Antibodies targeting ITGA2 and antibody-drug conjugates containing the same

Abstract

The present invention provides a series of antibodies or antigen-binding fragments thereof having a high specific binding ability to tumor cells expressing ITGA2 protein. The antibody or antigen-binding fragment thereof according to the present invention can be conjugated with a drug to form an antibody-drug conjugate, and then achieve an excellent killing effect on tumor cells.

Description

Technical Field

[0001] This application claims the priority of Chinese Patent Application No. 202210743539.0, filed on June 27, 2022, under the title "ANTIBODY TARGETING ITGA2 AND ANTIBODY-DRUG CONJUGATE COMPRISING THE SAME". This priority application is hereby incorporated by reference in its entirety into this specification.

[0002] Technical Field The present invention relates to the field of biopharmaceuticals. Specifically, the present invention relates to an antibody targeting ITGA2 or an antigen-binding fragment thereof, an antibody-drug conjugate comprising this antibody, and the use of this antibody and / or antibody-drug conjugate in the treatment of related diseases.

Background Art

[0003] Background Art Malignant tumors (cancers) have become the "number one cause of death" threatening the lives and health of people around the world. There are more than 14 million cancer cases worldwide every year, among which, in China alone, more than 3 million new cancer patients occur every year.

[0004] The fundamental causes of the high mortality rate of cancer are the spread and metastasis of cancer cells, as well as the recurrence and drug resistance of most patients after treatment. Among the currently clinically available treatments, surgery, radiotherapy, and chemotherapy have little or only short-term effects on cancer cell metastasis, recurrence, and drug resistance, so they cannot change the long-term survival rate of patients. Currently, resection is effective for about 10-20% of early-stage patients, but has little effect on patients with spread and metastasis. Radiotherapy can only treat local lesions and is often used as adjuvant therapy before and after surgery and radical treatment for several types of cancer. Chemotherapy can be used for patients with cancer spread and metastasis, but due to its strong toxicity and side effects and its tendency to induce short-term or long-term drug resistance, it can only provide a significant short-term treatment effect for about 20-30% of patients. Even using comprehensive treatment methods that integrate surgery, radiotherapy, and chemotherapy, the long-term treatment effect of its 5-year survival remains at 20%-30% over the years, and about 70%-80% of patients die within 5 years after treatment due to metastasis, recurrence, and drug resistance. Even for early-stage cancer patients without metastasis at the time of admission, some patients still die due to metastasis and recurrence after treatment.

[0005] Currently, it is effective to treat tumors by identifying tumor-associated antigens, preparing drugs in the form of antibody-drug conjugates, and then administering the drugs to tumor cells. This drug form has both the advantages of monoclonal antibodies targeting tumor cells and the advantages of small molecule cytotoxins that bring strong killing to tumors, thereby not only significantly reducing the toxicity and side effects of small molecule cytotoxins, but also improving the effectiveness of the drugs and bringing great therapeutic advantages. Summary of the Invention Means for Solving the Problems

[0006] Summary of the Invention The inventors have found that ITGA2 is a tumor-associated antigen specifically overexpressed by tumor cells, which is upregulated in most solid tumors, and is particularly overexpressed in cancers such as colorectal cancer, cholangiocarcinoma, pancreatic cancer, and skin cancer. However, existing antibodies that can target ITGA2 alone do not have a good inhibitory effect on the growth of tumor cells. Therefore, the inventors have developed a series of antibodies with high specific binding ability to tumor cells expressing ITGA2 protein, and this antibody targets ITGA2-positive tumor cells in the form of an antibody-drug conjugate to achieve an excellent killing effect on cells.

[0007] In one aspect, the present invention is an isolated antibody or antigen-binding fragment thereof that specifically binds to ITGA2 protein, comprising a heavy chain variable region containing HCDR1, HCDR2, and HCDR3 sequences, and a light chain variable region containing LCDR1, LCDR2, and LCDR3 sequences, wherein the antibody or antigen-binding fragment thereof is selected from the following group: 1) (a) a heavy chain variable region comprising HCDR1 set forth in SEQ ID NO: 112, (b) HCDR2 set forth in SEQ ID NO: 113, and (c) HCDR3 set forth in SEQ ID NO: 114, and (d) a light chain variable region comprising LCDR1 set forth in SEQ ID NO: 38, (e) LCDR2 set forth in SEQ ID NO: 39, and (f) LCDR3 set forth in SEQ ID NO: 40; 2) (a) a heavy chain variable region comprising HCDR1 set forth in SEQ ID NO: 116, (b) HCDR2 set forth in SEQ ID NO: 117, and (c) HCDR3 set forth in SEQ ID NO: 118, and (d) a light chain variable region comprising LCDR1 set forth in SEQ ID NO: 42, (e) LCDR2 set forth in SEQ ID NO: 43, and (f) LCDR3 set forth in SEQ ID NO: 44; 3) (a) a heavy chain variable region comprising HCDR1 set forth in SEQ ID NO: 120, (b) HCDR2 set forth in SEQ ID NO: 121, and (c) HCDR3 set forth in SEQ ID NO: 122, and (d) a light chain variable region comprising LCDR1 set forth in SEQ ID NO: 46, (e) LCDR2 set forth in SEQ ID NO: 47, and (f) LCDR3 set forth in SEQ ID NO: 48; 4) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 124, (b) HCDR2 set forth in SEQ ID NO: 125, and (c) HCDR3 set forth in SEQ ID NO: 126, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 50, (e) LCDR2 set forth in SEQ ID NO: 51, and (f) LCDR3 set forth in SEQ ID NO: 52; 5) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 128, (b) HCDR2 set forth in SEQ ID NO: 129, and (c) HCDR3 set forth in SEQ ID NO: 130, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 54, (e) LCDR2 set forth in SEQ ID NO: 55, and (f) LCDR3 set forth in SEQ ID NO: 56; 6) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 132, (b) HCDR2 set forth in SEQ ID NO: 133, and (c) HCDR3 set forth in SEQ ID NO: 134, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 58, (e) LCDR2 set forth in SEQ ID NO: 59, and (f) LCDR3 set forth in SEQ ID NO: 60; 7) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 136, (b) HCDR2 set forth in SEQ ID NO: 137, and (c) HCDR3 set forth in SEQ ID NO: 138, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 62, (e) LCDR2 set forth in SEQ ID NO: 63, and (f) LCDR3 set forth in SEQ ID NO: 64; 8) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 140, (b) HCDR2 set forth in SEQ ID NO: 141, and (c) HCDR3 set forth in SEQ ID NO: 142, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 66, (e) LCDR2 set forth in SEQ ID NO: 67, and (f) LCDR3 set forth in SEQ ID NO: 68; 9) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 144, (b) HCDR2 set forth in SEQ ID NO: 145, and (c) HCDR3 set forth in SEQ ID NO: 146, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 70, (e) LCDR2 set forth in SEQ ID NO: 71, and (f) LCDR3 set forth in SEQ ID NO: 72; 10) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 148, (b) HCDR2 set forth in SEQ ID NO: 149, and (c) HCDR3 set forth in SEQ ID NO: 150, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 74, (e) LCDR2 set forth in SEQ ID NO: 75, and (f) LCDR3 set forth in SEQ ID NO: 76; 11) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 152, (b) HCDR2 set forth in SEQ ID NO: 153, and (c) HCDR3 set forth in SEQ ID NO: 154, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 78, (e) LCDR2 set forth in SEQ ID NO: 79, and (f) LCDR3 set forth in SEQ ID NO: 80; 12) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 156, (b) HCDR2 set forth in SEQ ID NO: 157, and (c) HCDR3 set forth in SEQ ID NO: 158, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 82, (e) LCDR2 set forth in SEQ ID NO: 83, and (f) LCDR3 set forth in SEQ ID NO: 84; 13) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 160, (b) HCDR2 set forth in SEQ ID NO: 161, and (c) HCDR3 set forth in SEQ ID NO: 162, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 86, (e) LCDR2 set forth in SEQ ID NO: 87, and (f) LCDR3 set forth in SEQ ID NO: 88; 14) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 164, (b) HCDR2 set forth in SEQ ID NO: 165, and (c) HCDR3 set forth in SEQ ID NO: 166, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 90, (e) LCDR2 set forth in SEQ ID NO: 91, and (f) LCDR3 set forth in SEQ ID NO: 92; (a) a heavy chain variable region comprising HCDR1 set forth in SEQ ID NO: 168, (b) HCDR2 set forth in SEQ ID NO: 169, and (c) HCDR3 set forth in SEQ ID NO: 170, and (d) a light chain variable region comprising LCDR1 set forth in SEQ ID NO: 94, (e) LCDR2 set forth in SEQ ID NO: 95, and (f) LCDR3 set forth in SEQ ID NO: 96; 16) (a) a heavy chain variable region comprising HCDR1 set forth in SEQ ID NO: 172, (b) HCDR2 set forth in SEQ ID NO: 173, and (c) HCDR3 set forth in SEQ ID NO: 174, and (d) a light chain variable region comprising LCDR1 set forth in SEQ ID NO: 98, (e) LCDR2 set forth in SEQ ID NO: 99, and (f) LCDR3 set forth in SEQ ID NO: 100; 17) (a) a heavy chain variable region comprising HCDR1 set forth in SEQ ID NO: 176, (b) HCDR2 set forth in SEQ ID NO: 177, and (c) HCDR3 set forth in SEQ ID NO: 178, and (d) a light chain variable region comprising LCDR1 set forth in SEQ ID NO: 102, (e) LCDR2 set forth in SEQ ID NO: 103, and (f) LCDR3 set forth in SEQ ID NO: 104; and 18) (a) a heavy chain variable region comprising HCDR1 set forth in SEQ ID NO: 180, (b) HCDR2 set forth in SEQ ID NO: 181, and (c) HCDR3 set forth in SEQ ID NO: 182, and (d) a light chain variable region comprising LCDR1 set forth in SEQ ID NO: 106, (e) LCDR2 set forth in SEQ ID NO: 107, and (f) LCDR3 set forth in SEQ ID NO: 108 There is provided an isolated antibody or an antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region selected from at least one of the above.

[0008] In another aspect, the present invention is an isolated antibody or an antigen-binding fragment thereof that specifically binds to an ITGA2 protein, wherein the isolated antibody or an antigen-binding fragment thereof is selected from the following group: 1) An amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 19, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 19, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 19, and An amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 1, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 1, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 1; 2) An amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 20, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 20, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 20, and An amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 2, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 2, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 2; 3) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 21, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 21, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 21, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 3, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 3, or a light chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 3; 4) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 22, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 22, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 22, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 4, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 4, or a light chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 4; 5) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 23, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 23, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 23, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 5, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 5, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 5; 6) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 24, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 24, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 24, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 6, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 6, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 6; 7) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 25, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 25, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 25, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 7, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 7, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 7; 8) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 26, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 26, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 26, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 8, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 8, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 8; 9) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 27, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 27, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 27, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 9, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 9, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 9; 10) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 28, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 28, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 28, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 10, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 10, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 10; 11) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 29, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 29, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 29, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 11, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 11, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 11; 12) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 30, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 30, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 30, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 12, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 12, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 12; 13) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 31, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 31, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 31, and The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 13, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 13, or a light chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 13; 14) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 32, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 32, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 32, and The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 14, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 14, or a light chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 14; (15) An amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 33, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 33, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 33, and an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 15, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 15, or a light chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 15; (16) An amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 34, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 34, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 34, and an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 16, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 16, or a light chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 16; 17) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 35, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 35, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 35, and The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 17, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 17, or a light chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 17; and 18) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 36, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 36, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 36, and The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 18, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 18, or a light chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 18 Provided is an isolated antibody or an antigen-binding fragment thereof comprising a heavy chain and a light chain selected from at least one of the above.

[0009] In yet another aspect, the present invention provides an isolated nucleic acid molecule encoding the monoclonal antibody or an antigen-binding fragment thereof according to the present invention.

[0010] In yet another aspect, the present invention provides an expression vector comprising the nucleic acid molecule according to the present invention.

[0011] In yet another aspect, the present invention provides a host cell comprising the nucleic acid molecule according to the present invention or the expression vector according to the present invention.

[0012] In yet another aspect, the present invention provides a hybridoma cell expressing the monoclonal antibody or an antigen-binding fragment thereof according to the present invention.

[0013] In yet another aspect, the present invention provides the use of the monoclonal antibody or an antigen-binding fragment thereof according to the present invention or the antibody-drug conjugate according to the present invention in the preparation of a pharmaceutical composition; optionally, the pharmaceutical composition is used to treat a malignant tumor in a patient or to prevent and / or treat the metastasis or recurrence of a malignant tumor.

[0014] In yet another aspect, the present invention provides a method for treating a malignant tumor in a patient and for preventing and / or treating the metastasis or recurrence of a malignant tumor, the method comprising administering to the patient an effective amount of the monoclonal antibody or an antigen-binding fragment thereof according to the present invention, the antibody-drug conjugate according to the present invention, or the pharmaceutical composition according to the present invention.

[0015] In yet another aspect, the present invention provides the use of the monoclonal antibody or an antigen-binding fragment thereof according to the present invention or the antibody-drug conjugate according to the present invention in the preparation of a diagnostic / predictive composition; optionally, the diagnostic / predictive composition is used to detect the presence of a malignant tumor in a patient; optionally, the diagnostic / predictive composition is used to predict the recurrence or progression of a malignant tumor in a patient.

[0016] In yet another aspect, the present invention is a method for predicting recurrence or progression of a malignant tumor in a patient, comprising: (a) isolating a biological sample containing tumor cells from the patient; (b) contacting the biological sample containing tumor cells with the monoclonal antibody or antigen-binding fragment thereof according to the present invention; and (c) identifying the presence of tumor cells that bind to the monoclonal antibody or antigen-binding fragment thereof, thereby providing a method comprising predicting recurrence or progression of a malignant tumor in the patient.

[0017] In yet another aspect, the present invention is a method for detecting / diagnosing the presence of a malignant tumor in a patient, comprising: a) contacting a biological sample obtained from the patient with the monoclonal antibody or antigen-binding fragment thereof according to the present invention or the antibody-drug conjugate according to the present invention; b) detecting the binding of the monoclonal antibody or antigen-binding fragment thereof to the target antigen in the biological sample, wherein the detected binding indicates the presence of a malignant tumor in the patient.

[0018] In yet another aspect, the present invention is a method for detecting the presence of tumor cells in a biological sample, comprising: a) contacting the biological sample with the monoclonal antibody or antigen-binding fragment thereof according to the present invention or the antibody-drug conjugate according to the present invention; 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, wherein the detected binding indicates the presence of tumor cells in the biological sample.

[0019] In yet another aspect, the present invention is a method for isolating tumor cells, comprising: (a) providing a cell population suspected of containing tumor cells; (b) Identifying a subpopulation of cells that bind to the monoclonal antibody, antigen-binding fragment thereof, or antibody-drug conjugate according to the present invention; and (c) Providing a method comprising isolating this subpopulation.

[0020] In yet another aspect, the present invention provides a method for producing a monoclonal antibody or an antigen-binding fragment thereof that targets human tumor cells expressing ITGA2, comprising: (i) Culturing the host cell of the present invention under conditions suitable for expressing a nucleic acid molecule or an expression vector; and (ii) Isolating and purifying the antibody or an antigen-binding fragment thereof expressed by the nucleic acid molecule or the expression vector.

[0021] The antibody according to the present invention has excellent binding ability to the ITGA2 protein and can bind to tumor cells expressing ITGA2, particularly colorectal cancer cells, cholangiocarcinoma cells, pancreatic cancer cells, and skin cancer cells. The antibody-drug conjugate according to the present invention has excellent killing effect on tumor cells expressing ITGA2, particularly colorectal cancer cells, cholangiocarcinoma cells, pancreatic cancer cells, and skin cancer cells.

[0022] Sequence information: In the following table, the leftmost column lists the sequence numbering (SEQ ID NO.) of the present invention.

[0023] [Table 1]

[0024] [Table 2]

[0025] [Table 3]

[0026]

Table 4

[0027]

Table 5

[0028]

Table 6

[0029]

Table 7

[0030]

Table 8

[0031]

Table 9

[0032]

Table 10

[0033]

Table 11

[0034]

Table 12

[0035]

Table 13

[0036]

Table 14

[0037]

Table 15

[0038]

Table 16

[0039]

Table 17

[0040]

Table 18

BEST MODE FOR CARRYING OUT THE INVENTION

[0041] Detailed Description of the Invention I. General Definitions In the present invention, scientific terms and technical terms used in this specification have meanings generally understood by those skilled in the art, unless otherwise specified. Also, terms related to protein and nucleic acid chemistry, molecular biology, cell and tissue culture, microbiology, immunology, and experimental procedures used in this specification are terms and general procedures widely used in the corresponding fields. Also, the following definitions and explanations of related terms are provided for better understanding of the present invention.

