SEQ ID NO:226 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:226, 2) The light chain comprising the amino acid sequence of SEQ ID NO:227 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:227, and the heavy chain comprising the amino acid sequence of SEQ ID NO:228 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:228, 3) The light chain comprising the amino acid sequence of SEQ ID NO:229 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:229, and the heavy chain comprising the amino acid sequence of SEQ ID NO:230 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:230, and 4) The isolated antibody or antigen-binding fragment portion thereof according to any one of Technical Proposals 1 to 3, comprising the light chain containing the amino acid sequence of SEQ ID NO:231 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:231, and the heavy chain containing the amino acid sequence of SEQ ID NO:232 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:232.

[0272] 5. The isolated antibody or its antigen-binding fragment portion consists of at least one group of light and heavy chains selected from the following: 1) A light chain consisting of the amino acid sequence of SEQ ID NO:225, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:226, 2) A light chain consisting of the amino acid sequence of SEQ ID NO:227, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:228, 3) A light chain consisting of the amino acid sequence of SEQ ID NO:229, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:230, and 4) An isolated antibody or antigen-binding fragment thereof according to any one of Technical Proposals 1 to 4, comprising a light chain consisting of the amino acid sequence of SEQ ID NO:231 and the heavy chain consisting of the amino acid sequence of SEQ ID NO:232.

[0273] 6. An isolated antibody or antigen-binding fragment thereof that specifically binds to the ITGA2 protein, wherein the isolated antibody or antigen-binding fragment thereof has at least one group of light chains and heavy chains selected from the following: 1) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:23, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:23, or consists 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 an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:24, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:24. 2) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:25, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:25, 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 an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:26, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:26. 3) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:27, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:27, or consists 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 an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:28, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:28. 4) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:29, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:29, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:29. The heavy chain comprises an isolated antibody or its antigen-binding fragment portion, which includes an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:30, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:30, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:30.

[0274] 7. The antibody can conjugate to the ITGA2 protein in vitro with an EC50 of less than 1 nM, and / or The aforementioned antibody can bind to the ITGA2 protein on the surface of HuCCT1 cells with an EC50 of less than 5 nM. and / or, the antibody is a monoclonal antibody, a polyclonal antibody, a chimeric antibody, or a humanized antibody, as described in any one of the Technical Claims 1 to 6, an isolated antibody or its antigen-binding fragment portion.

[0275] 8. An isolated nucleic acid molecule that encodes an antibody or antigen-binding fragment thereof as described in any one of the technical proposals 1 to 7, or The nucleic acid molecule is SEQ ID NO:23 and SEQ ID NO:24, SEQ ID NO:25 and SEQ ID NO:26, SEQ ID NO:27 and SEQ ID NO:28, and An isolated nucleic acid molecule containing or consisting of a nucleotide sequence shown in any one combination selected from SEQ ID NO:29 and SEQ ID NO:30.

[0276] 9. The nucleic acid molecule is an isolated nucleic acid molecule according to Technical Proposal 8, wherein the nucleic acid molecule is operably linked to an expression regulatory sequence.

[0277] 10. An expression vector containing a nucleic acid molecule as described in Technical Proposal 8 or 9.

[0278] 11. A host cell containing a nucleic acid molecule described in Technical Proposal 8 or 9, or an expression vector described in Technical Proposal 10.

[0279] 12. Hybridoma cells expressing an antibody or its antigen-binding fragment portion as described in any one of Technical Proposals 1 to 7.

[0280] 13. An antibody-drug conjugate shown in the following formula, Ab-LD, and here, The symbol "Ab" represents at least one of the antibodies of the present invention described above or its antigen-binding fragment portion, The symbol "L" represents a linker that connects the antibody portion and the partner molecule. The symbol "D" represents a partner molecule. or Ab-(LD)p, where The symbol "Ab" represents at least one of the antibodies of the present invention described above or its antigen-binding fragment portion, The symbol "L" represents a linker that connects the antibody portion and the partner molecule. The symbol "D" represents a partner molecule. The symbol "p" represents the number of linker / partner molecules (preferably drug payloads) conjugated to the antibody or antigen-binding fragment portion of the present invention as described above. Optionally, p can be 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. An antibody-drug conjugate selected from the following values: 0.8, 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.

