Treatment of metastatic brain tumors with antibody-drug conjugates

Abstract

To provide an agent for the treatment for a metastatic brain tumor.SOLUTION: The present invention provides a therapeutic agent for a metastatic brain tumor comprising, as an active component, an antibody-drug conjugate in which a drug-linker represented by the following formula (where A represents a connecting position to an antibody) is conjugated to the antibody via a thioether bond, and / or a method for treatment for a metastatic brain tumor, comprising administering the antibody-drug conjugate to an individual in need of the treatment for the metastatic brain tumor.SELECTED DRAWING: Figure 9

Description

[Technical Field]

[0001] The present invention relates to a therapeutic agent for metastatic brain tumors containing a specific antibody-drug conjugate, and / or a method for treating metastatic brain tumors, which comprises administering a specific antibody-drug conjugate to an individual. [Background technology]

[0002] Metastatic brain tumors are diseases that develop when a primary cancer metastasizes to the brain, and are known to occur in 20-40% of cancer patients. Because brain metastasis not only has a significant impact on prognosis but also leads to a significant decline in quality of life, there is a need for the development of effective treatments for metastatic brain tumors (Non-Patent Documents 1 and 2).

[0003] Primary cancers of metastatic brain tumors include lung cancer, breast cancer, melanoma, renal cell carcinoma, kidney cancer, colon cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, liver cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, endometrial cancer, thyroid cancer, malignant lymphoma, and sarcoma. Of these, it is known that a particularly high proportion of metastatic brain tumors originate from lung cancer, breast cancer, and melanoma as primary cancers (Non-Patent Documents 1 and 2).

[0004] As a treatment for metastatic brain tumors with lung cancer as the primary cancer, clinical studies using epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib (Non-Patent Document 3), erlotinib (Non-Patent Document 4), afatinib (Non-Patent Document 5), and osimertinib (Non-Patent Document 6), as well as the ALK inhibitor crizotinib (Non-Patent Document 7), etc. are known.

[0005] Clinical studies using anti-HER2 antibody trastuzumab (Non-Patent Document 8) and human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor lapatinib (Non-Patent Document 9) are known to treat metastatic brain tumors originating from breast cancer.

[0006] As a treatment for metastatic brain tumors caused by melanoma as the primary cancer, clinical studies using BRAF inhibitors such as vemurafenib (Non-Patent Document 10) are known.

[0007] However, such drug therapy has not been established as a standard treatment, and radiation therapy or surgery is considered the first choice.

[0008] Antibody-drug conjugates (ADCs), which combine a cytotoxic drug with an antibody that can bind to an antigen expressed on the surface of cancer cells and be internalized into the cells, are expected to be able to selectively deliver drugs to cancer cells, thereby accumulating the drug within the cancer cells and killing them (Non-Patent Documents 11 to 15).

[0009] One known example of an antibody-drug conjugate is one that comprises an antibody and a derivative of exatecan, a topoisomerase I inhibitor, as components (Patent Documents 1 to 5, Non-Patent Documents 16 to 19). These antibody-drug conjugates have excellent antitumor effects and safety, and clinical trials are currently underway.

[0010] As for the treatment of metastatic brain tumors using antibody-drug conjugates, non-clinical and clinical studies are known regarding the treatment of metastatic brain tumors originating from breast cancer using trastuzumab emtansine, an anti-HER2 antibody-drug conjugate containing the tubulin inhibitor DM1 as a component (Non-Patent Documents 20 to 23). [Prior art documents] [Chartered documents]

[0011]

Patent Document 1

Patent document 2

Patent document 3

Patent document 4

Patent document 5

Non-licensed literature

[0012] [Non-licensed document 1] Lorenzo R., et al., Ther Adv Med Oncol. 2017 Dec; 9(12): 781-796. [Non-licensed document 2] Rahmathulla G., et al., Journal of Oncology 2012, Article ID 723541. [Non-licensed document 3] Kim JE., et al., Lung Cancer 2009; 65: 351-354.

