ITGA2-TARGETING ANTIBODIES AND ANTIBODY-DRUG CONJUGATES CONTAINING THEM

Abstract

The present invention provides a series of antibodies or antigen-binding fragment parts thereof with high specific binding capacity to tumor cells expressing an ITGA2 protein. After being conjugated with a drug to form antibody-drug conjugates, the antibodies or the antigen-binding fragment parts thereof of the present invention can achieve an excellent killing effect on tumor cells.

Description

Antibodies targeting ITGA2 and antibody-drug conjugates containing the same

[0001] This application claims priority to Chinese patent application No. 202210743539.0, filed on June 27, 2022, entitled “Antibodies targeting ITGA2 and antibody-drug conjugates comprising the same”, the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present invention relates to the field of biomedicine. Specifically, the present invention relates to an antibody or antigen-binding fragment thereof targeting ITGA2, an antibody-drug conjugate comprising the antibody, and uses of the antibody and / or antibody-drug conjugate in treating related diseases. Background Art

[0003] Malignant tumors (cancer) have become the number one killer threatening the lives and health of people around the world. Over 14 million people worldwide develop cancer each year, and in my country alone, over 3 million new cancer patients are diagnosed each year.

[0004] The fundamental reason for the high mortality rate of cancer is the spread and metastasis of cancer cells, as well as the high incidence of recurrence and drug resistance in most patients after treatment. Existing clinical treatments—surgery, radiotherapy, and chemotherapy—are minimally effective or only offer short-term benefits for metastasis, recurrence, and drug resistance, failing to alter long-term survival. Currently, surgical resection is effective in approximately 10-20% of patients with early-stage cancer, but is virtually ineffective in patients with advanced metastatic disease. Radiotherapy can only treat localized lesions and is often used as an adjuvant therapy before or after surgery, or as a radical treatment for a few types of cancer. Chemotherapy can be used for patients with advanced metastatic disease, but due to significant side effects and the potential for developing both short-term and long-term drug resistance, it only offers significant short-term benefits in approximately 20-30% of patients. Even with combined treatments combining surgery, radiotherapy, and chemotherapy, the long-term survival rate over five years has hovered between 20-30%, and approximately 70-80% of patients die within five years of treatment due to metastasis, recurrence, and drug resistance. Even patients with early-stage cancer who present without metastasis still develop metastasis and relapse after treatment, leading to their death.

[0005] Currently, identifying tumor-associated antigens and then delivering drugs to tumor cells through the preparation of antibody-drug conjugates is an effective method for treating tumors. This drug form combines the tumor cell targeting properties of monoclonal antibodies with the powerful tumor-killing properties of small molecule cytotoxins, significantly reducing the toxic side effects of small molecule toxins while improving drug efficacy, offering significant therapeutic advantages.

[0006] Summary of the Invention

[0007] The inventors discovered that ITGA2 is a tumor-associated antigen that is specifically overexpressed by tumor cells. Its expression is upregulated in most solid tumors, with significant overexpression in colorectal cancer, bile duct cancer, pancreatic cancer, and skin cancer. However, currently available antibodies that target ITGA2 alone have limited inhibitory effects on tumor cell growth. Therefore, the inventors have developed a series of antibodies with highly specific binding to tumor cells expressing ITGA2. These antibodies, developed as antibody-drug conjugates, target ITGA2-positive tumor cells, achieving superior cell-killing effects.

[0008] In one aspect, the present invention provides an isolated antibody or antigen-binding fragment portion thereof that specifically binds to an ITGA2 protein, wherein the isolated antibody or antigen-binding fragment portion thereof comprises a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3 sequences; and a light chain variable region comprising LCDR1, LCDR2, and LCDR3 sequences, wherein the antibody or antigen-binding fragment portion thereof has a heavy chain variable region and a light chain variable region selected from at least one of the following groups:

[0009] 1) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 112, (b) HCDR2 of SEQ ID NO: 113, and (c) HCDR3 of SEQ ID NO: 114, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 38, (e) LCDR2 of SEQ ID NO: 39, and (f) LCDR3 of SEQ ID NO: 40;

[0010] 2) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 116, (b) HCDR2 of SEQ ID NO: 117, and (c) HCDR3 of SEQ ID NO: 118, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 42, (e) LCDR2 of SEQ ID NO: 43, and (f) LCDR3 of SEQ ID NO: 44;

[0011] 3) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 120, (b) HCDR2 of SEQ ID NO: 121, and (c) HCDR3 of SEQ ID NO: 122, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 46, (e) LCDR2 of SEQ ID NO: 47, and (f) LCDR3 of SEQ ID NO: 48;

[0012] 4) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 124, (b) HCDR2 of SEQ ID NO: 125, and (c) HCDR3 of SEQ ID NO: 126, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 50, (e) LCDR2 of SEQ ID NO: 51, and (f) LCDR3 of SEQ ID NO: 52;

[0013] 5) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 128, (b) HCDR2 of SEQ ID NO: 129, and (c) HCDR3 of SEQ ID NO: 130, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 54, (e) LCDR2 of SEQ ID NO: 55, and (f) LCDR3 of SEQ ID NO: 56;

[0014] 6) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 132, (b) HCDR2 of SEQ ID NO: 133, and (c) HCDR3 of SEQ ID NO: 134, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 58, (e) LCDR2 of SEQ ID NO: 59, and (f) LCDR3 of SEQ ID NO: 60;

[0015] 7) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 136, (b) HCDR2 of SEQ ID NO: 137, and (c) HCDR3 of SEQ ID NO: 138, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 62, (e) LCDR2 of SEQ ID NO: 63, and (f) LCDR3 of SEQ ID NO: 64;

[0016] 8) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 140, (b) HCDR2 of SEQ ID NO: 141, and (c) HCDR3 of SEQ ID NO: 142, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68;

[0017] 9) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 144, (b) HCDR2 of SEQ ID NO: 145, and (c) HCDR3 of SEQ ID NO: 146, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 70, (e) LCDR2 of SEQ ID NO: 71, and (f) LCDR3 of SEQ ID NO: 72;

[0018] 10) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 148, (b) HCDR2 of SEQ ID NO: 149, and (c) HCDR3 of SEQ ID NO: 150, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 74, (e) LCDR2 of SEQ ID NO: 75, and (f) LCDR3 of SEQ ID NO: 76;

[0019] 11) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 152, (b) HCDR2 of SEQ ID NO: 153, and (c) HCDR3 of SEQ ID NO: 154, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 78, (e) LCDR2 of SEQ ID NO: 79, and (f) LCDR3 of SEQ ID NO: 80;

[0020] 12) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 156, (b) HCDR2 of SEQ ID NO: 157, and (c) HCDR3 of SEQ ID NO: 158, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 82, (e) LCDR2 of SEQ ID NO: 83, and (f) LCDR3 of SEQ ID NO: 84;

[0021] 13) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 160, (b) HCDR2 of SEQ ID NO: 161, and (c) HCDR3 of SEQ ID NO: 162, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 86, (e) LCDR2 of SEQ ID NO: 87, and (f) LCDR3 of SEQ ID NO: 88;

[0022] 14) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 164, (b) HCDR2 of SEQ ID NO: 165, and (c) HCDR3 of SEQ ID NO: 166, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 90, (e) LCDR2 of SEQ ID NO: 91, and (f) LCDR3 of SEQ ID NO: 92;

[0023] 15) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 168, (b) HCDR2 of SEQ ID NO: 169, and (c) HCDR3 of SEQ ID NO: 170, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 94, (e) LCDR2 of SEQ ID NO: 95, and (f) LCDR3 of SEQ ID NO: 96;

[0024] 16) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 172, (b) HCDR2 of SEQ ID NO: 173, and (c) HCDR3 of SEQ ID NO: 174, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 98, (e) LCDR2 of SEQ ID NO: 99, and (f) LCDR3 of SEQ ID NO: 100;

[0025] 17) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 176, (b) HCDR2 of SEQ ID NO: 177, and (c) HCDR3 of SEQ ID NO: 178, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 102, (e) LCDR2 of SEQ ID NO: 103, and (f) LCDR3 of SEQ ID NO: 104; and

[0026] 18) The heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 180, (b) HCDR2 of SEQ ID NO: 181, and (c) HCDR3 of SEQ ID NO: 182, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 106, (e) LCDR2 of SEQ ID NO: 107, and (f) LCDR3 of SEQ ID NO: 108.

[0027] In another aspect, the present invention provides an isolated antibody or antigen-binding fragment portion thereof that specifically binds to an ITGA2 protein, wherein the isolated antibody or antigen-binding fragment portion thereof has a heavy chain and a light chain selected from at least one of the following groups:

[0028] 1) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 19, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 19, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 19, and

[0029] The light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence 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;

[0030] 2) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 20, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 20, and

[0031] The light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2;

[0032] 3) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 21, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 21, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 21, and

[0033] The light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 3, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence 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;

[0034] 4) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 22, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 22, and

[0035] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 4, or comprising an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 4, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 4;

[0036] 5) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 23, or comprises and consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 23, and

[0037] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 5, or comprising an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 5, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 5;

[0038] 6) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 24, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 24, and

[0039] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6, or comprising an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6;

[0040] 7) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 25, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 25, and

[0041] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 7, or comprising an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 7, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 7;

[0042] 8) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26, and

[0043] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 8, or comprising an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 8, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 8;

[0044] 9) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 27, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 27, and

[0045] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 9, or comprising an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 9, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 9;

[0046] 10) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 28, or comprises and consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 28, and

[0047] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 10, or comprising and consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 10;

[0048] 11) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 29, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 29, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 29, and

[0049] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 11, or comprising and consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 11;

[0050] 12) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30, and

[0051] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 12, or comprising and consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 12;

[0052] 13) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31, and

[0053] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 13, or comprising and consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 13;

[0054] 14) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 32, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 32, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 32, and

[0055] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 14, or comprising and consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 14;

[0056] 15) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33, and

[0057] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 15, or comprising and consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 15;

[0058] 16) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34, and

[0059] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 16, or comprising and consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 16;

[0060] 17) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35, and

[0061] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 17, or comprising or consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 17; and

[0062] 18) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36, and

[0063] The light chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 18, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 18, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 18.

[0064] In yet another aspect, the present invention provides an isolated nucleic acid molecule encoding the monoclonal antibody or antigen-binding fragment thereof of the present invention.

[0065] In yet another aspect, the present invention provides an expression vector comprising the nucleic acid molecule of the present invention.

[0066] In another aspect, the present invention provides a host cell comprising the nucleic acid molecule of the present invention or the expression vector of the present invention.

[0067] In yet another aspect, the present invention provides a hybridoma cell that expresses a monoclonal antibody or antigen-binding fragment thereof of the present invention.

[0068] In another aspect, the present invention provides use of the monoclonal antibody or antigen-binding fragment thereof of the present invention or the antibody-drug conjugate of the present invention in preparing a pharmaceutical composition; optionally, the pharmaceutical composition is used to treat malignant tumors, prevent and / or treat malignant tumor metastasis or recurrence in patients.

[0069] In another aspect, the present invention provides a method for treating a malignant tumor, 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 the monoclonal antibody or antigen-binding fragment thereof of the present invention, the antibody-drug conjugate of the present invention, or the pharmaceutical composition of the present invention.

[0070] In another aspect, the present invention provides use of the monoclonal antibody or antigen-binding fragment thereof of the present invention or the antibody-drug conjugate of the present invention in the preparation of a diagnostic / prognostic composition; optionally, the diagnostic / prognostic composition is used to detect the presence of a malignant tumor in a patient; optionally, the diagnostic / prognostic composition is used to prognose the recurrence or progression of a malignant tumor in a patient.

[0071] In yet another aspect, the present invention provides a method for prognosing recurrence or progression of a malignant tumor in a patient, the method comprising:

[0072] (a) isolating a biological sample comprising tumor cells from the patient;

[0073] (b) contacting the biological sample containing tumor cells with the monoclonal antibody or antigen-binding fragment thereof of the present invention or the antibody drug conjugate of the present invention; and

[0074] (c) identifying the presence of tumor cells that bind to the monoclonal antibody or antigen-binding fragment thereof,

[0075] The recurrence or progression of the malignancy in said patient is thereby prognosed.

[0076] In yet another aspect, the present invention provides a method for detecting / diagnosing the presence of a malignant tumor in a patient, comprising:

[0077] a) contacting a biological sample obtained from the patient with the monoclonal antibody or antigen-binding fragment thereof of the present invention or the antibody drug conjugate of the present invention;

[0078] b) detecting binding of the monoclonal antibody or antigen-binding fragment thereof to a target antigen in the biological sample, wherein detection of the binding indicates the presence of a malignant tumor in the patient.

[0079] In another aspect, the present invention provides a method for detecting the presence of tumor cells in a biological sample, comprising:

[0080] a) contacting the biological sample with the monoclonal antibody or antigen-binding fragment thereof of the present invention or the antibody-drug conjugate of the present invention;

[0081] b) detecting the binding of the monoclonal antibody or antigen-binding fragment thereof or the antibody drug conjugate to the target antigen in the biological sample,

[0082] Detection of the binding indicates the presence of tumor cells in the biological sample.

[0083] In another aspect, the present invention provides a method for isolating tumor cells, comprising:

[0084] (a) providing a cell population suspected of containing tumor cells;

[0085] (b) identifying a subpopulation of cells that binds to the monoclonal antibody or antigen-binding fragment thereof or the antibody drug conjugate of the present invention; and

[0086] (c) isolating the subpopulation.

[0087] In another aspect, the present invention provides a method for producing a monoclonal antibody or an antigen-binding fragment thereof targeting human tumor cells expressing ITGA2, comprising:

[0088] (i) culturing the host cell of the present invention under conditions suitable for expression of the nucleic acid molecule or expression vector, and

[0089] (ii) isolating and purifying the antibody or antigen-binding fragment thereof expressed by the nucleic acid molecule or expression vector.

[0090] The antibodies of the present invention have excellent binding to the ITGA2 protein and are capable of binding to tumor cells expressing ITGA2, particularly colorectal cancer cells, bile duct cancer cells, pancreatic cancer cells, and skin cancer cells. The antibody-drug conjugates of the present invention have excellent killing effects on tumor cells expressing ITGA2, particularly colorectal cancer cells, bile duct cancer cells, pancreatic cancer cells, and skin cancer cells.

[0091] Sequence Description:

[0092] The leftmost column in the following Table 1 is the sequence number (SEQ ID NO:) of the present invention.

[0093] Table 1a Nucleic acid coding sequences of light and heavy chains of antibodies of the present invention SEQ ID NO: 1-36

[0094] Table 1b Amino acid sequences of the variable regions, CDRs, and constant regions of the light and heavy chains of the antibodies of the present invention (SEQ ID NOs: 37-183)

[0095] Note: The sequences marked in bold and underlined in the amino acid sequences in the table are the corresponding CDR sequences

[0096] Table 1c Amino acid sequences of the light and heavy chains of the antibodies of the present invention (SEQ ID NOs: 184-219).

[0097] Note: The sequences marked in bold and underlined in the amino acid sequences in the table are the corresponding CDR sequences DETAILED DESCRIPTION

[0098] (1) General definition

[0099] Unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, terms and laboratory procedures related to protein and nucleic acid chemistry, molecular biology, cell and tissue culture, microbiology, and immunology used herein are those widely used in the respective fields and are standard procedures. To facilitate a better understanding of the present invention, definitions and explanations of relevant terms are provided below.

[0100] As used herein, "antibody" refers to immunoglobulins and immunoglobulin fragments, whether natural or partially or completely synthetically (e.g., recombinantly), including any fragment thereof that retains the binding specificity of a full-length immunoglobulin comprising at least a portion of the variable region of an immunoglobulin molecule. Thus, antibodies include any protein having a binding domain that is homologous or substantially homologous to an immunoglobulin antigen-binding domain (antibody binding site). Antibodies include antibody fragments, such as anti-tumor stem cell antibody fragments. As used herein, the term antibody includes synthetic antibodies, recombinantly produced antibodies, multispecific antibodies (e.g., bispecific antibodies), human antibodies, non-human antibodies, humanized antibodies, chimeric antibodies, intrabodies, and antibody fragments, such as, but not limited to, Fab fragments, Fab' fragments, F(ab')2 fragments, Fv fragments, disulfide-linked Fv (dsFv), Fd fragments, Fd' fragments, single-chain Fv (scFv), single-chain Fab (scFab), diabodies, anti-idiotypic (anti-Id) antibodies, or antigen-binding fragments of any of the above antibodies. The antibodies provided herein include members of any immunoglobulin class (e.g., IgG, IgM, IgD, IgE, IgA, and IgY), any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass (e.g., IgG2a and IgG2b).

[0101] 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 full-length but contains at least a portion of the variable region of the antibody that binds to an antigen (e.g., one or more CDRs and / or one or more antibody binding sites) and thus retains binding specificity and at least part of the specific binding ability of the full-length antibody. Thus, an antigen-binding fragment refers to an antibody fragment that contains an antigen-binding portion that binds to the same antigen as the antibody from which the antibody fragment was derived. Antibody fragments include antibody derivatives produced by enzymatic treatment of full-length antibodies, as well as synthetically produced derivatives, such as recombinantly produced derivatives. Antibodies include antibody fragments. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, single-chain Fv (scFv), Fv, dsFv, diabodies, Fd and Fd' fragments, and other fragments, including modified fragments (see, e.g., Methods in Molecular Biology, Vol 207: Recombinant Antibodies for Cancer Therapy Methods and Protocols (2003); Chapter 1; p 3-25, Kipriyanov). The fragments may comprise multiple chains linked together, for example, by disulfide bonds and / or by peptide linkers. Antibody fragments generally contain at least or about 50 amino acids, and typically at least or about 200 amino acids. Antigen-binding fragments include any antibody fragment that, when inserted into an antibody framework (e.g., by replacing the corresponding region), obtains immunospecific binding (i.e., exhibits at least or at least about 10 7 -10 8 M -1 Antibodies to the Ka) antigen.

[0102] As used herein, "monoclonal antibody" refers to a population of identical antibodies, meaning that each individual antibody molecule in the monoclonal antibody population is identical to other antibody molecules. This characteristic is in contrast to the characteristic of a polyclonal population of antibodies, which comprises antibodies with a variety of different sequences. Monoclonal antibodies can be prepared by many 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 prepared by immortalized B cells, for example, by fusion with myeloma cells to produce hybridoma cell lines or by infecting B cells with viruses such as EBV. Recombinant technology can also be used to prepare antibodies from a clonal population of host cells in vitro by transforming host cells with a plasmid carrying an artificial sequence of nucleotides encoding the antibody.

[0103] As used herein, the term "hybridoma" or "hybridoma cell" refers to a cell or cell line (usually a myeloma or lymphoma cell) produced by the fusion of an antibody-producing lymphocyte and a non-antibody-producing cancer cell. As known to those of ordinary skill in the art, hybridomas can proliferate and continuously produce a specific monoclonal antibody. Methods for producing hybridomas are known in the art (see, for example, Harlow & Lane, 1988). When referring to the term "hybridoma" or "hybridoma cell," it also includes subclones and progeny cells of the hybridoma.

[0104] As used herein, a "conventional antibody" refers to an antibody comprising two heavy chains (which may be designated H and H') and two light chains (which may be designated L and L'), and two antigen-binding sites, wherein each heavy chain may be a full-length immunoglobulin heavy chain or any functional region thereof that retains antigen-binding ability (e.g., heavy chains include but are not limited to V and L'). H Chain, V H -C H 1 chain and V H -C H 1-C H 2-C H 3 chains), and each light chain can be a full-length light chain or any functional region (e.g., a light chain including but not limited to V L Chain and V L -C L Each heavy chain (H and H') is paired with a light chain (L and L', respectively).

[0105] As used herein, a full-length antibody is one having 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 hinge regions, such as antibodies naturally produced by antibody-secreting B cells and synthetically produced antibodies having the same domains.

[0106] As used herein, dsFv refers to a fragment having a stable V H -V L Fv with engineered intermolecular disulfide bonds.

[0107] 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, for example, produced by recombinant synthesis. Land C L ) and another chain comprising the variable domain of the heavy chain (V H ) and a constant region domain of the heavy chain (C H 1).