[0281] 14. The antibody-drug conjugate according to proposal 13, wherein the linker is selected from one of vc, mc-GGFG, AcLysvc, mc, MalPeg6, m(H2O)c, and m(H2O)cvc, and / or the linker is cleavable.

[0282] 15. The partner molecule is a drug payload, the drug payload is a therapeutic molecule, and optionally the drug payload is selected from one of cytotoxic agents, cell inhibitors, immunomodulators and chemotherapeutic agents, and optionally the drug payload is selected from one of 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 antibody-drug conjugate according to proposal 13 or 14, wherein the partner molecule is a labeling molecule, and optionally, the labeling molecule is selected from one of the following: radiolabeling (e.g., isotope), fluorescent labeling (e.g., fluorescent dye), chemical substance, and a detectably modified enzyme and tag.

[0283] 16. A pharmaceutical composition comprising an antibody or an antigen-binding fragment thereof as described in any one of Technical Proposals 1 to 7, or an antibody-drug conjugate as described in any one of Technical Proposals 13 to 15, and optionally, a pharmaceutically acceptable carrier.

[0284] 17. Uses in the manufacture of a pharmaceutical composition of an antibody or antigen-binding fragment thereof as described in any one of Technical Proposals 1 to 7, or an antibody-drug conjugate as described in any one of Technical Proposals 13 to 15, wherein the pharmaceutical composition is optionally used to treat a malignant tumor in a patient, prevent and / or treat the metastasis or recurrence of the malignant tumor, optionally used to detect the presence of a malignant tumor in a patient, and optionally used for the prognosis of the recurrence or progression of a malignant tumor in a patient.

[0285] 18. A method for preventing and / or treating metastasis or recurrence of a malignant tumor in a patient, the method comprising administering to the patient an effective amount of an antibody or antigen-binding fragment thereof described in any one of Technical Proposals 1 to 7, an antibody-drug conjugate described in any one of Technical Proposals 13 to 15, or a pharmaceutical composition described in Technical Proposal 16.

[0286] 19. The method according to Technical Proposal 18, wherein the malignant tumor is selected from the group consisting of breast cancer, colorectal cancer, skin cancer, pancreatic cancer, prostate cancer, liver cancer, lung cancer, stomach cancer, leukemia, bile duct cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, head and neck cancer, lymphoma, medullary thyroid carcinoma, non-Hodgkin lymphoma, ovarian cancer, glioma, melanoma, and bladder cancer, and preferably the malignant tumor is selected from the group consisting of colorectal cancer, bile duct cancer, pancreatic cancer, and skin cancer.

[0287] 20. The method according to proposal 18 or 19, further comprising administering to the patient other antitumor treatment means, for example, a chemotherapeutic agent, an antibody targeting another tumor-specific antigen, or radiotherapy.

[0288] 21. A method for detecting the presence of tumor cells in a biological sample, a) Contacting the biological sample with an antibody or its antigen-binding fragment portion described in any one of Technical Proposals 1 to 7, b) The process includes detecting the binding of the antibody or its antigen-binding fragment to the target antigen in the biological sample, Here, the detection of the binding indicates the presence of tumor cells in the biological sample.

[0289] 22. A method for detecting the presence of a malignant tumor in a patient, a) Contacting the biological sample obtained from the patient with an antibody or its antigen-binding fragment described in any one of Technical Proposals 1 to 7, b) A method comprising detecting the binding of the antibody or its antigen-binding fragment portion to a target antigen in the biological sample, wherein the detection of the binding indicates the presence of a malignant tumor in the patient.

[0290] 23. A method for determining the prognosis of recurrence or progression of malignant tumors in patients, wherein the method is: (a) Isolating a biological sample containing tumor cells from the patient, (b) Contacting the biological sample containing the tumor cells with an antibody or its antigen-binding fragment described in any one of the technical proposals 1 to 7, (c) Identifying the presence of tumor cells that bind to the antibody or its antigen-binding fragment portion, A method for determining the prognosis of recurrence or progression of a malignant tumor in the aforementioned patient.

[0291] 24. The method according to the proposal 23, wherein the progression of the malignant tumor includes metastasis in the patient with the malignant tumor.

[0292] 25. The method according to Technical Proposal 23 or 24, wherein the biological sample is selected from one of a blood sample, a tissue sample, and a lymph sample.