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

Non-licensed Document 13

Non-licensed Document 14

Non-licensed Document 15

Non-licensed Document 16

Non-licensed Document 17

[0013] Although small molecules and antibodies are used as cancer therapeutics, they generally have difficulty crossing the blood-brain barrier (BBB). Antibodies, in particular, are extremely large, making their penetration across the BBB highly unlikely (Bendell JC, et al., Cancer 2003;97(12):2972-7). However, there have been reports of intravenously administered antibodies for the treatment of metastatic brain tumors crossing the BBB (Tamura K, et al., J. Nucl. Med. 2013;54(11):1869-75). This is thought to be due to the disruption of the BBB by metastatic tumors, which increases the antibody's ability to penetrate the brain.

[0014] However, there have been reports that even when small molecule compounds or antibodies reach a significant concentration in the brain, the expected therapeutic effect was not achieved. This is thought to be due to the brain metastasis of tumors acquiring drug resistance (e.g., genetic mutations affecting downstream signaling or drug excretion mechanisms such as P-glycoprotein) (Saunus JM., et al., J. Pathol. 2015;237:363-78, Brastianos PK., et al., Cancer Discov. 2015;5:1164-77).

[0015] It is also known that a blood-tumor barrier (BTB) forms between brain metastatic tumors and normal tissue in the brain, resulting in drug resistance (Quail DF. et al., Cancer Cell 2017;31:326-41).

[0016] The present invention aims to verify whether a specific antibody-drug conjugate comprising an exatecan derivative as a component can cross the blood-brain barrier and whether it exhibits a desired antitumor effect against metastatic brain tumors that have acquired drug resistance, and to provide a therapeutic agent for metastatic brain tumors that contains the antibody-drug conjugate and / or a method for treating metastatic brain tumors that comprises administering the antibody-drug conjugate to an individual. [Means for solving the problem]

[0017] The present inventors conducted extensive research to solve the above problems and discovered that a specific antibody-drug conjugate containing an exatecan derivative as a component exhibits excellent antitumor effects against metastatic brain tumors, thereby completing the present invention.

[0018] That is, the present invention provides the following [1] to

[0272] . [1] formula

[0019] [ka]

[0020] (wherein A represents the binding site to the antibody) and an antibody-drug conjugate formed by bonding an antibody to a drug linker represented by the formula (I) via a thioether bond. [2] The therapeutic agent according to [1], wherein the primary cancer of the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer, melanoma, renal cell carcinoma, kidney cancer, colorectal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, liver cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, endometrial cancer, thyroid cancer, malignant lymphoma, and sarcoma. [3] The therapeutic agent according to [1], wherein the primary cancer of the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer, and melanoma. [4] The therapeutic agent according to [1], wherein the primary cancer of the metastatic brain tumor is breast cancer. [5] The therapeutic agent according to [1], wherein the primary cancer of the metastatic brain tumor is lung cancer. [6] The therapeutic agent according to [1], wherein the primary cancer of the metastatic brain tumor is melanoma. [7] The therapeutic agent according to any one of [1] to [6], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody. [8] The therapeutic agent according to [7], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody. [9] The therapeutic agent according to [8], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO: 2.

[10] The therapeutic agent according to [8], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2.

[0021]

[11] The therapeutic agent according to any one of [8] to

[10] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[12] The therapeutic agent according to [7], wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[13] The therapeutic agent according to

[12] , wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 4.

[14] The therapeutic agent according to

[13] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-HER3 antibody is deleted.

[15] The therapeutic agent according to any one of

[12] to

[14] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[16] The therapeutic agent according to [7], wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[17] The therapeutic agent according to

[16] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO: 5 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO: 6.

[18] The therapeutic agent according to

[17] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-TROP2 antibody is deleted.

[19] The therapeutic agent according to any one of

[16] to

[18] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[20] The therapeutic agent according to [7], wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[0022] [twenty one] The therapeutic agent according to

[20] , wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO: 7 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 of SEQ ID NO: 8. [twenty two] The therapeutic agent according to

[21] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted. [twenty three] The therapeutic agent according to any one of

[20] to

[22] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5. [twenty four] The therapeutic agent according to [7], wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody. [twenty five] The therapeutic agent according to

[24] , wherein the anti-GPR20 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 472 of SEQ ID NO: 9 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO: 10.

[26] The therapeutic agent according to

[25] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-GPR20 antibody is deleted.

[27] The therapeutic agent according to any one of

[24] to

[26] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[28] The therapeutic agent according to [7], wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[29] The therapeutic agent according to

[28] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO: 11 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 of SEQ ID NO: 12.