[0108] As used herein, a F(ab')2 fragment is an antibody fragment resulting from pepsin digestion of an immunoglobulin at pH 4.0-4.5, or a fragment having the same structure produced synthetically, for example, by recombinant methods. A F(ab')2 fragment essentially comprises two Fab fragments, each heavy chain portion of which contains several additional amino acids, including cysteine, which forms a disulfide bond linking the two fragments.

[0109] As used herein, a Fab' fragment is a fragment comprising half (one heavy chain and one light chain) of a F(ab')2 fragment.

[0110] As used herein, a scFv fragment refers to a fragment comprising variable light chains (V L ) and variable heavy chain (V H The length of the linker is such that the two variable domains are bridged without substantial interference. An exemplary linker is (Gly-Ser) with some Glu or Lys residues interspersed to increase solubility. n residue.

[0111] The term "chimeric antibody" refers to antibodies in which the variable region sequences are derived from one species and the constant region sequences are derived from another species, such as antibodies in which the variable region sequences are derived from a mouse antibody and the constant region sequences are derived from a human antibody.

[0112] "Humanized" antibodies refer to non-human (e.g., mouse) antibody forms that are chimeric immunoglobulins, immunoglobulin chains, or fragments thereof (e.g., Fv, Fab, Fab', F(ab')2, or other antigen-binding subsequences of antibodies) that contain minimal sequence derived from non-human immunoglobulin. Preferably, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a complementarity determining region (CDR) of the recipient antibody are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat, or rabbit having the desired specificity, affinity, and capacity.

[0113] In addition, in humanization, it is also possible to mutate the amino acid residues in the CDR1, CDR2 and / or CDR3 regions of VH and / or VL to thereby improve one or more binding properties (e.g., affinity) of the antibody. For example, PCR-mediated mutations can be used to introduce mutations, and their impact on antibody binding or other functional properties can be evaluated using in vitro or in vivo tests as described herein. Typically, conservative mutations are introduced. Such mutations can be amino acid substitutions, additions, or deletions. In addition, the mutations in the CDRs are typically no more than one or two. Therefore, the humanized antibodies of the present invention also encompass antibodies comprising one or two amino acid mutations in the CDRs.

[0114] As used herein, the term "epitope" refers to any antigenic determinant on an antigen to which the paratope of an antibody binds. Epitopic determinants typically comprise chemically active surface patterns of molecules, such as amino acids or sugar side chains, and typically have specific three-dimensional structural characteristics as well as specific charge characteristics.

[0115] As used herein, a variable domain or variable region is a specific Ig domain of an antibody heavy or light chain that contains an amino acid sequence that varies between different antibodies. Each light chain and each heavy chain has one variable region domain, V L and V H The variable domain provides antigen specificity and is therefore responsible for antigen recognition. Each variable region comprises CDRs, which are part of the antigen binding site domain, and framework regions (FRs).

[0116] As used herein, "antigen binding domain" and "antigen-binding site" are used synonymously to refer to the domain within an antibody that recognizes and physically interacts with a cognate antigen. A natural, conventional full-length antibody molecule has two conventional antigen-binding sites, each comprising a heavy chain variable region portion and a light chain variable region portion. A conventional antigen-binding site comprises loops connecting antiparallel beta chains within the variable region domain. An antigen-binding site may comprise other portions of the variable region domain. Each conventional antigen-binding site comprises three hypervariable regions from the heavy chain and three hypervariable regions from the light chain. Hypervariable regions are also referred to as complementarity determining regions (CDRs).

[0117] As used herein, "hypervariable region," "HV," "complementarity determining region," "CDR," and "antibody CDR" are used interchangeably to refer to one of the multiple portions within each variable region that together form the antigen binding site of an antibody. Each variable region domain comprises three CDRs, designated CDR1, CDR2, and CDR3. For example, the light chain variable region domain comprises three CDRs, designated VL CDR1, VL CDR2, and VL CDR3; the heavy chain variable region domain comprises three CDRs, designated VH CDR1, VH CDR2, and VH CDR3. The three CDRs in the variable region are discontinuous along the linear amino acid sequence, but are proximal in the folded polypeptide. The CDRs are located within loops connecting the parallel strands of the beta sheet of the variable domain. As described herein, those skilled in the art will recognize and can identify CDRs based on Kabat or Chothia numbering (see, e.g., Kabat, EA et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91-3242, and Chothia, C. et al. (1987) J. Mol. Biol. 196: 901-917). In the present invention, the abbreviations "VH CDR" and "HCDR" and "VL CDR" and "LCDR" have the same meaning.

[0118] As used herein, framework regions (FRs) are domains within the antibody variable region domains that are located within the beta sheets; in terms of amino acid sequence, FR regions are relatively more conserved than hypervariable regions.

[0119] As used herein, a "constant region" domain is a domain in an antibody heavy or light chain that comprises an amino acid sequence that is relatively more conserved than the amino acid sequence of the variable region domain. In a conventional full-length antibody molecule, each light chain has a single light chain constant region (C L ) domain, and each heavy chain comprises one or more heavy chain constant regions (C H ) domain, including C H 1. C H 2. C H 3 and C H 4. Full-length IgA, IgD, and IgG isotypes contain C H 1. C H 2. C H 3 and hinge regions, while IgE and IgM contain C H 1. C H 2. C H 3 and CH 4. C H 1 and C L The domains extend the Fab arms of the antibody molecule, thereby assisting in interacting with the antigen and rotating the antibody arms. The antibody constant region can serve effector functions such as, but not limited to, clearing the antigen, pathogen, and toxin to which the antibody specifically binds, for example, by interacting with various cells, biomolecules, and tissues.

[0120] As used herein, a functional region of an antibody is a region comprising at least V H 、V L 、C H (For example, C H 1. C H 2 or C H 3) C L or the hinge region domain or at least the functional region thereof.

[0121] As used herein, V H The functional area of ​​the domain is to retain the complete V H at least part of the binding specificity of the V H One or more CDRs of the structural domain) H domain, so that the V H The functional region of the antibody domain alone or in combination with another antibody domain (e.g., V L domain) or a combination of regions thereof that bind to an antigen. H The functional region of the domain is the V H The regions of CDR1, CDR2 and / or CDR3 of the domain.

[0122] As used herein, V L The functional area of ​​the domain is to retain the complete V L at least part of the binding specificity of the V L One or more CDRs of the structural domain) L domain, so that the V L The functional region of the antibody domain alone or in combination with another antibody domain (e.g., V H domain) or a combination of regions thereof that bind to an antigen. L The functional region of the domain is the V L The regions of CDR1, CDR2 and / or CDR3 of the domain.

[0123] As used herein, "specifically binds" or "immunospecifically binds" with respect to an antibody or antigen-binding fragment thereof are used interchangeably herein and refer to the ability of an antibody or antigen-binding fragment to form one or more non-covalent bonds with the same antigen through non-covalent interactions between the antibody combining sites of the antibody and the antigen. The antigen can be an isolated antigen or present on a tumor cell.

[0124] As used herein, the terms "Kassoc" or "Ka" are intended to refer to the association rate of a particular antibody-antigen interaction, while the terms "Kdis" or "Kd" are intended to refer to the dissociation rate of a particular antibody-antigen interaction. As used herein, the term "KD" is intended to refer to the dissociation constant, which is obtained by the ratio of Kd to Ka (i.e., Kd / Ka) and is expressed as a molar concentration (M). The KD value of an antibody can be determined using methods known in the art. The method for determining the KD of an antibody can be, 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, e.g., Paul, ed., Fundamental Immunology, 2nd ed., Raven Press, New York, pages 332-336 (1989); see also U.S. Pat. No. 7,229,619 describing exemplary SPR and ITC methods for calculating the binding affinity of an antibody). Instruments and methods for real-time detection and monitoring of binding rates are known and commercially available (see, BiaCore 2000, Biacore AB, Upsala, Sweden and GE Healthcare Life Sciences; Malmqvist (2000) Biochem. Soc. Trans. 27:335).

[0125] As used herein, the term "conservative sequence modifications" or "conservative amino acid modifications" or "conservative amino acid substitutions" refers to amino acid modifications that do not significantly affect or alter the binding properties of an antibody containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions, and deletions. Modifications can be introduced into the antibodies of the present invention by standard techniques well known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. "Conservative amino acid modifications" or "conservative amino acid substitutions" are substitutions in which an amino acid residue is replaced with an amino acid residue having similar properties and / or structure. Families of amino acid residues with similar side chains have been defined in the art.

[0126] There are 20 common amino acids, which can be classified in many ways. For example, amino acids can be classified based on their binding groups into aliphatic, aromatic, heterocyclic, sulfur-containing, and iodine-containing amino acids. Aliphatic amino acids include alanine, valine, leucine, isoleucine, methionine, aspartic acid, glutamic acid, lysine, arginine, glycine, serine, threonine, cysteine, asparagine, and glutamine. Aromatic amino acids include phenylalanine and tyrosine. Heterocyclic amino acids include histidine and tryptophan. Heterocyclic imino acids include proline. Amino acids can be classified based on their chemical properties into acidic, basic, and neutral amino acids. Neutral amino acids include glycine, alanine, leucine, isoleucine, valine, cystine, cysteine, methionine, threonine, serine, phenylalanine, tyrosine, tryptophan, proline, methionine, and hydroxyproline. Acidic amino acids include glutamic acid and aspartic acid. Basic amino acids include lysine, arginine, and histidine.

[0127] Additionally, amino acids can be further classified as follows: amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), non-polar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).

[0128] As used herein, "polypeptide" refers to two or more amino acids covalently linked. The terms "polypeptide" and "protein" are used interchangeably herein.

[0129] An "isolated protein," "isolated polypeptide," or "isolated antibody" means that the protein, polypeptide, or antibody is (1) not associated with naturally associated components that accompany it in its native state, (2) free of other proteins from the same species, (3) expressed by cells from a different species, or (4) not occurring in nature. Thus, a polypeptide that is chemically synthesized or synthesized in a cellular system different from the cells from which the polypeptide originates would be "isolated" from its naturally associated components. A protein can also be rendered substantially free of naturally associated components by isolation, i.e., using protein purification techniques well known in the art.

[0130] "Substitution", "deletion" or "addition" of an amino acid residue refers to a conservative amino acid modification in a peptide or protein that does not alter the function and / or biological activity of the peptide or protein. For example, the substitution of an amino acid residue can be a conservative amino acid substitution. Suitable conservative amino acid substitutions are known to those skilled in the art and can generally be made without altering the biological activity of the resulting molecule. Generally, those skilled in the art recognize that single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, for example, Watson et al., Molecular Biology of the Gene, 4th Edition, 1987, The Benjamin / Cummings Pub.co., p. 224).

[0131] As used herein, the terms "polynucleotide" and "nucleic acid molecule" refer to an oligomer or polymer comprising at least two linked nucleotides or nucleotide derivatives, including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), usually linked together by phosphodiester bonds.

[0132] As used herein, isolated nucleic acid molecules are nucleic acid molecules isolated from other nucleic acid molecules present in the natural origin of nucleic acid molecules. " Isolated " nucleic acid molecules such as cDNA molecules can be substantially free of other cellular materials or culture medium when prepared by recombinant technology, or substantially free of chemical precursors or other chemical compositions when chemosynthesis. The exemplary isolated nucleic acid molecules provided herein comprise the isolated nucleic acid molecules of the antibody or Fab provided by coding.

[0133] Sequence "identity" has a meaning recognized in the art, and the percentage of sequence identity between two nucleic acid or polypeptide molecules or regions can be calculated using published techniques. Sequence identity can be measured along the entire length of a polynucleotide or polypeptide or along a region of the molecule. (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). While there are many methods to measure the identity between two polynucleotides or polypeptides, the term "identity" is well known to those of skill in the art (Carrillo, H. & Lipman, D., SIAM J Applied Math 48: 1073 (1988)).

[0134] 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 each other. For example, a promoter can be operably linked to a nucleic acid encoding a polypeptide such that the promoter regulates or mediates transcription of the nucleic acid.

[0135] As used herein, "expression" refers to the process of producing a polypeptide through transcription and translation of a polynucleotide. The expression level of a polypeptide can be assessed using any method known in the art, including, for example, methods for measuring the amount of polypeptide produced by a host cell. Such methods may include, but are not limited to, quantification of polypeptides in cell lysates by ELISA, gel electrophoresis followed by Coomassie blue staining, Lowry protein assay, and Bradford protein assay.

[0136] As used herein, a "host cell" is a cell that is used to receive, maintain, replicate, and amplify a vector. Host cells can also be used to express polypeptides encoded by the vector. When the host cell divides, the nucleic acid contained in the vector replicates, thereby amplifying the nucleic acid. The host cell can be a eukaryotic cell or a prokaryotic cell. Suitable host cells include, but are not limited to, CHO cells, various COS cells, HeLa cells, and HEK cells, such as HEK 293 cells.

[0137] As used herein, a "vector" is a replicable nucleic acid that, when transformed into an appropriate host cell, can express one or more heterologous proteins from the vector. Vectors include those into which nucleic acids encoding polypeptides or fragments thereof can be introduced, typically by restriction digestion and ligation. Vectors also include those that contain nucleic acids encoding polypeptides. Vectors are used to introduce nucleic acids encoding polypeptides into host cells for the purpose of amplifying nucleic acids or for expressing / displaying polypeptides encoded by nucleic acids. Vectors are typically kept episomal, but can be designed to integrate genes or portions thereof into chromosomes of the genome. Artificial chromosome vectors, such as yeast artificial vectors and mammalian artificial chromosomes, are also contemplated. The selection and use of such vectors are well known to those skilled in the art.

[0138] As used herein, "expression vector" includes a vector capable of expressing DNA that is operably linked to a regulatory sequence such as a promoter region that can affect the expression of such DNA fragments. Such additional fragments may include promoter and terminator sequences, and may optionally include one or more origins of replication, one or more selection markers, enhancers, polyadenylation signals, etc. Expression vectors are generally derived from plasmid or viral DNA, or may contain elements of both. Therefore, 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 an appropriate host cell, results in the expression of the cloned DNA. Suitable expression vectors are well known to those skilled in the art and include expression vectors that are replicable in eukaryotic cells and / or prokaryotic cells, as well as expression vectors that remain episomal or that are integrated into the host cell genome.

[0139] As used herein, "treating" an individual suffering from a disease or condition means that the individual's symptoms are partially or completely alleviated, or remain unchanged after treatment. Thus, treatment includes prevention, treatment, and / or cure. Prevention refers to preventing the underlying disease and / or preventing the worsening of symptoms or progression of the disease. Treatment also includes any pharmaceutical use of any of the antibodies or antigen-binding fragments thereof provided, as well as the compositions provided herein.

[0140] As used herein, "therapeutic effect" refers to an effect resulting from treatment of a subject that alters, typically ameliorates or improves the symptoms of a disease or condition, or cures the disease or condition.

[0141] As used herein, "therapeutically effective amount" or "therapeutically effective dose" refers to an amount of a substance, compound, material, or composition comprising a compound that is at least sufficient to produce a therapeutic effect after administration to a subject. Thus, it is the amount necessary to prevent, cure, ameliorate, arrest, or partially arrest the symptoms of a disease or condition.

[0142] As used herein, a "prophylactically effective amount" or "prophylactically effective dose" refers to an amount of a substance, compound, material, or composition comprising a compound that, when administered to a subject, will have the desired prophylactic effect, e.g., preventing or delaying the onset or recurrence of a disease or symptom, or reducing the likelihood of the onset or recurrence of a disease or symptom. A fully prophylactically effective dose need not occur by administering one dose, and may occur only after administering a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations.

[0143] As used herein, the term "patient" refers to a mammal, such as a human.

[0144] (II) Antibodies targeting ITGA2 protein

[0145] The full name of ITGA2 is Integrin alpha-2. The human ITGA2 protein is numbered P17301 in the Uniprot database (see https: / / www.uniprot.org / uniprot / P17301).

[0146] The inventors discovered that ITGA2 is a tumor-associated antigen that is specifically overexpressed on tumor cells, particularly in patients with colorectal cancer, bile duct cancer, pancreatic cancer, and skin cancer. Based on this discovery, the inventors designed a variety of humanized antibodies targeting the ITGA2 protein. Experiments in the Examples demonstrate that the antibodies of the present invention have excellent binding affinity for the ITGA2 protein (EC50 <1 nM) and also for HuCCT1 cells, which overexpress ITGA2 (EC50 <5 nM). Leveraging the excellent binding capacity of the monoclonal antibodies of the present invention, partner molecules, such as cytotoxins, can be effectively delivered to tumor cells.

[0147] Therefore, in one aspect, the present invention provides an isolated antibody or antigen-binding fragment portion thereof that specifically binds to ITGA2 protein, wherein the isolated antibody or antigen-binding fragment portion thereof comprises a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3 sequences:

[0148] 1) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 112, (b) HCDR2 of SEQ ID NO: 113, and (c) HCDR3 of SEQ ID NO: 114;

[0149] 2) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 116, (b) HCDR2 of SEQ ID NO: 117, and (c) HCDR3 of SEQ ID NO: 118;

[0150] 3) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 120, (b) HCDR2 of SEQ ID NO: 121, and (c) HCDR3 of SEQ ID NO: 122;

[0151] 4) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 124, (b) HCDR2 of SEQ ID NO: 125, and (c) HCDR3 of SEQ ID NO: 126;

[0152] 5) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 128, (b) HCDR2 of SEQ ID NO: 129, and (c) HCDR3 of SEQ ID NO: 130;

[0153] 6) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 132, (b) HCDR2 of SEQ ID NO: 133, and (c) HCDR3 of SEQ ID NO: 134;

[0154] 7) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 136, (b) HCDR2 of SEQ ID NO: 137, and (c) HCDR3 of SEQ ID NO: 138;

[0155] 8) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 140, (b) HCDR2 of SEQ ID NO: 141, and (c) HCDR3 of SEQ ID NO: 142;

[0156] 9) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 144, (b) HCDR2 of SEQ ID NO: 145, and (c) HCDR3 of SEQ ID NO: 146;

[0157] 10) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 148, (b) HCDR2 of SEQ ID NO: 149, and (c) HCDR3 of SEQ ID NO: 150;

[0158] 11) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 152, (b) HCDR2 of SEQ ID NO: 153, and (c) HCDR3 of SEQ ID NO: 154;

[0159] 12) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 156, (b) HCDR2 of SEQ ID NO: 157, and (c) HCDR3 of SEQ ID NO: 158;

[0160] 13) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 160, (b) HCDR2 of SEQ ID NO: 161, and (c) HCDR3 of SEQ ID NO: 162;

[0161] 14) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 164, (b) HCDR2 of SEQ ID NO: 165, and (c) HCDR3 of SEQ ID NO: 166;

[0162] 15) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 168, (b) HCDR2 of SEQ ID NO: 169, and (c) HCDR3 of SEQ ID NO: 170;

[0163] 16) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 172, (b) HCDR2 of SEQ ID NO: 173, and (c) HCDR3 of SEQ ID NO: 174;

[0164] 17) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 176, (b) HCDR2 of SEQ ID NO: 177, and (c) HCDR3 of SEQ ID NO: 178; and

[0165] 18) The heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 180, (b) HCDR2 of SEQ ID NO: 181, and (c) HCDR3 of SEQ ID NO: 182.