[0293] 26. The method according to any one of Technical Claims 23 to 25, wherein the malignant tumor is selected from the group consisting of breast cancer, colorectal cancer, colon cancer, skin cancer, pancreatic cancer, prostate cancer, liver cancer, lung cancer, stomach cancer, leukemia, bile duct cancer, cervical cancer, endometrial cancer, esophageal cancer, head and neck cancer, lymphoma, medullary thyroid carcinoma, non-Hodgkin lymphoma, ovarian cancer, glioma, melanoma, and bladder cancer, and preferably the malignant tumor is selected from the group consisting of colorectal cancer, bile duct cancer, pancreatic cancer, and skin cancer.

[0294] 27. A method for producing an antibody or an antigen-binding fragment thereof that targets human tumor cells expressing ITGA2, (i) Culturing the host cells of the technical proposal 11 under conditions suitable for the expression of the nucleic acid molecule or expression vector, (ii) A method comprising isolating and purifying an antibody or an antigen-binding fragment thereof expressed by the nucleic acid molecule or expression vector.

[0295] Summary of Technical Proposals D 1. An isolated antibody or antigen-binding fragment thereof that specifically binds to the ITGA2 protein, wherein the isolated antibody or antigen-binding fragment thereof comprises a light chain variable region containing LCDR1, LCDR2, LCDR3 sequences and a heavy chain variable region containing HCDR1, HCDR2, HCDR3 sequences, wherein the antibody or antigen-binding fragment thereof has at least one group of light chain variable regions and heavy chain variable regions selected from the following: 1) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 162, (b) LCDR2 with SEQ ID NO: 163, and (c) LCDR3 with SEQ ID NO: 164, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 166, (e) HCDR2 with SEQ ID NO: 167, and (f) HCDR3 with SEQ ID NO: 168. 2) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 170, (b) LCDR2 with SEQ ID NO: 171, and (c) LCDR3 with SEQ ID NO: 172, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 174, (e) HCDR2 with SEQ ID NO: 175, and (f) HCDR3 with SEQ ID NO: 176. 3) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 178, (b) LCDR2 with SEQ ID NO: 179, and (c) LCDR3 with SEQ ID NO: 180, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 182, (e) HCDR2 with SEQ ID NO: 183, and (f) HCDR3 with SEQ ID NO: 184. 4) The light chain variable region includes (a) LCDR1 with SEQ ID NO: 186, (b) LCDR2 with SEQ ID NO: 187, and (c) LCDR3 with SEQ ID NO: 188, and the heavy chain variable region includes (d) HCDR1 with SEQ ID NO: 190, (e) HCDR2 with SEQ ID NO: 191, and (f) HCDR3 with SEQ ID NO: 192. 5) An isolated antibody or antigen-binding fragment thereof, wherein the light chain variable region includes (a) LCDR1 of SEQ ID NO: 194, (b) LCDR2 of SEQ ID NO: 195, and (c) LCDR3 of SEQ ID NO: 196, and the heavy chain variable region includes (d) HCDR1 of SEQ ID NO: 198, (e) HCDR2 of SEQ ID NO: 199, and (f) HCDR3 of SEQ ID NO: 200.

[0296] 2. The isolated antibody or its antigen-binding fragment portion comprises a light chain variable region and a heavy chain variable region having at least one group selected from the following, i.e. 1) The light chain variable region comprising the amino acid sequence of SEQ ID NO:161 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:161, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:165 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:165, 2) The light chain variable region comprising the amino acid sequence of SEQ ID NO:169 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:169, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:173 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:173, 3) The light chain variable region comprising the amino acid sequence of SEQ ID NO:177 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:177, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:181 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:181, 4) The light chain variable region comprising the amino acid sequence of SEQ ID NO:185 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:185, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:189 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:189, and 5) The isolated antibody or antigen-binding fragment portion thereof according to Technical Proposal 1, comprising the light chain variable region containing the amino acid sequence of SEQ ID NO:193 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:193, and the heavy chain variable region containing the amino acid sequence of SEQ ID NO:197 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:197.

[0297] 3. The isolated antibody or its antigen-binding fragment portion further comprises a light chain constant region and a heavy chain constant region, The light chain constant region includes the amino acid sequence of SEQ ID NO:201 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:201. The heavy chain constant region comprises the amino acid sequence of SEQ ID NO:202 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:202, as described in Technical Proposal 1 or 2, an isolated antibody or its antigen-binding fragment portion.