[30] The therapeutic agent according to

[29] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.

[0023]

[31] The therapeutic agent according to any one of

[28] to

[30] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[32] formula

[0024] [ka]

[0025] (wherein the formula, the drug linker is bound to the antibody via a thioether bond, and n represents the average number of drug linkers bound per antibody). A therapeutic agent for metastatic brain tumors, comprising an antibody-drug conjugate represented by the formula (I) as an active ingredient.

[33] The therapeutic agent according to

[32] , wherein the primary cancer of the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer, melanoma, renal cell carcinoma, kidney cancer, colorectal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, liver cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, endometrial cancer, thyroid cancer, malignant lymphoma, and sarcoma.

[34] The therapeutic agent according to

[32] , wherein the primary cancer of the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer, and melanoma.

[35] The therapeutic agent according to

[32] , wherein the primary cancer of the metastatic brain tumor is breast cancer.

[36] The therapeutic agent according to

[32] , wherein the primary cancer of the metastatic brain tumor is lung cancer.

[37] The therapeutic agent according to

[32] , wherein the primary cancer of the metastatic brain tumor is melanoma.

[38] The therapeutic agent according to any one of

[32] to

[37] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[39] The therapeutic agent according to

[38] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[40] The therapeutic agent according to

[39] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 of SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 of SEQ ID NO: 2.

[0026]

[41] The therapeutic agent according to

[39] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2.

[42] The therapeutic agent according to any one of

[39] to

[41] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[43] The therapeutic agent according to

[38] , wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[44] The therapeutic agent according to

[43] , wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 4.

[45] The therapeutic agent according to

[44] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-HER3 antibody is deleted.

[46] The therapeutic agent according to any one of

[43] to

[45] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[47] The therapeutic agent according to

[38] , wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[48] The therapeutic agent according to

[47] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO: 5 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO: 6.

[49] The therapeutic agent according to

[48] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-TROP2 antibody is deleted.

[50] The therapeutic agent according to any one of

[47] to

[49] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[0027]

[51] The therapeutic agent according to

[38] , wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[52] The therapeutic agent according to

[51] , wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO: 7 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 of SEQ ID NO: 8.

[53] The therapeutic agent according to

[52] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted.

[54] The therapeutic agent according to any one of

[51] to

[53] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[55] The therapeutic agent according to

[38] , wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[56] The therapeutic agent according to

[55] , wherein the anti-GPR20 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 472 of SEQ ID NO: 9 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO: 10.

[57] The therapeutic agent according to

[56] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-GPR20 antibody is deleted.

[58] The therapeutic agent according to any one of

[55] to

[57] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[59] The therapeutic agent according to

[38] , wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[60] The therapeutic agent according to

[59] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO: 11 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 of SEQ ID NO: 12.

[0028]

[61] The therapeutic agent according to

[60] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.

[62] The therapeutic agent according to any one of

[59] to

[61] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[63] formula

[0029] [ka]

[0030] (wherein A represents the binding site to the antibody) and an antibody via a thioether bond, to an individual in need of treatment for metastatic brain tumors.

[64] The treatment method described in

[63] , wherein the primary cancer of the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer, melanoma, renal cell carcinoma, kidney cancer, colorectal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, liver cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, endometrial cancer, thyroid cancer, malignant lymphoma, and sarcoma.

[65] The treatment method according to

[63] , wherein the primary cancer of the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer, and melanoma.

[66] The treatment method described in

[63] , wherein the primary cancer of the metastatic brain tumor is breast cancer.

[67] The treatment method described in

[63] , wherein the primary cancer of the metastatic brain tumor is lung cancer.

[68] The treatment method described in

[63] , wherein the primary cancer of the metastatic brain tumor is melanoma.

[69] The method of treatment according to any one of

[63] to

[68] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[70] The treatment method according to

[69] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[0031]

[71] The treatment method described in

[70] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO: 2.

[72] The treatment method described in

[70] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2.

[73] The method of any one of

[70] to

[72] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[74] The treatment method according to

[69] , wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[75] The treatment method described in

[74] , wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 4.

[76] The therapeutic method according to

[75] , wherein the anti-HER3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[77] The method for treatment according to any one of

[74] to

[76] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[78] The treatment method according to

[69] , wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[79] The treatment method described in

[78] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO: 5 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO: 6.