[0166] 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 comprises a light chain variable region comprising LCDR1, LCDR2, and LCDR3 sequences:

[0167] 1) the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 38, (e) LCDR2 of SEQ ID NO: 39, and (f) LCDR3 of SEQ ID NO: 40;

[0168] 2) the light chain variable region, wherein the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 42, (e) LCDR2 of SEQ ID NO: 43, and (f) LCDR3 of SEQ ID NO: 44;

[0169] 3) the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 46, (e) LCDR2 of SEQ ID NO: 47, and (f) LCDR3 of SEQ ID NO: 48;

[0170] 4) the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 50, (e) LCDR2 of SEQ ID NO: 51, and (f) LCDR3 of SEQ ID NO: 52;

[0171] 5) the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 54, (e) LCDR2 of SEQ ID NO: 55, and (f) LCDR3 of SEQ ID NO: 56;

[0172] 6) the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 58, (e) LCDR2 of SEQ ID NO: 59, and (f) LCDR3 of SEQ ID NO: 60;

[0173] 7) the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 62, (e) LCDR2 of SEQ ID NO: 63, and (f) LCDR3 of SEQ ID NO: 64;

[0174] 8) the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68;

[0175] 9) the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 70, (e) LCDR2 of SEQ ID NO: 71, and (f) LCDR3 of SEQ ID NO: 72;

[0176] 10) the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 74, (e) LCDR2 of SEQ ID NO: 75, and (f) LCDR3 of SEQ ID NO: 76;

[0177] 11) the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 78, (e) LCDR2 of SEQ ID NO: 79, and (f) LCDR3 of SEQ ID NO: 80;

[0178] 12) the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 82, (e) LCDR2 of SEQ ID NO: 83, and (f) LCDR3 of SEQ ID NO: 84;

[0179] 13) the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 86, (e) LCDR2 of SEQ ID NO: 87, and (f) LCDR3 of SEQ ID NO: 88;

[0180] 14) the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 90, (e) LCDR2 of SEQ ID NO: 91, and (f) LCDR3 of SEQ ID NO: 92;

[0181] 15) the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 94, (e) LCDR2 of SEQ ID NO: 95, and (f) LCDR3 of SEQ ID NO: 96;

[0182] 16) the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 98, (e) LCDR2 of SEQ ID NO: 99, and (f) LCDR3 of SEQ ID NO: 100;

[0183] 17) the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 102, (e) LCDR2 of SEQ ID NO: 103, and (f) LCDR3 of SEQ ID NO: 104; and

[0184] 18) The light chain variable region comprises (d) LCDR1 of SEQ ID NO: 106, (e) LCDR2 of SEQ ID NO: 107, and (f) LCDR3 of SEQ ID NO: 108.

[0185] In some embodiments, the isolated antibody or antigen-binding fragment portion thereof comprises a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3 sequences; and a light chain variable region comprising LCDR1, LCDR2, and LCDR3 sequences, wherein the antibody or antigen-binding fragment portion thereof has a heavy chain variable region and a light chain variable region selected from at least one of the following groups:

[0186] 1) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 112, (b) HCDR2 of SEQ ID NO: 113, and (c) HCDR3 of SEQ ID NO: 114, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 38, (e) LCDR2 of SEQ ID NO: 39, and (f) LCDR3 of SEQ ID NO: 40;

[0187] 2) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 116, (b) HCDR2 of SEQ ID NO: 117, and (c) HCDR3 of SEQ ID NO: 118, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 42, (e) LCDR2 of SEQ ID NO: 43, and (f) LCDR3 of SEQ ID NO: 44;

[0188] 3) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 120, (b) HCDR2 of SEQ ID NO: 121, and (c) HCDR3 of SEQ ID NO: 122, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 46, (e) LCDR2 of SEQ ID NO: 47, and (f) LCDR3 of SEQ ID NO: 48;

[0189] 4) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 124, (b) HCDR2 of SEQ ID NO: 125, and (c) HCDR3 of SEQ ID NO: 126, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 50, (e) LCDR2 of SEQ ID NO: 51, and (f) LCDR3 of SEQ ID NO: 52;

[0190] 5) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 128, (b) HCDR2 of SEQ ID NO: 129, and (c) HCDR3 of SEQ ID NO: 130, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 54, (e) LCDR2 of SEQ ID NO: 55, and (f) LCDR3 of SEQ ID NO: 56;

[0191] 6) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 132, (b) HCDR2 of SEQ ID NO: 133, and (c) HCDR3 of SEQ ID NO: 134, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 58, (e) LCDR2 of SEQ ID NO: 59, and (f) LCDR3 of SEQ ID NO: 60;

[0192] 7) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 136, (b) HCDR2 of SEQ ID NO: 137, and (c) HCDR3 of SEQ ID NO: 138, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 62, (e) LCDR2 of SEQ ID NO: 63, and (f) LCDR3 of SEQ ID NO: 64;

[0193] 8) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 140, (b) HCDR2 of SEQ ID NO: 141, and (c) HCDR3 of SEQ ID NO: 142, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68;

[0194] 9) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 144, (b) HCDR2 of SEQ ID NO: 145, and (c) HCDR3 of SEQ ID NO: 146, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 70, (e) LCDR2 of SEQ ID NO: 71, and (f) LCDR3 of SEQ ID NO: 72;

[0195] 10) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 148, (b) HCDR2 of SEQ ID NO: 149, and (c) HCDR3 of SEQ ID NO: 150, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 74, (e) LCDR2 of SEQ ID NO: 75, and (f) LCDR3 of SEQ ID NO: 76;

[0196] 11) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 152, (b) HCDR2 of SEQ ID NO: 153, and (c) HCDR3 of SEQ ID NO: 154, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 78, (e) LCDR2 of SEQ ID NO: 79, and (f) LCDR3 of SEQ ID NO: 80;

[0197] 12) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 156, (b) HCDR2 of SEQ ID NO: 157, and (c) HCDR3 of SEQ ID NO: 158, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 82, (e) LCDR2 of SEQ ID NO: 83, and (f) LCDR3 of SEQ ID NO: 84;

[0198] 13) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 160, (b) HCDR2 of SEQ ID NO: 161, and (c) HCDR3 of SEQ ID NO: 162, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 86, (e) LCDR2 of SEQ ID NO: 87, and (f) LCDR3 of SEQ ID NO: 88;

[0199] 14) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 164, (b) HCDR2 of SEQ ID NO: 165, and (c) HCDR3 of SEQ ID NO: 166, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 90, (e) LCDR2 of SEQ ID NO: 91, and (f) LCDR3 of SEQ ID NO: 92;

[0200] 15) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 168, (b) HCDR2 of SEQ ID NO: 169, and (c) HCDR3 of SEQ ID NO: 170, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 94, (e) LCDR2 of SEQ ID NO: 95, and (f) LCDR3 of SEQ ID NO: 96;

[0201] 16) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 172, (b) HCDR2 of SEQ ID NO: 173, and (c) HCDR3 of SEQ ID NO: 174, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 98, (e) LCDR2 of SEQ ID NO: 99, and (f) LCDR3 of SEQ ID NO: 100;

[0202] 17) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 176, (b) HCDR2 of SEQ ID NO: 177, and (c) HCDR3 of SEQ ID NO: 178, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 102, (e) LCDR2 of SEQ ID NO: 103, and (f) LCDR3 of SEQ ID NO: 104; and

[0203] 18) The heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 180, (b) HCDR2 of SEQ ID NO: 181, and (c) HCDR3 of SEQ ID NO: 182, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 106, (e) LCDR2 of SEQ ID NO: 107, and (f) LCDR3 of SEQ ID NO: 108.

[0204] In some embodiments, the isolated antibody or antigen-binding fragment thereof comprises a heavy chain variable region selected from at least one of the following groups:

[0205] 1) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 111, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 111;

[0206] 2) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 115, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 115;

[0207] 3) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 119, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 119;

[0208] 4) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 123, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 123;

[0209] 5) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 127, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 127;

[0210] 6) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 131, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 131;

[0211] 7) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 135, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 135;

[0212] 8) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 139, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 139;

[0213] 9) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 143, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 143;

[0214] 10) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 147, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 147;

[0215] 11) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 151, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 151;

[0216] 12) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 155, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 155;

[0217] 13) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 159, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 159;

[0218] 14) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 163, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 163;

[0219] 15) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 167, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 167;

[0220] 16) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 171, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 171;

[0221] 17) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 175, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 175; and

[0222] 18) The heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 179 or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 179.

[0223] In some embodiments, the isolated antibody or antigen-binding fragment thereof comprises a light chain variable region selected from at least one of the following groups:

[0224] 1) the light chain variable region comprising the amino acid sequence of SEQ ID NO: 37, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 37;

[0225] 2) the light chain variable region comprising the amino acid sequence of SEQ ID NO:41, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:41;

[0226] 3) the light chain variable region comprising the amino acid sequence of SEQ ID NO:45, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:45;

[0227] 4) the light chain variable region comprising the amino acid sequence of SEQ ID NO:49, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:49;

[0228] 5) the light chain variable region comprising the amino acid sequence of SEQ ID NO: 53, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 53;

[0229] 6) the light chain variable region comprising the amino acid sequence of SEQ ID NO: 57, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 57;

[0230] 7) the light chain variable region comprising the amino acid sequence of SEQ ID NO:61, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:61;

[0231] 8) the light chain variable region comprising the amino acid sequence of SEQ ID NO: 65, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 65;

[0232] 9) the light chain variable region comprising the amino acid sequence of SEQ ID NO:69, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:69;

[0233] 10) the light chain variable region comprising the amino acid sequence of SEQ ID NO: 73, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 73;

[0234] 11) the light chain variable region comprising the amino acid sequence of SEQ ID NO: 77 or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 77;

[0235] 12) the light chain variable region comprising the amino acid sequence of SEQ ID NO:81, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:81;

[0236] 13) the light chain variable region comprising the amino acid sequence of SEQ ID NO: 85, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 85;

[0237] 14) the light chain variable region comprising the amino acid sequence of SEQ ID NO: 89, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 89;

[0238] 15) the light chain variable region comprising the amino acid sequence of SEQ ID NO: 93, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 93;

[0239] 16) the light chain variable region comprising the amino acid sequence of SEQ ID NO: 97, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 97;

[0240] 17) the light chain variable region comprising the amino acid sequence of SEQ ID NO: 101, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 101; and

[0241] 18) The light chain variable region comprises the amino acid sequence of SEQ ID NO: 105 or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 105.

[0242] In some embodiments, the isolated antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region selected from at least one of the following groups:

[0243] 1) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:111, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:111, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:37, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:37;

[0244] 2) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:115, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:115, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:41, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:41;

[0245] 3) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:119, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:119, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:45, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:45;

[0246] 4) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:123, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:123, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:49, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:49;

[0247] 5) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:127, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:127, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:53, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:53;

[0248] 6) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:131, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:131, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:57, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:57;

[0249] 7) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:135, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:135, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:61, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:61;

[0250] 8) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:139, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:139, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:65, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:65;

[0251] 9) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:143, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:143, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:69, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:69;

[0252] 10) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:147, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:147, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:73, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:73;

[0253] 11) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:151, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:151, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:77, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:77;

[0254] 12) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:155, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:155, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:81, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:81;

[0255] 13) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:159, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:159, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:85, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:85;

[0256] 14) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:163, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:163, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:89, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:89;

[0257] 15) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:167, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:167, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:93, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:93;

[0258] 16) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 171, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 171, and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 97, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 97;

[0259] 17) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 175, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 175, and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 101, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 101; and

[0260] 18) The heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 179 or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 179, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 105 or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 105.

[0261] 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 to the amino acid sequence of the heavy chain variable region (SEQ ID NOs: 111, 115, 119, 123, 127, 131, 135, 139, 143, 147, 151, 155, 159, 163, 167, 171, 175, 179) and / or the amino acid sequence of the light chain variable region (SEQ ID NOs: 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 97, 101, 105) of the antibody of the invention has the same or similar biological function and / or activity as the antibody of the invention.

[0262] In some embodiments, an antibody that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of the heavy chain variable region (SEQ ID NOs: 111, 115, 119, 123, 127, 131, 135, 139, 143, 147, 151, 155, 159, 163, 167, 171, 175, 179) and / or the amino acid sequence of the light chain variable region (SEQ ID NOs: 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 97, 101, 105) of the antibody of the present invention can also specifically bind to the ITGA2 protein.

[0263] In some embodiments, the amino acid sequence of the heavy chain variable region (SEQ ID NOs: 111, 115, 119, 123, 127, 131, 135, 139, 143, 147, 151, 155, 159, 163, 167, 171, 175, 179) and / or the amino acid sequence of the light chain variable region (SEQ ID NOs: 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 97, 101, 105) having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the antibodies of the present invention, having the same heavy chain and / or light chain variable region CDRs as the antibodies of the present invention, and having conservative amino acid substitutions only at other positions (e.g., framework regions) of the heavy chain and / or light chain variable region other than the CDRs, and the conservative amino acid substitutions do not alter the biological function and / or activity of the corresponding antibody;

[0264] Optionally, the aforementioned antibodies that are at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequences of the heavy chain variable regions (SEQ ID NOs: 111, 115, 119, 123, 127, 131, 135, 139, 143, 147, 151, 155, 159, 163, 167, 171, 175, 179) and / or the amino acid sequences of the light chain variable regions (SEQ ID NOs: 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 97, 101, 105) of the antibodies of the present invention can also specifically bind to the ITGA2 protein.

[0265] In some embodiments, the amino acid sequence of the heavy chain variable region (SEQ ID NOs: 111, 115, 119, 123, 127, 131, 135, 139, 143, 147, 151, 155, 159, 163, 167, 171, 175, 179) and / or the amino acid sequence of the light chain variable region (SEQ ID NOs: 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 97, 101, 105) have at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the antibodies of the present invention, have the same heavy chain and / or light chain variable region CDRs as the antibodies of the present invention, and have conservative amino acid substitutions only in the framework regions of the heavy chain variable region and / or light chain variable region, and the conservative amino acid substitutions do not change the biological function and / or activity of the corresponding antibodies, and the aforementioned antibodies can also specifically bind to ITGA2 protein.

[0266] In some embodiments, the isolated antibody or antigen-binding fragment thereof further comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 183 or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 183.

[0267] In some embodiments, the isolated antibody or antigen-binding fragment portion thereof further comprises a light chain constant region comprising the amino acid sequence of SEQ ID NO: 109, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 109; or the light chain constant region comprises the amino acid sequence of SEQ ID NO: 110, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 110.

[0268] In some embodiments, the isolated antibody or antigen-binding fragment thereof further comprises a heavy chain constant region and / or a light chain constant region,

[0269] the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 183, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 183,

[0270] The light chain constant region comprises the amino acid sequence of SEQ ID NO: 109, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 109; or the light chain constant region comprises the amino acid sequence of SEQ ID NO: 110, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 110.

[0271] In some embodiments, the isolated antibody or antigen-binding fragment thereof comprises a heavy chain selected from at least one of the following groups:

[0272] 1) the heavy chain comprising the amino acid sequence of SEQ ID NO:202, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:202;

[0273] 2) the heavy chain comprising the amino acid sequence of SEQ ID NO:203, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:203;

[0274] 3) the heavy chain comprising the amino acid sequence of SEQ ID NO:204, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:204;

[0275] 4) the heavy chain comprising the amino acid sequence of SEQ ID NO:205, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:205;

[0276] 5) the heavy chain comprising the amino acid sequence of SEQ ID NO:206, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:206;

[0277] 6) the heavy chain comprising the amino acid sequence of SEQ ID NO:207, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:207;

[0278] 7) the heavy chain comprising the amino acid sequence of SEQ ID NO:208, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:208;

[0279] 8) the heavy chain comprising the amino acid sequence of SEQ ID NO:209, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:209;

[0280] 9) the heavy chain comprising the amino acid sequence of SEQ ID NO: 210, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 210;

[0281] 10) the heavy chain comprising the amino acid sequence of SEQ ID NO: 211, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 211;

[0282] 11) the heavy chain comprising the amino acid sequence of SEQ ID NO: 212, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 212;

[0283] 12) the heavy chain comprising the amino acid sequence of SEQ ID NO: 213, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 213;

[0284] 13) the heavy chain comprising the amino acid sequence of SEQ ID NO: 214, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 214;

[0285] 14) the heavy chain comprising the amino acid sequence of SEQ ID NO: 215, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 215;

[0286] 15) the heavy chain comprising the amino acid sequence of SEQ ID NO: 216, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 216;

[0287] 16) The heavy chain comprising the amino acid sequence of SEQ ID NO: 217, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 217;

[0288] 17) the heavy chain comprising the amino acid sequence of SEQ ID NO: 218, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 218; and

[0289] 18) The heavy chain comprises the amino acid sequence of SEQ ID NO: 219 or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 219.

[0290] In some embodiments, the isolated antibody or antigen-binding fragment thereof comprises a light chain selected from at least one of the following groups:

[0291] 1) the light chain comprising the amino acid sequence of SEQ ID NO: 184, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 184;

[0292] 2) the light chain comprising the amino acid sequence of SEQ ID NO: 185, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 185;

[0293] 3) the light chain comprising the amino acid sequence of SEQ ID NO: 186, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 186;

[0294] 4) the light chain comprising the amino acid sequence of SEQ ID NO: 187, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 187;

[0295] 5) the light chain comprising the amino acid sequence of SEQ ID NO:188, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:188;

[0296] 6) the light chain comprising the amino acid sequence of SEQ ID NO:189, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:189;

[0297] 7) the light chain comprising the amino acid sequence of SEQ ID NO: 190, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 190;

[0298] 8) the light chain comprising the amino acid sequence of SEQ ID NO: 191, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 191;

[0299] 9) the light chain comprising the amino acid sequence of SEQ ID NO: 192, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 192;

[0300] 10) the light chain comprising the amino acid sequence of SEQ ID NO: 193, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 193;

[0301] 11) The light chain comprising the amino acid sequence of SEQ ID NO: 194, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 194;

[0302] 12) the light chain comprising the amino acid sequence of SEQ ID NO: 195, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 195;

[0303] 13) The light chain comprising the amino acid sequence of SEQ ID NO: 196, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 196;

[0304] 14) the light chain comprising the amino acid sequence of SEQ ID NO: 197, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 197;

[0305] 15) The light chain comprising the amino acid sequence of SEQ ID NO: 198, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 198;

[0306] 16) The light chain comprising the amino acid sequence of SEQ ID NO: 199, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 199;

[0307] 17) The light chain comprising the amino acid sequence of SEQ ID NO: 200, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 200; and

[0308] 18) The light chain comprises the amino acid sequence of SEQ ID NO: 201 or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 201.

[0309] In some embodiments, the isolated antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain selected from at least one of the following groups:

[0310] 1) the heavy chain comprising the amino acid sequence of SEQ ID NO:202, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:202, and the light chain comprising the amino acid sequence of SEQ ID NO:184, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:184;

[0311] 2) the heavy chain comprising the amino acid sequence of SEQ ID NO:203, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:203, and the light chain comprising the amino acid sequence of SEQ ID NO:185, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:185;

[0312] 3) the heavy chain comprising the amino acid sequence of SEQ ID NO:204, or a sequence of amino acids that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:204, and the light chain comprising the amino acid sequence of SEQ ID NO:186, or a sequence of amino acids that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:186;

[0313] 4) the heavy chain comprising the amino acid sequence of SEQ ID NO:205, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:205, and the light chain comprising the amino acid sequence of SEQ ID NO:187, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:187;

[0314] 5) the heavy chain comprising the amino acid sequence of SEQ ID NO:206, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:206, and the light chain comprising the amino acid sequence of SEQ ID NO:188, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:188;

[0315] 6) the heavy chain comprising the amino acid sequence of SEQ ID NO:207, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:207, and the light chain comprising the amino acid sequence of SEQ ID NO:189, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:189;

[0316] 7) the heavy chain comprising the amino acid sequence of SEQ ID NO:208, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:208, and the light chain comprising the amino acid sequence of SEQ ID NO:190, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:190;

[0317] 8) the heavy chain comprising the amino acid sequence of SEQ ID NO:209, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:209, and the light chain comprising the amino acid sequence of SEQ ID NO:191, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:191;

[0318] 9) the heavy chain comprising the amino acid sequence of SEQ ID NO:210, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:210, and the light chain comprising the amino acid sequence of SEQ ID NO:192, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:192;

[0319] 10) the heavy chain comprising the amino acid sequence of SEQ ID NO:211, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:211, and the light chain comprising the amino acid sequence of SEQ ID NO:193, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:193;

[0320] 11) the heavy chain comprising the amino acid sequence of SEQ ID NO:212, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:212, and the light chain comprising the amino acid sequence of SEQ ID NO:194, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:194;

[0321] 12) the heavy chain comprising the amino acid sequence of SEQ ID NO:213, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:213, and the light chain comprising the amino acid sequence of SEQ ID NO:195, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:195;

[0322] 13) the heavy chain comprising the amino acid sequence of SEQ ID NO:214, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:214, and the light chain comprising the amino acid sequence of SEQ ID NO:196, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:196;

[0323] 14) the heavy chain comprising the amino acid sequence of SEQ ID NO:215, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:215, and the light chain comprising the amino acid sequence of SEQ ID NO:197, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:197;

[0324] 15) the heavy chain comprising the amino acid sequence of SEQ ID NO:216, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:216, and the light chain comprising the amino acid sequence of SEQ ID NO:198, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:198;

[0325] 16) the heavy chain comprising the amino acid sequence of SEQ ID NO:217, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:217, and the light chain comprising the amino acid sequence of SEQ ID NO:199, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:199;

[0326] 17) the heavy chain comprising the amino acid sequence of SEQ ID NO:218, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:218, and the light chain comprising the amino acid sequence of SEQ ID NO:200, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:200; and

[0327] 18) The heavy chain comprises the amino acid sequence of SEQ ID NO: 219, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 219, and the light chain comprises the amino acid sequence of SEQ ID NO: 201, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 201.