[0298] 4. The isolated antibody or its antigen-binding fragment portion comprises a light chain and a heavy chain having at least one group selected from the following, i.e. 1) The light chain comprising the amino acid sequence of SEQ ID NO:233 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:233, and the heavy chain comprising the amino acid sequence of SEQ ID NO:234 ​​or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:234, 2) The light chain comprising the amino acid sequence of SEQ ID NO:235 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:235, and the heavy chain comprising the amino acid sequence of SEQ ID NO:236 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:236, 3) The light chain comprising the amino acid sequence of SEQ ID NO:237 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:237, and the heavy chain comprising the amino acid sequence of SEQ ID NO:238 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:238, 4) The light chain comprising the amino acid sequence of SEQ ID NO:239 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:239, and the heavy chain comprising the amino acid sequence of SEQ ID NO:240 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:240, and 5) The isolated antibody or antigen-binding fragment portion thereof according to any one of Technical Proposals 1 to 3, comprising the light chain containing the amino acid sequence of SEQ ID NO:241 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:241, and the heavy chain containing the amino acid sequence of SEQ ID NO:242 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:242.

[0299] 5. The isolated antibody or its antigen-binding fragment portion consists of at least one group of light and heavy chains selected from the following: 1) A light chain consisting of the amino acid sequence of SEQ ID NO:233, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:234, 2) A light chain consisting of the amino acid sequence of SEQ ID NO:235, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:236, 3) A light chain consisting of the amino acid sequence of SEQ ID NO:237, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:238, 4) A light chain consisting of the amino acid sequence of SEQ ID NO:239, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:240, and 5) An isolated antibody or antigen-binding fragment thereof according to any one of Technical Proposals 1 to 4, comprising a light chain consisting of the amino acid sequence of SEQ ID NO: 241 and the heavy chain consisting of the amino acid sequence of SEQ ID NO: 242.

[0300] 6. An isolated antibody or antigen-binding fragment thereof that specifically binds to the ITGA2 protein, wherein the isolated antibody or antigen-binding fragment thereof has at least one group of light chains and heavy chains selected from the following: 1) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:31, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:31, or consists 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 an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:32, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:32. 2) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:33, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:33, or consists 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 an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:34, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:34. 3) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:35, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:35, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:35. The heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:36, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:36, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:36. 4) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:37, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:37, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:37. The heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:38, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:38, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:38. 5) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:39, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:39, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:39. The heavy chain comprises an isolated antibody or its antigen-binding fragment portion, which includes an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:40, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:40, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:40.

[0301] 7. The antibody can bind to the ITGA2 protein in vitro with an EC50 of less than 1 nM, and / or The aforementioned antibody can bind to the ITGA2 protein on the surface of HuCCT1 cells with an EC50 of less than 5 nM. and / or, the antibody is a monoclonal antibody, a polyclonal antibody, a chimeric antibody, or a humanized antibody, as described in any one of the Technical Claims 1 to 6, an isolated antibody or its antigen-binding fragment portion.

[0302] 8. An isolated nucleic acid molecule that encodes an antibody or antigen-binding fragment thereof as described in any one of the technical proposals 1 to 7, or The nucleic acid molecule is SEQ ID NO:31 and SEQ ID NO:32, SEQ ID NO:33 and SEQ ID NO:34, SEQ ID NO:35 and SEQ ID NO:36, SEQ ID NO:37 and SEQ ID NO:38, and An isolated nucleic acid molecule containing or consisting of a nucleotide sequence shown in any one combination selected from SEQ ID NO:39 and SEQ ID NO:40.

[0303] 9. The nucleic acid molecule is an isolated nucleic acid molecule according to Technical Proposal 8, wherein the nucleic acid molecule is operably linked to an expression regulatory sequence.

[0304] 10. An expression vector containing a nucleic acid molecule as described in Technical Proposal 8 or 9.

[0305] 11. A host cell containing a nucleic acid molecule described in Technical Proposal 8 or 9, or an expression vector described in Technical Proposal 10.

[0306] 12. Hybridoma cells expressing an antibody or its antigen-binding fragment portion as described in any one of Technical Proposals 1 to 7.