[80] The treatment method described in

[79] , wherein the anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0032]

[81] The method of treatment according to any one of

[78] to

[80] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[82] The treatment method according to

[69] , wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[83] The therapeutic method described in

[82] , wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO: 7 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 of SEQ ID NO: 8.

[84] The therapeutic method according to

[83] , wherein the anti-B7-H3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[85] The method of any one of

[82] to

[84] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[86] The treatment method according to

[69] , wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[87] The treatment method described in

[86] , wherein the anti-GPR20 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 472 of SEQ ID NO: 9 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO: 10.

[88] The therapeutic method according to

[87] , wherein the anti-GPR20 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[89] The method of treatment according to any one of

[86] to

[88] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[90] The treatment method according to

[69] , wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[0033]

[91] The treatment method described in

[90] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO: 11 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 of SEQ ID NO: 12.

[92] The therapeutic method according to

[91] , wherein the anti-CDH6 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[93] The method of treatment according to any one of

[90] to

[92] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[94] formula

[0034] [ka]

[0035] (wherein the formula, the drug linker is bound to the antibody via a thioether bond, and n represents the average number of drug linkers bound per antibody). A method for treating metastatic brain tumors, comprising administering an antibody-drug conjugate represented by the formula:

[95] The treatment method described in

[94] , wherein the primary cancer of the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer, melanoma, renal cell carcinoma, kidney cancer, colorectal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, liver cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, endometrial cancer, thyroid cancer, malignant lymphoma, and sarcoma.

[96] The treatment method according to

[94] , wherein the primary cancer of the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer, and melanoma.

[97] The treatment method described in

[94] , wherein the primary cancer of the metastatic brain tumor is breast cancer.

[98] The treatment method described in

[94] , wherein the primary cancer of the metastatic brain tumor is lung cancer.

[99] The treatment method described in

[94] , wherein the primary cancer of the metastatic brain tumor is melanoma.

[0100] The method for treatment according to any one of

[94] to

[99] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[0036]

[0101] A therapeutic method described in

[0100] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[0102] A therapeutic method described in

[0101] , in which the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in sequence number 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in sequence number 2.

[0103] A therapeutic method described in

[0101] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2.

[0104] A treatment method described in any one of

[0101] to

[0103] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0105] A therapeutic method described in

[0100] , wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[0106] A therapeutic method described in

[0105] , wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 4.

[0107] A therapeutic method described in

[0106] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-HER3 antibody is deleted.

[0108] A treatment method described in any one of

[0105] to

[0107] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0109] A therapeutic method described in

[0100] , wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[0110] A therapeutic method described in

[0109] , in which the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 470 in SEQ ID NO: 5 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 6.

[0037]

[0111] A therapeutic method described in

[0110] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-TROP2 antibody is deleted.

[0112] A treatment method described in any one of

[0109] to

[0111] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[0113] A therapeutic method described in

[0100] , wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[0114] A therapeutic method described in

[0113] , in which the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO: 7 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 8.

[0115] A therapeutic method described in

[0114] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted.

[0116] A therapeutic method described in any one of

[0113] to

[0115] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[0117] A therapeutic method described in

[0100] , wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[0118] A therapeutic method described in

[0117] , wherein the anti-GPR20 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 472 in SEQ ID NO: 9 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 10.

[0119] A therapeutic method described in

[0118] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-GPR20 antibody is deleted.

[0120] A treatment method described in any one of

[0117] to

[0119] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0038]

[0121] A therapeutic method described in

[0100] , wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[0122] A therapeutic method described in

[0121] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in sequence number 11 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in sequence number 12.

[0123] A therapeutic method described in

[0122] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.

[0124] A treatment method described in any one of

[0121] to

[0123] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0125] For the treatment of metastatic brain tumors, formula

[0039] [ka]

[0040] (wherein A represents the binding site to the antibody) An antibody-drug conjugate in which a drug linker represented by the formula: is bonded to an antibody via a thioether bond.

[0126] The antibody-drug conjugate described in

[0125] , wherein the primary cancer of the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer, melanoma, renal cell carcinoma, kidney cancer, colorectal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, liver cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, endometrial cancer, thyroid cancer, malignant lymphoma, and sarcoma.