[0042] As used herein, "antibody" refers to an immunoglobulin or immunoglobulin fragment that is produced naturally or partially or fully synthetically (e.g., recombinantly) and that contains at least a portion of the variable region of an immunoglobulin molecule and retains the binding specificity of a full-length immunoglobulin. Thus, an antibody includes any protein having a binding structural domain that coincides with or is substantially identical to an immunoglobulin antigen-binding structural domain (antibody-binding site). Antibodies include antibody fragments such as antibody fragments against tumor stem cells. As used herein, therefore, the term "antibody" includes synthetic antibodies, recombinantly produced antibodies, multispecific antibodies (e.g., bispecific antibodies), human antibodies, non-human antibodies, humanized antibodies, chimeric antibodies, intracellular antibodies, and antibody fragments, e.g., but not limited to, Fab fragments, Fab' fragments, F(ab')2 fragments, Fv fragments, disulfide-bonded Fv (dsFv), Fd fragments, Fd' fragments, single-chain Fv (scFv), single-chain Fab (scFab), diabodies, anti-idiotype (anti-Id) antibodies, or antigen-binding fragments of any of the above antibodies. 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).

[0043] 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 binds to an antigen (e.g., one or more CDRs and / or one or more antibody-binding sites), and thus includes at least a portion of the variable region of the antibody that retains at least a portion of the binding specificity and specific binding ability of the full-length antibody. Thus, an antigen-binding fragment refers to an antibody fragment that includes an antigen-binding portion that binds to the same antigen as the antibody from which the antibody fragment is derived. Antibody fragments include antibody derivatives produced by enzymatic treatment of a full-length antibody, as well as derivatives produced synthetically, e.g., recombinantly produced derivatives. An antibody includes 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). Fragments can include multiple chains joined together, e.g., by disulfide bonds and / or by a peptide linker. Antibody fragments typically include at least or about 50 amino acids, typically at least or about 200 amino acids. An antigen-binding fragment includes any antibody fragment that, when inserted into an antibody framework (e.g., by substituting the corresponding region), binds immunospecifically to an antigen (i.e., at least or at least about 10 7 -10 8 M -1 Ka is shown) antibody is obtained.

[0044] As used herein, "monoclonal antibody" refers to a population of identical antibodies, where each antibody molecule is identical to other antibody molecules in the population of monoclonal antibodies. In contrast to the polyclonal nature of antibodies, a polyclonal population of antibodies includes antibodies having multiple different sequences. Monoclonal antibodies can be prepared by several 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 fusing with myeloma cells to produce a hybridoma cell line, or by infecting B cells with a virus such as EBV. Using recombinant techniques, antibodies can also be prepared in vitro from a clonal population of host cells by transforming the host cells with a plasmid having an artificial sequence of nucleotides encoding the antibody.

[0045] As used herein, the term "hybridoma" or "hybridoma cell" refers to a cell or cell line (typically, a myeloma or lymphoma cell) produced by fusing an antibody-producing lymphocyte and a non-antibody-producing cancer cell. As is known to those skilled in the art, hybridomas can grow and continue to be supplied to produce specific monoclonal antibodies. 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 subcloned cells and progeny cells of the hybridoma.

[0046] As used herein, "conventional antibody" refers to an antibody that includes two heavy chains (which may be designated H and H'), two light chains (which may be designated L and L'), and two antigen-binding sites, where each heavy chain is either a full-length immunoglobulin heavy chain or a functional region thereof that retains antigen-binding ability (e.g., but not limited to, V H chain, V H -C H 1 chain, and VH -C H 1-C H 2-C H It can be a heavy chain containing 3 chains), and each light chain can be a full-length light chain or any functional region (e.g., but not limited to, V L chain and V L -C L a light chain containing a chain). Each heavy chain (H and H’) pairs with a light chain (L and L’ respectively).

[0047] As used herein, a full-length antibody is 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), two full-length light chains (V L -C L ), and an antibody having a hinge region, e.g., an antibody naturally produced by secretion of B cells by an antibody, and a synthetically produced antibody having the same structural domains.

[0048] As used herein, dsFv refers to an Fv having engineered intermolecular disulfide bonds that stabilize the V H -V L pair.

[0049] As used herein, a Fab fragment is an antibody fragment obtained by papain digestion of a full-length immunoglobulin, or a fragment having the same structure produced, for example, by recombinant methods. A Fab fragment includes a light chain (V L and C L including) as well as another chain including the variable structural domain of the heavy chain (V H ) and the constant region structural domain of the heavy chain (C H 1).

[0050] As used herein, an F(ab’)2 fragment is an antibody fragment obtained from pepsin digestion of an immunoglobulin at pH 4.0 - 4.5, or a fragment of the same structure produced, for example, by recombinant methods. The F(ab’)2 fragment substantially contains two Fab fragments, where each heavy chain portion contains several additional amino acids including cysteine that forms a disulfide bond linking the two fragments.

[0051] As used herein, a Fab’ fragment is a fragment that contains half of an F(ab’)2 fragment (one heavy chain and one light chain).

[0052] As used herein, an scFv fragment refers to an antibody fragment containing a variable light chain (V L ) and a variable heavy chain (V H ) covalently linked in any arrangement by a polypeptide linker. The length of the linker cross-links the two variable structural domains substantially without interference. An exemplary linker is a (Gly-Ser) n residue having several Glu or Lys residues dispersed to increase solubility.

[0053] The term "chimeric antibody" refers to such an antibody in which the variable region sequence is derived from one species and the constant region sequence is derived from another species, for example, an antibody in which the variable region sequence is derived from a mouse antibody and the constant region sequence is derived from a human antibody.

[0054] A "humanized" antibody is a chimeric immunoglobulin, immunoglobulin chain or fragment thereof (e.g., the Fv, Fab, Fab’, F(ab’)2 or other antigen-binding portion sequence of an antibody) that contains a minimal sequence derived from a non-human immunoglobulin, in a non-human (e.g., mouse) antibody form. Preferably, a humanized antibody is a human immunoglobulin (recipient antibody) in which the residues of the complementarity determining regions (CDRs) of the recipient antibody are replaced with the CDR residues of a non-human species (donor antibody) such as mouse, rat or rabbit having the expected specificity, affinity and capacity.

[0055] Furthermore, in humanization, it is also possible to mutate amino acid residues within the CDR1, CDR2, and / or CDR3 regions of VH and / or VL, thereby improving one or more binding properties (e.g., affinity) of the antibody. Mutations such as PCR-mediated mutations can be introduced, where the effect of the mutations on antibody binding or other functional properties can be evaluated using in vitro or in vivo assays as described herein. Typically, conservative mutations are introduced. Such mutations can be amino acid substitutions, additions, or deletions. Furthermore, typically, there are at most one or two mutations within the CDR. Thus, the humanized antibodies according to the invention also include antibodies containing one or two amino acid mutations within the CDR.

[0056] As used herein, the term "epitope" refers to any antigenic determinant cluster in an antigen to which the paratope of an antibody binds. Epitope determinant clusters typically include chemically active surface types of molecules, such as amino acids or sugar side chains, and typically have specific three-dimensional structural properties as well as specific charge properties.

[0057] As used herein, a variable structural domain or variable region is a specific Ig structural 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 variable region structural domains V L and V H respectively. The variable structural domain provides antigen specificity and thus is involved in antigen recognition. Each variable region includes complementarity-determining regions (CDRs) and framework regions (FRs), where the CDRs are part of the antigen-binding site structural domain.

[0058] As used herein, the terms "antigen-binding structural domain" and "antigen-binding site" are used interchangeably to refer to the structural domain within an antibody that recognizes and physically interacts with a cognate antigen. A typical native full-length antibody molecule has two antigen-binding sites, each of which comprises a heavy-chain variable region portion and a light-chain variable region portion. A typical antigen-binding site includes loops that connect antiparallel beta (β) strands within the variable region structural domain. An antigen-binding site may include other portions of the variable region structural domain. Each typical antigen-binding site comprises three hypervariable regions from the heavy chain and three hypervariable regions from the light chain. Hypervariable regions are also known as complementarity-determining regions (CDRs).

[0059] As used herein, the terms "hypervariable region", "HV", "complementarity determining region", "CDR", and "antibody CDR" can be used interchangeably to refer to one of the plurality of portions of each variable region of the antigen-binding site that together form an antibody. Each variable region structural domain contains three CDRs designated as CDR1, CDR2, and CDR3. For example, the light chain variable region structural domain contains three CDRs designated as VL CDR1, VL CDR2, and VL CDR3; the heavy chain variable region structural domain contains three CDRs designated as VH CDR1, VH CDR2, and VH CDR3. The three CDRs in the variable region are discontinuous along the linear amino acid sequence but are close together in the folded polypeptide. The CDRs are located within loops that connect parallel strands within the β-sheets of the variable structural domain. As described herein, one of ordinary skill in the art can recognize and identify CDRs based on Kabat or Chothia numbering (see, e.g., Kabat, E.A. et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242, and Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917). In the present invention, the abbreviations "VH CDR", "HCDR", "VL CDR", and "LCDR" have the same meaning.

[0060] As used herein, the framework region (FR) is a structural domain within the antibody variable region structural domain within the β-sheet. With respect to the amino acid sequence, the FR region is relatively conserved compared to the hypervariable region.

[0061] As used herein, the "constant region" structural domain is a structural domain in an antibody heavy or light chain that contains an amino acid sequence that is relatively conserved compared to the amino acid sequence of the variable region structural domain. In a typical full-length antibody molecule, each light chain has a single light chain constant region (C L) having a structural domain, each heavy chain comprising C H 1, C H 2, C H 3, and C H 4 or more heavy chain constant regions (C H ) including a structural domain. Full-length IgA, IgD, and IgG isotypes include C H 1, C H 2, C H 3, and a hinge region, while IgE and IgM include C H 1, C H 2, C H 3, and C H 4. C H 1 and C L structural domains extend the Fab arms of the antibody molecule and thus facilitate interaction with antigens and rotation of the antibody arms. Antibody constant regions can serve effector functions such as removal of antigens, pathogens, and toxins to which the antibody specifically binds, by interaction with various cells, biomolecules, and tissues, among others.

[0062] As used herein, a functional region of an antibody is an antibody portion that includes at least V H , V L , C H (e.g., C H 1, C H 2 or C H 3), C L or a hinge region structural domain or at least a functional region of the antibody.

[0063] As used herein, the functional region of the V H structural domain is such that the functional region of the V H structural domain binds to an antigen, either alone or in combination with another antibody structural domain (e.g., the V L structural domain) or a region thereof, (e.g., by retaining one or more CDRs of the complete V H structural domain) and retains at least a portion of the binding specificity of the complete V H structural domain, and is at least a portion of the complete V H structural domain. Exemplary V HThe functional region of the V H structural domain is a region containing CDR1, CDR2, and / or CDR3 of the V structural domain.

[0064] As used herein, the V L functional region of the V L functional region of the V structural domain is such that, alone or in combination with another antibody structural domain (e.g., a V H structural domain) or a region thereof, it binds to an antigen (e.g., by retaining one or more CDRs of the complete V L structural domain), and retains at least a portion of the binding specificity of the complete V L structural domain. The functional region of the V L structural domain is at least a portion of the complete V structural domain. Exemplary V L functional regions of the V L structural domain are regions containing CDR1, CDR2, and / or CDR3 of the V structural domain.

[0065] As used herein, "specific binding" or "immunologically specific binding" in relation to an antibody or an antigen-binding fragment thereof are used synonymously and refer to the ability of an antibody or an antigen-binding fragment thereof to form one or more non-covalent bonds with an alloantigen by non-covalent interactions between the antibody and the antibody-binding site of the antigen. The antigen can be an isolated antigen or can be present within a tumor cell.

[0066] As used herein, the terms "Kassoc" or "Ka" are intended to indicate the association rate of a specific antibody-antigen interaction, while the terms "Kdis" or "Kd" are intended to indicate the dissociation rate of a specific antibody-antigen interaction. The term "KD" as used herein is intended to represent the dissociation constant, which is derived from the ratio of Kd to Ka (i.e., Kd / Ka) and is expressed as molar concentration (M). The KD value of an antibody can be determined using methods known in the art. The KD of an antibody can be determined, for example, by 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 determination methods known in the art (see, for example, Paul, ed., Fundamental Immunology, 2nd ed., Raven Press, New York, pages 332-336 (1989); see also U.S. Patent No. 7,229,619, which describes exemplary SPR and ITC methods for calculating the binding affinity of an antibody). Instruments and methods for detecting and monitoring the association rate in real time are known and commercially available (see BiaCore 2000, Biacore AB, Upsala, Sweden and GE Healthcare Life Sciences; Malmqvist (2000) Biochem. Soc. Trans. 27:335).

[0067] As used herein, the terms "conservative sequence modification" or "conservative amino acid modification" or "conservative amino acid substitution" refer to amino acid modifications that do not substantially affect or alter the binding properties of an antibody comprising the amino acid sequence. Such conservative modifications include amino acid substitutions, additions, and deletions. The modifications can be introduced into the antibodies of the invention by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. "Conservative amino acid modification" or "conservative amino acid substitution" refers to a substitution in which an amino acid residue is replaced with an amino acid residue having similar properties and / or structure. Families of amino acid residues having similar side chains are well defined in the art.

[0068] There are 20 common amino acids and many ways to classify amino acids. For example, based on the groups attached to the amino acids, amino acids can be divided into aliphatic amino acids, aromatic amino acids, heterocyclic amino acids, sulfur-containing amino acids, and iodine-containing amino acids. Aliphatic amino acids include alanine, valine, leucine, isoleucine, methionine, aspartic acid, glutamic acid, lysine, arginine, glycine, serine, threonine, cysteine, asparagine, and glutamine. Aromatic amino acids include phenylalanine and tyrosine. Heterocyclic amino acids include histidine and tryptophan. Proline can be included as a heterocyclic amino acid. Based on the chemical properties of amino acids, amino acids can be divided into acidic amino acids, basic amino acids, and neutral amino acids. Neutral amino acids include glycine, alanine, leucine, isoleucine, valine, cystine, cysteine, methionine, threonine, serine, phenylalanine, tyrosine, tryptophan, proline, methionine, and hydroxyproline. Acidic amino acids include glutamic acid and aspartic acid. Basic amino acids include lysine, arginine, and histidine.

[0069] Furthermore, amino acids can also be classified as follows: amino acids with basic side chains (e.g., lysine, arginine, histidine), amino acids with acidic side chains (e.g., aspartic acid, glutamic acid), amino acids with uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), amino acids with nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), amino acids with β-branched side chains (e.g., threonine, valine, isoleucine), and amino acids with aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).

[0070] As used herein, "polypeptide" refers to two or more amino acids covalently linked. The terms "polypeptide" and "protein" are used interchangeably herein.

[0071] The terms "isolated protein", "isolated polypeptide", or "isolated antibody" mean that the protein, polypeptide, or antibody (1) is not bound to the components to which it is naturally bound in its native state, (2) does not contain other proteins from the same species, (3) is expressed by cells from a different species, or (4) does not exist in nature. Thus, a chemically synthesized polypeptide or a polypeptide synthesized in a cell line other than the natural source cell of the polypeptide will be "isolated" from its naturally bound components. Isolation can also be achieved, i.e., using protein purification techniques well known in the art, to substantially exclude the components to which the protein is naturally bound.

[0072] "Substitution", "deletion", or "addition" of an amino acid residue refers to a conservative amino acid modification in a peptide or protein that does not change the function and / or biological activity of the peptide or protein. For example, 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 generally can be made without changing the biological activity of the resulting molecule. Generally, those skilled in the art recognize that a single amino acid substitution in a non-essential region of a polypeptide does not substantially change its biological activity (see, e.g., Watson et al., Molecular Biology of the Gene, 4th Edition, 1987, The Benjamin / Cummings Pub.co., p. 224).

[0073] 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, typically including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) linked together by phosphodiester bonds.