[0307] 13. An antibody-drug conjugate shown in the following formula, Ab-LD, and here, The symbol "Ab" represents at least one of the antibodies of the present invention described above or its antigen-binding fragment portion, The symbol "L" represents a linker that connects the antibody portion and the partner molecule. The symbol "D" represents a partner molecule. or Ab-(LD)p, where The symbol "Ab" represents at least one of the antibodies of the present invention described above or its antigen-binding fragment portion, The symbol "L" represents a linker that connects the antibody portion and the partner molecule. The symbol "D" represents a partner molecule. The symbol "p" represents the number of linker / partner molecules (preferably drug payloads) conjugated to the antibody or antigen-binding fragment portion of the present invention as described above. Optionally, p can be 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. An antibody-drug conjugate selected from the following values: 0.8, 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.

[0308] 14. The antibody-drug conjugate according to proposal 13, wherein the linker is selected from one of vc, mc-GGFG, AcLysvc, mc, MalPeg6, m(H2O)c, and m(H2O)cvc, and / or the linker is cleavable.

[0309] 15. The partner molecule is a drug payload, the drug payload is a therapeutic molecule, and optionally the drug payload is selected from one of cytotoxic agents, cell inhibitors, immunomodulators and chemotherapeutic agents, and optionally the drug payload is selected from one of 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 antibody-drug conjugate according to proposal 13 or 14, wherein the partner molecule is a labeling molecule, and optionally, the labeling molecule is selected from one of the following: radiolabeling (e.g., isotope), fluorescent labeling (e.g., fluorescent dye), chemical substance, and a detectably modified enzyme and tag.

[0310] 16. A pharmaceutical composition comprising an antibody or an antigen-binding fragment thereof as described in any one of Technical Proposals 1 to 7, or an antibody-drug conjugate as described in any one of Technical Proposals 13 to 15, and optionally, a pharmaceutically acceptable carrier.

[0311] 17. Uses in the manufacture of a pharmaceutical composition of an antibody or antigen-binding fragment thereof as described in any one of Technical Proposals 1 to 7, or an antibody-drug conjugate as described in any one of Technical Proposals 13 to 15, wherein the pharmaceutical composition is optionally used to treat a malignant tumor in a patient, prevent and / or treat the metastasis or recurrence of the malignant tumor, optionally used to detect the presence of a malignant tumor in a patient, and optionally used for the prognosis of the recurrence or progression of a malignant tumor in a patient.

[0312] 18. A method for preventing and / or treating metastasis or recurrence of a malignant tumor in a patient, the method comprising administering to the patient an effective amount of an antibody or antigen-binding fragment thereof described in any one of Technical Proposals 1 to 7, an antibody-drug conjugate described in any one of Technical Proposals 13 to 15, or a pharmaceutical composition described in Technical Proposal 16.

[0313] 19. The method according to Technical Proposal 18, wherein the malignant tumor is selected from the group consisting of breast cancer, colorectal cancer, skin cancer, pancreatic cancer, prostate cancer, liver cancer, lung cancer, stomach cancer, leukemia, bile duct cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, head and neck cancer, lymphoma, medullary thyroid carcinoma, non-Hodgkin lymphoma, ovarian cancer, glioma, melanoma, and bladder cancer, and preferably the malignant tumor is selected from the group consisting of colorectal cancer, bile duct cancer, pancreatic cancer, and skin cancer.

[0314] 20. The method according to proposal 18 or 19, further comprising administering to the patient other antitumor treatment means, for example, a chemotherapeutic agent, an antibody targeting another tumor-specific antigen, or radiotherapy.

[0315] 21. A method for detecting the presence of tumor cells in a biological sample, a) Contacting the biological sample with an antibody or its antigen-binding fragment portion described in any one of Technical Proposals 1 to 7, b) The process includes detecting the binding of the antibody or its antigen-binding fragment to the target antigen in the biological sample, Here, the detection of the binding indicates the presence of tumor cells in the biological sample.

[0316] 22. A method for detecting the presence of a malignant tumor in a patient, a) Contacting the biological sample obtained from the patient with an antibody or its antigen-binding fragment described in any one of Technical Proposals 1 to 7, b) A method comprising detecting the binding of the antibody or its antigen-binding fragment portion to a target antigen in the biological sample, wherein the detection of the binding indicates the presence of a malignant tumor in the patient.