[0328] In some embodiments, an antibody that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of the heavy chain (SEQ ID NOs: 202-219) and / or the amino acid sequence of the light chain (SEQ ID NOs: 184-201) of the antibody of the invention has the same or similar biological function and / or activity as the antibody of the invention.

[0329] In some embodiments, antibodies that are at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of the heavy chain (SEQ ID NOs: 202-219) and / or the amino acid sequence of the light chain (SEQ ID NOs: 184-201) of the antibody of the present invention can also specifically bind to the ITGA2 protein.

[0330] 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 to the amino acid sequence of the heavy chain (SEQ ID NOs: 202-219) and / or the amino acid sequence of the light chain (SEQ ID NOs: 184-201) of the antibody of the invention has the same heavy chain and / or light chain variable region as the antibody of the invention, and only has conservative amino acid substitutions at other positions of the heavy chain and / or light chain (e.g., the constant region of the heavy chain and / or light chain) other than the heavy chain and / or light chain variable region, and the conservative amino acid substitutions do not alter the biological function and / or activity of the corresponding antibody;

[0331] Optionally, the aforementioned antibodies that have at least 85%, at 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 heavy chain (SEQ ID NOs: 202-219) and / or the amino acid sequence of the light chain (SEQ ID NOs: 184-201) of the antibody of the present invention can also specifically bind to the ITGA2 protein.

[0332] 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 to the amino acid sequence of the heavy chain (SEQ ID NOs: 202-219) and / or the amino acid sequence of the light chain (SEQ ID NOs: 184-201) of the antibody of the present invention has the same heavy chain and / or light chain variable regions as the antibody of the present invention, and only has conservative amino acid substitutions in the constant region of the heavy chain and / or light chain, and the conservative amino acid substitutions do not change the biological function and / or activity of the corresponding antibody, and the aforementioned antibody can also specifically bind to ITGA2 protein.

[0333] In some embodiments, the isolated antibody or antigen-binding fragment thereof is composed in part of a heavy chain and a light chain selected from at least one of the following groups:

[0334] 1) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 202, and the light chain consisting of the amino acid sequence of SEQ ID NO: 184;

[0335] 2) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 203, and the light chain consisting of the amino acid sequence of SEQ ID NO: 185;

[0336] 3) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 204, and the light chain consisting of the amino acid sequence of SEQ ID NO: 186;

[0337] 4) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 205, and the light chain consisting of the amino acid sequence of SEQ ID NO: 187;

[0338] 5) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 206, and the light chain consisting of the amino acid sequence of SEQ ID NO: 188;

[0339] 6) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 207, and the light chain consisting of the amino acid sequence of SEQ ID NO: 189;

[0340] 7) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 208, and the light chain consisting of the amino acid sequence of SEQ ID NO: 190;

[0341] 8) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 209, and the light chain consisting of the amino acid sequence of SEQ ID NO: 191;

[0342] 9) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 210, and the light chain consisting of the amino acid sequence of SEQ ID NO: 192;

[0343] 10) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 211, and the light chain consisting of the amino acid sequence of SEQ ID NO: 193;

[0344] 11) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 212, and the light chain consisting of the amino acid sequence of SEQ ID NO: 194;

[0345] 12) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 213, and the light chain consisting of the amino acid sequence of SEQ ID NO: 195;

[0346] 13) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 214, and the light chain consisting of the amino acid sequence of SEQ ID NO: 196;

[0347] 14) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 215, and the light chain consisting of the amino acid sequence of SEQ ID NO: 197;

[0348] 15) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 216, and the light chain consisting of the amino acid sequence of SEQ ID NO: 198;

[0349] 16) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 217, and the light chain consisting of the amino acid sequence of SEQ ID NO: 199;

[0350] 17) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 218, and the light chain consisting of the amino acid sequence of SEQ ID NO: 200; and

[0351] 18) The heavy chain consisting of the amino acid sequence of SEQ ID NO: 219, and the light chain consisting of the amino acid sequence of SEQ ID NO: 201.

[0352] The amino acid sequence numbers (SEQ ID NO:) of the antibodies of the present invention and their corresponding structures are summarized in Table 2 below:

[0353] In some embodiments, the isolated antibody or antigen-binding fragment thereof is composed in part of a heavy chain selected from at least one of the following groups:

[0354] 1) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 19, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 19;

[0355] 2) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 20, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 20;

[0356] 3) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 21, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 21;

[0357] 4) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 22, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 22;

[0358] 5) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 23, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 23;

[0359] 6) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 24, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 24;

[0360] 7) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 25, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 25;

[0361] 8) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26;

[0362] 9) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 27, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 27;

[0363] 10) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 28, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 28;

[0364] 11) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 29, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 29;

[0365] 12) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30, or comprises and consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30;

[0366] 13) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31, or comprises and consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31;

[0367] 14) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 32, or comprises and consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 32;

[0368] 15) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33, or comprises and consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33;

[0369] 16) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34, or comprises and consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34;

[0370] 17) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35, or comprises and consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35; and

[0371] 18) The heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36.

[0372] In some embodiments, the isolated antibody or antigen-binding fragment thereof is composed in part of a light chain selected from at least one of the following groups:

[0373] 1) the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence 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;

[0374] 2) the light chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2;

[0375] 3) the light chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 3, or comprises and consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 3;

[0376] 4) the light chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 4, or comprises and consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 4;

[0377] 5) the light chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 5, or comprises and consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 5;

[0378] 6) the light chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6, or comprises and consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6;

[0379] 7) the light chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 7, or comprises and consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 7;

[0380] 8) the light chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 8, or comprises and consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 8;

[0381] 9) the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 9, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence 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;

[0382] 10) the light chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 10, or comprises and consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 10;

[0383] 11) the light chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 11, or comprises and consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 11;

[0384] 12) the light chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 12, or comprises and consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 12;

[0385] 13) the light chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 13, or comprises and consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 13;

[0386] 14) the light chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 14, or comprises and consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 14;

[0387] 15) the light chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 15, or comprises and consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 15;

[0388] 16) the light chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 16, or comprises and consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 16;

[0389] 17) the light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 17, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence 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; and

[0390] 18) The light chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 18, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 18, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 18.

[0391] In some embodiments, the isolated antibody or antigen-binding fragment thereof is composed in part of a heavy chain and a light chain selected from at least one of the following groups:

[0392] 1) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 19, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 19, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 19, and

[0393] The light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence 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;

[0394] 2) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 20, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 20, and

[0395] The light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2;

[0396] 3) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 21, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 21, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 21, and

[0397] The light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 3, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence 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;

[0398] 4) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 22, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 22, and

[0399] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 4, or comprising an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 4, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 4;

[0400] 5) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 23, or comprises and consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 23, and

[0401] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 5, or comprising an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 5, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 5;

[0402] 6) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 24, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 24, and

[0403] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6, or comprising an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6;

[0404] 7) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 25, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 25, and

[0405] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 7, or comprising an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 7, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 7;

[0406] 8) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26, and

[0407] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 8, or comprising an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 8, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 8;

[0408] 9) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 27, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 27, and

[0409] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 9, or comprising an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 9, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 9;

[0410] 10) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 28, or comprises and consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 28, and

[0411] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 10, or comprising and consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 10;

[0412] 11) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 29, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 29, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 29, and

[0413] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 11, or comprising and consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 11;

[0414] 12) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30, and

[0415] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 12, or comprising and consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 12;

[0416] 13) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31, and

[0417] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 13, or comprising and consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 13;

[0418] 14) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 32, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 32, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 32, and

[0419] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 14, or comprising and consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 14;

[0420] 15) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33, and

[0421] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 15, or comprising and consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 15;

[0422] 16) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34, and

[0423] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 16, or comprising and consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 16;

[0424] 17) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35, and

[0425] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 17, or comprising or consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 17; and

[0426] 18) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36, and

[0427] The light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 18, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence 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.

[0428] In some embodiments, an antibody that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of the heavy chain of the antibody of the present invention encoded by the aforementioned nucleotide sequences of the present invention (SEQ ID NOs: 19-36) and / or to the amino acid sequence of the light chain of the antibody of the present invention encoded by the aforementioned nucleotide sequences of the present invention (SEQ ID NOs: 1-18) has the same or similar biological function and / or activity as the antibody of the present invention.

[0429] In some embodiments, antibodies that are at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of the heavy chain of the antibody of the present invention encoded by the aforementioned nucleotide sequences of the present invention (SEQ ID NOs: 19-36) and / or to the amino acid sequence of the light chain of the antibody of the present invention encoded by the aforementioned nucleotide sequences of the present invention (SEQ ID NOs: 1-18) can also specifically bind to ITGA2 protein.

[0430] 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 to the amino acid sequence of the heavy chain of the antibody of the invention encoded by the aforementioned nucleotide sequences of the invention (SEQ ID NOs: 19-36) and / or the amino acid sequence of the light chain of the antibody of the invention encoded by the aforementioned nucleotide sequences of the invention (SEQ ID NOs: 1-18) has the same heavy chain and / or light chain variable region as the antibody of the invention, and only has conservative amino acid substitutions at other positions of the heavy chain and / or light chain (e.g., the constant region of the heavy chain and / or light chain) other than the heavy chain and / or light chain variable region, and the conservative amino acid substitutions do not alter the biological function and / or activity of the corresponding antibody;

[0431] Alternatively, an antibody that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of the heavy chain of the antibody of the present invention encoded by the aforementioned nucleotide sequence of the present invention (SEQ ID NOs: 19-36) and / or to the amino acid sequence of the light chain of the antibody of the present invention encoded by the aforementioned nucleotide sequence of the present invention (SEQ ID NOs: 1-18) can also specifically bind to the ITGA2 protein.

[0432] 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 to the amino acid sequence of the heavy chain of the antibody of the present invention encoded by the aforementioned nucleotide sequences of the present invention (SEQ ID NOs: 19-36) and / or the amino acid sequence of the light chain of the antibody of the present invention encoded by the aforementioned nucleotide sequences of the present invention (SEQ ID NOs: 1-18) has the same heavy chain and / or light chain variable regions as the antibody of the present invention, and only has conservative amino acid substitutions in the constant regions of the heavy chain and / or light chain, wherein the conservative amino acid substitutions do not alter the biological function and / or activity of the corresponding antibody, and the aforementioned antibody can also specifically bind to ITGA2 protein.

[0433] In some embodiments, the antibody or antigen-binding fragment portion is capable of binding to ITGA2 protein in vitro with an EC50 of less than 1 nM.

[0434] In some embodiments, the antibody or antigen-binding fragment portion is capable of binding to ITGA2 protein on the surface of HuCCT1 cells with an EC50 of less than 5 nM.

[0435] In some embodiments, the antibody is a monoclonal antibody, a polyclonal antibody, a chimeric antibody, or a humanized antibody.

[0436] (III) Nucleic Acids, Vectors, Host Cells, Hybridomas, and Antibody Production Methods

[0437] On the one hand, the present invention provides isolated nucleic acid molecules, which encode the aforementioned antibody of the present invention or its Fab.In some embodiments, each CDR in the heavy chain and / or light chain variable region, heavy chain and / or light chain variable region of the aforementioned antibody of the present invention of nucleic acid molecule encoding of the present invention, and heavy chain and / or light chain constant region.In some embodiments, the nucleotide sequence of the nucleic acid molecules is codon optimized for the host cell for expression.In some embodiments, nucleic acid molecules of the present invention are operably connected with expression control sequence.

[0438] The present invention also provides an isolated nucleic acid molecule that encodes and is capable of producing a portion of an antibody or antigen-binding fragment thereof.

[0439] In some embodiments, the nucleic acid molecule comprises or consists of a nucleotide sequence selected from any one of the following: SEQ ID NOs: 1-18, and / or the nucleic acid molecule comprises or consists of a nucleotide sequence selected from any one of the following: SEQ ID NOs: 19-36.

[0440] In some embodiments, the nucleic acid molecule comprises or consists of a nucleotide sequence selected from any one of the following combinations: SEQ ID NO: 1 and SEQ ID NO: 19, SEQ ID NO: 2 and SEQ ID NO: 20, SEQ ID NO: 3 and SEQ ID NO: 21, SEQ ID NO: 4 and SEQ ID NO: 22, SEQ ID NO: 5 and SEQ ID NO: 23, SEQ ID NO: 6 and SEQ ID NO: 24, SEQ ID NO: 7 and SEQ ID NO: 25, SEQ ID NO: 8 and SEQ ID NO: 26, SEQ ID NO: 9 and SEQ ID NO: 27, SEQ ID NO: 10 and SEQ ID NO: 28, SEQ ID NO: 11 and SEQ ID NO: 29, SEQ ID NO: 12 and SEQ ID NO: 30, SEQ ID NO: 13 and SEQ ID NO: 31, SEQ ID NO: 14 and SEQ ID NO: 32, SEQ ID NO: 15 and SEQ ID NO: 33, SEQ ID NO: 16 and SEQ ID NO: 34, SEQ ID NO: 17 and SEQ ID NO: 35. NO:35, and SEQ ID NO:18 and SEQ ID NO:36.

[0441] In some embodiments, the nucleic acid molecule is operably linked to an expression control sequence.

[0442] The nucleotide sequence numbers (SEQ ID NO:) of the antibodies of the present invention and their corresponding structures are summarized in Table 3 below.

[0443] The present invention also provides an expression vector comprising at least one of the aforementioned nucleic acid molecules of the present invention.

[0444] The present invention also provides a host cell transformed with at least one of the aforementioned nucleic acid molecules or expression vectors of the present invention.

[0445] The present invention also provides hybridoma cells that express at least one of the aforementioned antibodies or antigen-binding fragments thereof of the present invention.

[0446] The present invention also provides a method for producing the antibody or antigen-binding fragment thereof of the present invention, comprising:

[0447] (i) culturing the host cell of the present invention under conditions suitable for expression of the nucleic acid molecule or expression vector, and

[0448] (ii) isolating and purifying the antibody or antigen-binding fragment thereof expressed by the host cell.

[0449] In some embodiments, the nucleotide sequence of the nucleic acid molecule is codon-optimized for the host cell used for expression. In some embodiments, the nucleic acid molecule is operably linked to an expression control sequence.

[0450] The present invention also provides a method for producing the antibody or antigen-binding fragment thereof of the present invention, comprising:

[0451] (i) preparing hybridoma cells capable of expressing a monoclonal antibody or antigen-binding fragment thereof of the present invention, and

[0452] (ii) isolating and purifying the antibody or antigen-binding fragment thereof expressed by the hybridoma cell.

[0453] (IV) Antibody-drug conjugates

[0454] In one aspect, the present invention provides an antibody-drug conjugate (ADC) prepared from the antibody or antigen-binding fragment thereof of the present invention.

[0455] Specifically, the present invention provides an antibody drug conjugate, Ab-LD, of the following formula, wherein:

[0456] The symbol "Ab" represents at least one of the aforementioned monoclonal antibodies of the present invention or an antigen-binding fragment thereof;

[0457] The symbol "L" represents a linker that connects the antibody portion and the partner molecule; and

[0458] The symbol "D" represents a partner molecule.

[0459] As used herein, ADCs are prepared by linking a partner molecule to an antibody or antigen-binding fragment thereof via a linker. In the ADCs of the present invention, the antibody performs a targeting function: by binding to the target tissue or cell where its antigen is found, the antibody directs the conjugate to that target tissue or cell. There, the linker is, for example, cleaved, releasing the partner molecule to perform its desired biological function.

[0460] The partner molecule can be a drug payload or a labeling molecule. The drug payload can be a therapeutic agent, for example, a cytotoxic agent, a chemotherapeutic agent, a cytostatic agent, an immunomodulatory agent, etc. In some embodiments, the therapeutic agent is a cytotoxic agent, i.e., a cytotoxin. As used herein, the terms "cytotoxic agent" and "cytotoxin" are used interchangeably.

[0461] The labeling molecule can be any label that produces a detectable signal, such as a radioactive label, a fluorescent label, or an enzyme that catalyzes a detectable modification of a substrate.

[0462] As used herein, the terms "drug," "payload," and "drug payload" are used interchangeably. As used herein, an antibody-drug conjugate (ADC) encompasses a conjugate formed by linking an antibody of the invention or an antigen-binding fragment thereof to a drug payload, as well as a conjugate formed by linking an antibody of the invention or an antigen-binding fragment thereof to a labeling molecule.

[0463] The ratio of partner molecules attached to the antibody can vary depending on factors such as the amount of partner molecules used during the conjugation reaction and the experimental conditions. The ratio of partner molecules to antibody can be 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1 to 1.5.

[0464] Therefore, the present invention also provides an antibody drug conjugate of the following formula, Ab-(LD)p, wherein:

[0465] The symbol "Ab" represents at least one of the aforementioned monoclonal antibodies of the present invention or an antigen-binding fragment thereof;

[0466] The symbol “L” represents a linker connecting the antibody portion and the partner molecule;

[0467] The symbol "D" represents a partner molecule; and

[0468] The symbol "p" represents the number of linker / partner molecules (preferably drug cargo) conjugated to the aforementioned portion of the monoclonal antibody or antigen-binding fragment thereof of the present invention.

[0469] In some embodiments, p is selected from the following values: 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7 , 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, and 8.0.

[0470] In some embodiments, the linker of the present invention is selected from the group consisting of vc, mc-GGFG, AcLysvc, mc, MalPeg6, m(H20)c, and m(H20)cvc; and / or the linker is cleavable. In some embodiments, the linker of the present invention is vc.

[0471] In some embodiments, the partner molecule of the present invention is a drug payload, and the drug payload is a therapeutic molecule; optionally, the drug payload is selected from one of the following: a cytotoxic agent, a cytostatic agent, an immunomodulatory agent, and a chemotherapeutic agent; optionally, the drug payload is selected from one of the following: MMAE, MMAF, DM1, DM4, Dxd, SN-38, Topotecan and its derivatives, Exatecan and its derivatives, Belotecan and its derivatives, Camptothecin, Calichemicin, and PBD.

[0472] In some embodiments, the drug cargo is MMAE. "MMAE" refers to monomethyl auristatin E, as shown in the figure below, where the wavy line indicates the covalent attachment to the linker (L) of the antibody drug conjugate:

[0473] In some embodiments, the drug cargo is MMAF. MMAF refers to monomethyl auristatin F, where the wavy line indicates covalent attachment to the linker (L) of the antibody drug conjugate (US2005 / 0238649):

[0474] In some embodiments, the linker-partner molecule is vcMMAE. vcMMAE drug linker moieties and conjugation methods are disclosed in WO2004010957, US7659241, US7829531, US7851437, and US 11 / 833,028 (Seattle Genetics, Inc.), which are incorporated herein by reference. Using methods similar to those disclosed in the above-mentioned literature, the vcMMAE drug linker moiety is conjugated to the antibodies of the present invention.

[0475] For further discussion of types of cytotoxins, linkers and methods for conjugating therapeutic agents to 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; Senter, PD and Springer, CJ (2001) Adv. Drug Deliv. Rev. 53: 247-264, which are incorporated herein by reference.

[0476] In some embodiments, the drug payload may further be a radioisotope, thereby producing a cytotoxic radiopharmaceutical (also known as an antibody radioisotope conjugate). Examples of radioisotopes that are cytotoxic to tumor cells include, but are not limited to, iodine-131, indium-111, yttrium-90, and lutetium-177. Methods for preparing antibody radioisotope conjugates are known in the art.

[0477] In some embodiments, the partner molecule of the present invention is a labeling molecule; optionally, the labeling molecule is selected from the group consisting of a radioactive label, a fluorescent label, and a detectably modified enzyme. In some embodiments, the radioactive label is a radioisotope, such as iodine-131, indium-111, yttrium-90, and lutetium-177.

[0478] Experiments have shown that ITGA2 protein can be used as an effective target for antibody-drug conjugates. The antibody-drug conjugates obtained by coupling antibodies with small molecule toxins can produce excellent killing effects on tumors expressing ITGA2 protein.