[0074] As used herein, an isolated nucleic acid molecule is a nucleic acid molecule isolated from other nucleic acid molecules present in a natural nucleic acid molecule source. An "isolated" nucleic acid molecule, such as a cDNA molecule, when prepared by recombinant techniques, may not substantially contain other cellular material or culture medium, or may not substantially contain chemical precursors or other chemical components in chemical synthesis. Exemplary isolated nucleic acid molecules provided herein include isolated nucleic acid molecules encoding the provided antibodies or antigen-binding fragments.

[0075] "Sequence identity" has its well-known meaning in the art, and the percentage of sequence identity between two nucleic acid or polypeptide molecules or regions can be calculated using the disclosed techniques. Sequence identity can be measured along the full length of a polynucleotide or polypeptide, or along a region of the molecule. (See, for example: Computational Molecular Biology, Lesk, A.M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D.W., ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part I, Griffin, A.M., and Griffin, H.G., eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991). There are many methods for measuring identity between two polynucleotides or polypeptides, but the term "sequence identity" is well-known to those of skill in the art (Carrillo, H. & Lipman, D., SIAM J Applied Math 48:1073 (1988)).

[0076] As used herein, "operably linked" in reference to a nucleic acid sequence, region, element or structural domain 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.

[0077] As used herein, "expression" refers to the process by which a polypeptide is produced by transcription and translation of a polynucleotide. The level of expression of a polypeptide can be evaluated using any method known in the art, including, but not limited to, methods for determining the amount of polypeptide produced from a host cell. Such methods can include, but are not limited to, quantification of the polypeptide in cell lysates by ELISA, Coomassie blue staining after gel electrophoresis, protein determination by the Lowry method, and protein determination by the Bradford method.

[0078] As used herein, "host cell" is a cell that is used to accommodate, maintain, replicate, and amplify a vector. A host cell can also be used to express a polypeptide encoded by a vector. When the host cell divides, the nucleic acid contained in the vector replicates, thereby amplifying the nucleic acid. A host cell can be a eukaryotic cell or a prokaryotic cell. Suitable host cells include, but are not limited to, CHO cells, COS cells, HeLa cells, HEK cells, such as HEK 293 cells.

[0079] As used herein, "vector" is a replicable nucleic acid that can express one or more heterologous proteins when the vector is transformed into a suitable host cell. Vectors include those into which a nucleic acid encoding a polypeptide or a fragment thereof can typically be introduced by restriction of enzymatic digestion and ligation. Vectors containing a nucleic acid encoding a polypeptide are also included in the vector. A vector is used to introduce a nucleic acid encoding a polypeptide into a host cell to amplify the nucleic acid or to express / present the polypeptide encoded by the nucleic acid. A vector is typically free, but can be designed to integrate a gene or a part thereof into a chromosome of the genome. Vectors of artificial chromosomes, 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.

[0080] As used herein, an "expression vector" includes a vector capable of expressing DNA operably linked to regulatory sequences, such as regulatory sequences in a promoter region capable of affecting the expression of a DNA fragment. Such additional fragments may include a promoter and a termination sequence and may optionally include one or more origins of replication, one or more selectable markers, enhancers, polyadenylation signals, and the like. Expression vectors typically are derived from plasmid or viral DNA or may contain elements of both. Thus, an expression vector refers to a recombinant DNA or RNA construct, such as a plasmid, phage, recombinant virus, or other vector that, when introduced into a suitable host cell, results in the expression of cloned DNA. Suitable expression vectors are well known to those skilled in the art and include expression vectors that are replicable in eukaryotic and / or prokaryotic cells and expression vectors that either retain free expression vectors or integrate into the genome of the host cell.

[0081] As used herein, "treating" an individual having a disease or disorder means partially or totally alleviating the symptoms of the individual or showing no change after treatment. Thus, treatment includes prevention, therapy, and / or cure. Prevention refers to preventing the underlying disease and / or preventing the worsening of symptoms or the progression of the disease. Treatment also includes any pharmaceutical use of either the provided antibody or its antigen-binding fragment, as well as any of the compositions provided herein.

[0082] As used herein, a "therapeutic effect" refers to an effect caused by the treatment of an individual that modifies the symptoms of a disease or disorder, generally improving or alleviating them, or curing the disease or disorder.

[0083] As used herein, a "therapeutically effective amount" or "therapeutically effective dosage" refers to an amount of a substance, compound, material, or composition containing a compound that is at least sufficient to produce a therapeutic effect upon administration to a subject. Thus, it is the amount necessary to prevent, cure, ameliorate, suppress, or partially suppress the symptoms of a disease or disorder.

[0084] As used herein, "preventively effective amount" or "preventively effective dosage" refers to the amount of a substance, compound, material, or composition containing a compound that, upon administration to a subject, provides the desired preventive effect, e.g., prevents or delays the onset or recurrence of a disease or medical condition, or reduces the likelihood of the onset or recurrence of a disease or medical condition. A complete preventively effective dosage need not be obtained by administering a single dose and may only be obtained after administering a series of doses. Thus, a preventively effective amount may be administered in one or more administrations.

[0085] As used herein, the term "patient" refers to mammals such as humans.

[0086] II. Antibodies Targeting ITGA2 Protein The official name of ITGA2 is integrin alpha-2, and the human ITGA2 protein is numbered as P17301 in the Uniprot database. See https: / / www.uniprot.org / uniprot / P17301.

[0087] The inventors have found that ITGA2 is a tumor-associated antigen that is specifically overexpressed by tumor cells, particularly in patients suffering from cancers such as colorectal cancer, cholangiocarcinoma, pancreatic cancer, and skin cancer. Based on this, the inventors have designed various different humanized antibodies targeting the ITGA2 protein. Experiments in the examples demonstrate that the antibodies according to the present invention have excellent binding ability to the ITGA2 protein (EC50 < 1 nM) and also have excellent binding ability to HuCCT1 cells that highly express ITGA2 (EC50 < 5 nM). Due to the excellent binding ability of the monoclonal antibodies according to the present invention, partner molecules such as cytotoxins can be effectively delivered to tumor cells.

[0088] Accordingly, in one aspect, the present invention provides an isolated antibody or an antigen-binding fragment thereof that specifically binds to the ITGA2 protein, wherein the isolated antibody or antigen-binding fragment thereof comprises a heavy-chain variable region comprising HCDR1, HCDR2, and HCDR3 sequences: 1) The heavy-chain variable region comprises (a) HCDR1 set forth in SEQ ID NO: 112, (b) HCDR2 set forth in SEQ ID NO: 113, and (c) HCDR3 set forth in SEQ ID NO: 114; 2) The heavy-chain variable region comprises (a) HCDR1 set forth in SEQ ID NO: 116, (b) HCDR2 set forth in SEQ ID NO: 117, and (c) HCDR3 set forth in SEQ ID NO: 118; 3) The heavy-chain variable region comprises (a) HCDR1 set forth in SEQ ID NO: 120, (b) HCDR2 set forth in SEQ ID NO: 121, and (c) HCDR3 set forth in SEQ ID NO: 122; 4) The heavy-chain variable region comprises (a) HCDR1 set forth in SEQ ID NO: 124, (b) HCDR2 set forth in SEQ ID NO: 125, and (c) HCDR3 set forth in SEQ ID NO: 126; 5) The heavy-chain variable region comprises (a) HCDR1 set forth in SEQ ID NO: 128, (b) HCDR2 set forth in SEQ ID NO: 129, and (c) HCDR3 set forth in SEQ ID NO: 130; 6) The heavy-chain variable region comprises (a) HCDR1 set forth in SEQ ID NO: 132, (b) HCDR2 set forth in SEQ ID NO: 133, and (c) HCDR3 set forth in SEQ ID NO: 134; 7) The heavy-chain variable region comprises (a) HCDR1 set forth in SEQ ID NO: 136, (b) HCDR2 set forth in SEQ ID NO: 137, and (c) HCDR3 set forth in SEQ ID NO: 138; 8) The heavy-chain variable region comprises (a) HCDR1 set forth in SEQ ID NO: 140, (b) HCDR2 set forth in SEQ ID NO: 141, and (c) HCDR3 set forth in SEQ ID NO: 142; 9) The heavy-chain variable region comprises (a) HCDR1 set forth in SEQ ID NO: 144, (b) HCDR2 set forth in SEQ ID NO: 145, and (c) HCDR3 set forth in SEQ ID NO: 146; 10) The heavy chain variable region comprises: (a) HCDR1 set forth in SEQ ID NO: 148, (b) HCDR2 set forth in SEQ ID NO: 149, and (c) HCDR3 set forth in SEQ ID NO: 150; 11) The heavy chain variable region comprises: (a) HCDR1 set forth in SEQ ID NO: 152, (b) HCDR2 set forth in SEQ ID NO: 153, and (c) HCDR3 set forth in SEQ ID NO: 154; 12) The heavy chain variable region comprises: (a) HCDR1 set forth in SEQ ID NO: 156, (b) HCDR2 set forth in SEQ ID NO: 157, and (c) HCDR3 set forth in SEQ ID NO: 158; 13) The heavy chain variable region comprises: (a) HCDR1 set forth in SEQ ID NO: 160, (b) HCDR2 set forth in SEQ ID NO: 161, and (c) HCDR3 set forth in SEQ ID NO: 162; 14) The heavy chain variable region comprises: (a) HCDR1 set forth in SEQ ID NO: 164, (b) HCDR2 set forth in SEQ ID NO: 165, and (c) HCDR3 set forth in SEQ ID NO: 166; 15) The heavy chain variable region comprises: (a) HCDR1 set forth in SEQ ID NO: 168, (b) HCDR2 set forth in SEQ ID NO: 169, and (c) HCDR3 set forth in SEQ ID NO: 170; 16) The heavy chain variable region comprises: (a) HCDR1 set forth in SEQ ID NO: 172, (b) HCDR2 set forth in SEQ ID NO: 173, and (c) HCDR3 set forth in SEQ ID NO: 174; 17) The heavy chain variable region comprises: (a) HCDR1 set forth in SEQ ID NO: 176, (b) HCDR2 set forth in SEQ ID NO: 177, and (c) HCDR3 set forth in SEQ ID NO: 178; and 18) The heavy chain variable region comprises: (a) HCDR1 set forth in SEQ ID NO: 180, (b) HCDR2 set forth in SEQ ID NO: 181, and (c) HCDR3 set forth in SEQ ID NO: 182.

[0089] In another aspect, the present invention provides an isolated antibody or an antigen-binding fragment thereof that specifically binds to an ITGA2 protein, wherein the isolated antibody or its antigen-binding fragment comprises a light chain variable region containing LCDR1, LCDR2, and LCDR3 sequences: 1) The light chain variable region comprises (d) LCDR1 set forth in SEQ ID NO: 38, (e) LCDR2 set forth in SEQ ID NO: 39, and (f) LCDR3 set forth in SEQ ID NO: 40; 2) The light chain variable region comprises (d) LCDR1 set forth in SEQ ID NO: 42, (e) LCDR2 set forth in SEQ ID NO: 43, and (f) LCDR3 set forth in SEQ ID NO: 44; 3) The light chain variable region comprises (d) LCDR1 set forth in SEQ ID NO: 46, (e) LCDR2 set forth in SEQ ID NO: 47, and (f) LCDR3 set forth in SEQ ID NO: 48; 4) The light chain variable region comprises (d) LCDR1 set forth in SEQ ID NO: 50, (e) LCDR2 set forth in SEQ ID NO: 51, and (f) LCDR3 set forth in SEQ ID NO: 52; 5) The light chain variable region comprises (d) LCDR1 set forth in SEQ ID NO: 54, (e) LCDR2 set forth in SEQ ID NO: 55, and (f) LCDR3 set forth in SEQ ID NO: 56; 6) The light chain variable region comprises (d) LCDR1 set forth in SEQ ID NO: 58, (e) LCDR2 set forth in SEQ ID NO: 59, and (f) LCDR3 set forth in SEQ ID NO: 60; 7) The light chain variable region comprises (d) LCDR1 set forth in SEQ ID NO: 62, (e) LCDR2 set forth in SEQ ID NO: 63, and (f) LCDR3 set forth in SEQ ID NO: 64; 8) The light chain variable region comprises (d) LCDR1 set forth in SEQ ID NO: 66, (e) LCDR2 set forth in SEQ ID NO: 67, and (f) LCDR3 set forth in SEQ ID NO: 68; 9) The light chain variable region comprises (d) LCDR1 set forth in SEQ ID NO: 70, (e) LCDR2 set forth in SEQ ID NO: 71, and (f) LCDR3 set forth in SEQ ID NO: 72; 10) The light chain variable region comprises (d) LCDR1 set forth in SEQ ID NO: 74, (e) LCDR2 set forth in SEQ ID NO: 75, and (f) LCDR3 set forth in SEQ ID NO: 76; 11) The light chain variable region comprises (d) LCDR1 set forth in SEQ ID NO: 78, (e) LCDR2 set forth in SEQ ID NO: 79, and (f) LCDR3 set forth in SEQ ID NO: 80; 12) The light chain variable region comprises: (d) LCDR1 set forth in SEQ ID NO: 82, (e) LCDR2 set forth in SEQ ID NO: 83, and (f) LCDR3 set forth in SEQ ID NO: 84; 13) The light chain variable region comprises: (d) LCDR1 set forth in SEQ ID NO: 86, (e) LCDR2 set forth in SEQ ID NO: 87, and (f) LCDR3 set forth in SEQ ID NO: 88; 14) The light chain variable region comprises: (d) LCDR1 set forth in SEQ ID NO: 90, (e) LCDR2 set forth in SEQ ID NO: 91, and (f) LCDR3 set forth in SEQ ID NO: 92; 15) The light chain variable region comprises: (d) LCDR1 set forth in SEQ ID NO: 94, (e) LCDR2 set forth in SEQ ID NO: 95, and (f) LCDR3 set forth in SEQ ID NO: 96; 16) The light chain variable region comprises: (d) LCDR1 set forth in SEQ ID NO: 98, (e) LCDR2 set forth in SEQ ID NO: 99, and (f) LCDR3 set forth in SEQ ID NO: 100; 17) The light chain variable region comprises: (d) LCDR1 set forth in SEQ ID NO: 102, (e) LCDR2 set forth in SEQ ID NO: 103, and (f) LCDR3 set forth in SEQ ID NO: 104; and 18) The light chain variable region comprises: (d) LCDR1 set forth in SEQ ID NO: 106, (e) LCDR2 set forth in SEQ ID NO: 107, and (f) LCDR3 set forth in SEQ ID NO: 108.