[0317] 23. A method for determining the prognosis of recurrence or progression of malignant tumors in patients, wherein the method is: (a) Isolating a biological sample containing tumor cells from the patient, (b) Contacting the biological sample containing the tumor cells with an antibody or its antigen-binding fragment described in any one of the technical proposals 1 to 7, (c) Identifying the presence of tumor cells that bind to the antibody or its antigen-binding fragment portion, A method for determining the prognosis of recurrence or progression of a malignant tumor in the aforementioned patient.

[0318] 24. The method according to the proposal 23, wherein the progression of the malignant tumor includes metastasis in the patient with the malignant tumor.

[0319] 25. The method according to Technical Proposal 23 or 24, wherein the biological sample is selected from one of a blood sample, a tissue sample, and a lymph sample.

[0320] 26. The method according to any one of Technical Claims 23 to 25, wherein the malignant tumor is selected from the group consisting of breast cancer, colorectal cancer, colon cancer, skin cancer, pancreatic cancer, prostate cancer, liver cancer, lung cancer, stomach cancer, leukemia, bile duct cancer, cervical cancer, endometrial cancer, esophageal cancer, head and neck cancer, lymphoma, medullary thyroid carcinoma, non-Hodgkin lymphoma, ovarian cancer, glioma, melanoma, and bladder cancer, and preferably the malignant tumor is selected from the group consisting of colorectal cancer, bile duct cancer, pancreatic cancer, and skin cancer.

[0321] 27. A method for producing an antibody or an antigen-binding fragment thereof that targets human tumor cells expressing ITGA2, (i) Culturing the host cells of the technical proposal 11 under conditions suitable for the expression of the nucleic acid molecule or expression vector, (ii) A method comprising isolating and purifying an antibody or an antigen-binding fragment thereof expressed by the nucleic acid molecule or expression vector.

Claims

1. An isolated antibody or antigen-binding fragment thereof that specifically binds to the ITGA2 protein, wherein the isolated antibody or antigen-binding fragment thereof comprises a light chain variable region containing the LCDR1, LCDR2, LCDR3 sequences and a heavy chain variable region containing the HCDR1, HCDR2, HCDR3 sequences, wherein the antibody or antigen-binding fragment thereof has at least one group of light chain variable regions and heavy chain variable regions selected from the following: 1) The light chain variable region includes (a) LCDR1 of SEQ ID NO: 162, (b) LCDR2 of SEQ ID NO: 163, and (c) LCDR3 of SEQ ID NO: 164, and the heavy chain variable region includes (d) HCDR1 of SEQ ID NO: 166, (e) HCDR2 of SEQ ID NO: 167, and (f) HCDR3 of SEQ ID NO:

168. 2) The light chain variable region includes (a) LCDR1 of SEQ ID NO: 170, (b) LCDR2 of SEQ ID NO: 171, and (c) LCDR3 of SEQ ID NO: 172, and the heavy chain variable region includes (d) HCDR1 of SEQ ID NO: 174, (e) HCDR2 of SEQ ID NO: 175, and (f) HCDR3 of SEQ ID NO:

176. 3) The light chain variable region includes (a) LCDR1 of SEQ ID NO: 178, (b) LCDR2 of SEQ ID NO: 179, and (c) LCDR3 of SEQ ID NO: 180, and the heavy chain variable region includes (d) HCDR1 of SEQ ID NO: 182, (e) HCDR2 of SEQ ID NO: 183, and (f) HCDR3 of SEQ ID NO:

184. 4) The light chain variable region includes (a) LCDR1 of SEQ ID NO: 186, (b) LCDR2 of SEQ ID NO: 187, and (c) LCDR3 of SEQ ID NO: 188, and the heavy chain variable region includes (d) HCDR1 of SEQ ID NO: 190, (e) HCDR2 of SEQ ID NO: 191, and (f) HCDR3 of SEQ ID NO:

192. 5) An isolated antibody or its antigen-binding fragment portion, wherein the light chain variable region includes (a) LCDR1 of SEQ ID NO: 194, (b) LCDR2 of SEQ ID NO: 195, and (c) LCDR3 of SEQ ID NO: 196, and the heavy chain variable region includes (d) HCDR1 of SEQ ID NO: 198, (e) HCDR2 of SEQ ID NO: 199, and (f) HCDR3 of SEQ ID NO:

200.