[0479] (V) Pharmaceutical compositions, therapeutic uses and methods

[0480] The present invention provides pharmaceutical compositions comprising a therapeutically effective amount of at least one monoclonal antibody or antigen-binding fragment thereof of the present invention, or at least one antibody-drug conjugate of the present invention, as well as therapeutic uses and methods of treatment thereof. In the antibody-drug conjugates of the present invention, the antibody of the present invention is conjugated to a drug cargo.

[0481] In one aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of at least one monoclonal antibody or antigen-binding fragment thereof of the present invention or at least one antibody-drug conjugate of the present invention. In some embodiments, the pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier.

[0482] A "therapeutically effective amount" of at least one of the aforementioned monoclonal antibodies or antigen-binding fragment portions thereof, or at least one of the aforementioned antibody-drug conjugates of the present invention, preferably results in a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease-free periods, or prevents impairment or disability caused by the affliction of the disease. For example, for the treatment of tumors, a "therapeutically effective amount" of at least one of the aforementioned monoclonal antibodies or antigen-binding fragment portions thereof, or at least one of the aforementioned antibody-drug conjugates of the present invention, preferably inhibits cell growth 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%, relative to an untreated subject. The ability to inhibit tumor growth can be evaluated in animal model systems that are predictive of efficacy against human tumors. Alternatively, it can be evaluated by examining the ability to inhibit cell growth, which inhibition can be measured in vitro using assays known to those skilled in the art. An effective amount of an antibody or antigen-binding fragment thereof of the present invention is capable of reducing tumor size or otherwise alleviating symptoms in a subject, such as preventing and / or treating metastasis or recurrence. Such an amount can be determined by those skilled in the art based on factors such as the size of the subject, the severity of the subject's symptoms, and the specific composition or route of administration selected.

[0483] In another aspect, the present invention provides the use of at least one monoclonal antibody or antigen-binding fragment thereof of the present invention or at least one antibody-drug conjugate of the present invention in preparing a pharmaceutical composition. In some embodiments, the pharmaceutical composition is used to treat a malignant tumor, prevent and / or treat metastasis or recurrence of a malignant tumor in a patient.

[0484] In another aspect, the present invention provides a pharmaceutical composition comprising at least one monoclonal antibody or antigen-binding fragment thereof of the present invention or at least one antibody-drug conjugate of the present invention, for use in a method for treating a malignant tumor, preventing and / or treating metastasis or recurrence of a malignant tumor in a patient.

[0485] In another aspect, the present invention provides a method for treating a malignant tumor, preventing and / or treating metastasis or recurrence of a malignant tumor in a patient, comprising administering to the patient an effective amount of at least one of the aforementioned monoclonal antibodies or antigen-binding fragments thereof of the present invention, at least one of the aforementioned antibody-drug conjugates of the present invention, and / or at least one of the aforementioned pharmaceutical compositions of the present invention.

[0486] In some embodiments, the malignant tumor is a tumor that expresses ITGA2 protein. The malignant tumor is selected from the group consisting of breast cancer, colorectal cancer, large intestine cancer, skin cancer, pancreatic cancer, prostate cancer, liver cancer, lung cancer, gastric cancer, leukemia, bile duct cancer, cervical cancer, endometrial cancer, esophageal cancer, head and neck cancer, lymphoma, medullary thyroid cancer, non-Hodgkin's lymphoma, ovarian cancer, glioma, melanoma, and bladder cancer. 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.

[0487] (VI) Diagnostic / prognostic compositions, diagnostic / prognostic uses, and methods

[0488] As described in this article, ITGA2 is a tumor-associated antigen that is specifically overexpressed in tumor cells, especially in patients with cancers such as colorectal cancer, bile duct cancer, pancreatic cancer and skin cancer, and is expressed on the surface of tumor cells.

[0489] The present invention provides diagnostic / prognostic compositions comprising at least one monoclonal antibody or antigen-binding fragment thereof of the present invention, or at least one antibody-drug conjugate of the present invention, diagnostic / prognostic uses of such compositions, and diagnostic / prognostic methods. In the diagnostic / prognostic drug conjugates of the present invention, the antibody of the present invention is conjugated to a marker molecule. For purposes of diagnostic / prognostic compositions, diagnostic / prognostic uses, and diagnostic / prognostic methods, the antibody-drug conjugate of the present invention refers to a conjugate formed by linking an antibody of the present invention or its antigen-binding fragment to a marker molecule.

[0490] In one aspect, the present invention provides the use of at least one of the aforementioned monoclonal antibodies or antigen-binding fragments thereof of the present invention, or at least one of the aforementioned antibody-drug conjugates of the present invention, in the preparation of a diagnostic / prognostic composition. In some embodiments, the diagnostic composition is used to detect the presence of a malignant tumor in a patient. In some embodiments, the prognostic composition is used to predict the recurrence or progression of a malignant tumor in a patient.

[0491] In another aspect, the present invention provides a method for detecting / diagnosing the presence of a malignant tumor in a patient, comprising administering to the patient an effective amount of at least one of the aforementioned monoclonal antibodies or antigen-binding fragments thereof of the present invention, at least one of the aforementioned antibody-drug conjugates of the present invention, and / or at least one of the aforementioned diagnostic / prognostic compositions of the present invention.

[0492] In some embodiments, the present invention provides a method for detecting / diagnosing the presence of a malignant tumor in a patient, comprising:

[0493] a) contacting a biological sample obtained from the patient with at least one of the aforementioned monoclonal antibodies or antigen-binding fragments thereof of the present invention, at least one of the aforementioned antibody-drug conjugates of the present invention, and / or at least one of the aforementioned diagnostic / prognostic compositions of the present invention;

[0494] b) detecting binding of at least one of the aforementioned monoclonal antibodies of the present invention or antigen-binding fragments thereof, at least one of the aforementioned antibody drug conjugates of the present invention, and / or at least one of the aforementioned diagnostic / prognostic compositions of the present invention to a target antigen in the biological sample, wherein detection of binding of the antibody to the target antigen indicates the presence of a malignant tumor in the patient.

[0495] In another aspect, the present invention provides a method for prognosing recurrence or progression of a malignant tumor in a patient, comprising administering to the patient an effective amount of at least one of the aforementioned monoclonal antibodies or antigen-binding fragments thereof of the present invention, at least one of the aforementioned antibody-drug conjugates of the present invention, and / or at least one of the aforementioned diagnostic / prognostic compositions of the present invention.

[0496] In some embodiments, the present invention provides a method for prognosing recurrence or progression of a malignant tumor in a patient, the method comprising:

[0497] (a) isolating a biological sample comprising tumor cells from the patient;

[0498] (b) contacting the biological sample comprising tumor cells with at least one of the aforementioned monoclonal antibodies or antigen-binding fragments thereof of the present invention, at least one of the aforementioned antibody-drug conjugates of the present invention, and / or at least one of the aforementioned diagnostic / prognostic compositions of the present invention; and

[0499] (c) identifying that the binding of the antibody to the tumor cell represents the presence of the tumor cell,

[0500] The recurrence or progression of the malignancy in said patient is thereby prognosed.

[0501] In some embodiments, the progression of the malignancy comprises metastasis of the malignancy in the patient.

[0502] In some embodiments, the presence of tumor cells identified to which at least one of the aforementioned monoclonal antibodies or antigen-binding fragments thereof of the invention, at least one of the aforementioned antibody drug conjugates of the invention, and / or at least one of the aforementioned diagnostic / prognostic compositions of the invention is bound indicates a high risk of recurrence or progression of the malignancy in the patient.

[0503] In some embodiments, the partner molecule of the present invention is a labeling molecule; optionally, the labeling molecule is selected from the following: a radioactive label (eg, an isotope), a fluorescent label (eg, a fluorescent dye), a chemical substance, and a detectably modified enzyme and tag.

[0504] In some embodiments, the biological sample is selected from one of the following: a blood sample, a tissue sample, and a lymph sample.

[0505] Methods for detecting antibody-antigen binding are known in the art, such as ELISA and the like.

[0506] (VII) Test kit

[0507] Also within the scope of the present invention are kits for use in the methods of the present invention, comprising at least one aforementioned monoclonal antibody or antigen-binding fragment thereof of the present invention, at least one aforementioned antibody-drug conjugate of the present invention, at least one aforementioned pharmaceutical composition of the present invention, or one aforementioned diagnostic / prognostic composition of the present invention, and instructions for use.

[0508] In some embodiments, the kit may further include at least one additional detection reagent for detecting the presence of at least one of the aforementioned monoclonal antibodies or antigen-binding fragments thereof of the present invention, at least one of the aforementioned antibody-drug conjugates of the present invention, at least one of the aforementioned pharmaceutical compositions of the present invention, or one of the aforementioned diagnostic / prognostic compositions of the present invention. The kit generally includes a label indicating the intended use and / or method of use of the contents of the kit. The term label includes any written or recorded material provided on or with the kit or otherwise provided with the kit.

[0509] Example

[0510] A further understanding of the present invention may be obtained by reference to some of the specific embodiments provided herein, which are intended to illustrate the present invention only and are not intended to limit the scope of the present invention in any way. Obviously, various modifications and variations may be made to the present invention without departing from the spirit of the present invention, and therefore, such modifications and variations are also within the scope of the present application.

[0511] Example 1 - ITGA2 protein is specifically overexpressed on the surface of various cancer cells

[0512] HuCC-T1 (human cholangiocarcinoma cell line; Meisen Cell: CTCC-003-0103), HCCC-9810 (human cholangiocarcinoma cell line; Wuhan Punocell: CL-0095), AsPC-1 (human metastatic pancreatic cancer cell line; Wuhan Punocell: CL-0027), BxPC-3 (human orthotopic pancreatic adenocarcinoma cell line; Meisen Cell: CTCC-001-0360), A431 (human epidermal carcinoma cell line; Wuhan Punocell: CL-0015), HT-29 (human colorectal adenocarcinoma cell line; Wuhan Punocell: CL-0118), and CHO (hamster ovary cell line; Wuhan Punocell: CL-0061) cells were plated into 96-deep-well plates. 50,000 cells / 100 μL were plated into each well, with three wells plated for each cell type. The cells were then washed twice with PBS, repeatedly pipetting and homogenizing. Add 1% FBS PBS solution to each well, the addition amount is 100 μL / well, and incubate in a 4°C refrigerator for 30 minutes. Dilute FITC-labeled mouse anti-human ITGA2 antibody solution (BD Pharmingen: 555498) to the working concentration, 20 μL / well, and incubate in a 4°C refrigerator in the dark for 30 minutes. After incubation, wash the cells twice with 500ul 1% FBS, and then add 250ul PBS to resuspend the cells. The blank reference solution is 250μL PBS solution containing the reference control solution. The ITGA2 protein copy number of each cell line was collected and analyzed by flow cytometry, and the equivalent soluble fluorescent pigment molecules (Molecules of Equivalent Soluble Fluorochrome, MESF) were used. The results are shown in Table 3 below.

[0513] Table 3

[0514] As shown in Table 3, under the same antibody concentration and treatment conditions, ITGA2 protein expression was high on the surface of HuCCT1, BxPC-3, HCCC-9810, ASPC-1, and A431 cells (MESF>150,000), while there was almost no expression on the surface of the negative control CHO cells (MESF<1000, which can be regarded as the background value at the experimental technical level).

[0515] Example 2 - Preparation of ITGA2 Antibody

[0516] 1. Vector Construction

[0517] The design, vector construction, expression, purification, and identification of the ITGA2 antibody sequence of the present invention were all completed by Sanyou Biopharmaceuticals (Shanghai) Co., Ltd. The construction process mainly involved constructing the ITGA2 antibody sequence on the pcDNA3.4 vector, and then obtaining the plasmid through PCR, enzyme digestion, ligation, transformation, identification, sequencing, alignment, and extraction.

[0518] The vectors containing the light chain and heavy chain sequences of the ITGA2 antibody of the present invention are shown in Table 4 below:

[0519] Sixteen light chain plasmids were Kappa type, and two plasmids were Lambda type; 18 heavy chain plasmids were IgG1 type.

[0520] The coding sequences of the light and heavy chains in the plasmid vectors in the above table are as follows (the shaded areas correspond to the constant region sequences):

[0521] Light chain:

[0522] Humanized antibody light chain coding sequence: FS002-A1-LC (Kappa) (SEQ ID NO: 1), which is used to express humanized light chain variable region + human light chain constant region

[0523] Humanized antibody light chain coding sequence: FS002-A5-LC (Kappa) (SEQ ID NO: 2), which is used to express humanized light chain variable region + human light chain constant region

[0524] Humanized antibody light chain coding sequence: FS002-A15-LC (Kappa) (SEQ ID NO: 3), which is used to express humanized light chain variable region + human light chain constant region

[0525] Humanized antibody light chain coding sequence: FS002-A36-LC (Kappa) (SEQ ID NO: 4), which is used to express humanized light chain variable region + human light chain constant region

[0526] Humanized antibody light chain coding sequence: FS002-A66-LC (Kappa) (SEQ ID NO: 5), which is used to express humanized light chain variable region + human light chain constant region

[0527] Humanized antibody light chain coding sequence: FS002-A10-LC (Kappa-2) (SEQ ID NO: 6), which is used to express humanized light chain variable region + human light chain constant region

[0528] Humanized antibody light chain coding sequence: FS002-C9-LC (Kappa-2) (SEQ ID NO: 7), which is used to express humanized light chain variable region + human light chain constant region

[0529] Humanized antibody light chain coding sequence: FS002-C11-LC (Kappa-2) (SEQ ID NO: 8), which is used to express humanized light chain variable region + human light chain constant region

[0530] Humanized antibody light chain coding sequence: FS002-C216-LC (Kappa-2) (SEQ ID NO: 9), which is used to express humanized light chain variable region + human light chain constant region

[0531] Humanized antibody light chain coding sequence: FS002-C375-LC (Kappa-2) (SEQ ID NO: 10), which is used to express humanized light chain variable region + human light chain constant region

[0532] Humanized antibody light chain coding sequence: FS002-C417-LC (Kappa-2) (SEQ ID NO: 11), which is used to express humanized light chain variable region + human light chain constant region

[0533] Humanized antibody light chain coding sequence: FS002-B27-LC (Kappa-2) (SEQ ID NO: 12), which is used to express humanized light chain variable region + human light chain constant region

[0534] Humanized antibody light chain coding sequence: FS002-C330-LC (Kappa-2) (SEQ ID NO: 13), which is used to express humanized light chain variable region + human light chain constant region

[0535] Humanized antibody light chain coding sequence: FS002-C153-LC (LambdaC2)-2 (SEQ ID NO: 14), which is used to express humanized light chain variable region + human light chain constant region

[0536] Humanized antibody light chain coding sequence: FS002-C241-LC (LambdaC2)-2 (SEQ ID NO: 15), which is used to express humanized light chain variable region + human light chain constant region

[0537] Humanized antibody light chain coding sequence: FS002-C15-LC (Kappa-2) (SEQ ID NO: 16), which is used to express humanized light chain variable region + human light chain constant region

[0538] Humanized antibody light chain coding sequence: FS002-C58-LC (Kappa-2) (SEQ ID NO: 17), which is used to express humanized light chain variable region + human light chain constant region

[0539] Humanized antibody light chain coding sequence: FS002-A72-LC (Kappa-2) (SEQ ID NO: 18), which is used to express humanized light chain variable region + human light chain constant region

[0540] Heavy chain:

[0541] Humanized antibody heavy chain coding sequence: FS002-A1-HC (IgG1) (SEQ ID NO: 19), which is used to express humanized heavy chain variable region + human heavy chain constant region

[0542] Humanized antibody heavy chain coding sequence: FS002-A5-HC (IgG1) (SEQ ID NO: 20), which is used to express humanized heavy chain variable region + human heavy chain constant region

[0543] Humanized antibody heavy chain coding sequence: FS002-A15-HC (IgG1) (SEQ ID NO: 21), which is used to express humanized heavy chain variable region + human heavy chain constant region

[0544] Humanized antibody heavy chain coding sequence: FS002-36-HC (IgG1) (SEQ ID NO: 22), which is used to express humanized heavy chain variable region + human heavy chain constant region

[0545] Humanized antibody heavy chain coding sequence: FS002-A66-HC (IgG1) (SEQ ID NO: 23), which is used to express humanized heavy chain variable region + human heavy chain constant region

[0546] Humanized antibody heavy chain coding sequence: FS002-A10-HC (IgG1) (SEQ ID NO: 24), which is used to express humanized heavy chain variable region + human heavy chain constant region

[0547] Humanized antibody heavy chain coding sequence: FS002-C9-HC (IgG1) (SEQ ID NO: 25), which is used to express humanized heavy chain variable region + human heavy chain constant region

[0548] Humanized antibody heavy chain coding sequence: FS002-C11-HC (IgG1) (SEQ ID NO: 26), which is used to express humanized heavy chain variable region + human heavy chain constant region

[0549] Humanized antibody heavy chain coding sequence: FS002-C216-HC (IgG1) (SEQ ID NO: 27), which is used to express humanized heavy chain variable region + human heavy chain constant region

[0550] Humanized antibody heavy chain coding sequence: FS002-C375-HC (IgG1) (SEQ ID NO: 28), which is used to express humanized heavy chain variable region + human heavy chain constant region

[0551] Humanized antibody heavy chain coding sequence: FS002-C417-HC (IgG1) (SEQ ID NO: 29), which is used to express humanized heavy chain variable region + human heavy chain constant region

[0552] Humanized antibody heavy chain coding sequence: FS002-B27-HC (IgG1) (SEQ ID NO: 30), which is used to express humanized heavy chain variable region + human heavy chain constant region

[0553] Humanized antibody heavy chain coding sequence: FS002-C330-HC (IgG1) (SEQ ID NO: 31), which is used to express humanized heavy chain variable region + human heavy chain constant region

[0554] Humanized antibody heavy chain coding sequence: FS002-C153-HC (IgG1) (SEQ ID NO: 32), which is used to express humanized heavy chain variable region + human heavy chain constant region

[0555] Humanized antibody heavy chain coding sequence: FS002-C241-HC (IgG1) (SEQ ID NO: 33), which is used to express humanized heavy chain variable region + human heavy chain constant region

[0556] Humanized antibody heavy chain coding sequence: FS002-C15-HC (IgG1) (SEQ ID NO: 34), which is used to express humanized heavy chain variable region + human heavy chain constant region

[0557] Humanized antibody heavy chain coding sequence: FS002-C58-HC (IgG1) (SEQ ID NO: 35), which is used to express humanized heavy chain variable region + human heavy chain constant region

[0558] Humanized antibody heavy chain coding sequence: FS002-A72-HC (IgG1) (SEQ ID NO: 36), which is used to express humanized heavy chain variable region + human heavy chain constant region

[0559] The amino acid sequences of the light chain variable region and heavy chain variable region of the antibody expressed by the above vector are as follows:

[0560] Light chain variable region (amino acid sequence):

[0561] FS002-A1-LC (Kappa) light chain variable region (SEQ ID NO: 37)

[0562] The underlined italic parts indicate VL-CDR1 (SEQ ID NO: 38: ), VL-CDR2 (SEQ ID NO: 39: )、VL-CDR3 (SEQ ID NO: 40: ).

[0563] FS002-A5-LC (Kappa) light chain variable region (SEQ ID NO: 41)

[0564] The underlined italic parts indicate VL-CDR1 (SEQ ID NO: 42: ), VL-CDR2 (SEQ ID NO: 43: )、VL-CDR3 (SEQ ID NO: 44: ).

[0565] FS002-A15-LC (Kappa) light chain variable region (SEQ ID NO: 45)

[0566] The underlined italic parts indicate VL-CDR1 (SEQ ID NO: 46: )、VL-CDR2 (SEQ ID NO: 47: ), VL-CDR3 (SEQ ID NO: 48: ).

[0567] FS002-A36-LC (Kappa) light chain variable region (SEQ ID NO: 49)

[0568] The underlined italic parts indicate VL-CDR1 (SEQ ID NO: 50: )、VL-CDR2(SEQ ID NO:51: )、VL-CDR3 (SEQ ID NO: 52: ).

[0569] FS002-A66-LC (Kappa) light chain variable region (SEQ ID NO: 53)

[0570] The underlined italic parts indicate VL-CDR1 (SEQ ID NO: 54: ), VL-CDR2 (SEQ ID NO: 55: )、VL-CDR3 (SEQ ID NO: 56: ).