[0090] In some embodiments, 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, and the antibody or antigen-binding fragment thereof is selected from the following group: 1) A heavy chain variable region comprising: (a) HCDR1 set forth in SEQ ID NO: 112, (b) HCDR2 set forth in SEQ ID NO: 113, and (c) HCDR3 set forth in SEQ ID NO: 114, and a light chain variable region comprising: (d) LCDR1 set forth in SEQ ID NO: 38, (e) LCDR2 set forth in SEQ ID NO: 39, and (f) LCDR3 set forth in SEQ ID NO: 40; 2) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 116, (b) HCDR2 set forth in SEQ ID NO: 117, and (c) HCDR3 set forth in SEQ ID NO: 118, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 42, (e) LCDR2 set forth in SEQ ID NO: 43, and (f) LCDR3 set forth in SEQ ID NO: 44; 3) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 120, (b) HCDR2 set forth in SEQ ID NO: 121, and (c) HCDR3 set forth in SEQ ID NO: 122, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 46, (e) LCDR2 set forth in SEQ ID NO: 47, and (f) LCDR3 set forth in SEQ ID NO: 48; 4) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 124, (b) HCDR2 set forth in SEQ ID NO: 125, and (c) HCDR3 set forth in SEQ ID NO: 126, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 50, (e) LCDR2 set forth in SEQ ID NO: 51, and (f) LCDR3 set forth in SEQ ID NO: 52; 5) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 128, (b) HCDR2 set forth in SEQ ID NO: 129, and (c) HCDR3 set forth in SEQ ID NO: 130, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 54, (e) LCDR2 set forth in SEQ ID NO: 55, and (f) LCDR3 set forth in SEQ ID NO: 56; 6) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 132, (b) HCDR2 set forth in SEQ ID NO: 133, and (c) HCDR3 set forth in SEQ ID NO: 134, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 58, (e) LCDR2 set forth in SEQ ID NO: 59, and (f) LCDR3 set forth in SEQ ID NO: 60; 7) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 136, (b) HCDR2 set forth in SEQ ID NO: 137, and (c) HCDR3 set forth in SEQ ID NO: 138, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 62, (e) LCDR2 set forth in SEQ ID NO: 63, and (f) LCDR3 set forth in SEQ ID NO: 64; 8) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 140, (b) HCDR2 set forth in SEQ ID NO: 141, and (c) HCDR3 set forth in SEQ ID NO: 142, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 66, (e) LCDR2 set forth in SEQ ID NO: 67, and (f) LCDR3 set forth in SEQ ID NO: 68; 9) The heavy chain variable region comprises (a) HCDR1 set forth in SEQ ID NO: 144, (b) HCDR2 set forth in SEQ ID NO: 145, and (c) HCDR3 set forth in SEQ ID NO: 146, and the light chain variable region comprises (d) LCDR1 set forth in SEQ ID NO: 70, (e) LCDR2 set forth in SEQ ID NO: 71, and (f) LCDR3 set forth in SEQ ID NO: 72; 10) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 148, (b) HCDR2 set forth in SEQ ID NO: 149, and (c) HCDR3 set forth in SEQ ID NO: 150, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 74, (e) LCDR2 set forth in SEQ ID NO: 75, and (f) LCDR3 set forth in SEQ ID NO: 76; 11) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 152, (b) HCDR2 set forth in SEQ ID NO: 153, and (c) HCDR3 set forth in SEQ ID NO: 154, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 78, (e) LCDR2 set forth in SEQ ID NO: 79, and (f) LCDR3 set forth in SEQ ID NO: 80; 12) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 156, (b) HCDR2 set forth in SEQ ID NO: 157, and (c) HCDR3 set forth in SEQ ID NO: 158, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 82, (e) LCDR2 set forth in SEQ ID NO: 83, and (f) LCDR3 set forth in SEQ ID NO: 84; 13) The heavy chain variable region comprises (a) HCDR1 set forth in SEQ ID NO: 160, (b) HCDR2 set forth in SEQ ID NO: 161, and (c) HCDR3 set forth in SEQ ID NO: 162, and the light chain variable region comprises (d) LCDR1 set forth in SEQ ID NO: 86, (e) LCDR2 set forth in SEQ ID NO: 87, and (f) LCDR3 set forth in SEQ ID NO: 88; 14) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 164, (b) HCDR2 set forth in SEQ ID NO: 165, and (c) HCDR3 set forth in SEQ ID NO: 166, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 90, (e) LCDR2 set forth in SEQ ID NO: 91, and (f) LCDR3 set forth in SEQ ID NO: 92; 15) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 168, (b) HCDR2 set forth in SEQ ID NO: 169, and (c) HCDR3 set forth in SEQ ID NO: 170, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 94, (e) LCDR2 set forth in SEQ ID NO: 95, and (f) LCDR3 set forth in SEQ ID NO: 96; 16) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 172, (b) HCDR2 set forth in SEQ ID NO: 173, and (c) HCDR3 set forth in SEQ ID NO: 174, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 98, (e) LCDR2 set forth in SEQ ID NO: 99, and (f) LCDR3 set forth in SEQ ID NO: 100; 17) The heavy chain variable region comprises (a) HCDR1 set forth in SEQ ID NO: 176, (b) HCDR2 set forth in SEQ ID NO: 177, and (c) HCDR3 set forth in SEQ ID NO: 178, and the light chain variable region comprises (d) LCDR1 set forth in SEQ ID NO: 102, (e) LCDR2 set forth in SEQ ID NO: 103, and (f) LCDR3 set forth in SEQ ID NO: 104; and The heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 180, (b) HCDR2 set forth in SEQ ID NO: 181, and (c) HCDR3 set forth in SEQ ID NO: 182, and the light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 106, (e) LCDR2 set forth in SEQ ID NO: 107, and (f) LCDR3 set forth in SEQ ID NO: 108 comprises a heavy chain variable region and a light chain variable region selected from at least one of

[0091] In some embodiments, the isolated antibody or antigen-binding fragment thereof is in the following group: 1) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 111; 2) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 115; 3) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 119; 4) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 123; 5) The heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 127; 6) The heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 131; 7) The heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 135; 8) The heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 139; 9) The heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 143; 10) The heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 147; 11) The heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 151; 12) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 155; 13) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 159; 14) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 163; 15) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 167; 16) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 171; 17) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 175; and 18) The heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 179 comprises a heavy chain variable region selected from at least one of the following:

[0092] In some embodiments, the isolated antibody or antigen-binding fragment thereof is from the following group: 1) The light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 37; 2) The light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 41; 3) The light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 45; 4) The light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 49; 5) The light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 53; 6) A light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 57; 7) A light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 61; 8) A light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 65; 9) A light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 69; 10) A light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 73; 11) A light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 77; 12) A light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 81; 13) A light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 85; 14) A light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 89; 15) A light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 93; 16) A light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 97; 17) A light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 101; and 18) A light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 105 and comprises a light chain variable region selected from at least one of the foregoing.

[0093] In some embodiments, the isolated antibody or antigen-binding fragment thereof is the following group: 1) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 111, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 37; 2) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 115, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 41; 3) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 119, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 45; 4) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 123, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 49; 5) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 127, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 53; 6) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 131, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 57; 7) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 135, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 61; 8) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 139, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 65; 9) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 143, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 69; 10) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 147, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 73; 11) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 151, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 77; 12) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 155, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 81; 13) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 159, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 85; 14) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 163, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 89; 15) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 167, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 93; 16) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 171, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 97; 17) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 175, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 101; and 18) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 179, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 105 comprising a heavy chain variable region and a light chain variable region selected from at least one of the above.

[0094] 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 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 according to the present invention also have the same or similar biological functions and / or activities as the antibody according to the present invention.

[0095] 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 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 according to the present invention can also specifically bind to the ITGA2 protein.

[0096] 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 according to the present invention has the same CDRs in the heavy chain and / or light chain variable regions and has conservative amino acid substitutions only at positions in the heavy chain and / or light chain variable regions other than the CDRs (such as framework regions), where the conservative amino acid substitutions do not change the biological function and / or activity of the corresponding antibody.

[0097] Optionally, 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 according to the present invention can also specifically bind to the ITGA2 protein.

[0098] In some embodiments, an antibody having an amino acid sequence of the heavy chain variable region of the antibody according to the present invention (SEQ ID NOs: 111, 115, 119, 123, 127, 131, 135, 139, 143, 147, 151, 155, 159, 163, 167, 171, 175, 179) and / or an 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) that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical has the same CDRs of the heavy chain and / or light chain as the antibody according to the present invention and has conservative amino acid substitutions only in the framework regions of the heavy chain and / or light chain variable regions, where the conservative amino acid substitutions do not change the biological function and / or activity of the corresponding antibody, and the antibody can also specifically bind to the ITGA2 protein.

[0099] In some embodiments, the isolated antibody or its antigen-binding fragment further comprises a heavy chain constant region, where the heavy chain constant region comprises the amino acid sequence set forth in 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 set forth in SEQ ID NO: 183.

[0100] In some embodiments, the isolated antibody or its antigen-binding fragment further comprises a light chain constant region, where the light chain constant region comprises the amino acid sequence set forth in 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 set forth in SEQ ID NO: 109, or the light chain constant region comprises the amino acid sequence set forth in 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 set forth in SEQ ID NO: 110.

[0101] 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, the heavy chain constant region comprises the amino acid sequence set forth in 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 set forth in SEQ ID NO: 183, the light chain constant region comprises the amino acid sequence set forth in 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 set forth in SEQ ID NO: 109, or the light chain constant region comprises the amino acid sequence set forth in 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 set forth in SEQ ID NO: 110.

[0102] In some embodiments, the isolated antibody or antigen-binding fragment thereof is in the following group: 1) a heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 202; 2) a heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 203; 3) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 204; 4) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 205; 5) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 206; 6) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 207; 7) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 208; 8) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 209; 9) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 210; 10) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 211; 11) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 212; 12) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 213; 13) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 214; 14) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 215; 15) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 216; 16) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 217; 17) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 218; and 18) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 219 and comprising a heavy chain selected from at least one of the above.

[0103] In some embodiments, the isolated antibody or antigen-binding fragment thereof is from the following group: 1) A light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 184; 2) A light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 185; 3) A light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 186; 4) A light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 187; 5) A light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 188; 6) A light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 189; 7) A light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 190; 8) A light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 191; 9) A light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 192; 10) A light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 193; 11) A light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 194; 12) A light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 195; 13) A light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 196; 14) A light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 197; 15) A light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 198; 16) A light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 199; 17) A light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 200; and 18) A light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 201 comprising a light chain selected from at least one of them.

[0104] In some embodiments, the isolated antibody or antigen-binding fragment thereof is from the following group: 1) a heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 202, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 184; 2) a heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 203, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 185; 3) a heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 204, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 186; 4) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 205, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 187; 5) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 206, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 188; 6) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 207, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 189; 7) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 208, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 190; 8) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 209, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 191; 9) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 210, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 192; 10) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 211, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 193; 11) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 212, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 194; 12) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 213, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 195; 13) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 214, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 196; 14) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 215, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 197; 15) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 216, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 198; 16) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 217, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 199; 17) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 218, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 200; and 18) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 219, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 201 comprising a heavy chain and a light chain selected from at least one of the above.

[0105] 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 according to the present invention have the same or similar biological functions and / or activities as the antibody according to the present invention.

[0106] 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 according to the present invention can also specifically bind to the ITGA2 protein.

[0107] 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 according to the present invention have the same heavy chain and / or light chain variable regions as the antibody according to the present invention, and have conservative amino acid substitutions only at locations of the heavy chain and / or light chain other than the heavy chain and / or light chain variable regions (such as the heavy chain and / or light chain constant regions), where the conservative amino acid substitutions do not change the biological function and / or activity of the corresponding antibody.

[0108] Optionally, 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 according to the present invention can also specifically bind to the ITGA2 protein.

[0109] In some embodiments, an antibody having an amino acid sequence of the heavy chain (SEQ ID NOs: 202-219) and / or the light chain (SEQ ID NOs: 184-201) of the antibody according to the present invention that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical has the same heavy chain and / or light chain variable regions as the antibody according to the present invention and has conservative amino acid substitutions only in the constant regions of the heavy chain and / or light chain, where the conservative amino acid substitutions do not change the biological function and / or activity of the corresponding antibody, and the antibody can also specifically bind to the ITGA2 protein.

[0110] In some embodiments, the isolated antibody or antigen-binding fragment thereof is in the following group: 1) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 202 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 184; 2) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 203 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 185; 3) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 204 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 186; 4) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 205 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 187; 5) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 206 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 188; 6) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 207 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 189; 7) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 208 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 190; 8) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 209 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 191; 9) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 210 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 192; 10) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 211 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 193; 11) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 212 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 194; 12) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 213 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 195; 13) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 214 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 196; 14) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 215 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 197; 15) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 216 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 198; 16) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 217 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 199; 17) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 218 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 200; and 18) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 219 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 201 comprising a heavy chain and a light chain selected from at least one of them.

[0111] The antibody according to the present invention and the amino acid sequence numbering (SEQ ID NO) of its corresponding structure are summarized in Table 2 below:

[0112]

Table 19

[0113]

Table 20

[0114] In some embodiments, the isolated antibody or antigen-binding fragment thereof is selected from the following group: 1) an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 19, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 19, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 19; 2) an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 20, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 20, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 20; 3) an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 21, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 21, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 21; 4) an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 22, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 22, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 22; 5) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 23, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 23, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 23; 6) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 24, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 24, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 24; 7) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 25, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 25, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 25; 8) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 26, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 26, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 26; 9) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 27, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 27, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 27; 10) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 28, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 28, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 28; 11) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 29, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 29, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 29; 12) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 30, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 30, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 30; 13) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 31, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 31, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 31; 14) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 32, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 32, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 32; 15) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 33, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 33, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 33; 16) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 34, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 34, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 34; 17) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 35, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 35, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 35; and 18) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 36, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 36, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 36 comprising a heavy chain selected from at least one of the above.

[0115] In some embodiments, the isolated antibody or antigen-binding fragment thereof is from the following group: 1) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 1, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 1, or a light chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 1; 2) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 2, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 2, or a light chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 2; 3) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 3, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 3, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 3; 4) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 4, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 4, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 4; 5) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 5, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 5, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 5; 6) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 6, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 6, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 6; 7) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 7, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 7, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 7; 8) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 8, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 8, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 8; 9) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 9, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 9, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 9; 10) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 10, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 10, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 10; 11) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 11, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 11, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 11; 12) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 12, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 12, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 12; 13) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 13, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 13, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 13; 14) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 14, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 14, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 14; 15) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 15, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 15, or a light chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 15; 16) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 16, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 16, or a light chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 16; 17) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 17, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 17, or a light chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 17; and 18) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 18, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 18, or a light chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 18 consisting of a light chain selected from at least one of the above.

[0116] In some embodiments, the isolated antibody or antigen-binding fragment thereof is the following group: 1) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 19, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 19, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 19, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 1, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 1, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 1; 2) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 20, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 20, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 20, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 2, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 2, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 2; 3) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 21, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 21, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 21, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 3, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 3, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 3; 4) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 22, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 22, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 22, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 4, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 4, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 4; 5) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 23, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 23, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 23, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 5, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 5, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 5; 6) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 24, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 24, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 24, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 6, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 6, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 6; 7) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 25, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 25, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 25, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 7, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 7, or a light chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 7; 8) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 26, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 26, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 26, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 8, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 8, or a light chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 8; 9) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 27, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 27, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 27, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 9, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 9, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 9; 10) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 28, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 28, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 28, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 10, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 10, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 10; 11) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 29, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 29, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 29, and The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 11, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 11, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 11; 12) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 30, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 30, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 30, and The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 12, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 12, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 12; 13) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 31, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 31, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 31, and The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 13, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 13, or a light chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 13; 14) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 32, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 32, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 32, and The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 14, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 14, or a light chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 14; 15) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 33, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 33, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 33, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 15, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 15, or a light chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 15; 16) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 34, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 34, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 34, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 16, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 16, or a light chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 16; 17) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 35, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 35, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 35, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 17, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 17, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 17; and 18) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 36, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 36, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 36, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 18, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 18, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 18 comprising a heavy chain and a light chain selected from at least one of the above.

[0117] 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 according to the present invention encoded by the nucleotide sequence (SEQ ID NOs: 19-36) according to the present invention and / or the amino acid sequence of the light chain of the antibody according to the present invention encoded by the nucleotide sequence (SEQ ID NOs: 1-18) according to the present invention has the same or similar biological function and / or activity as the antibody according to the present invention.

[0118] 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 according to the present invention encoded by the nucleotide sequence (SEQ ID NOs: 19-36) according to the present invention and / or the amino acid sequence of the light chain of the antibody according to the present invention encoded by the nucleotide sequence (SEQ ID NOs: 1-18) according to the present invention can also specifically bind to the ITGA2 protein.

[0119] 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 according to the present invention encoded by the nucleotide sequence (SEQ ID NOs: 19-36) according to the present invention and / or the amino acid sequence of the light chain of the antibody according to the present invention encoded by the nucleotide sequence (SEQ ID NOs: 1-18) according to the present invention has the same heavy chain and / or light chain variable regions as the antibody according to the present invention and has conservative amino acid substitutions only at locations of the heavy chain and / or light chain other than the heavy chain and / or light chain variable regions (such as heavy chain and / or light chain constant regions), where the conservative amino acid substitutions do not change the biological function and / or activity of the corresponding antibody.

[0120] Optionally, 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 according to the invention encoded by the nucleotide sequence according to the invention (SEQ ID NOs: 19-36) and / or the amino acid sequence of the light chain of the antibody according to the invention encoded by the nucleotide sequence according to the invention (SEQ ID NOs: 1-18) can also specifically bind to the ITGA2 protein.

[0121] 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 according to the invention encoded by the nucleotide sequence according to the invention (SEQ ID NOs: 19-36) and / or the amino acid sequence of the light chain of the antibody according to the invention encoded by the nucleotide sequence according to the invention (SEQ ID NOs: 1-18) has the same heavy chain and / or light chain variable regions as the antibody according to the invention and has conservative amino acid substitutions only in the heavy chain and / or light chain constant regions of the heavy chain and / or light chain, where the conservative amino acid substitutions do not change the biological function and / or activity of the corresponding antibody, and the antibody can also specifically bind to the ITGA2 protein.

[0122] In some embodiments, the antibody or its antigen-binding fragment can bind to the ITGA2 protein in vitro with an EC50 of less than 1 nM.

[0123] In some embodiments, the antibody or its antigen-binding fragment can bind to the ITGA2 protein on the surface of HuCCT1 cells with an EC50 of less than 5 nM.