2. The isolated antibody or its antigen-binding fragment portion comprises a light chain variable region and a heavy chain variable region having at least one group selected from the following, i.e. 1) The light chain variable region comprising the amino acid sequence of SEQ ID NO: 161 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO: 161, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 165 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO: 165, 2) The light chain variable region comprising the amino acid sequence of SEQ ID NO: 169 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO: 169, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 173 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO: 173, 3) The light chain variable region comprising the amino acid sequence of SEQ ID NO: 177 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO: 177, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 181 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO: 181, 4) The light chain variable region comprising the amino acid sequence of SEQ ID NO: 185 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO: 185, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 189 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO: 189, and 5) The isolated antibody or antigen-binding fragment portion thereof according to claim 1, comprising the light chain variable region comprising the amino acid sequence of SEQ ID NO: 193 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO: 193, and the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 197 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:

197.

3. The isolated antibody or its antigen-binding fragment portion further comprises a light chain constant region and a heavy chain constant region, The light chain constant region includes the amino acid sequence of SEQ ID NO: 201 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:

201. The isolated antibody or antigen-binding fragment portion thereof according to claim 1 or 2, wherein the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 202 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:

202.

4. The isolated antibody or its antigen-binding fragment portion comprises a light chain and a heavy chain having at least one group selected from the following, i.e. 1) The light chain comprising the amino acid sequence of SEQ ID NO: 233 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO: 233, and the heavy chain comprising the amino acid sequence of SEQ ID NO: 234 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO: 234, 2) The light chain comprising the amino acid sequence of SEQ ID NO: 235 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO: 235, and the heavy chain comprising the amino acid sequence of SEQ ID NO: 236 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO: 236, 3) The light chain comprising the amino acid sequence of SEQ ID NO: 237 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO: 237, and the heavy chain comprising the amino acid sequence of SEQ ID NO: 238 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO: 238, 4) The light chain comprising the amino acid sequence of SEQ ID NO: 239 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO: 239, and the heavy chain comprising the amino acid sequence of SEQ ID NO: 240 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO: 240, and 5) The isolated antibody or antigen-binding fragment portion thereof according to any one of claims 1 to 3, comprising the light chain comprising the amino acid sequence of SEQ ID NO: 241 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO: 241, and the heavy chain comprising the amino acid sequence of SEQ ID NO: 242 or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO:

242.

5. The isolated antibody or its antigen-binding fragment portion consists of at least one group of light and heavy chains selected from the following, namely, 1) A light chain consisting of the amino acid sequence of SEQ ID NO: 233, and the heavy chain consisting of the amino acid sequence of SEQ ID NO: 234, 2) A light chain consisting of the amino acid sequence of SEQ ID NO: 235, and the heavy chain consisting of the amino acid sequence of SEQ ID NO: 236, 3) A light chain consisting of the amino acid sequence of SEQ ID NO: 237, and the heavy chain consisting of the amino acid sequence of SEQ ID NO: 238, 4) A light chain consisting of the amino acid sequence of SEQ ID NO: 239, and the heavy chain consisting of the amino acid sequence of SEQ ID NO: 240, and 5) An isolated antibody or antigen-binding fragment portion thereof according to any one of claims 1 to 4, comprising a light chain consisting of the amino acid sequence of SEQ ID NO: 241 and the heavy chain consisting of the amino acid sequence of SEQ ID NO:

242.

6. An isolated antibody or its antigen-binding fragment portion that specifically binds to the ITGA2 protein, wherein the isolated antibody or its antigen-binding fragment portion has at least one group of light chains and heavy chains selected from the following: 1) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31, or consists 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 an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:32, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:

32. 2) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33, or consists 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 an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:34, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:

34. 3) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:

35. The heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:

36. 4) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 37, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 37, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:

37. The heavy chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 38, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 38, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:

38. 5) The light chain contains an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 39, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 39, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:

39. The heavy chain comprises an isolated antibody or its antigen-binding fragment portion, which includes an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 40, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 40, or consists of an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:

40.