[0127] The antibody-drug conjugate described in

[0125] , wherein the primary cancer of the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer, and melanoma.

[0128] An antibody-drug conjugate described in

[0125] , wherein the primary cancer of the metastatic brain tumor is breast cancer.

[0129] An antibody-drug conjugate described in

[0125] , wherein the primary cancer of the metastatic brain tumor is lung cancer.

[0130] An antibody-drug conjugate described in

[0125] , wherein the primary cancer of the metastatic brain tumor is melanoma.

[0041]

[0131] An antibody-drug conjugate according to any one of

[0125] to

[0130] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[0132] An antibody-drug conjugate described in

[0131] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[0133] An antibody-drug conjugate described in

[0132] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO: 2.

[0134] An antibody-drug conjugate described in

[0132] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2.

[0135] An antibody-drug conjugate according to any one of

[0132] to

[0134] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0136] An antibody-drug conjugate described in

[0131] , wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[0137] An antibody-drug conjugate described in

[0136] , wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 4.

[0138] An antibody-drug conjugate described in

[0137] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-HER3 antibody is deleted.

[0139] An antibody-drug conjugate according to any one of

[0136] to

[0138] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0140] An antibody-drug conjugate described in

[0131] , wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[0042]

[0141] An antibody-drug conjugate described in

[0140] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 470 in SEQ ID NO: 5 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 6.

[0142] An antibody-drug conjugate described in

[0141] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-TROP2 antibody is deleted.

[0143] An antibody-drug conjugate described in any one of

[0140] to

[0142] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[0144] An antibody-drug conjugate according to

[0131] , wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[0145] An antibody-drug conjugate described in

[0144] , wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO: 7 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 8.

[0146] An antibody-drug conjugate described in

[0145] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted.

[0147] An antibody-drug conjugate described in any one of

[0144] to

[0146] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[0148] An antibody-drug conjugate described in

[0131] , wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[0149] An antibody-drug conjugate described in

[0148] , wherein the anti-GPR20 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 472 in SEQ ID NO: 9 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 10.

[0150] An antibody-drug conjugate described in

[0149] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-GPR20 antibody is deleted.

[0043]

[0151] An antibody-drug conjugate described in any one of

[0148] to

[0150] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0152] An antibody-drug conjugate described in

[0131] , wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[0153] An antibody-drug conjugate described in

[0152] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in sequence number 11 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in sequence number 12.

[0154] An antibody-drug conjugate described in

[0153] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.

[0155] An antibody-drug conjugate described in any one of

[0152] to

[0154] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0156] For the treatment of metastatic brain tumors, formula

[0044] [ka]

[0045] (wherein the formula, the drug linker is bound to the antibody via a thioether bond, and n represents the average number of drug linkers bound per antibody). The antibody-drug conjugate shown in

[0157] The antibody-drug conjugate described in

[0156] , wherein the primary cancer of the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer, melanoma, renal cell carcinoma, kidney cancer, colorectal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, liver cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, endometrial cancer, thyroid cancer, malignant lymphoma, and sarcoma.

[0158] The antibody-drug conjugate described in

[0156] , wherein the primary cancer of the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer, and melanoma.

[0159] An antibody-drug conjugate described in

[0156] , wherein the primary cancer of the metastatic brain tumor is breast cancer.

[0160] An antibody-drug conjugate described in

[0156] , wherein the primary cancer of the metastatic brain tumor is lung cancer.

[0046]

[0161] An antibody-drug conjugate described in

[0156] , wherein the primary cancer of the metastatic brain tumor is melanoma.

[0162] An antibody-drug conjugate according to any one of

[0156] to

[0161] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[0163] An antibody-drug conjugate described in

[0162] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[0164] An antibody-drug conjugate described in

[0163] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO: 2.

[0165] An antibody-drug conjugate described in

[0163] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2.

[0166] An antibody-drug conjugate according to any one of

[0163] to

[0165] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0167] An antibody-drug conjugate described in

[0162] , wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[0168] An antibody-drug conjugate described in

[0167] , wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 4.

[0169] An antibody-drug conjugate described in

[0168] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-HER3 antibody is deleted.