[0124] In some embodiments, the antibody is a monoclonal antibody, a polyclonal antibody, a chimeric antibody, or a humanized antibody.

[0125] III. Methods for preparing nucleic acids, vectors, host cells, hybridomas, and antibodies In one aspect, the present invention provides an isolated nucleic acid molecule encoding the antibody or antigen-binding fragment thereof according to the present invention. In some embodiments, the nucleic acid molecule according to the present invention encodes the heavy chain and / or light chain variable regions of the antibody according to the present invention, each CDR in the heavy chain and / or light chain variable regions, and the heavy chain and / or light chain constant regions. In some embodiments, the nucleotide sequence of the nucleic acid molecule is codon-optimized for the host cell for expression. In some embodiments, the nucleic acid molecule according to the present invention is operably linked to an expression regulatory sequence.

[0126] The present invention further provides an isolated nucleic acid molecule encoding the antibody or antigen-binding fragment thereof according to the present invention.

[0127] In some embodiments, the nucleic acid molecule comprises or consists of a nucleotide sequence selected from any of the following nucleotide sequences set forth in SEQ ID NOs: 1-18, and / or the nucleic acid molecule comprises or consists of a nucleotide sequence selected from any of the following nucleotide sequences set forth in SEQ ID NOs: 19-36.

[0128] In some embodiments, the nucleic acid molecule comprises or consists of a nucleotide sequence combination selected from any one of the following nucleotide sequence 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.

[0129] In some embodiments, the nucleic acid molecule is operably linked to an expression regulatory sequence.

[0130] The antibody according to the present invention and the nucleotide sequence numbering (SEQ ID NO) of its corresponding structure are summarized in Table 3 below:

[0131] [Table 21]

[0132] [Table 22]

[0133] The present invention further provides an expression vector comprising at least one of the nucleic acid molecules according to the present invention as described above.

[0134] The present invention further provides a host cell transformed with at least one of the nucleic acid molecules or expression vectors according to the present invention as described above.

[0135] The present invention further provides a hybridoma cell expressing at least one of the antibody or its antigen-binding fragment according to the present invention as described above.

[0136] The present invention further provides a method for producing the antibody or its antigen-binding fragment according to the present invention, comprising (i) culturing the host cell of the present invention under conditions suitable for expressing the nucleic acid molecule or expression vector, and (ii) isolating and purifying the antibody or its antigen-binding fragment expressed by the host cell.

[0137] In some embodiments, the nucleotide sequence of the nucleic acid molecule is codon-optimized for the host cell for expression. In some embodiments, the nucleic acid molecule is operably linked to an expression regulatory sequence.

[0138] The present invention further provides a method for producing the antibody or its antigen-binding fragment according to the present invention, comprising (i) Preparing a hybridoma cell capable of expressing the monoclonal antibody or its antigen-binding fragment according to the present invention, and (ii) providing a method comprising isolating and purifying an antibody or its antigen-binding fragment expressed by the hybridoma cell.

[0139] IV. Antibody-Drug Conjugate In one aspect, the present invention provides an antibody-drug conjugate (ADC) prepared by the antibody or its antigen-binding fragment according to the present invention.

[0140] Specifically, the present invention provides an antibody-drug conjugate of the formula Ab-L-D, wherein: "Ab" represents at least one monoclonal antibody or its antigen-binding fragment according to the present invention described above; "L" represents a linker that binds the antibody moiety to the partner molecule; "D" represents a partner molecule.

[0141] As used herein, an ADC is prepared by a linker that binds a partner molecule to an antibody or its antigen-binding fragment. In the ADC according to the present invention, the antibody serves a targeting function by binding to the target tissue or cell of the antigen where the target tissue or cell is found, and the antibody directs the conjugate to the target tissue or cell. At that location, the linker is cleaved, for example, to release the partner molecule to perform its desired biological function.

[0142] The partner molecule can be a drug payload or a marker molecule. The drug payload can be a therapeutic agent, where, for example, the therapeutic agent can be a cytotoxic agent, a chemotherapeutic agent, a cell growth inhibitor, 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 synonymously.

[0143] The marker molecule can be any marker that generates a detectable signal, such as a radioactive label, a fluorescent label, or a detectable modifying enzyme for a catalytic substrate.

[0144] As used herein, the terms "drug", "payload", and "drug payload" are used synonymously. As used herein, an antibody-drug conjugate (ADC) includes a conjugate formed by binding an antibody or an antigen-binding fragment thereof according to the present invention to a drug payload, and a conjugate formed by binding an antibody or an antigen-binding fragment thereof according to the present invention to a marker molecule.

[0145] The ratio of the partner molecule bound to the antibody can vary depending on factors such as the amount of partner molecule used during the conjugation reaction and the experimental conditions. The ratio of partner molecule to antibody can be 1:6, 1:5, 1:4, 1:3, 1:2, or 1:1.5.

[0146] Accordingly, the present invention provides an antibody-drug conjugate of the formula Ab-(L-D)p, wherein: "Ab" represents at least one monoclonal antibody or an antigen-binding fragment thereof according to the present invention as described above; "L" represents a linker that binds the antibody moiety to the partner molecule; "D" represents the partner molecule; "p" represents the number of linker / partner molecules (preferably, drug payloads) conjugated to the monoclonal antibody or an antigen-binding fragment thereof according to the present invention as described above.

[0147] 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.

[0148] In some embodiments, the linker according to the present invention is selected from one of the following: vc, mc-GGFG, AcLysvc, mc, MalPeg6, m(H20)c, and m(H20)cvc; and / or the linker is cleavable. In some embodiments, the linker according to the present invention is vc.

[0149] In some embodiments, the partner molecule according to the present invention is a drug payload, where the drug payload is a therapeutic molecule. Optionally, the drug payload is selected from a cytotoxic agent, a cell growth inhibitor, an immunomodulator, and a chemotherapeutic agent. Optionally, the drug payload is selected from MMAE, MMAF, DM1, DM4, Dxd, SN-38, topotecan and its derivatives, exatecan and its derivatives, belotecan and its derivatives, camptothecin, calicheamicin, and PBD.

[0150] In some embodiments, the drug payload is MMAE. "MMAE" refers to monomethyl auristatin E, as shown in the following figure, where the wavy line indicates that it is covalently bonded to the linker (L) of the antibody-drug conjugate:

Chemical formula

[0151] In some embodiments, the drug payload is MMAF. "MMAF" refers to monomethyl auristatin F, where the wavy line indicates that it is covalently attached to the linker (L) of the antibody-drug conjugate (U.S. Patent Application Publication No. 2005 / 0238649):

Chemical Structure

[0152] In some embodiments, the linker-partner molecule is vcMMAE. The drug linker moiety and conjugation methods for vcMMAE are disclosed in International Publication No. 2004 / 010957, U.S. Patent No. 7,659,241, U.S. Patent No. 7,829,531, U.S. Patent No. 7,851,437, and U.S. Patent Application No. 11 / 833,028 (Seattle Genetics, Inc.), which are hereby incorporated by reference herein. Using methods similar to those disclosed in the following documents, the drug linker of vcMMAE is conjugated to the antibody according to the present invention.

[0153] For further description of the types of methods for conjugating cytotoxins, linkers, and therapeutic agents to antibodies, see also Saito, G. et al. (2003) Adv. Drug Deliv. Rev. 55:199-215; Trail, P.A. et al. (2003) Cancer Immunol. Immunother. 52:328-337; Payne, G. (2003) Cancer Cell 3:207-212; Allen, T.M. (2002) Nat. Rev. Cancer 2:750-763; Pastan, I. and Kreitman, R.J. (2002) Curr. Opin. Investig. Drugs 3:1089-1091; Senter, P.D. and Springer, C.J. (2001) Adv. Drug Deliv. Rev. 53:247-264 (all of which are hereby incorporated by reference herein).

[0154] In some embodiments, in particular, the drug payload can be a radioisotope that results in a cytotoxic radiopharmaceutical (also known as an antibody-radioisotope conjugate). Examples of radioisotopes that kill 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.

[0155] In some embodiments, the partner molecule according to the present invention is a marker molecule. Optionally, the marker molecule is selected from one of a radiolabel, a fluorescent label, and an enzyme capable of detecting a modification. In some embodiments, the radiolabel is a radioisotope, such as iodine-131, indium-111, yttrium-90, and lutetium-177.

[0156] Experimentally, it has been shown that the ITGA2 protein can be used as an effective target for antibody-drug conjugates. Antibody-drug conjugates obtained by conjugating an antibody to a small molecule toxin can produce an excellent killing effect on tumors expressing the ITGA2 protein.

[0157] V. Pharmaceutical Compositions, Therapeutic Uses, and Treatment Methods The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of at least one monoclonal antibody or antigen-binding fragment thereof according to the present invention as described above or at least one antibody-drug conjugate according to the present invention as described above, a therapeutic use of the pharmaceutical composition, and a treatment method. In the antibody-drug conjugate according to the present invention, the antibody according to the present invention is conjugated to a drug payload.

[0158] 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 according to the present invention as described above or at least one antibody-drug conjugate according to the present invention as described above. In some embodiments, the pharmaceutical composition according to the present invention may further comprise a pharmaceutically acceptable carrier.

[0159] The "pharmaceutical amount" of at least one monoclonal antibody or antigen-binding fragment thereof according to the present invention or at least one antibody-drug conjugate according to the present invention preferably results in a reduction in the severity of the symptoms of the disease, an increase in the frequency and duration of the asymptomatic period of the disease, or the prevention of damage or physical impairment caused by the pain of the disease. For example, for treating a tumor, the "therapeutically effective amount" of at least one monoclonal antibody or antigen-binding fragment thereof according to the present invention or at least one antibody-drug conjugate according to 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%, or more preferably at least about 80% compared to an untreated subject. The ability to inhibit tumor growth can be evaluated in an animal model system that predicts the therapeutic effect on human tumors. Alternatively, it can also be evaluated by examining the ability to inhibit cell growth, which can be determined in vitro by tests well known to those skilled in the art. An effective amount of the antibody or antigen-binding fragment thereof according to the present invention can reduce the size of the tumor or alleviate the symptoms of the subject in other forms such as preventing and / or treating metastasis or recurrence. Those skilled in the art can determine such amounts based on factors such as the size of the subject, the severity of the symptoms of the subject, and the specific composition or administration route selected.

[0160] In another aspect, the present invention provides the use of at least one monoclonal antibody or antigen-binding fragment thereof according to the present invention or at least one antibody-drug conjugate according to the present invention in the preparation of a pharmaceutical composition. In some embodiments, the pharmaceutical composition is used to treat a malignant tumor in a patient and prevent and / or treat metastasis or recurrence of the malignant tumor.

[0161] In another aspect, the present invention provides a pharmaceutical composition comprising at least one monoclonal antibody or an antigen-binding fragment thereof according to the present invention as described above, or an antibody-drug conjugate according to the present invention as described above, wherein the pharmaceutical composition is used for a method of treating a malignant tumor in a patient or preventing and / or treating metastasis or recurrence of a malignant tumor.

[0162] In another aspect, the present invention provides a method for treating a malignant tumor in a patient and preventing and / or treating metastasis or recurrence of a malignant tumor, the method comprising administering to the patient an effective amount of at least one monoclonal antibody or an antigen-binding fragment thereof according to the present invention as described above, at least one antibody-drug conjugate according to the present invention as described above, and / or at least one pharmaceutical composition according to the present invention as described above.

[0163] In some embodiments, the malignant tumor is a tumor that expresses the ITGA2 protein. The malignant tumor is selected from the group consisting of: breast cancer, colorectal cancer, colon cancer, skin cancer, pancreatic cancer, prostate cancer, liver cancer, lung cancer, gastric cancer, leukemia, cholangiocarcinoma, cervical cancer, endometrial cancer, esophageal cancer, head and neck cancer, lymphoma, medullary thyroid cancer, non-Hodgkin lymphoma, ovarian cancer, glioma, melanoma, and bladder cancer. In some embodiments, the malignant tumor is selected from the group consisting of: colorectal cancer, cholangiocarcinoma, pancreatic cancer, and skin cancer. In some embodiments, the malignant tumor is colorectal cancer. In some embodiments, the malignant tumor is cholangiocarcinoma. In some embodiments, the malignant tumor is pancreatic cancer. In some embodiments, the malignant tumor is skin cancer.

[0164] VI. Diagnostic / Predictive Compositions, Diagnostic / Predictive Uses, and Methods As described herein, ITGA2 is a tumor-associated antigen that is specifically overexpressed by tumor cells, particularly in patients suffering from cancers such as colorectal cancer, cholangiocarcinoma, pancreatic cancer, and skin cancer, and is expressed on the surface of tumor cells.

[0165] The present invention provides a diagnostic / predictive composition comprising at least one monoclonal antibody or an antigen-binding fragment thereof according to the present invention as described above, or at least one antibody-drug conjugate according to the present invention as described above, the diagnostic / predictive use of this composition, and a diagnostic / predictive method. In the diagnostic / predictive drug conjugate according to the present invention, the antibody according to the present invention is conjugated to a marker molecule. For the diagnostic / predictive composition, the diagnostic / predictive use, and the diagnostic / predictive method, the antibody-drug conjugate according to the present invention as described above refers to a conjugate formed by binding the antibody or an antigen-binding fragment thereof of the present invention to a marker molecule.

[0166] In one aspect, the present invention provides the use of at least one monoclonal antibody or an antigen-binding fragment thereof according to the present invention as described above, or at least one antibody-drug conjugate according to the present invention as described above, in the preparation of a diagnostic / predictive composition. In some embodiments, the diagnostic composition is used to detect the presence of ITGA2a malignancies in a patient. In some embodiments, the predictive composition is used to predict the recurrence or progression of malignancies in a patient.

[0167] In another aspect, the present invention provides a method for detecting / diagnosing the presence of a malignancy in a patient, the method comprising administering to the patient an effective amount of at least one monoclonal antibody or an antigen-binding fragment thereof according to the present invention as described above, at least one antibody-drug conjugate according to the present invention as described above, and / or at least one diagnostic / predictive composition according to the present invention as described above.

[0168] In some embodiments, the present invention provides a method for detecting / diagnosing the presence of a malignancy in a patient, comprising a) contacting a biological sample obtained from the patient with at least one monoclonal antibody or an antigen-binding fragment thereof according to the present invention as described above, at least one antibody-drug conjugate according to the present invention as described above, and / or at least one diagnostic / predictive composition according to the present invention as described above; b) detecting the binding in a biological sample of at least one monoclonal antibody or antigen-binding fragment thereof, at least one antibody-drug conjugate, and / or at least one diagnostic / predictive composition according to the present invention to a target antigen, wherein the detected binding of the antibody to the target antigen indicates the presence of a malignant tumor in a patient, and providing a method.

[0169] In another aspect, the present invention provides a method for predicting recurrence or progression of a malignant tumor in a patient, the method comprising administering to the patient an effective amount of at least one monoclonal antibody or antigen-binding fragment thereof, at least one antibody-drug conjugate, and / or at least one diagnostic / predictive composition according to the present invention.

[0170] In some embodiments, the present invention provides a method for predicting recurrence or progression of a malignant tumor in a patient, comprising: (a) isolating a biological sample containing tumor cells from the patient; (b) contacting the biological sample containing tumor cells with at least one monoclonal antibody or antigen-binding fragment thereof, at least one antibody-drug conjugate, and / or at least one diagnostic / predictive composition according to the present invention; and (c) identifying the binding of the antibody to the tumor cells, which indicates the presence of the tumor cells, and thereby predicting recurrence or progression of the malignant tumor in the patient, and providing a method.

[0171] In some embodiments, progression of the malignant tumor indicates metastasis of the malignant tumor in the patient.

[0172] In some embodiments, the detected binding of tumor cells to at least one monoclonal antibody or antigen-binding fragment thereof, at least one antibody-drug conjugate, and / or at least one diagnostic / predictive composition according to the present invention described above indicates a high risk of recurrence or progression of malignant tumors in a patient.

[0173] In some embodiments, the partner molecule according to the present invention is a marker molecule. Optionally, the marker molecule is selected from one of a radioactive label (e.g., an isotope), a fluorescent label (e.g., a fluorochrome), a chemical substance, and an enzyme or label capable of detecting a modification.

[0174] In some embodiments, the biological sample is selected from one of a blood sample, a tissue sample, and a lymph fluid sample.

[0175] Methods for detecting the binding of an antibody to an antigen, such as ELISA, are known in the art.