[0571] FS002-A10-LC (Kappa-2) light chain variable region (SEQ ID NO: 57)

[0572] The underlined italic parts indicate VL-CDR1 (SEQ ID NO: 58: ), VL-CDR2 (SEQ ID NO: 59: )、VL-CDR3 (SEQ ID NO: 60: ).

[0573] FS002-C9-LC (Kappa-2) light chain variable region (SEQ ID NO: 61)

[0574] The underlined italic parts indicate VL-CDR1 (SEQ ID NO: 62: ), VL-CDR2 (SEQ ID NO: 63: ), VL-CDR3 (SEQ ID NO: 64: ).

[0575] FS002-C11-LC (Kappa-2) light chain variable region (SEQ ID NO: 65)

[0576] The underlined italic parts indicate VL-CDR1 (SEQ ID NO: 66: ), VL-CDR2 (SEQ ID NO: 67: ), VL-CDR3 (SEQ ID NO: 68: ).

[0577] FS002-C216-LC (Kappa-2) light chain variable region (SEQ ID NO: 69)

[0578] The underlined italic parts indicate VL-CDR1 (SEQ ID NO: 70: )、VL-CDR2(SEQ ID NO:71: )、VL-CDR3 (SEQ ID NO: 72: ).

[0579] FS002-C375-LC (Kappa-2) light chain variable region (SEQ ID NO: 73)

[0580] The underlined italic parts indicate VL-CDR1 (SEQ ID NO: 74: ), VL-CDR2 (SEQ ID NO: 75: ), VL-CDR3 (SEQ ID NO: 76: ).

[0581] FS002-C417-LC (Kappa-2) light chain variable region (SEQ ID NO: 77)

[0582] The underlined italic parts indicate VL-CDR1 (SEQ ID NO: 78: )、VL-CDR2 (SEQ ID NO: 79: )、VL-CDR3 (SEQ ID NO80: ).

[0583] FS002-B27-LC (Kappa-2) light chain variable region (SEQ ID NO: 81)

[0584] The underlined italic parts indicate VL-CDR1 (SEQ ID NO: 82: ), VL-CDR2 (SEQ ID NO: 83: ), VL-CDR3 (SEQ ID NO: 84: ).

[0585] FS002-C330-LC (Kappa-2) light chain variable region (SEQ ID NO: 85)

[0586] The underlined italic parts indicate VL-CDR1 (SEQ ID NO: 86: ), VL-CDR2 (SEQ ID NO: 87: ), VL-CDR3 (SEQ ID NO: 88: ).

[0587] FS002-C153-LC (LambdaC2)-2 light chain variable region (SEQ ID NO: 89)

[0588] The underlined italic parts indicate VL-CDR1 (SEQ ID NO: 90: )、VL-CDR2(SEQ ID NO:91: )、VL-CDR3 (SEQ ID NO:92: ).

[0589] FS002-C241-LC (LambdaC2)-2 light chain variable region (SEQ ID NO: 93)

[0590] The underlined italic parts indicate VL-CDR1 (SEQ ID NO: 94: )、VL-CDR2 (SEQ ID NO:95: ), VL-CDR3 (SEQ ID NO: 96: ).

[0591] FS002-C15-LC (Kappa-2) light chain variable region (SEQ ID NO: 97)

[0592] The underlined italic parts indicate VL-CDR1 (SEQ ID NO: 98: ), VL-CDR2 (SEQ ID NO: 99: )、VL-CDR3 (SEQ ID NO: 100: ).

[0593] FS002-C58-LC (Kappa-2) light chain variable region (SEQ ID NO: 101)

[0594] The underlined italic parts indicate VL-CDR1 (SEQ ID NO: 102: ), VL-CDR2 (SEQ ID NO: 103: )、VL-CDR3 (SEQ ID NO: 104: ).

[0595] FS002-A72-LC (Kappa-2) light chain variable region (SEQ ID NO: 105)

[0596] The underlined italic parts indicate VL-CDR1 (SEQ ID NO: 106: ), VL-CDR2 (SEQ ID NO: 107: ), VL-CDR3 (SEQ ID NO: 108: ).

[0597] Light chain constant region (amino acid sequence):

[0598] Kappa type light chain constant region sequence (SEQ ID NO: 109)

[0599] Lambda-type light chain constant region sequence (SEQ ID NO: 110)

[0600] Heavy chain variable region (amino acid sequence):

[0601] FS002-A1-HC (IgG1) heavy chain variable region (SEQ ID NO: 111)

[0602] The underlined italic parts indicate VH-CDR1 (SEQ ID NO: 112: ), VH-CDR2 (SEQ ID NO: 113: ), VH-CDR3 (SEQ ID NO: 114: ).

[0603] FS002-A5-HC (IgG1) heavy chain variable region (SEQ ID NO: 115)

[0604] The underlined italic parts indicate VH-CDR1 (SEQ ID NO: 116: ), VH-CDR2 (SEQ ID NO: 117: ), VH-CDR3 (SEQ ID NO: 118: ).

[0605] FS002-A15-HC (IgG1) heavy chain variable region (SEQ ID NO: 119)

[0606] The underlined italic parts indicate VH-CDR1 (SEQ ID NO: 120: ), VH-CDR2 (SEQ ID NO: 121: ), VH-CDR3 (SEQ ID NO: 122: ).

[0607] FS002-A36-HC (IgG1) heavy chain variable region (SEQ ID NO: 123)

[0608] The underlined italic parts indicate VH-CDR1 (SEQ ID NO: 124: ), VH-CDR2 (SEQ ID NO: 125: ), VH-CDR3 (SEQ ID NO: 126: ).

[0609] FS002-A66-HC (IgG1) heavy chain variable region (SEQ ID NO: 127)

[0610] The underlined italic parts indicate VH-CDR1 (SEQ ID NO: 128: ), VH-CDR2 (SEQ ID NO: 129: ), VH-CDR3 (SEQ ID NO: 130: ).

[0611] FS002-A10-HC (IgG1) heavy chain variable region (SEQ ID NO: 131)

[0612] The underlined italic parts indicate VH-CDR1 (SEQ ID NO: 132: ), VH-CDR2 (SEQ ID NO: 133: ), VH-CDR3 (SEQ ID NO: 134: ).

[0613] FS002-C9-HC (IgG1) heavy chain variable region (SEQ ID NO: 135)

[0614] The underlined italic parts indicate VH-CDR1 (SEQ ID NO: 136: ), VH-CDR2 (SEQ ID NO: 137: ), VH-CDR3 (SEQ ID NO: 138: ).

[0615] FS002-C11-HC (IgG1) heavy chain variable region (SEQ ID NO: 139)

[0616] The underlined italic parts indicate VH-CDR1 (SEQ ID NO: 140: ), VH-CDR2 (SEQ ID NO: 141: ), VH-CDR3 (SEQ ID NO: 142: ).

[0617] FS002-C216-HC (IgG1) heavy chain variable region (SEQ ID NO: 143)

[0618] The underlined italic parts indicate VH-CDR1 (SEQ ID NO: 144: ), VH-CDR2 (SEQ ID NO: 145: ), VH-CDR3 (SEQ ID NO: 146: ).

[0619] FS002-C375-HC (IgG1) heavy chain variable region (SEQ ID NO: 147)

[0620] The underlined italic parts indicate VH-CDR1 (SEQ ID NO: 148: ), VH-CDR2 (SEQ ID NO: 149: ), VH-CDR3 (SEQ ID NO: 150: ).

[0621] FS002-C417-HC (IgG1) heavy chain variable region (SEQ ID NO: 151)

[0622] The underlined italic parts indicate VH-CDR1 (SEQ ID NO: 152: ), VH-CDR2 (SEQ ID NO: 153: ), VH-CDR3 (SEQ ID NO: 154: ).

[0623] FS002-B27-HC (IgG1) heavy chain variable region (SEQ ID NO: 155)

[0624] The underlined italic parts indicate VH-CDR1 (SEQ ID NO: 156: ), VH-CDR2 (SEQ ID NO: 157: ), VH-CDR3 (SEQ ID NO: 158: ).

[0625] FS002-C330-HC (IgG1) heavy chain variable region (SEQ ID NO: 159)

[0626] The underlined italic parts indicate VH-CDR1 (SEQ ID NO: 160: ), VH-CDR2 (SEQ ID NO: 161: ), VH-CDR3 (SEQ ID NO: 162: ).

[0627] FS002-C153-HC (IgG1) heavy chain variable region (SEQ ID NO: 163)

[0628] The underlined italic parts indicate VH-CDR1 (SEQ ID NO: 164: ), VH-CDR2 (SEQ ID NO: 165: ), VH-CDR3 (SEQ ID NO: 166: ).

[0629] FS002-C241-HC (IgG1) heavy chain variable region (SEQ ID NO: 167)

[0630] The underlined italic parts indicate VH-CDR1 (SEQ ID NO: 168: ), VH-CDR2 (SEQ ID NO: 169: ), VH-CDR3 (SEQ ID NO: 170: .

[0631] FS002-C15-HC (IgG1) heavy chain variable region (SEQ ID NO: 171)

[0632] The underlined italic parts indicate VH-CDR1 (SEQ ID NO: 172: ), VH-CDR2 (SEQ ID NO: 173: ), VH-CDR3 (SEQ ID NO: 174: ).

[0633] FS002-C58-HC (IgG1) heavy chain variable region (SEQ ID NO: 175)

[0634] The underlined italic parts indicate VH-CDR1 (SEQ ID NO: 176: ), VH-CDR2 (SEQ ID NO: 177: ), VH-CDR3 (SEQ ID NO: 178: ).

[0635] FS002-A72-HC (IgG1) heavy chain variable region (SEQ ID NO: 179)

[0636] The underlined italic parts indicate VH-CDR1 (SEQ ID NO: 180: ), VH-CDR2 (SEQ ID NO: 181: ), VH-CDR3 (SEQ ID NO: 182: ).

[0637] IgG1 heavy chain constant region (SEQ ID NO: 183)

[0638] The full-length amino acid sequence of the antibody light chain is as follows (the shaded portion corresponds to the constant region sequence):

[0639] FS002-A1-LC (Kappa) light chain (SEQ ID NO: 184)

[0640] FS002-A5-LC (Kappa) light chain (SEQ ID NO: 185)

[0641] FS002-A15-LC (Kappa) light chain (SEQ ID NO: 186)

[0642] FS002-A36-LC (Kappa) light chain (SEQ ID NO: 187)

[0643] FS002-A66-LC (Kappa) light chain (SEQ ID NO: 188)

[0644] FS002-A10-LC (Kappa-2) light chain (SEQ ID NO: 189)

[0645] FS002-C9-LC (Kappa-2) light chain (SEQ ID NO: 190)

[0646] FS002-C11-LC (Kappa-2) light chain (SEQ ID NO: 191)

[0647] FS002-C216-LC (Kappa-2) light chain (SEQ ID NO: 192)

[0648] FS002-C375-LC (Kappa-2) light chain (SEQ ID NO: 193)

[0649] FS002-C417-LC (Kappa-2) light chain (SEQ ID NO: 194)

[0650] FS002-B27-LC (Kappa-2) light chain (SEQ ID NO: 195)

[0651] FS002-C330-LC (Kappa-2) light chain (SEQ ID NO: 196)

[0652] FS002-C153-LC (LambdaC2)-2 light chain (SEQ ID NO: 197)

[0653] FS002-C241-LC (LambdaC2)-2 light chain (SEQ ID NO: 198)

[0654] FS002-C15-LC (Kappa-2) light chain (SEQ ID NO: 199)

[0655] FS002-C58-LC (Kappa-2) light chain (SEQ ID NO: 200)

[0656] FS002-A72-LC (Kappa-2) light chain (SEQ ID NO: 201)

[0657] The full-length amino acid sequence of the antibody heavy chain is as follows (the shaded portion corresponds to the constant region sequence):

[0658] FS002-A1-HC (IgG1) heavy chain (SEQ ID NO: 202)

[0659] FS002-A5-HC (IgG1) heavy chain (SEQ ID NO: 203)

[0660] FS002-A15-HC (IgG1) heavy chain (SEQ ID NO: 204)

[0661] FS002-A36-HC (IgG1) heavy chain (SEQ ID NO: 205)

[0662] FS002-A66-HC (IgG1) heavy chain (SEQ ID NO: 206)

[0663] FS002-A10-HC (IgG1) heavy chain (SEQ ID NO: 207)

[0664] FS002-C9-HC (IgG1) heavy chain (SEQ ID NO: 208)

[0665] FS002-C11-HC (IgG1) heavy chain (SEQ ID NO: 209)

[0666] FS002-C216-HC (IgG1) heavy chain (SEQ ID NO: 210)

[0667] FS002-C375-HC (IgG1) heavy chain (SEQ ID NO: 211)

[0668] FS002-C417-HC (IgG1) heavy chain (SEQ ID NO: 212)

[0669] FS002-B27-HC (IgG1) heavy chain (SEQ ID NO: 213)

[0670] FS002-C330-HC (IgG1) heavy chain (SEQ ID NO: 214)

[0671] FS002-C153-HC (IgG1) heavy chain (SEQ ID NO: 215)

[0672] FS002-C241-HC (IgG1) heavy chain (SEQ ID NO: 216)

[0673] FS002-C15-HC (IgG1) heavy chain (SEQ ID NO: 217)

[0674] FS002-C58-HC (IgG1) heavy chain (SEQ ID NO: 218)

[0675] FS002-A72-HC (IgG1) heavy chain (SEQ ID NO: 219)

[0676] Table 5: Heavy chain, light chain, constant region, variable region of the aforementioned antibodies. The sequence numbers of each CDR are summarized as follows (SEQ ID NO:

[0677] 2. Antibody expression and purification, and SDS-PAGE identification

[0678] The plasmid was expressed in CHO cells for 7 days as required using the ExpiCHO-s expression system, and the antibody was purified by Protein A affinity chromatography on the 6th day of expression.

[0679] Subsequently, the purity of the resulting antibody was tested by SDS-PAGE. In SDS-PAGE, the purity of the reduced band, or the combined purity of the reduced heavy and light chains, was calculated using ImageJ using the peak area normalization method. The non-reduced band of the reference IPI had a molecular weight of approximately 150 kDa, indicating a purity greater than 90%. The reduced heavy chain had a molecular weight of approximately 55 kDa, and the light chain had a molecular weight of approximately 25 kDa, indicating a purity greater than 90% for both heavy and light chains.

[0680] Example 3 - Evaluation of the affinity of anti-ITGA2 antibodies to ITGA2 protein at the protein level by ELISA

[0681] The affinity of ITGA2 antibodies to ITGA2 protein at the protein level was determined using the following method, including coating an ELISA plate with 2ug / mL ITGA2-His. The plate was washed three times with PBST and blocked with 5% PBS-Milk at room temperature for 2 hours. The plate was washed three times with PBST, and then the diluted antibody was added to the ELISA plate, 30μL per well, and placed at room temperature for 60 minutes. The plate was washed three times with PBST, and then anti-human IgG-Fc-HRP (abcam; ab97225) was added to the ELISA plate and placed at room temperature for 60 minutes. TMB was added and the reaction was terminated with 2M stop solution and OD450 was read. Finally, the binding ability of each antibody to ITGA2-his was compared by EC50. The antibody Vatelizumab (purchased from Baiying Bio) was used as a positive control. The result data of the determination are shown in Table 6 below.

[0682] Table 6

[0683] As shown in the table above, 17 of the 18 antibodies tested had good binding activity to ITGA2-His (EC50 < 1 nM).

[0684] Example 4 - Determination of the affinity of anti-ITGA2 antibodies for ITGA2 at the cellular level by flow cytometry

[0685] Human cholangiocarcinoma cell lines, HuCCT1, were plated into 96-well plates at 50,000 cells per well. The cells were then washed twice with PBS by pipetting, and the PBS was discarded. The primary antibody against ITGA2 to be tested was prepared at a working concentration of 30 nM in 1% FBS / PBS and diluted three-fold to a total of five specific concentrations. The prepared antibody dilutions were added to the corresponding 96-well plates and incubated at 4°C for 30 minutes. The cells were then washed twice with 1% FBS / PBS by pipetting, and the PBS was discarded by centrifugation. The supernatant was then discarded. A secondary goat anti-human IgG (H+L) antibody, designed to eliminate cross-recognition from other species, was prepared at a 1:300 dilution in 10% FBS / PBS and added to the 96-well plates for 30 minutes at 4°C. The cells were collected and analyzed by flow cytometry, and the EC50 value was used to evaluate the affinity of the antibody for the ITGA2 target. Vatelizumab (purchased from Bio-Bio) was used as a positive control antibody for ITGA2 binding.

[0686] The results of EC50 determination are shown in Table 7. As shown in Table 7, among these 18 antibodies, 14 antibodies had EC50 values ​​less than 5 nM, indicating that they could bind well to ITGA2-positive cells HuCCT1.

[0687] Table 7

[0688] Example 5 - Preparation of Antibody-Drug Conjugate (ADC)

[0689] Antibody-drug conjugates were prepared using the following method

[0690] Materials and methods:

[0691] Coupling buffer: 25mM Na2B4O7, 25mM NaCl, 1mM DPTA, pH 7.4

[0692] Dialysis buffer: 1× PBS, pH 7.4

[0693] Antibody reduction concentration: 5mg / mL

[0694] Tris(2-chloroethyl) phosphate (TCEP): 5 mM, binding buffer

[0695] TCEP:antibody=2.3:1

[0696] Payload: 10 mM linker-payload, dimethyl sulfoxide (DMSO)

[0697] DMSO in final reaction: 10%

[0698] Payload:antibody=10:1

[0699] Reduction temperature and time: 25°C and 2 hours

[0700] Coupling temperature and time: 25 °C and 4 hours

[0701] Coupling steps:

[0702] Thaw and dialyze the antibody using coupling buffer at 4°C for >4 hours;

[0703] If necessary, concentrate the antibody solution to 2-5 mg / ml;

[0704] Add TCEP working solution to reduce the antibody and incubate in a 25°C water bath;

[0705] Prepare linker-load solution in DMSO (10 mM);

[0706] The volume of the effective linker-load solution for each conjugation was calculated based on the molar concentration;

[0707] Mix the antibody with the linker-load at the desired molar ratio and incubate in a 25°C water bath;

[0708] Dialyze the conjugate against ADC storage buffer at 4°C for greater than 4 hours, changing the buffer at least every 4 hours; and

[0709] ADCs were extracted and filtered using a 0.22 μm filter and samples were submitted for SEC-HPLC and HIC-HPLC analysis.

[0710] By the above method, using vc-MMAE (mc-vc-PAB-MMAE, C68H105N11O15, provided by Ruizhi Chemical) as a linker-payload, antibody-drug conjugates of the antibodies FS002-A1, FS002-A15, FS002-A36 of the present invention and the positive control antibody Vatelizumab were prepared in this example.

[0711] Table 8

[0712] Example 6 - Biological activity of antibody-drug conjugates (ADCs) against cancer cells

[0713] This example tests the biological activity of the antibody of the present invention in killing cancer cells after being conjugated to a toxin to form an ADC.

[0714] Human cholangiocarcinoma cells HuCC-T1 from Zhejiang Meisen, human epidermal carcinoma cells A431 from Wuhan Punosai, and negative control Chinese hamster ovary (CHO) cells from ATCC were plated into 96-well plates at 2,500 cells per well. The plates were incubated overnight at 37°C in a 5% CO2 incubator. The next day, half of the culture medium was removed from the cell plates. Complete culture medium was used to prepare 2x concentrations of hIgG1 (negative control antibody, provided by Bio-Bio), Vatelizumab, FS002-A1-vc-MMAE, FS002-A15-vc-MMAE, FS002-A36-vc-MMAE, Vatelizumab-vc-MMAE, and hIgG1-vcMMAE (negative control ADC, provided by Ruizhi Chemistry). These concentrations were then serially diluted 3-fold to a total of 11 specific concentration points. Serial dilutions of these 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 plate, mixed on a plate shaker for 2 minutes, and equilibrated at room temperature for 10 minutes. The plate was then read using a microplate reader. IC50 values ​​were used to compare the biological activity of the ADC against various cell lines.