[0170] An antibody-drug conjugate according to any one of

[0167] to

[0169] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0047]

[0171] An antibody-drug conjugate described in

[0162] , wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[0172] An antibody-drug conjugate described in

[0171] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 470 in SEQ ID NO: 5 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 6.

[0173] An antibody-drug conjugate described in

[0172] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-TROP2 antibody is deleted.

[0174] An antibody-drug conjugate described in any one of

[0171] to

[0173] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[0175] An antibody-drug conjugate according to

[0162] , wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[0176] An antibody-drug conjugate described in

[0175] , wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO: 7 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 8.

[0177] An antibody-drug conjugate described in

[0176] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted.

[0178] An antibody-drug conjugate described in any one of

[0175] to

[0177] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[0179] An antibody-drug conjugate described in

[0162] , wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[0180] An antibody-drug conjugate described in

[0179] , wherein the anti-GPR20 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 472 in SEQ ID NO: 9 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 10.

[0048]

[0181] An antibody-drug conjugate described in

[0180] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-GPR20 antibody is deleted.

[0182] An antibody-drug conjugate described in any one of

[0179] to

[0181] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0183] An antibody-drug conjugate described in

[0162] , wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[0184] An antibody-drug conjugate described in

[0183] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in sequence number 11 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in sequence number 12.

[0185] An antibody-drug conjugate described in

[0184] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.

[0186] An antibody-drug conjugate described in any one of

[0183] to

[0185] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0187] For the manufacture of a medicament for the treatment of metastatic brain tumors, formula

[0049] [ka]

[0050] (wherein A represents the binding site to the antibody) and an antibody-drug conjugate in which the drug linker represented by the formula (I) is linked to the antibody via a thioether bond.

[0188] The use described in

[0187] , wherein the primary cancer of the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer, melanoma, renal cell carcinoma, kidney cancer, colorectal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, liver cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, endometrial cancer, thyroid cancer, malignant lymphoma, and sarcoma.

[0189] The use described in

[0187] , wherein the primary cancer of the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer, and melanoma.

[0190] The use described in

[0187] , wherein the primary cancer of the metastatic brain tumor is breast cancer.

[0051]

[0191] The use described in

[0187] , wherein the primary cancer of the metastatic brain tumor is lung cancer.

[0192] The use described in

[0187] , wherein the primary cancer of the metastatic brain tumor is melanoma.

[0193] The use described in any one of

[0187] to

[0192] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[0194] The use described in

[0193] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[0195] The use described in

[0194] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO: 2.

[0196] The use described in

[0194] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2.

[0197] The use described in any one of

[0194] to

[0196] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0198] The use described in

[0193] , wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[0199] The use described in

[0198] , wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 4.

[0200] The use described in

[0199] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-HER3 antibody is deleted.

[0052]

[0201] The use described in any one of

[0198] to

[0200] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0202] The use described in

[0193] , wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[0203] The use described in

[0202] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 470 in SEQ ID NO: 5 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 6.

[0204] The use described in

[0203] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-TROP2 antibody is deleted.

[0205] The use described in any one of

[0202] to

[0204] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[0206] The use described in

[0193] , wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[0207] The use described in

[0206] , wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO: 7 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 8.

[0208] The use described in

[0207] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted.

[0209] The use described in any one of

[0206] to

[0208] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[0210] The use described in

[0193] , wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[0053]

[0211] The use described in

[0210] , wherein the anti-GPR20 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 472 in SEQ ID NO: 9 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 10.

[0212] The use described in

[0211] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-GPR20 antibody is deleted.

[0213] The use described in any one of

[0210] to

[0212] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0214] The use described in

[0193] , wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[0215] The use described in

[0214] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO: 11 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 12.

[0216] The use described in

[0215] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.

[0217] The use described in any one of

[0214] to

[0216] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0218] For the manufacture of a medicament for the treatment of metastatic brain tumors, formula

[0054] [ka]

[0055] (wherein the formula, the drug linker is bound to the antibody via a thioether bond, and n represents the average number of drug linkers bound per antibody). The use of an antibody-drug conjugate as shown in

[0219] The use described in

[0218] , wherein the primary cancer of the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer, melanoma, renal cell carcinoma, kidney cancer, colorectal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, liver cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, endometrial cancer, thyroid cancer, malignant lymphoma, and sarcoma.