[0176] VII. Kit The scope of the present invention further includes a kit for the method according to the present invention, wherein the kit includes at least one monoclonal antibody or antigen-binding fragment thereof according to the present invention described above, at least one antibody-drug conjugate according to the present invention described above, at least one pharmaceutical composition according to the present invention described above, or a diagnostic / predictive composition according to the present invention described above, and instructions for use.

[0177] In some embodiments, the kit may further comprise at least one additional detection reagent used to detect the presence of at least one monoclonal antibody or antigen-binding fragment thereof according to the present invention described above, at least one antibody-drug conjugate according to the present invention described above, at least one pharmaceutical composition according to the present invention described above, or the diagnostic / predictive composition according to the present invention described above. The kit generally includes a label that indicates the intended use and / or method of use of the contents of the kit. The term "label" includes any description or recorded material provided on or with the kit or provided with the kit.

Example

[0178] Example The present invention can be further understood by reference to the specific examples described herein, which are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. Various changes and modifications can be made to the present invention without departing from the spirit of the present invention, and thus it is clear that such changes and modifications are included within the scope of the claims of the present invention.

[0179] Example 1 - Specific overexpression of ITGA2 protein on the surface of various cancer cells HuCC-T1 (human cholangiocarcinoma cells; Meisen CTCC: CTCC-003-0103), HCCC-9810 (human cholangiocarcinoma cells; Procell Life Science & Technology Co., Ltd. (Wuhan): CL-0095), AsPC-1 (human metastatic pancreatic cancer cells; Procell Life Science & Technology Co., Ltd. (Wuhan): CL-0027), BxPC-3 (human pancreatic adenocarcinoma cells; Meisen CTCC: CTCC-001-0360), A431 (human epidermoid carcinoma cells; Procell Life Science & Technology Co., Ltd. (Wuhan): CL-0015), HT-29 (human colorectal adenocarcinoma cell line; Procell Life Science & Technology Co., Ltd. (Wuhan): CL-0118) and CHO (hamster ovary cells; Procell Life Science & Technology Co., Ltd. (Wuhan): CL-0061) cells were seeded into deep 96-well plates. The cells were seeded into each well at 50,000 cells / 100 μL, and each cell was seeded into three wells. Next, PBS was uniformly sprayed onto them and washed twice. To each well, a PBS solution containing 1% FBS was added in an amount of 100 μL / well, and then the plate was incubated in a 4°C freezer for 30 minutes. The FITC-labeled mouse anti-human ITGA2 antibody solution (BD Pharmingen: 555498) was diluted to an effective concentration of 20 μL / well and incubated in a 4°C freezer in the dark for 30 minutes. After incubation, the cells were washed twice with 500 μL of 1% FBS and then 250 μL of PBS was added and resuspended again. The blank reference solution was a 250 μL PBS solution containing the reference control solution. Using flow cytometry, the number of ITGA2 protein copies of each cell line in the molecules of equivalent soluble fluorescent dyes (MESF) was collected and analyzed. The results are shown in Table 3 below.

[0180]

Table 23

[0181] As shown in Table 3, the ITGA2 protein had higher expression on the surface of HuCCT1, BxPC-3, HCCC-9810, ASPC-1, and A431 cells (MESF > 150,000), and had almost no expression on the surface of the negative control cells CHO (MESF < 1000, which can be regarded as the background value at the experimental technology level).

[0182] Example 2 - Preparation of ITGA2 Antibody 1. Construction of Vector The design, construction, expression, purification, and identification of the ITGA2 antibody sequence of the present invention were entrusted to Sanyou Biopharmaceuticals Co., Ltd. The construction process mainly included constructing the sequence of the ITGA2 antibody on the pcDNA3.4 vector, and obtaining plasmids by PCR, enzymatic digestion, ligation, transformation, identification, sequencing, alignment, and extraction.

[0183] Vectors containing the light chain and heavy chain sequences of the ITGA2 antibody according to the present invention are shown in Table 4 below:

[0184]

Table 24

[0185]

Table 25

[0186] Sixteen plasmids of the light chain were of the κ type, two plasmids were of the λ type; eighteen plasmids of the heavy chain were of the IgG1 type.

[0187] The coding sequences of the light chain and heavy chain in each plasmid vector in the above table are as follows (the shaded part corresponds to the constant region sequence): Light chain: Humanized antibody light chain coding sequence: FS002-A1-LC(κ) (SEQ ID NO: 1) (used to express humanized light chain variable region + human light chain constant region)

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[0188] FS002-A5-LC(κ) light chain variable region (SEQ ID NO: 41) [Chemical formula] The italicized and underlined parts respectively represent [Chemical formula] as shown below.

[0189] FS002-A15-LC(κ) variable light chain region (SEQ ID NO: 45) [Chemical formula] The italicized and underlined parts respectively represent [Chemical formula] as shown below.

[0190] FS002-A36-LC(κ) variable light chain region (SEQ ID NO: 49) [Chemical formula] The italicized and underlined parts respectively represent [Chemical formula] as shown below.

[0191] FS002-A66-LC(κ) variable light chain region (SEQ ID NO: 53) [Chemical formula] The italicized and underlined parts respectively represent [Chemical formula] as shown below.

[0192] FS002-A10-LC(κ-2) variable light chain region (SEQ ID NO: 57) [Chemical formula] The italicized and underlined parts respectively [Chemical formula] indicate.

[0193] FS002-C9-LC(κ-2) light chain variable region (SEQ ID NO: 61) [Chemical formula] The italicized and underlined parts respectively [Chemical formula] indicate.

[0194] FS002-C11-LC(κ-2) light chain variable region (SEQ ID NO: 65) [Chemical formula] The italicized and underlined parts respectively [Chemical formula] indicate.

[0195] FS002-C216-LC(κ-2) light chain variable region (SEQ ID NO: 69) [Chemical formula] The italicized and underlined parts respectively [Chemical formula] indicate.

[0196] FS002-C375-LC(κ-2) light chain variable region (SEQ ID NO: 73) [Chemical formula] The italicized and underlined parts respectively represent [Chemical formula] as shown below.

[0197] FS002-C417-LC(κ-2) light chain variable region (SEQ ID NO: 77) [Chemical formula] The italicized and underlined parts respectively represent [Chemical formula] as shown below.

[0198] FS002-B27-LC(κ-2) light chain variable region (SEQ ID NO: 81) [Chemical formula] The italicized and underlined parts respectively represent [Chemical formula] as shown below.

[0199] FS002-C330-LC(κ-2) light chain variable region (SEQ ID NO: 85) [Chemical formula] The italicized and underlined parts respectively represent [Chemical formula] [[ID=7S]]as shown below.

[0200] FS002-C153-LC(λC2)-2 light chain variable region (SEQ ID NO: 89) [Chem.] The italicized and underlined parts respectively represent [Chem.] as follows.

[0201] FS002-C241-LC(λC2)-2 light chain variable region (SEQ ID NO: 93) [Chem.] The italicized and underlined parts respectively represent [Chem.] as follows.

[0202] FS002-C15-LC(κ-2) light chain variable region (SEQ ID NO: 97) [Chem.] The italicized and underlined parts respectively represent [Chem.] as follows.

[0203] FS002-C58-LC(κ-2) light chain variable region (SEQ ID NO: 101) [Chem.] The italicized and underlined parts respectively represent [Chem.] as follows.

[0204] FS002-A72-LC(κ-2) light chain variable region (SEQ ID NO: 105) [Chem.] The italicized and underlined parts respectively [Chem.] indicate.

[0205] Light chain constant region (amino acid sequence): κ light chain constant region sequence (SEQ ID NO: 109) RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC λ light chain constant region sequence (SEQ ID NO: 110) GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS

[0206] Heavy chain variable region (amino acid sequence): FS002-A1-HC (IgG1) heavy chain variable region (SEQ ID NO: 111) [Chem.] The italicized and underlined parts respectively [Chem.] indicate.

[0207] FS002-A5-HC (IgG1) heavy chain variable region (SEQ ID NO: 115) [Chem.] The italicized and underlined parts respectively

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[0208] FS002-A15-HC (IgG1) heavy chain variable region (SEQ ID NO: 119)

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[0209] FS002-A36-HC (IgG1) heavy chain variable region (SEQ ID NO: 123)

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[0210] FS002-A66-HC (IgG1) heavy chain variable region (SEQ ID NO: 127)

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[0211] FS002-A10-HC (IgG1) heavy chain variable region (SEQ ID NO: 131)

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[0212] FS002-C9-HC (IgG1) heavy chain variable region (SEQ ID NO: 135)

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[0213] FS002-C11-HC (IgG1) heavy chain variable region (SEQ ID NO: 139)

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[0214] FS002-C216-HC (IgG1) heavy chain variable region (SEQ ID NO: 143)

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[0215] FS002-C375-HC (IgG1) heavy chain variable region (SEQ ID NO: 147)

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[0216] FS002-C417-HC (IgG1) heavy chain variable region (SEQ ID NO: 151)

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[0217] FS002-B27-HC (IgG1) heavy chain variable region (SEQ ID NO: 155)

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[0218] FS002-C330-HC (IgG1) heavy chain variable region (SEQ ID NO: 159)

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[0219] FS002-C153-HC (IgG1) heavy chain variable region (SEQ ID NO: 163)

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[0220] FS002-C241-HC (IgG1) heavy chain variable region (SEQ ID NO: 167)

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[0221] FS002-C15-HC (IgG1) heavy chain variable region (SEQ ID NO: 171)

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[0222] FS002-C58-HC (IgG1) heavy chain variable region (SEQ ID NO: 175)

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[0223] FS002-A72-HC (IgG1) heavy chain variable region (SEQ ID NO: 179)

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[0224] IgG1 heavy chain constant region (SEQ ID NO: 183) [Chemical formula] The full-length amino acid sequence of the light chain of the antibody is as follows (the shaded part corresponds to the constant region sequence): FS002-A1-LC(κ) light chain (SEQ ID NO: 184) [Chemical formula] FS002-A5-LC(κ) light chain (SEQ ID NO: 185) [Chemical formula] FS002-A15-LC(κ) light chain (SEQ ID NO: 186) [Chemical formula] FS002-A36-LC(κ) light chain (SEQ ID NO: 187) [Chemical formula] FS002-A66-LC(κ) light chain (SEQ ID NO: 188) [Chemical formula] FS002-A10-LC(κ-2) light chain (SEQ ID NO: 189) [Chemical formula] FS002-C9-LC(κ-2) light chain (SEQ ID NO: 190)

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[0225]

Table 26

[0226] 2. Antibody Expression, Purification, and SDS-PAGE Identification The above plasmid was expressed in CHO cells for 7 days using the ExpiCHO-s expression system as needed, and the antibody was obtained by purifying it using protein A affinity chromatography on the 6th day of expression.

[0227] Subsequently, the purity of the obtained antibody was measured by SDS-PAGE. In SDS-PAGE, the purity of the reduced band or the sum of the reduced heavy and light chains was calculated using ImageJ by peak area normalization. Here, the non-reduced band of the reference IPI had a molecular weight of approximately 150 kDa and a purity of over 90%. The reduced heavy chain had a molecular weight of approximately 55 kDa, the light chain had a molecular weight of approximately 25 kDa, and the heavy and light chains had a purity of over 90%.

[0228] Example 3 - Evaluation of the Affinity of Anti-ITGA2 Antibody for ITGA2 Protein at the Protein Level by ELISA Method The affinity of the ITGA2 antibody for the ITGA2 protein at the protein level was determined using the following method, which included coating an ELISA plate with 2 μg / mL of ITGA2-His. The plate was washed three times with PBST and blocked with 5% PBS-Milk for 2 hours at room temperature. The plate was washed three times with PBST, and then, 30 μL per well of the diluted antibody was added to the ELISA plate and allowed to stand 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 allowed to stand at room temperature for 60 minutes. Then, TMB was added. The reaction was stopped using 2 M stop solution, and OD450 was read. Finally, the binding ability of each antibody to ITGA2-his was compared using EC50. Antibody batelizumab (purchased from Biointron) was used as a positive control. The results are shown in Table 6 below.

[0229]

Table 27

[0230] As shown in the above table, 17 out of the 18 tested antibodies have good binding activity to ITGA2-His (EC50 < 1 nM).

[0231] Example 4 - Determination of the affinity of anti-ITGA2 antibodies for ITGA2 at the cell level by flow cytometry Human cholangiocarcinoma HuCCT1 cells were seeded in a 96-well plate at 50,000 cells per well, uniformly sprayed with PBS, and washed twice with PBS. Next, the PBS was aspirated and discarded. The ITGA2 antibody to be tested was used as the primary antibody and prepared to an effective concentration of 30 nM with a 1% FBS / PBS solution. It was serially diluted 3-fold at a total of five specific concentration points. The prepared antibody dilutions were added to the corresponding 96-well plates and incubated at 4°C for 30 minutes. Next, 1% FBS / PBS solution was sprayed onto it and washed twice with it. After aspirating and discarding the PBS, the solution was centrifuged, the antibody supernatant was aspirated and discarded. Goat anti-human secondary antibody IgG(H+L) with cross-recognition ability from other species taken out was prepared with a PBS solution containing 10% FBS at 1:300. Next, it was added to the 96-well plate and incubated at 4°C for 30 minutes. Flow cytometry was used for collection and analysis, and finally, the affinity of the antibody for the ITGA2 target was evaluated by EC50. Antibody batirizumab (purchased from Biointron) was used as a positive control antibody for binding to ITGA2.

[0232] The results of the EC50 determination are shown in Table 7. As shown in Table 7, 14 of these 18 antibodies have an EC50 of less than 5 nM and bind well to ITGA2-positive HuCCT1 cells.

[0233]

Table 28

[0234] Example 5 - Preparation of Antibody-Drug Conjugate (ADC) The antibody-drug conjugate was prepared by the following method.

[0235] Materials and Methods: Conjugate buffer: 25 mM Na2B4O7, 25 mM NaCl, 1 mM DPTA, pH 7.4 Dialysis buffer: 1×PBS, pH 7.4 Antibody reduction concentration: 5 mg / mL Tris(2-chloroethyl) phosphate (TCEP): 5 mM, binding buffer TCEP:Antibody = 2.3:1 Payload: 10 mM linker-payload, dimethyl sulfoxide (DMSO) DMSO in the final reaction: 10% Payload:Antibody = 10:1 Reduction temperature and time: 25 °C and 2 hours Conjugation temperature and time: 25 °C and 4 hours

[0236] Conjugation process: Over 4 hours at 4 °C, thaw and dialyze the antibody using conjugation buffer; If necessary, concentrate the antibody solution to 2 - 5 mg / ml; Add the TCEP working solution to reduce the antibody and incubate it in a 25 °C water bath; Prepare the linker-payload solution in DMSO (10 mM); Calculate the volume of the effective linker-payload solution for each conjugation based on molar concentration; Mix the antibody with the linker-payload at the desired molar ratio and incubate it in a 25 °C water bath; Dialyze the complex over 4 hours at 4 °C using ADC storage buffer and change the buffer at least every 4 hours; Extract and filter the ADC using a 0.22 μm filter and send the sample for SEC-HPLC and HIC-HPLC analysis.

[0237] By the above method, antibody-drug conjugates of the antibodies FS002-A1, FS002-A15, FS002-A36 of the present invention and the positive control antibody batirizumab were prepared in this example using vc-MMAE (mc-vc-PAB-MMAE, C68H105N11O15, provided by ChemPartner) as the linker-payload.

[0238]

Table 29

[0239] Example 6 - Biological Activity of Antibody - Drug Conjugates (ADCs) for Killing Cancer Cells This example tests the biological activity of an ADC prepared from a toxin conjugated to the antibody of the present invention for killing cancer cells.

[0240] Human cholangiocarcinoma cells HuCC - T1 available from Zhejiang MeisenCTCC, human epidermoid carcinoma cells A431 available from Procell Life Science & Technology Co., Ltd. (Wuhan), and Chinese hamster ovary cells CHO from the negative control ATCC were seeded in a 96 - well plate at 2500 cells / well. Next, it was incubated in a 5% CO₂ incubator at 37°C overnight. Half of the medium was removed from the cell plate the next day. 2x hIgG1 (negative control antibody, provided by Biointron), batirizumab, FS002 - A1 - vc - MMAE, FS002 - A15 - vc - MMAE, FS002 - A36 - vc - MMAE, batirizumab - vc - MMAE, hIgG1 - vcMMAE (negative control ADC, provided by ChemPartner) were prepared using complete culture medium and then diluted at 3 - fold gradients at a total of 11 specific concentration points. Serial dilutions of the above molecules were added to appropriate wells and then incubated in a 5% CO₂ incubator at 37°C for 5 days. After incubation, 100 uL of Cell - Titer - Glo 2.0 reagent was added to the 96 - well plate. Next, it was mixed well on a plate shaker for 2 minutes and finally equilibrated at room temperature for 10 minutes. Readings were taken using a microplate reader. Finally, the biological activity of the ADC against each cell line was compared using IC50.