7. The antibody can bind to the ITGA2 protein in vitro with an EC50 of less than 1 nM, and / or The aforementioned antibody can bind to the ITGA2 protein on the surface of HuCCT1 cells with an EC50 of less than 5 nM. and / or, the isolated antibody or antigen-binding fragment thereof according to any one of claims 1 to 6, wherein the antibody is a monoclonal antibody, a polyclonal antibody, a chimeric antibody, or a humanized antibody.

8. An isolated nucleic acid molecule encoding an antibody or antigen-binding fragment thereof as described in any one of claims 1 to 7, or The nucleic acid molecule is SEQ ID NO: 31 and SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: 34, SEQ ID NO: 35 and SEQ ID NO: 36, SEQ ID NO: 37 and SEQ ID NO: 38, and An isolated nucleic acid molecule containing or consisting of a nucleotide sequence shown in any one combination selected from SEQ ID NO: 39 and SEQ ID NO:

40.

9. The antibody-drug conjugate shown in the following formula, Ab-L-D, and here, The symbol "Ab" represents at least one isolated antibody or antigen-binding fragment portion thereof as described in any one of claims 1 to 7. The symbol "L" represents a linker that connects the antibody portion and the partner molecule. The symbol "D" represents a partner molecule. or Ab - (L - D)p, where, The symbol "Ab" represents at least one isolated antibody or antigen-binding fragment portion thereof as described in any one of claims 1 to 7. The symbol "L" represents a linker that connects the antibody portion and the partner molecule. The symbol "D" represents a partner molecule. The symbol "p" represents the number of linker / partner molecules (preferably drug payloads) conjugated to the isolated antibody or its antigen-binding fragment portion according to any one of claims 1 to 7, and optionally p can be 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 An antibody-drug conjugate selected from the following values: 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.

10. The antibody-drug conjugate according to claim 9, wherein the linker is selected from one of vc, mc-GGFG, AcLysvc, mc, MalPEG6, m(H2O)c and m(H2O)cvc, and / or the linker is cleavable.

11. The partner molecule is a drug payload, the drug payload is a therapeutic molecule, and optionally the drug payload is selected from one of cytotoxic agents, cell inhibitors, immunomodulators and chemotherapeutic agents, and optionally the drug payload is selected from one of MMAE, MMAF, DM1, DM4, Dxd, SN-38, Topotecan and its derivatives, Exatecan and its derivatives, Belotecan and its derivatives, Camptothecin, Calichemicin and PBD, or The antibody-drug conjugate according to claim 9 or 10, wherein the partner molecule is a labeling molecule, and optionally, the labeling molecule is selected from one of the following: radiolabeling (e.g., isotopes), fluorescent labeling (e.g., fluorescent dyes), chemical substances, and a detectably modified enzyme and tag.

12. A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof according to any one of claims 1 to 7, or an antibody-drug conjugate according to claim 9 or 10, and optionally a pharmaceutically acceptable carrier.

13. Uses in the manufacture of a pharmaceutical composition of an antibody or antigen-binding fragment portion thereof according to any one of claims 1 to 7 or an antibody-drug conjugate according to claim 9 or 10, wherein the pharmaceutical composition is optionally used to treat a malignant tumor in a patient, prevent and / or treat metastasis or recurrence of the malignant tumor, optionally used to detect the presence of a malignant tumor in a patient, and optionally used for the prognosis of recurrence or progression of a malignant tumor in a patient.

14. A method for preventing and / or treating metastasis or recurrence of a malignant tumor in a patient, the method comprising administering to the patient an effective amount of an antibody or antigen-binding fragment thereof according to any one of claims 1 to 7, an antibody-drug conjugate according to claim 9 or 10, or a pharmaceutical composition according to claim 12.

15. The method according to claim 14, wherein the malignant tumor is selected from the group consisting of breast cancer, colorectal cancer, skin cancer, pancreatic cancer, prostate cancer, liver cancer, lung cancer, stomach cancer, leukemia, bile duct cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, head and neck cancer, lymphoma, medullary thyroid carcinoma, non-Hodgkin lymphoma, ovarian cancer, glioma, melanoma, and bladder cancer, and preferably the malignant tumor is selected from the group consisting of colorectal cancer, bile duct cancer, pancreatic cancer, and skin cancer.

16. The method according to claim 14 or 15, further comprising administering to the patient other antitumor treatment means, for example, a chemotherapeutic agent, an antibody targeting another tumor-specific antigen, or radiotherapy.

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