[0715] The results are shown in Table 9. As shown in Table 9, FS002-A1-vc-MMAE, FS002-A15-vc-MMAE, FS002-A36-vc-MMAE, and Vatelizumab-vc-MMAE all had significant cytotoxic effects on HuCC-T1 and A431 cells, but had no cytotoxic effects on the negative control CHO cells. Negative control antibody hIgG1, unconjugated vc-MMAE-conjugated ITGA2 antibody Vatelizumab, or negative control hIgG1-vc-MMAE were also ineffective in cytotoxicity against HuCC-T1 and A431 cells.

[0716] Table 9

[0717] The above results suggest that ITGA2 antibodies alone cannot kill tumor cells in vitro. However, surprisingly, ITGA2 protein has been found to be an effective target for antibody-drug conjugates. The antibody-drug conjugates obtained by coupling antibodies to small molecule toxins in the present invention can produce excellent killing effects on tumors expressing ITGA2 protein. Technical solution collection:

[0718] 1. An isolated antibody or antigen-binding fragment portion thereof that specifically binds to an ITGA2 protein, wherein the isolated antibody or antigen-binding fragment portion thereof comprises a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3 sequences; and a light chain variable region comprising LCDR1, LCDR2, and LCDR3 sequences, wherein the antibody or antigen-binding fragment portion thereof comprises a heavy chain variable region and a light chain variable region selected from at least one of the following groups:

[0719] 1) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 112, (b) HCDR2 of SEQ ID NO: 113, and (c) HCDR3 of SEQ ID NO: 114, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 38, (e) LCDR2 of SEQ ID NO: 39, and (f) LCDR3 of SEQ ID NO: 40;

[0720] 2) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 116, (b) HCDR2 of SEQ ID NO: 117, and (c) HCDR3 of SEQ ID NO: 118, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 42, (e) LCDR2 of SEQ ID NO: 43, and (f) LCDR3 of SEQ ID NO: 44;

[0721] 3) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 120, (b) HCDR2 of SEQ ID NO: 121, and (c) HCDR3 of SEQ ID NO: 122, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 46, (e) LCDR2 of SEQ ID NO: 47, and (f) LCDR3 of SEQ ID NO: 48;

[0722] 4) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 124, (b) HCDR2 of SEQ ID NO: 125, and (c) HCDR3 of SEQ ID NO: 126, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 50, (e) LCDR2 of SEQ ID NO: 51, and (f) LCDR3 of SEQ ID NO: 52;

[0723] 5) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 128, (b) HCDR2 of SEQ ID NO: 129, and (c) HCDR3 of SEQ ID NO: 130, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 54, (e) LCDR2 of SEQ ID NO: 55, and (f) LCDR3 of SEQ ID NO: 56;

[0724] 6) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 132, (b) HCDR2 of SEQ ID NO: 133, and (c) HCDR3 of SEQ ID NO: 134, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 58, (e) LCDR2 of SEQ ID NO: 59, and (f) LCDR3 of SEQ ID NO: 60;

[0725] 7) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 136, (b) HCDR2 of SEQ ID NO: 137, and (c) HCDR3 of SEQ ID NO: 138, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 62, (e) LCDR2 of SEQ ID NO: 63, and (f) LCDR3 of SEQ ID NO: 64;

[0726] 8) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 140, (b) HCDR2 of SEQ ID NO: 141, and (c) HCDR3 of SEQ ID NO: 142, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68;

[0727] 9) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 144, (b) HCDR2 of SEQ ID NO: 145, and (c) HCDR3 of SEQ ID NO: 146, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 70, (e) LCDR2 of SEQ ID NO: 71, and (f) LCDR3 of SEQ ID NO: 72;

[0728] 10) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 148, (b) HCDR2 of SEQ ID NO: 149, and (c) HCDR3 of SEQ ID NO: 150, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 74, (e) LCDR2 of SEQ ID NO: 75, and (f) LCDR3 of SEQ ID NO: 76;

[0729] 11) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 152, (b) HCDR2 of SEQ ID NO: 153, and (c) HCDR3 of SEQ ID NO: 154, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 78, (e) LCDR2 of SEQ ID NO: 79, and (f) LCDR3 of SEQ ID NO: 80;

[0730] 12) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 156, (b) HCDR2 of SEQ ID NO: 157, and (c) HCDR3 of SEQ ID NO: 158, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 82, (e) LCDR2 of SEQ ID NO: 83, and (f) LCDR3 of SEQ ID NO: 84;

[0731] 13) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 160, (b) HCDR2 of SEQ ID NO: 161, and (c) HCDR3 of SEQ ID NO: 162, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 86, (e) LCDR2 of SEQ ID NO: 87, and (f) LCDR3 of SEQ ID NO: 88;

[0732] 14) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 164, (b) HCDR2 of SEQ ID NO: 165, and (c) HCDR3 of SEQ ID NO: 166, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 90, (e) LCDR2 of SEQ ID NO: 91, and (f) LCDR3 of SEQ ID NO: 92;

[0733] 15) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 168, (b) HCDR2 of SEQ ID NO: 169, and (c) HCDR3 of SEQ ID NO: 170, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 94, (e) LCDR2 of SEQ ID NO: 95, and (f) LCDR3 of SEQ ID NO: 96;

[0734] 16) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 172, (b) HCDR2 of SEQ ID NO: 173, and (c) HCDR3 of SEQ ID NO: 174, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 98, (e) LCDR2 of SEQ ID NO: 99, and (f) LCDR3 of SEQ ID NO: 100;

[0735] 17) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 176, (b) HCDR2 of SEQ ID NO: 177, and (c) HCDR3 of SEQ ID NO: 178, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 102, (e) LCDR2 of SEQ ID NO: 103, and (f) LCDR3 of SEQ ID NO: 104; and

[0736] 18) The heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 180, (b) HCDR2 of SEQ ID NO: 181, and (c) HCDR3 of SEQ ID NO: 182, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 106, (e) LCDR2 of SEQ ID NO: 107, and (f) LCDR3 of SEQ ID NO: 108.

[0737] 2. The isolated antibody or antigen-binding fragment thereof according to technical solution 1, wherein the isolated antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region selected from at least one of the following groups:

[0738] 1) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:111, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:111, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:37, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:37;

[0739] 2) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:115, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:115, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:41, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:41;

[0740] 3) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:119, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:119, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:45, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:45;

[0741] 4) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:123, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:123, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:49, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:49;

[0742] 5) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:127, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:127, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:53, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:53;

[0743] 6) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:131, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:131, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:57, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:57;

[0744] 7) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:135, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:135, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:61, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:61;

[0745] 8) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:139, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:139, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:65, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:65;

[0746] 9) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:143, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:143, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:69, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:69;

[0747] 10) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:147, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:147, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:73, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:73;

[0748] 11) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:151, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:151, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:77, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:77;

[0749] 12) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:155, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:155, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:81, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:81;

[0750] 13) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:159, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:159, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:85, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:85;

[0751] 14) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:163, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:163, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:89, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:89;

[0752] 15) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:167, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:167, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:93, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:93;

[0753] 16) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 171, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 171, and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 97, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 97;

[0754] 17) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 175, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 175, and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 101, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 101; and

[0755] 18) The heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 179 or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 179, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 105 or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 105.

[0756] 3. The isolated antibody or antigen-binding fragment thereof according to technical solution 1 or 2, wherein the isolated antibody or antigen-binding fragment thereof further comprises a heavy chain constant region and / or a light chain constant region,

[0757] the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 183, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 183,

[0758] The light chain constant region comprises the amino acid sequence of SEQ ID NO:109, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:109; or the light chain constant region comprises the amino acid sequence of SEQ ID NO:110, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:110.

[0759] 4. The isolated antibody or antigen-binding fragment thereof according to any one of technical solutions 1 to 3, wherein the isolated antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain selected from at least one group consisting of:

[0760] 1) the heavy chain comprising the amino acid sequence of SEQ ID NO:202, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:202, and the light chain comprising the amino acid sequence of SEQ ID NO:184, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:184;

[0761] 2) the heavy chain comprising the amino acid sequence of SEQ ID NO:203, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:203, and the light chain comprising the amino acid sequence of SEQ ID NO:185, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:185;

[0762] 3) the heavy chain comprising the amino acid sequence of SEQ ID NO:204, or a sequence of amino acids that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:204, and the light chain comprising the amino acid sequence of SEQ ID NO:186, or a sequence of amino acids that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:186;

[0763] 4) the heavy chain comprising the amino acid sequence of SEQ ID NO:205, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:205, and the light chain comprising the amino acid sequence of SEQ ID NO:187, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:187;

[0764] 5) the heavy chain comprising the amino acid sequence of SEQ ID NO:206, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:206, and the light chain comprising the amino acid sequence of SEQ ID NO:188, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:188;

[0765] 6) the heavy chain comprising the amino acid sequence of SEQ ID NO:207, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:207, and the light chain comprising the amino acid sequence of SEQ ID NO:189, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:189;

[0766] 7) the heavy chain comprising the amino acid sequence of SEQ ID NO:208, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:208, and the light chain comprising the amino acid sequence of SEQ ID NO:190, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:190;

[0767] 8) the heavy chain comprising the amino acid sequence of SEQ ID NO:209, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:209, and the light chain comprising the amino acid sequence of SEQ ID NO:191, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:191;

[0768] 9) the heavy chain comprising the amino acid sequence of SEQ ID NO:210, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:210, and the light chain comprising the amino acid sequence of SEQ ID NO:192, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:192;

[0769] 10) the heavy chain comprising the amino acid sequence of SEQ ID NO:211, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:211, and the light chain comprising the amino acid sequence of SEQ ID NO:193, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:193;

[0770] 11) the heavy chain comprising the amino acid sequence of SEQ ID NO:212, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:212, and the light chain comprising the amino acid sequence of SEQ ID NO:194, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:194;

[0771] 12) the heavy chain comprising the amino acid sequence of SEQ ID NO:213, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:213, and the light chain comprising the amino acid sequence of SEQ ID NO:195, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:195;

[0772] 13) the heavy chain comprising the amino acid sequence of SEQ ID NO:214, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:214, and the light chain comprising the amino acid sequence of SEQ ID NO:196, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:196;

[0773] 14) the heavy chain comprising the amino acid sequence of SEQ ID NO:215, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:215, and the light chain comprising the amino acid sequence of SEQ ID NO:197, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:197;

[0774] 15) the heavy chain comprising the amino acid sequence of SEQ ID NO:216, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:216, and the light chain comprising the amino acid sequence of SEQ ID NO:198, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:198;

[0775] 16) the heavy chain comprising the amino acid sequence of SEQ ID NO:217, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:217, and the light chain comprising the amino acid sequence of SEQ ID NO:199, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:199;

[0776] 17) the heavy chain comprising the amino acid sequence of SEQ ID NO:218, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:218, and the light chain comprising the amino acid sequence of SEQ ID NO:200, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:200; and

[0777] 18) The heavy chain comprises the amino acid sequence of SEQ ID NO: 219, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 219, and the light chain comprises the amino acid sequence of SEQ ID NO: 201, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 201.

[0778] 5. The isolated antibody or antigen-binding fragment thereof according to any one of technical solutions 1 to 4, wherein the isolated antibody or antigen-binding fragment thereof is composed of a heavy chain and a light chain selected from at least one group below:

[0779] 1) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 202, and the light chain consisting of the amino acid sequence of SEQ ID NO: 184;

[0780] 2) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 203, and the light chain consisting of the amino acid sequence of SEQ ID NO: 185;

[0781] 3) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 204, and the light chain consisting of the amino acid sequence of SEQ ID NO: 186;

[0782] 4) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 205, and the light chain consisting of the amino acid sequence of SEQ ID NO: 187;

[0783] 5) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 206, and the light chain consisting of the amino acid sequence of SEQ ID NO: 188;

[0784] 6) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 207, and the light chain consisting of the amino acid sequence of SEQ ID NO: 189;

[0785] 7) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 208, and the light chain consisting of the amino acid sequence of SEQ ID NO: 190;

[0786] 8) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 209, and the light chain consisting of the amino acid sequence of SEQ ID NO: 191;

[0787] 9) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 210, and the light chain consisting of the amino acid sequence of SEQ ID NO: 192;

[0788] 10) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 211, and the light chain consisting of the amino acid sequence of SEQ ID NO: 193;

[0789] 11) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 212, and the light chain consisting of the amino acid sequence of SEQ ID NO: 194;

[0790] 12) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 213, and the light chain consisting of the amino acid sequence of SEQ ID NO: 195;

[0791] 13) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 214, and the light chain consisting of the amino acid sequence of SEQ ID NO: 196;

[0792] 14) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 215, and the light chain consisting of the amino acid sequence of SEQ ID NO: 197;

[0793] 15) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 216, and the light chain consisting of the amino acid sequence of SEQ ID NO: 198;

[0794] 16) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 217, and the light chain consisting of the amino acid sequence of SEQ ID NO: 199;

[0795] 17) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 218, and the light chain consisting of the amino acid sequence of SEQ ID NO: 200; and

[0796] 18) The heavy chain consisting of the amino acid sequence of SEQ ID NO: 219, and the light chain consisting of the amino acid sequence of SEQ ID NO: 201.

[0797] 6. An isolated antibody or antigen-binding fragment portion thereof that specifically binds to an ITGA2 protein, wherein the isolated antibody or antigen-binding fragment portion thereof has a heavy chain and a light chain selected from at least one of the following groups:

[0798] 1) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 19, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 19, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 19, and

[0799] The light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence 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;

[0800] 2) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 20, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 20, and

[0801] The light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2;

[0802] 3) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 21, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 21, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 21, and

[0803] The light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 3, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence 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;

[0804] 4) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 22, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 22, and

[0805] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 4, or comprising an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 4, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 4;

[0806] 5) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 23, or comprises and consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 23, and

[0807] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 5, or comprising an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 5, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 5;

[0808] 6) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 24, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 24, and

[0809] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6, or comprising an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6;

[0810] 7) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 25, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 25, and

[0811] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 7, or comprising an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 7, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 7;

[0812] 8) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26, and

[0813] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 8, or comprising an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 8, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 8;

[0814] 9) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 27, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 27, and

[0815] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 9, or comprising an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 9, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 9;

[0816] 10) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 28, or comprises and consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 28, and

[0817] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 10, or comprising and consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 10;

[0818] 11) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 29, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 29, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 29, and

[0819] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 11, or comprising and consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 11;

[0820] 12) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30, and

[0821] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 12, or comprising and consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 12;

[0822] 13) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31, and

[0823] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 13, or comprising and consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 13;

[0824] 14) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 32, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 32, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 32, and

[0825] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 14, or comprising and consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 14;

[0826] 15) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33, and

[0827] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 15, or comprising and consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 15;

[0828] 16) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34, and

[0829] the light chain comprising the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 16, or comprising and consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 16;

[0830] 17) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35, and

[0831] the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 17, or comprising or consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 17; and

[0832] 18) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36, and

[0833] The light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 18, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence 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.

[0834] 7. The isolated antibody or antigen-binding fragment thereof according to any one of technical solutions 1 to 6,

[0835] wherein the antibody is capable of binding to ITGA2 protein in vitro with an EC50 of less than 1 nM; and / or

[0836] wherein the antibody is capable of binding to ITGA2 protein on the surface of HuCCT1 cells with an EC50 of less than 5 nM;

[0837] And / or wherein the antibody is a monoclonal antibody, a polyclonal antibody, a chimeric antibody, or a humanized antibody.

[0838] 8. An isolated nucleic acid molecule encoding the antibody or antigen-binding fragment thereof of any one of technical solutions 1-7; or

[0839] The nucleic acid molecule comprises or consists of a nucleotide sequence selected from any one of the following: SEQ ID NOs: 1-18, and / or the nucleic acid molecule comprises or consists of a nucleotide sequence selected from any one of the following: SEQ ID NOs: 19-36; or

[0840] The nucleic acid molecule comprises or consists of a nucleotide sequence selected from any one of the following combinations: SEQ ID NO: 1 and SEQ ID NO: 19, SEQ ID NO: 2 and SEQ ID NO: 20, SEQ ID NO: 3 and SEQ ID NO: 21, SEQ ID NO: 4 and SEQ ID NO: 22, SEQ ID NO: 5 and SEQ ID NO: 23, SEQ ID NO: 6 and SEQ ID NO: 24, SEQ ID NO: 7 and SEQ ID NO: 25, SEQ ID NO: 8 and SEQ ID NO: 26, SEQ ID NO: 9 and SEQ ID NO: 27, SEQ ID NO: 10 and SEQ ID NO: 28, SEQ ID NO: 11 and SEQ ID NO: 29, SEQ ID NO: 12 and SEQ ID NO: 30, SEQ ID NO: 13 and SEQ ID NO: 31, SEQ ID NO: 14 and SEQ ID NO: 32, SEQ ID NO: 15 and SEQ ID NO: 33, SEQ ID NO: 16 and SEQ ID NO: 34, SEQ ID NO: 17 and SEQ ID NO: 35 NO:35, and SEQ ID NO:18 and SEQ ID NO:36.

[0841] 9. The isolated nucleic acid molecule of technical solution 8, wherein the nucleic acid molecule is operably linked to an expression regulatory sequence.

[0842] 10. An expression vector comprising the nucleic acid molecule of technical solution 8 or 9.

[0843] 11. A host cell comprising the nucleic acid molecule of Technical Solution 8 or 9 or the expression vector of Technical Solution 10.

[0844] 12. A hybridoma cell expressing the antibody or antigen-binding fragment thereof according to any one of technical solutions 1 to 7.

[0845] 13. An antibody drug conjugate of the following formula:

[0846] Ab-LD, where:

[0847] The symbol "Ab" represents at least one of the aforementioned antibodies or antigen-binding fragments thereof of the present invention;

[0848] The symbol "L" represents a linker that connects the antibody portion and the partner molecule; and

[0849] The symbol “D” represents the partner molecule;

[0850] or

[0851] Ab-(LD)p, where:

[0852] The symbol "Ab" represents at least one of the aforementioned antibodies or antigen-binding fragments thereof of the present invention;

[0853] The symbol “L” represents a linker connecting the antibody portion and the partner molecule;

[0854] The symbol "D" represents a partner molecule; and

[0855] The symbol "p" represents the number of linker / partner molecules (preferably drug cargo) conjugated to the aforementioned antibody or antigen-binding fragment thereof of the present invention; alternatively, p is selected from the following values: 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7 , 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, and 8.0.

[0856] 14. The antibody-drug conjugate of claim 13, wherein the linker is selected from the group consisting of vc, mc-GGFG, AcLysvc, mc, MalPeg6, m(H20)c, and m(H20)cvc; and / or the linker is cleavable.

[0857] 15. The antibody drug conjugate of technical solution 13 or 14, wherein

[0858] The partner molecule is a drug payload, and the drug payload is a therapeutic molecule; optionally, the drug payload is selected from the group consisting of a cytotoxic agent, a cytostatic agent, an immunomodulatory agent, and a chemotherapeutic agent; optionally, the drug payload is selected from the group consisting 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

[0859] The partner molecule is a labeling molecule; optionally, the labeling molecule is selected from the group consisting of a radioactive label (eg, an isotope), a fluorescent label (eg, a fluorescent dye), a chemical substance, and a detectably modified enzyme and tag.

[0860] 16. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof according to any one of technical solutions 1 to 7 or the antibody-drug conjugate according to any one of technical solutions 13 to 15, and optionally a pharmaceutically acceptable carrier.

[0861] 17. Use of the antibody or antigen-binding fragment thereof of any one of technical solutions 1-7 or the antibody-drug conjugate of any one of technical solutions 13-15 in the preparation of a pharmaceutical composition; optionally, the pharmaceutical composition is used to treat a malignant tumor, prevent and / or treat metastasis or recurrence of a malignant tumor in a patient; optionally, the pharmaceutical composition is used to detect the presence of a malignant tumor in a patient; optionally, the pharmaceutical composition is used to prognose the recurrence or progression of a malignant tumor in a patient.

[0862] 18. A method for treating a malignant tumor, preventing and / or treating the metastasis or recurrence of a malignant tumor in a patient, the method comprising administering to the patient an effective amount of the antibody or antigen-binding fragment thereof of any one of technical solutions 1-7, the antibody-drug conjugate of any one of technical solutions 13-15, or the pharmaceutical composition of technical solution 16.