[0241] 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 batirizumab-vc-MMAE had good killing effects against HuCC-T1 and A431, but had no killing effect against the negative control cells CHO. The negative control antibody hIgG1, the ITGA2 antibody batirizumab not conjugated to vc-MMAE, and the negative control hIgG1-vc-MMAE could not effectively kill HuCC-T1 and A431 cells.

[0242]

Table 30

[0243] These results suggest that although the ITGA2 antibody alone cannot kill tumor cells in vitro, unexpectedly, the ITGA2 protein was found to be an effective target for antibody-drug conjugates. Antibody-drug conjugates obtained by conjugating an antibody to a small molecule toxin can bring about excellent killing effects against tumors expressing the ITGA2 protein.

[0244] A series of items 1. An isolated antibody or antigen-binding fragment thereof that specifically binds to the ITGA2 protein, comprising 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 is selected from the following group: 1) (a) A heavy chain variable region comprising HCDR1 set forth in SEQ ID NO: 112, (b) HCDR2 set forth in SEQ ID NO: 113, and (c) HCDR3 set forth in SEQ ID NO: 114, and (d) a light chain variable region comprising LCDR1 set forth in SEQ ID NO: 38, (e) LCDR2 set forth in SEQ ID NO: 39, and (f) LCDR3 set forth in SEQ ID NO: 40; 2) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 116, (b) HCDR2 set forth in SEQ ID NO: 117, and (c) HCDR3 set forth in SEQ ID NO: 118, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 42, (e) LCDR2 set forth in SEQ ID NO: 43, and (f) LCDR3 set forth in SEQ ID NO: 44; 3) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 120, (b) HCDR2 set forth in SEQ ID NO: 121, and (c) HCDR3 set forth in SEQ ID NO: 122, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 46, (e) LCDR2 set forth in SEQ ID NO: 47, and (f) LCDR3 set forth in SEQ ID NO: 48; 4) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 124, (b) HCDR2 set forth in SEQ ID NO: 125, and (c) HCDR3 set forth in SEQ ID NO: 126, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 50, (e) LCDR2 set forth in SEQ ID NO: 51, and (f) LCDR3 set forth in SEQ ID NO: 52; 5) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 128, (b) HCDR2 set forth in SEQ ID NO: 129, and (c) HCDR3 set forth in SEQ ID NO: 130, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 54, (e) LCDR2 set forth in SEQ ID NO: 55, and (f) LCDR3 set forth in SEQ ID NO: 56; 6) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 132, (b) HCDR2 set forth in SEQ ID NO: 133, and (c) HCDR3 set forth in SEQ ID NO: 134, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 58, (e) LCDR2 set forth in SEQ ID NO: 59, and (f) LCDR3 set forth in SEQ ID NO: 60; 7) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 136, (b) HCDR2 set forth in SEQ ID NO: 137, and (c) HCDR3 set forth in SEQ ID NO: 138, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 62, (e) LCDR2 set forth in SEQ ID NO: 63, and (f) LCDR3 set forth in SEQ ID NO: 64; 8) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 140, (b) HCDR2 set forth in SEQ ID NO: 141, and (c) HCDR3 set forth in SEQ ID NO: 142, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 66, (e) LCDR2 set forth in SEQ ID NO: 67, and (f) LCDR3 set forth in SEQ ID NO: 68; 9) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 144, (b) HCDR2 set forth in SEQ ID NO: 145, and (c) HCDR3 set forth in SEQ ID NO: 146, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 70, (e) LCDR2 set forth in SEQ ID NO: 71, and (f) LCDR3 set forth in SEQ ID NO: 72; 10) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 148, (b) HCDR2 set forth in SEQ ID NO: 149, and (c) HCDR3 set forth in SEQ ID NO: 150, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 74, (e) LCDR2 set forth in SEQ ID NO: 75, and (f) LCDR3 set forth in SEQ ID NO: 76; 11) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 152, (b) HCDR2 set forth in SEQ ID NO: 153, and (c) HCDR3 set forth in SEQ ID NO: 154, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 78, (e) LCDR2 set forth in SEQ ID NO: 79, and (f) LCDR3 set forth in SEQ ID NO: 80; 12) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 156, (b) HCDR2 set forth in SEQ ID NO: 157, and (c) HCDR3 set forth in SEQ ID NO: 158, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 82, (e) LCDR2 set forth in SEQ ID NO: 83, and (f) LCDR3 set forth in SEQ ID NO: 84; 13) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 160, (b) HCDR2 set forth in SEQ ID NO: 161, and (c) HCDR3 set forth in SEQ ID NO: 162, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 86, (e) LCDR2 set forth in SEQ ID NO: 87, and (f) LCDR3 set forth in SEQ ID NO: 88; 14) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 164, (b) HCDR2 set forth in SEQ ID NO: 165, and (c) HCDR3 set forth in SEQ ID NO: 166, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 90, (e) LCDR2 set forth in SEQ ID NO: 91, and (f) LCDR3 set forth in SEQ ID NO: 92; 15) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 168, (b) HCDR2 set forth in SEQ ID NO: 169, and (c) HCDR3 set forth in SEQ ID NO: 170, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 94, (e) LCDR2 set forth in SEQ ID NO: 95, and (f) LCDR3 set forth in SEQ ID NO: 96; 16) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 172, (b) HCDR2 set forth in SEQ ID NO: 173, and (c) HCDR3 set forth in SEQ ID NO: 174, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 98, (e) LCDR2 set forth in SEQ ID NO: 99, and (f) LCDR3 set forth in SEQ ID NO: 100; 17) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 176, (b) HCDR2 set forth in SEQ ID NO: 177, and (c) HCDR3 set forth in SEQ ID NO: 178, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 102, (e) LCDR2 set forth in SEQ ID NO: 103, and (f) LCDR3 set forth in SEQ ID NO: 104; and A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 180, (b) HCDR2 set forth in SEQ ID NO: 181, and (c) HCDR3 set forth in SEQ ID NO: 182, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 106, (e) LCDR2 set forth in SEQ ID NO: 107, and (f) LCDR3 set forth in SEQ ID NO: 108 An isolated antibody or an antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region selected from at least one of the following.

[0245] 2. An isolated antibody or an antigen-binding fragment thereof is selected from the following group: 1) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 111, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 37; 2) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 115, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 41; 3) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 119, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 45; 4) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 123, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 49; 5) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 127, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 53; 6) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 131, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 57; 7) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 135, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 61; 8) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 139, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 65; 9) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 143, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 69; 10) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 147, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 73; 11) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 151, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 77; 12) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 155, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 81; 13) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 159, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 85; 14) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 163, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 89; 15) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 167, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 93; 16) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 171, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 97; 17) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 175, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 101; and 18) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 179, and the amino acid sequence set forth in 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 set forth in SEQ ID NO: 105, a light chain variable region The isolated antibody or antigen-binding fragment thereof according to item 1, comprising a heavy chain variable region and a light chain variable region selected from at least one of the above.

[0246] 3. 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 set forth in 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 set forth in SEQ ID NO: 183, The light chain constant region comprises the amino acid sequence set forth in 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 set forth in SEQ ID NO: 109, or the light chain constant region comprises the amino acid sequence set forth in 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 set forth in SEQ ID NO: 110. The isolated antibody or antigen-binding fragment thereof according to item 1 or 2.

[0247] 4. The isolated antibody or antigen-binding fragment thereof is in the following group: 1) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 202, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 184; 2) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 203, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 185; 3) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 204, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 186; 4) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 205, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 187; 5) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 206, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 188; 6) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 207, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 189; 7) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 208, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 190; 8) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 209, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 191; 9) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 210, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 192; 10) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 211, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 193; 11) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 212, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 194; 12) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 213, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 195; 13) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 214, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 196; 14) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 215, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 197; 15) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 216, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 198; 16) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 217, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 199; 17) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 218, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 200; and 18) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 219, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 201 The isolated antibody or antigen-binding fragment thereof according to any one of items 1 to 3, comprising a heavy chain and a light chain selected from at least one of the above.

[0248] 5. The isolated antibody or antigen-binding fragment thereof is in the following group: 1) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 202, and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 184; 2) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 203 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 185; 3) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 204 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 186; 4) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 205 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 187; 5) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 206 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 188; 6) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 207 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 189; 7) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 208 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 190; 8) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 209 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 191; 9) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 210 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 192; 10) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 211 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 193; 11) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 212 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 194; 12) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 213 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 195; 13) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 214 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 196; 14) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 215 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 197; 15) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 216 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 198; 16) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 217 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 199; 17) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 218 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 200; and 18) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 219 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 201 An isolated antibody or an antigen-binding fragment thereof according to any one of items 1 to 4, comprising a heavy chain and a light chain selected from at least one of the following:

[0249] 6. An isolated antibody or an antigen-binding fragment thereof that specifically binds to the ITGA2 protein, wherein the isolated antibody or the antigen-binding fragment thereof is selected from the following group: 1) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 19, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 19, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 19, and The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 1, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 1, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 1; 2) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 20, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 20, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 20, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 2, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 2, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 2; 3) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 21, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 21, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 21, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 3, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 3, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 3; 4) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 22, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 22, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 22, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 4, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 4, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 4; 5) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 23, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 23, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 23, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 5, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 5, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 5; 6) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 24, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 24, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 24, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 6, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 6, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 6; 7) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 25, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 25, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 25, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 7, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 7, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 7; 8) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 26, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 26, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 26, and The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 8, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 8, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 8; 9) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 27, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 27, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 27, and The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 9, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 9, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 9; 10) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 28, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 28, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 28, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 10, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 10, or a light chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 10; 11) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 29, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 29, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 29, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 11, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 11, or a light chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 11; (12) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 30, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 30, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 30, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 12, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 12, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 12; (13) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 31, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 31, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 31, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 13, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 13, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 13; (14) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 32, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 32, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 32, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 14, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 14, or a light chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 14; (15) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 33, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 33, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 33, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 15, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 15, or a light chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 15; 16) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 34, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 34, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 34, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 16, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 16, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 16; 17) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 35, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 35, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 35, and the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 17, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 17, or a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 17; and 18) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 36, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 36, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 36, and The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 18, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 18, or a light chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 18 An isolated antibody or an antigen-binding fragment thereof comprising a heavy chain and a light chain selected from at least one of the above.

[0250] 7. The antibody is capable of binding to ITGA2 protein in vitro with an EC50 of less than 1 nM; and / or 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 the antibody is a monoclonal antibody, a polyclonal antibody, a chimeric antibody, or a humanized antibody. The isolated antibody or an antigen-binding fragment thereof according to any one of items 1 to 6.

[0251] 8. An isolated nucleic acid molecule encoding the antibody or an antigen-binding fragment thereof according to any one of items 1 to 7; or The nucleic acid molecule comprises or consists of a nucleotide sequence selected from any of the following nucleotide sequences set forth in SEQ ID NOs: 1 to 18, and / or the nucleic acid molecule comprises or consists of a nucleotide sequence selected from any of the following nucleotide sequences set forth in SEQ ID NOs: 19 to 36; or An isolated nucleic acid molecule comprising or consisting of a nucleotide sequence combination selected from any one of the following nucleotide sequences: 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.

[0252] 9. The isolated nucleic acid molecule according to item 8, wherein the nucleic acid molecule is operably linked to an expression regulatory sequence.

[0253] 10. An expression vector comprising the nucleic acid molecule according to item 8 or 9.

[0254] 11. A host cell comprising the nucleic acid molecule according to item 8 or 9 or the expression vector according to item 10.

[0255] 12. A hybridoma cell expressing the antibody according to any one of items 1 to 7 or an antigen-binding fragment thereof.

[0256] 13. Formula: Ab-L-D (wherein: "Ab" represents at least one antibody according to the present invention or an antigen-binding fragment thereof; "L" represents a linker that binds the antibody moiety to the partner molecule; "D" represents a partner molecule); Or Ab-(L-D)p (wherein: "Ab" represents at least one antibody according to the present invention or an antigen-binding fragment thereof; "L" represents a linker that binds the antibody moiety to the partner molecule; "D" represents a partner molecule; "p" represents the number of linker / partner molecules (preferably, drug payloads) conjugated to the antibody or antigen-binding fragment thereof according to the present invention described above; optionally, p is selected from the following values: 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, and 8.0) of the antibody-drug conjugate.

[0257] 14. The antibody-drug conjugate according to item 13, wherein the linker is selected from one of the following: vc, mc-GGFG, AcLysvc, mc, MalPeg6, m(H20)c, and m(H20)cvc; and / or the linker is cleavable.

[0258] 15. The partner molecule is a drug payload, and the drug payload is a therapeutic molecule; optionally, the drug payload is selected from a cytotoxic agent, a cell growth inhibitor, an immunomodulator, and a chemotherapeutic agent; optionally, the drug payload is selected from MMAE, MMAF, DM1, DM4, Dxd, SN-38, topotecan and its derivatives, exatecan and its derivatives, belotecan and its derivatives, camptothecin, calicheamicin, and PBD; or The partner molecule is a marker molecule; optionally, the marker molecule is selected from one of a radioactive label (e.g., an isotope), a fluorescent label (e.g., a fluorescent dye), a chemical substance, and an enzyme or label capable of detecting a modification. The antibody-drug conjugate according to item 13 or 14.

[0259] 16. A pharmaceutical composition comprising an antibody or an antigen-binding fragment thereof according to any one of items 1 to 7, or an antibody-drug conjugate according to any one of items 13 to 15, and optionally a pharmaceutically acceptable carrier.

[0260] 17. Use of an antibody or an antigen-binding fragment thereof according to any one of items 1 to 7 or an antibody-drug conjugate according to any one of items 13 to 15 in the preparation of a pharmaceutical composition, wherein optionally the pharmaceutical composition is used to treat a malignant tumor in a patient, prevent and / or treat metastasis or recurrence of the malignant tumor; optionally the pharmaceutical composition is used to detect the presence of a malignant tumor in a patient; optionally the pharmaceutical composition is used to predict recurrence or progression of a malignant tumor in a patient.

[0261] 18. A method for treating a malignant tumor in a patient, preventing and / or treating metastasis or recurrence of the malignant tumor, the method comprising administering to the patient an effective amount of an antibody or an antigen-binding fragment thereof according to any one of items 1 to 7, an antibody-drug conjugate according to any one of items 13 to 15, or a pharmaceutical composition according to item 16.

[0262] 19. The method according to item 18, wherein the malignant tumor is selected from the group consisting of breast cancer, colon cancer, skin cancer, pancreatic cancer, prostate cancer, liver cancer, lung cancer, gastric cancer, leukemia, cholangiocarcinoma, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, head and neck cancer, lymphoma, medullary thyroid cancer, non-Hodgkin lymphoma, ovarian cancer, glioma, melanoma, and bladder cancer; preferably, the malignant tumor is selected from the group consisting of colorectal cancer, cholangiocarcinoma, pancreatic cancer, and skin cancer.

[0263] 20. The method according to item 18 or 19, further comprising administering to the patient another anti-tumor therapeutic agent, such as a chemotherapeutic agent, an antibody targeting another tumor-specific antigen, or radiotherapy.

[0264] 21. A method for detecting the presence of tumor cells in a biological sample, a) contacting a biological sample with the antibody or an antigen-binding fragment thereof according to any one of items 1 to 7; b) detecting the binding of the antibody or an antigen-binding fragment thereof to the target antigen in the biological sample, wherein the detected binding indicates the presence of tumor cells in the biological sample.

[0265] 22. A method for detecting the presence of a malignant tumor in a patient, comprising: a) contacting a biological sample obtained from the patient with the antibody or an antigen-binding fragment thereof according to any one of items 1 to 7; b) detecting the binding of the antibody or an antigen-binding fragment thereof to the target antigen in the biological sample, wherein the detected binding indicates the presence of a malignant tumor in the patient.

[0266] 23. A method for predicting the recurrence or progression of a malignant tumor in a patient, comprising: (a) isolating a biological sample containing tumor cells from the patient; (b) contacting the biological sample containing tumor cells with the antibody or an antigen-binding fragment thereof according to any one of items 1 to 7; and (c) identifying the presence of tumor cells that bind to the antibody or an antigen-binding fragment thereof, thereby predicting the recurrence or progression of a malignant tumor in the patient.