[0863] 19. The method of technical solution 18, wherein the malignant tumor is selected from the following group: breast cancer, colorectal cancer, skin cancer, pancreatic cancer, prostate cancer, liver cancer, lung cancer, gastric cancer, leukemia, bile duct cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, head and neck cancer, lymphoma, medullary thyroid cancer, non-Hodgkin's lymphoma, ovarian cancer, glioma, melanoma, and bladder cancer; preferably, the malignant tumor is selected from the following group: colorectal cancer, bile duct cancer, pancreatic cancer and skin cancer.

[0864] 20. The method of technical solution 18 or 19 also includes administering other anti-tumor treatments to the patient, such as chemotherapy agents, antibodies targeting other tumor-specific antigens, or radiotherapy.

[0865] 21. A method for detecting the presence of tumor cells in a biological sample, comprising:

[0866] a) contacting the biological sample with the antibody or antigen-binding fragment thereof according to any one of technical solutions 1 to 7;

[0867] b) detecting binding of the antibody or antigen-binding fragment thereof to the target antigen in the biological sample,

[0868] Detection of the binding indicates the presence of tumor cells in the biological sample.

[0869] 22. A method of detecting the presence of a malignant tumor in a patient, comprising:

[0870] a) contacting a biological sample obtained from the patient with the antibody or antigen-binding fragment thereof according to any one of technical solutions 1 to 7;

[0871] b) detecting binding of the antibody or antigen-binding fragment thereof to the target antigen in the biological sample, wherein detection of the binding indicates the presence of a malignancy in the patient.

[0872] 23. A method for prognosing recurrence or progression of a malignant tumor in a patient, the method comprising:

[0873] (a) isolating a biological sample comprising tumor cells from the patient;

[0874] (b) contacting the biological sample containing tumor cells with the antibody or antigen-binding fragment thereof according to any one of technical solutions 1 to 7; and

[0875] (c) identifying the presence of tumor cells that bind to the antibody or antigen-binding fragment thereof,

[0876] The recurrence or progression of the malignancy in said patient is thereby prognosed.

[0877] 24. The method of technical solution 23, wherein the progression of the malignant tumor comprises the metastasis of the malignant tumor in the patient.

[0878] 25. The method of technical solution 23 or 24, wherein the biological sample is selected from the following: a blood sample, a tissue sample, and a lymph sample.

[0879] 26. The method of any one of technical solutions 23-25, 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, gastric cancer, leukemia, bile duct cancer, cervical cancer, endometrial cancer, esophageal cancer, head and neck cancer, lymphoma, medullary thyroid cancer, non-Hodgkin's lymphoma, ovarian cancer, glioma, melanoma, and bladder cancer; preferably, the malignant tumor is selected from the group consisting of: colorectal cancer, bile duct cancer, pancreatic cancer and skin cancer.

[0880] 27. A method for producing an antibody or antigen-binding fragment thereof that targets human tumor cells expressing ITGA2, comprising:

[0881] (i) culturing the host cell of technical solution 11 under conditions suitable for expression of the nucleic acid molecule or expression vector, and

[0882] (ii) isolating and purifying the antibody or 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 ITGA2 protein, wherein: The isolated antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3 sequences; and a light chain variable region comprising LCDR1, LCDR2, and LCDR3 sequences, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region selected from at least one of the following groups: 1) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 112, (b) HCDR2 of SEQ ID NO: 113, and (c) HCDR3 of SEQ ID NO: 114, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 38, (e) LCDR2 of SEQ ID NO: 39, and (f) LCDR3 of SEQ ID NO: 40; 2) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 116, (b) HCDR2 of SEQ ID NO: 117, and (c) HCDR3 of SEQ ID NO: 118, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 42, (e) LCDR2 of SEQ ID NO: 43, and (f) LCDR3 of SEQ ID NO: 44; 3) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 120, (b) HCDR2 of SEQ ID NO: 121, and (c) HCDR3 of SEQ ID NO: 122, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 46, (e) LCDR2 of SEQ ID NO: 47, and (f) LCDR3 of SEQ ID NO: 48; 4) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 124, (b) HCDR2 of SEQ ID NO: 125, and (c) HCDR3 of SEQ ID NO: 126, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 50, (e) LCDR2 of SEQ ID NO: 51, and (f) LCDR3 of SEQ ID NO: 52; 5) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 128, (b) HCDR2 of SEQ ID NO: 129, and (c) HCDR3 of SEQ ID NO: 130, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 54, (e) LCDR2 of SEQ ID NO: 55, and (f) LCDR3 of SEQ ID NO: 56; 6) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 132, (b) HCDR2 of SEQ ID NO: 133, and (c) HCDR3 of SEQ ID NO: 134, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 58, (e) LCDR2 of SEQ ID NO: 59, and (f) LCDR3 of SEQ ID NO: 60; 7) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 136, (b) HCDR2 of SEQ ID NO: 137, and (c) HCDR3 of SEQ ID NO: 138, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 62, (e) LCDR2 of SEQ ID NO: 63, and (f) LCDR3 of SEQ ID NO: 64; 8) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 140, (b) HCDR2 of SEQ ID NO: 141, and (c) HCDR3 of SEQ ID NO: 142, and the light chain variable region comprises (d) SEQ ID NO: 66 (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; 9) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 144, (b) HCDR2 of SEQ ID NO: 145, and (c) HCDR3 of SEQ ID NO: 146, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 70, (e) LCDR2 of SEQ ID NO: 71, and (f) LCDR3 of SEQ ID NO: 72; 10) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 148, (b) HCDR2 of SEQ ID NO: 149, and (c) HCDR3 of SEQ ID NO: 150, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 74, (e) LCDR2 of SEQ ID NO: 75, and (f) LCDR3 of SEQ ID NO: 76; 11) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 152, (b) HCDR2 of SEQ ID NO: 153, and (c) HCDR3 of SEQ ID NO: 154, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 78, (e) LCDR2 of SEQ ID NO: 79, and (f) LCDR3 of SEQ ID NO: 80; 12) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 156, (b) HCDR2 of SEQ ID NO: 157, and (c) HCDR3 of SEQ ID NO: 158, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 82, (e) LCDR2 of SEQ ID NO: 83, and (f) LCDR3 of SEQ ID NO: 84; 13) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 160, (b) HCDR2 of SEQ ID NO: 161, and (c) HCDR3 of SEQ ID NO: 162, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 86, (e) LCDR2 of SEQ ID NO: 87, and (f) LCDR3 of SEQ ID NO: 88; 14) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 164, (b) HCDR2 of SEQ ID NO: 165, and (c) HCDR3 of SEQ ID NO: 166, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 90, (e) LCDR2 of SEQ ID NO: 91, and (f) LCDR3 of SEQ ID NO: 92; 15) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 168, (b) HCDR2 of SEQ ID NO: 169, and (c) HCDR3 of SEQ ID NO: 170, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 94, (e) LCDR2 of SEQ ID NO: 95, and (f) LCDR3 of SEQ ID NO: 96; 16) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 172, (b) HCDR2 of SEQ ID NO: 173, and (c) HCDR3 of SEQ ID NO: 174, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 98, (e) LCDR2 of SEQ ID NO: 99, and (f) LCDR3 of SEQ ID NO: 100; 17) the heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 176, (b) HCDR2 of SEQ ID NO: 177, and (c) HCDR3 of SEQ ID NO: 178, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 102, (e) LCDR2 of SEQ ID NO: 103, and (f) LCDR3 of SEQ ID NO: 104; and 18) The heavy chain variable region comprises (a) HCDR1 of SEQ ID NO: 180, (b) HCDR2 of SEQ ID NO: 181, and (c) HCDR3 of SEQ ID NO: 182, and the light chain variable region comprises (d) LCDR1 of SEQ ID NO: 106, (e) LCDR2 of SEQ ID NO: 107, and (f) LCDR3 of SEQ ID NO:

108.

2. The isolated antibody or antigen-binding fragment thereof according to claim 1, wherein The isolated antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region selected from at least one of the following groups: 1) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:111, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:111, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:37, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:37; 2) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:115, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:115, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:41, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:41; 3) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:119, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:119, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:45, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:45; 4) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:123, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:123, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:49, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:49; 5) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:127, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:127, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:53, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:53; 6) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 131 or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 131, and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 57 an amino acid sequence, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 57; 7) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:135, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:135, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:61, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:61; 8) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:139, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:139, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:65, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:65; 9) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:143, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:143, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:69, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:69; 10) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:147, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:147, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:73, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:73; 11) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:151, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:151, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:77, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:77; 12) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 155 or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 155, and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 81 an amino acid sequence, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 81; 13) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:159, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:159, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:85, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:85; 14) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:163, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:163, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:89, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:89; 15) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:167, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:167, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:93, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:93; 16) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 171, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 171, and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 97, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 97; 17) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 175, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 175, and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 101, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 101; and 18) The heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 179 or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 179, and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 105 The invention also provides an amino acid sequence or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

105.

3. The isolated antibody or antigen-binding fragment thereof according to claim 1 or 2, wherein The isolated antibody or antigen-binding fragment thereof further comprises a heavy chain constant region and / or a light chain constant region, the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 183, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 183, The light chain constant region comprises the amino acid sequence of SEQ ID NO:109, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:109; or the light chain constant region comprises the amino acid sequence of SEQ ID NO:110, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

110.

4. The isolated antibody or antigen-binding fragment thereof according to claim 3, wherein The isolated antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain selected from at least one of the following groups: 1) the heavy chain comprising the amino acid sequence of SEQ ID NO:202, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:202, and the light chain comprising the amino acid sequence of SEQ ID NO:184, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:184; 2) the heavy chain comprising the amino acid sequence of SEQ ID NO:203, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:203, and the light chain comprising the amino acid sequence of SEQ ID NO:185, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:185; 3) the heavy chain comprising the amino acid sequence of SEQ ID NO:204, or a sequence of amino acids that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:204, and the light chain comprising the amino acid sequence of SEQ ID NO:186, or a sequence of amino acids that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:186; 4) The heavy chain comprising the amino acid sequence of SEQ ID NO: 205 or a sequence thereof : the light chain comprising an amino acid sequence of SEQ ID NO:187 or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:187; 5) the heavy chain comprising the amino acid sequence of SEQ ID NO:206, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:206, and the light chain comprising the amino acid sequence of SEQ ID NO:188, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:188; 6) the heavy chain comprising the amino acid sequence of SEQ ID NO:207, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:207, and the light chain comprising the amino acid sequence of SEQ ID NO:189, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:189; 7) the heavy chain comprising the amino acid sequence of SEQ ID NO:208, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:208, and the light chain comprising the amino acid sequence of SEQ ID NO:190, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:190; 8) the heavy chain comprising the amino acid sequence of SEQ ID NO:209, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:209, and the light chain comprising the amino acid sequence of SEQ ID NO:191, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO:191; 9) the heavy chain comprising the amino acid sequence of SEQ ID NO:210, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:210, and the light chain comprising the amino acid sequence of SEQ ID NO:192, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:192; 10) The heavy chain comprising the amino acid sequence of SEQ ID NO: 211 or a sequence thereof : the light chain comprising an amino acid sequence of SEQ ID NO: 193 or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO: 193; 11) the heavy chain comprising the amino acid sequence of SEQ ID NO:212, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:212, and the light chain comprising the amino acid sequence of SEQ ID NO:194, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:194; 12) the heavy chain comprising the amino acid sequence of SEQ ID NO:213, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:213, and the light chain comprising the amino acid sequence of SEQ ID NO:195, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:195; 13) the heavy chain comprising the amino acid sequence of SEQ ID NO:214, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:214, and the light chain comprising the amino acid sequence of SEQ ID NO:196, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:196; 14) the heavy chain comprising the amino acid sequence of SEQ ID NO:215, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:215, and the light chain comprising the amino acid sequence of SEQ ID NO:197, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:197; 15) the heavy chain comprising the amino acid sequence of SEQ ID NO:216, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:216, and the light chain comprising the amino acid sequence of SEQ ID NO:198, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:198; 16) The heavy chain comprising the amino acid sequence of SEQ ID NO: 217 or a sequence thereof : the light chain comprising an amino acid sequence of SEQ ID NO: 199 or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of SEQ ID NO: 199; 17) the heavy chain comprising the amino acid sequence of SEQ ID NO:218, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:218, and the light chain comprising the amino acid sequence of SEQ ID NO:200, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:200; and 18) The heavy chain comprises the amino acid sequence of SEQ ID NO: 219, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 219, and the light chain comprises the amino acid sequence of SEQ ID NO: 201, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

201.

5. The isolated antibody or antigen-binding fragment thereof according to claim 4, wherein The isolated antibody or antigen-binding fragment thereof is composed of a heavy chain and a light chain selected from at least one of the following groups: 1) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 202, and the light chain consisting of the amino acid sequence of SEQ ID NO: 184; 2) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 203, and the light chain consisting of the amino acid sequence of SEQ ID NO: 185; 3) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 204, and the light chain consisting of the amino acid sequence of SEQ ID NO: 186; 4) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 205, and the light chain consisting of the amino acid sequence of SEQ ID NO: 187; 5) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 206, and the light chain consisting of the amino acid sequence of SEQ ID NO: 188; 6) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 207, and the light chain consisting of the amino acid sequence of SEQ ID NO: 189; 7) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 208, and the light chain consisting of the amino acid sequence of SEQ ID NO: 190; 8) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 209, and the light chain consisting of the amino acid sequence of SEQ ID NO: 191; 9) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 210, and the light chain consisting of the amino acid sequence of SEQ ID NO: 192; 10) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 211, and the light chain consisting of the amino acid sequence of SEQ ID NO: 193; 11) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 212, and the light chain consisting of the amino acid sequence of SEQ ID NO: 194; 12) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 213, and the light chain consisting of the amino acid sequence of SEQ ID NO: 195; 13) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 214, and the light chain consisting of the amino acid sequence of SEQ ID NO: 196; 14) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 215, and the light chain consisting of the amino acid sequence of SEQ ID NO: 197; 15) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 216, and the light chain consisting of the amino acid sequence of SEQ ID NO: 198; 16) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 217, and the light chain consisting of the amino acid sequence of SEQ ID NO: 199; 17) the heavy chain consisting of the amino acid sequence of SEQ ID NO: 218, and the light chain consisting of the amino acid sequence of SEQ ID NO: 200; and 18) The heavy chain consisting of the amino acid sequence of SEQ ID NO: 219, and the light chain consisting of the amino acid sequence of SEQ ID NO:

201.

6. An isolated antibody or antigen-binding fragment thereof that specifically binds to ITGA2 protein, wherein: The isolated antibody or antigen-binding fragment thereof has a heavy chain and a light chain selected from at least one of the following groups: 1) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 19, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 19, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 19, and The light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, or more identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:

1. an amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to, or consists of, the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1; 2) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 20, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 20, and The light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2; 3) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 21, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 21, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 21, and The light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 3, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence 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; 4) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 22, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 22, and the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 4, or comprising an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 4, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 4; 5) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 23, or comprises and consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 23, and the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 5, or comprising an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 5, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 5; 6) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 24, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 24, and the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6, or comprising an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6; 7) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 25, or comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 25, and the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 7, or comprising an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 7, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 7; 8) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26, and the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 8, or comprising an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 8, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 8; 9) The heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 27, or comprises an amino acid sequence that is at least 85%, at least 90%, or at least 10% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:

27. an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to, or consists of, the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 27, and the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 9, or comprising an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 9, or consisting of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 9; 10) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 28, or comprises and consists of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 28, and the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 10, or comprising and consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 10; 11) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 29, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 29, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 29, and the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 11, or comprising and consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 11; 12) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30, and the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 12, or comprising and consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 12; 13) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 31, and the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 13, or comprising and consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 13; 14) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 32, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 32, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 32, and the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 14, or comprising and consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 14; 15) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 33, and the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 15, or comprising and consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 15; 16) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34, and The light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 16, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, or more identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:

16. an amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to, or consists of, the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 16; 17) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 35, and the light chain comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 17, or comprising or consisting of an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 17; and 18) the heavy chain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36, or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 36, and The light chain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 18, or comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence 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.

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

8. An isolated nucleic acid molecule encoding a portion of the antibody or antigen-binding fragment thereof of any one of claims 1 to 7; or The nucleic acid molecule comprises a nucleotide sequence selected from any one of the following or consists of the nucleotide sequence: SEQ ID NOs: 1-18, and / or the nucleic acid molecule comprises or consists of a nucleotide sequence selected from any one of the following: SEQ ID NOs: 19-36; or The nucleic acid molecule comprises or consists of a nucleotide sequence selected from any one of the following combinations: SEQ ID NO: 1 and SEQ ID NO: 19, SEQ ID NO: 2 and SEQ ID NO: 20, SEQ ID NO: 3 and SEQ ID NO: 21, SEQ ID NO: 4 and SEQ ID NO: 22, SEQ ID NO: 5 and SEQ ID NO: 23, SEQ ID NO:6 and SEQ ID NO:24, SEQ ID NO:7 and SEQ ID NO:25, SEQ ID NO:8 and SEQ ID NO:26, SEQ ID NO:9 and SEQ ID NO:27, SEQ ID NO:10 and SEQ ID NO:28, SEQ ID NO:11 and SEQ ID NO:29, SEQ ID NO:12 and SEQ ID NO:30, SEQ ID NO:13 and SEQ ID NO:31, SEQ ID NO:14 and SEQ ID NO:32, SEQ ID NO:15 and SEQ ID NO:33, SEQ ID NO:16 and SEQ ID NO:34, SEQ ID NO:17 and SEQ ID NO:35, and SEQ ID NO:18 and SEQ ID NO:

36.

9. An antibody drug conjugate of the following formula: Ab-LD, where: The symbol "Ab" represents at least one of the aforementioned antibodies or antigen-binding fragments thereof of the present invention; The symbol "L" represents a linker connecting the antibody portion and the partner molecule; and The symbol "D" represents the partner molecule; or Ab-(LD)p, where: The symbol "Ab" represents at least one of the aforementioned antibodies or antigen-binding fragments thereof of the present invention; The symbol "L" represents a linker connecting the antibody portion and the partner molecule; The symbol "D" represents a partner molecule; and The symbol "p" represents the number of linker / partner molecules (preferably drug cargo) conjugated to the aforementioned antibody or antigen-binding fragment thereof of the present invention; alternatively, p is selected from the following values: 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7 , 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, and 8.

0.

10. The antibody drug conjugate of claim 9, wherein the linker is selected from the group consisting of vc, mc-GGFG, AcLysvc, mc, MalPeg6, m(H20)c, and m(H20)cvc; and / or the linker is cleavable.

11. The antibody drug conjugate according to claim 9 or 10, wherein The partner molecule is a drug payload, and the drug payload is a therapeutic molecule; optionally, the drug payload is selected from the group consisting of a cytotoxic agent, a cytostatic agent, an immunomodulatory agent, and a chemotherapeutic agent; optionally, the drug payload is selected from the group consisting 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 partner molecule is a labeling molecule; optionally, the labeling molecule is selected from the group consisting of a radioactive label (eg, an isotope), a fluorescent label (eg, a fluorescent dye), a chemical substance, and a detectably modified enzyme and tag.

12. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof according to any one of claims 1 to 7 or the antibody drug conjugate according to any one of claims 9 to 11, and optionally a pharmaceutically acceptable carrier.

13. Use of the antibody or antigen-binding fragment portion thereof of any one of claims 1 to 7 or the antibody drug conjugate of any one of claims 9 to 11 in the preparation of a pharmaceutical composition; optionally, the pharmaceutical composition is used to treat a malignant tumor, prevent and / or treat metastasis or recurrence of a malignant tumor in a patient; optionally, the pharmaceutical composition is used to detect the presence of a malignant tumor in a patient; optionally, the pharmaceutical composition is used to prognose the recurrence or progression of a malignant tumor in a patient.

14. A method for treating a malignant tumor, 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 the antibody or antigen-binding fragment thereof of any one of claims 1 to 7, the antibody drug conjugate of any one of claims 9 to 11, or the pharmaceutical composition of claim 16.

15. The method of 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, gastric cancer, leukemia, bile duct cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, head and neck cancer, lymphoma, medullary thyroid cancer, non-Hodgkin's lymphoma, ovarian cancer, glioma, melanoma, and bladder cancer; preferably, the malignant tumor is selected from the group consisting of: colorectal cancer, bile duct cancer, pancreatic cancer and skin cancer.

16. The method of claim 14 or 15, further comprising administering to the patient other anti-tumor treatments, such as chemotherapeutic agents, antibodies targeting other tumor-specific antigens, or radiotherapy.