[0267] 24. The method according to item 23, wherein the progression of the malignant tumor includes metastasis of the malignant tumor in the patient.

[0268] 25. The method according to item 23 or 24, wherein the biological sample is selected from one of the following: a blood sample, a tissue sample, and a lymph fluid sample.

[0269] 26. The method according to any one of items 23 to 25, wherein the malignant tumor is selected from the group consisting of: breast cancer, colorectal cancer, colon cancer, skin cancer, pancreatic cancer, prostate cancer, liver cancer, lung cancer, gastric cancer, leukemia, cholangiocarcinoma, cervical cancer, endometrial cancer, esophageal cancer, head and neck cancer, lymphoma, medullary thyroid cancer, non-Hodgkin lymphoma, ovarian cancer, glioma, melanoma, and bladder cancer; preferably, the malignant tumor is selected from the group consisting of: colorectal cancer, cholangiocarcinoma, pancreatic cancer, and skin cancer.

[0270] 27. A method for producing an antibody or an antigen-binding fragment thereof that targets human tumor cells expressing ITGA2, comprising: (i) culturing the host cell according to item 11 under conditions suitable for expressing the nucleic acid molecule or the expression vector, and (ii) isolating and purifying the antibody or the antigen-binding fragment thereof expressed by the nucleic acid molecule or the expression vector.

Claims

**Claim 1** An isolated antibody or antigen-binding fragment thereof that specifically binds to the ITGA2 protein, comprising a heavy-chain variable region comprising HCDR1, HCDR2, and HCDR3 sequences, and a light-chain variable region comprising LCDR1, LCDR2, and LCDR3 sequences, wherein said antibody or said antigen-binding fragment thereof is selected from the following groups: 1) (a) an HCDR1 set forth in SEQ ID NO: 112, (b) an HCDR2 set forth in SEQ ID NO: 113, and (c) an HCDR3 set forth in SEQ ID NO: 114, and a heavy-chain variable region comprising the same, and (d) an LCDR1 set forth in SEQ ID NO: 38, (e) an LCDR2 set forth in SEQ ID NO: 39, and (f) an LCDR3 set forth in SEQ ID NO: 40, and a light-chain variable region comprising the same; 2) (a) an HCDR1 set forth in SEQ ID NO: 116, (b) an HCDR2 set forth in SEQ ID NO: 117, and (c) an HCDR3 set forth in SEQ ID NO: 118, and a heavy-chain variable region comprising the same, and (d) an LCDR1 set forth in SEQ ID NO: 42, (e) an LCDR2 set forth in SEQ ID NO: 43, and (f) an LCDR3 set forth in SEQ ID NO: 44, and a light-chain variable region comprising the same; 3) (a) an HCDR1 set forth in SEQ ID NO: 120, (b) an HCDR2 set forth in SEQ ID NO: 121, and (c) an HCDR3 set forth in SEQ ID NO: 122, and a heavy-chain variable region comprising the same, and (d) an LCDR1 set forth in SEQ ID NO: 46, (e) an LCDR2 set forth in SEQ ID NO: 47, and (f) an LCDR3 set forth in SEQ ID NO: 48, and a light-chain variable region comprising the same; 4) (a) an HCDR1 set forth in SEQ ID NO: 124, (b) an HCDR2 set forth in SEQ ID NO: 125, and (c) an HCDR3 set forth in SEQ ID NO: 126, and a heavy-chain variable region comprising the same, and (d) an LCDR1 set forth in SEQ ID NO: 50, (e) an LCDR2 set forth in SEQ ID NO: 51, and (f) an LCDR3 set forth in SEQ ID NO: 52, and a light-chain variable region comprising the same; 5) (a) an HCDR1 set forth in SEQ ID NO: 128, (b) an HCDR2 set forth in SEQ ID NO: 129, and (c) an HCDR3 set forth in SEQ ID NO: 130, and a heavy-chain variable region comprising the same, and (d) an LCDR1 set forth in SEQ ID NO: 54, (e) an LCDR2 set forth in SEQ ID NO: 55, and (f) an LCDR3 set forth in SEQ ID NO: 56, and a light-chain variable region comprising the same; 6) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 132, (b) HCDR2 set forth in SEQ ID NO: 133, and (c) HCDR3 set forth in SEQ ID NO: 134, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 58, (e) LCDR2 set forth in SEQ ID NO: 59, and (f) LCDR3 set forth in SEQ ID NO: 60; 7) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 136, (b) HCDR2 set forth in SEQ ID NO: 137, and (c) HCDR3 set forth in SEQ ID NO: 138, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 62, (e) LCDR2 set forth in SEQ ID NO: 63, and (f) LCDR3 set forth in SEQ ID NO: 64; 8) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 140, (b) HCDR2 set forth in SEQ ID NO: 141, and (c) HCDR3 set forth in SEQ ID NO: 142, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 66, (e) LCDR2 set forth in SEQ ID NO: 67, and (f) LCDR3 set forth in SEQ ID NO: 68; 9) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 144, (b) HCDR2 set forth in SEQ ID NO: 145, and (c) HCDR3 set forth in SEQ ID NO: 146, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 70, (e) LCDR2 set forth in SEQ ID NO: 71, and (f) LCDR3 set forth in SEQ ID NO: 72; 10) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 148, (b) HCDR2 set forth in SEQ ID NO: 149, and (c) HCDR3 set forth in SEQ ID NO: 150, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 74, (e) LCDR2 set forth in SEQ ID NO: 75, and (f) LCDR3 set forth in SEQ ID NO: 76; 11) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 152, (b) HCDR2 set forth in SEQ ID NO: 153, and (c) HCDR3 set forth in SEQ ID NO: 154, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 78, (e) LCDR2 set forth in SEQ ID NO: 79, and (f) LCDR3 set forth in SEQ ID NO: 80; 12) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 156, (b) HCDR2 set forth in SEQ ID NO: 157, and (c) HCDR3 set forth in SEQ ID NO: 158, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 82, (e) LCDR2 set forth in SEQ ID NO: 83, and (f) LCDR3 set forth in SEQ ID NO: 84; 13) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 160, (b) HCDR2 set forth in SEQ ID NO: 161, and (c) HCDR3 set forth in SEQ ID NO: 162, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 86, (e) LCDR2 set forth in SEQ ID NO: 87, and (f) LCDR3 set forth in SEQ ID NO: 88; 14) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 164, (b) HCDR2 set forth in SEQ ID NO: 165, and (c) HCDR3 set forth in SEQ ID NO: 166, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 90, (e) LCDR2 set forth in SEQ ID NO: 91, and (f) LCDR3 set forth in SEQ ID NO: 92; 15) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 168, (b) HCDR2 set forth in SEQ ID NO: 169, and (c) HCDR3 set forth in SEQ ID NO: 170, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 94, (e) LCDR2 set forth in SEQ ID NO: 95, and (f) LCDR3 set forth in SEQ ID NO: 96; 16) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 172, (b) HCDR2 set forth in SEQ ID NO: 173, and (c) HCDR3 set forth in SEQ ID NO: 174, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 98, (e) LCDR2 set forth in SEQ ID NO: 99, and (f) LCDR3 set forth in SEQ ID NO: 100; 17) A heavy chain variable region comprising (a) HCDR1 set forth in SEQ ID NO: 176, (b) HCDR2 set forth in SEQ ID NO: 177, and (c) HCDR3 set forth in SEQ ID NO: 178, and a light chain variable region comprising (d) LCDR1 set forth in SEQ ID NO: 102, (e) LCDR2 set forth in SEQ ID NO: 103, and (f) LCDR3 set forth in SEQ ID NO: 104; and (a) The heavy chain variable region comprising HCDR1 set forth in SEQ ID NO: 180, (b) HCDR2 set forth in SEQ ID NO: 181, and (c) HCDR3 set forth in SEQ ID NO: 182, and (d) LCDR1 set forth in SEQ ID NO: 106, (e) LCDR2 set forth in SEQ ID NO: 107, and (f) LCDR3 set forth in SEQ ID NO: 108 An isolated antibody or an antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region selected from at least one of the above. **Claim 2** The isolated antibody or the antigen-binding fragment thereof is selected from the following group: 1) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 111, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 37; 2) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 115, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 41; 3) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 119, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 45; 4) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 123, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 49; 5) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 127, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 53; 6) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 131, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 57; 7) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 135, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 61; 8) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 139, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 65; 9) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 143, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 69; 10) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 147, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 73; 11) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 151, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 77; 12) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 155, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 81; 13) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 159, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 85; 14) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 163, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 89; 15) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 167, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 93; 16) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 171, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 97; 17) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 175, and a light chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 101; and 18) A heavy chain variable region comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 179, and the amino acid sequence set forth in 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 set forth in SEQ ID NO: 105, and a light chain variable region The isolated antibody or antigen-binding fragment thereof according to claim 1, comprising a heavy chain variable region and a light chain variable region selected from at least one of the above.

3. 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 set forth in 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 set forth in SEQ ID NO: 183, The light chain constant region comprises the amino acid sequence set forth in 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 set forth in SEQ ID NO: 109, or the light chain constant region comprises the amino acid sequence set forth in 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 set forth in SEQ ID NO:

110. The isolated antibody or antigen-binding fragment thereof according to claim 1 or 2.

4. The isolated antibody or antigen-binding fragment thereof is in the following group: 1) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 202, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 184; 2) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 203, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 185; 3) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 204, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 186; 4) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 205, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 187; 5) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 206, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 188; 6) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 207, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 189; 7) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 208, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 190; 8) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 209, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 191; 9) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 210, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 192; 10) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 211, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 193; 11) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 212, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 194; 12) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 213, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 195; 13) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 214, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 196; 14) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 215, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 197; 15) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 216, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 198; 16) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 217, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 199; 17) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 218, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 200; and 18) A heavy chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 219, and a light chain comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 201 The isolated antibody or antigen-binding fragment thereof according to claim 3, comprising a heavy chain and a light chain selected from at least one of the above.

5. The isolated antibody or the antigen-binding fragment thereof is selected from the following group: 1) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 202 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 184; 2) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 203 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 185; 3) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 204 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 186; 4) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 205 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 187; 5) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 206 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 188; 6) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 207 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 189; 7) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 208 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 190; 8) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 209 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 191; 9) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 210 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 192; 10) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 211 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 193; 11) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 212 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 194; 12) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 213 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 195; 13) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 214 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 196; 14) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 215 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 197; 15) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 216 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 198; 16) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 217 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 199; 17) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 218 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 200; and 18) A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 219 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 201 The isolated antibody or antigen-binding fragment thereof according to claim 4, comprising a heavy chain and a light chain selected from at least one of the above.

6. An isolated antibody or antigen-binding fragment thereof that specifically binds to the ITGA2 protein, wherein the isolated antibody or the antigen-binding fragment thereof is selected from the following groups: 1) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 19, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 19, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 19, and a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 1, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 1; 2) The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 20, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 20, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 20, and a light chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 2, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 2; 3) an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 21, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 21, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 21, and a light chain consisting of an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 3, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 3; 4) an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 22, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 22, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 22, and a light chain consisting of an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 4, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 4; 5) an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 23, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 23, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 23, and a light chain consisting of an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 5, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 5; 6) an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 24, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 24, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 24, and a light chain consisting of an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 6, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 6; 7) An amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 25, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 25, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 25, and a light chain consisting of an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 7, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 7; 8) An amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 26, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 26, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 26, and a light chain consisting of an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 8, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 8; 9) an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 27, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 27, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 27, and a light chain comprising an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 9, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 9, or consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 9; 10) an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 28, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 28, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 28, and a light chain comprising an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 10, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 10, or consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 10; 11) an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 29, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 29, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 29, and a light chain comprising an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 11, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 11, or consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 11; 12) an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 30, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 30, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 30, and a light chain comprising an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 12, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 12, or consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 12; 13) an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 31, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 31, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 31, and a light chain comprising an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 13, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 13, or consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 13; 14) an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 32, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: ​ 15) An amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 33, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 33, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 33, and a light chain comprising an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 15, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 15, or consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 15; The amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 34, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 34, or a heavy chain comprising the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 34, and a light chain comprising an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 16, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 16, or consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 16; 17) an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 35, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 35, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 35, and a light chain comprising an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 17, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 17, or consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 17; and 18) an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 36, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 36, or a heavy chain consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 36, and a light chain comprising an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 18, or an amino acid sequence that is at least 85%, at 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 set forth in SEQ ID NO: 18, or consisting of the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 18 An isolated antibody or an antigen-binding fragment thereof comprising a heavy chain and a light chain selected from at least one of the above. **Claim 7** The antibody is capable of binding to ITGA2 protein in vitro with an EC50 of less than 1 nM; and / or The antibody is capable of binding to the ITGA2 protein on the surface of HuCCT1 cells with an EC50 of less than 5 nM; and / or The isolated antibody or antigen-binding fragment thereof according to any one of claims 1 to 6, wherein the antibody is a monoclonal antibody, a polyclonal antibody, a chimeric antibody, or a humanized antibody.

8. An isolated nucleic acid molecule encoding the antibody or antigen-binding fragment thereof according to any one of claims 1 to 7; or The nucleic acid molecule comprises or consists of a nucleotide sequence selected from any of the following nucleotide sequences set forth in SEQ ID NOs: 1 to 18, and / or the nucleic acid molecule comprises or consists of a nucleotide sequence selected from any of the following nucleotide sequences set forth in SEQ ID NOs: 19 to 36; or The nucleic acid molecule comprises or consists of a nucleotide sequence combination selected from any one of the following nucleotide sequences: 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, an isolated nucleic acid molecule.

9. Formula: Ab-L-D (wherein: "Ab" represents at least one antibody or antigen-binding fragment thereof according to the present invention as described above; "L" represents a linker that binds the antibody moiety to the partner molecule; "D" represents a partner molecule); Or Ab-(L-D)p (wherein: "Ab" represents at least one antibody or antigen-binding fragment thereof according to the present invention as described above; "L" represents a linker that binds the antibody moiety to the partner molecule; "D" represents a partner molecule; "p" represents the number of linker / partner molecules (preferably drug payloads) conjugated to the antibody or antigen-binding fragment thereof according to the present invention described above; optionally, p is one of 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) of the antibody-drug conjugate.

10. The antibody-drug conjugate according to claim 9, wherein the linker is selected from one of the following: vc, mc-GGFG, AcLysvc, mc, MalPeg6, m(H20)c, and m(H20)cv; and / or the linker is cleavable.

11. The partner molecule is a drug payload, and the drug payload is a therapeutic molecule; optionally, the drug payload is selected from cytotoxic agents, cell growth inhibitors, immunomodulators, and chemotherapeutic agents; optionally, the drug payload is selected from MMAE, MMAF, DM1, DM4, Dxd, SN-38, topotecan and its derivatives, exatecan and its derivatives, velotecan and its derivatives, camptothecin, calicheamicin, and PBD; or The partner molecule is a marker molecule; optionally, the marker molecule is selected from a radioactive label (e.g., an isotope), a fluorescent label (e.g., a fluorescent dye), a chemical substance, and an enzyme or label capable of detecting a modification, according to claim 9 or 10 of the antibody-drug conjugate.

12. An antibody or antigen-binding fragment thereof according to any one of claims 1 to 7, or an antibody-drug conjugate according to any one of claims 9 to 11, and optionally a pharmaceutically acceptable carrier, a pharmaceutical composition.

13. Use of an antibody or an antigen-binding fragment thereof according to any one of claims 1 to 7 or an antibody-drug conjugate according to 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 in a patient and to prevent and / or treat metastasis or recurrence of the malignant tumor; optionally, the pharmaceutical composition is used to detect the presence of a malignant tumor in a patient; optionally, the pharmaceutical composition is used to predict recurrence or progression of a malignant tumor in a patient.

14. A method for treating a malignant tumor in a patient and for preventing and / or treating metastasis or recurrence of the malignant tumor, the method comprising administering to the patient an effective amount of an antibody or an antigen-binding fragment thereof according to any one of claims 1 to 7, an antibody-drug conjugate according to any one of claims 9 to 11, or a pharmaceutical composition according to claim 16.

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

16. The method according to claim 14 or 15, further comprising administering to the patient other antitumor therapeutic agents such as chemotherapeutic agents, antibodies targeting other tumor-specific antigens, or radiotherapy.

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