[0220] The use described in

[0218] , wherein the primary cancer of the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer, and melanoma.

[0056]

[0221] The use described in

[0218] , wherein the primary cancer of the metastatic brain tumor is breast cancer.

[0222] The use described in

[0218] , wherein the primary cancer of the metastatic brain tumor is lung cancer.

[0223] The use described in

[0218] , wherein the primary cancer of the metastatic brain tumor is melanoma.

[0224] The use described in any one of

[0218] to

[0223] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[0225] The use described in

[0224] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[0226] The use described in

[0225] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO: 2.

[0227] The use described in

[0225] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2.

[0228] The use described in any one of

[0225] to

[0227] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0229] The use described in

[0224] , wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[0230] The use described in

[0229] , wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 4.

[0057]

[0231] The use described in

[0230] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-HER3 antibody is deleted.

[0232] The use described in any one of

[0229] to

[0231] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0233] The use described in

[0224] , wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[0234] The use described in

[0233] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 470 in SEQ ID NO: 5 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 6.

[0235] The use described in

[0234] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-TROP2 antibody is deleted.

[0236] The use described in any one of

[0233] to

[0235] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[0237] The use described in

[0224] , wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[0238] The use described in

[0237] , wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO: 7 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 8.

[0239] The use described in

[0238] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted.

[0240] The use described in any one of

[0237] to

[0239] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[0058]

[0241] The use described in

[0224] , wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[0242] The use described in

[0241] , wherein the anti-GPR20 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 472 in SEQ ID NO: 9 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 10.

[0243] The use described in

[0242] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-GPR20 antibody is deleted.

[0244] The use described in any one of

[0241] to

[0243] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0245] The use described in

[0244] , wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[0246] The use described in

[0245] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO: 11 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 12.

[0247] The use described in

[0246] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.

[0248] The use described in any one of

[0245] to

[0247] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0249] formula

[0059] [ka]

[0060] (wherein A represents the binding site to the antibody) and an antibody-drug conjugate formed by bonding an antibody to a drug linker represented by the formula (I) via a thioether bond.

[0250] The therapeutic agent described in

[0249] , wherein the metastatic cancer is at least one selected from the group consisting of metastatic brain tumor, metastatic bone tumor, metastatic lung tumor, and metastatic liver cancer.

[0061]

[0251] A therapeutic agent described in

[0250] , wherein the metastatic cancer is a metastatic bone tumor.

[0252] formula

[0062] [ka]

[0063] (wherein the formula, the drug linker is bound to the antibody via a thioether bond, and n represents the average number of drug linkers bound per antibody). A therapeutic agent for metastatic cancer, comprising as an active ingredient an antibody-drug conjugate represented by the formula:

[0253] The therapeutic agent described in

[0252] , wherein the metastatic cancer is at least one selected from the group consisting of metastatic brain tumor, metastatic bone tumor, metastatic lung tumor, and metastatic liver cancer.

[0254] A therapeutic agent described in

[0253] , wherein the metastatic cancer is a metastatic bone tumor.

[0255] formula

[0064] [ka]

[0065] (wherein A represents the binding site to the antibody) and an antibody via a thioether bond, to an individual in need of such treatment.

[0256] The treatment method described in

[0255] , wherein the metastatic cancer is at least one selected from the group consisting of metastatic brain tumor, metastatic bone tumor, metastatic lung tumor, and metastatic liver cancer.

[0257] A treatment method described in

[0256] , wherein the metastatic cancer is a metastatic bone tumor.

[0258] formula

[0066] [ka]

[0067] (wherein the formula, the drug linker is bound to the antibody via a thioether bond, and n represents the average number of drug linkers bound per antibody). A method for treating metastatic cancer, comprising administering an antibody-drug conjugate represented by the formula:

[0259] The treatment method described in

[0258] , wherein the metastatic cancer is at least one selected from the group consisting of metastatic brain tumor, metastatic bone tumor, metastatic lung tumor, and metastatic liver cancer.

[0260] A treatment method described in

[0259] , wherein the metastatic cancer is a metastatic bone tumor.

[0068]

[0261] For the treatment of metastatic cancer, formula

[0069] [ka]

[0070] (wherein A represents the binding site to the antibody) An antibody-drug conjugate in which a drug linker represented by the formula: is bonded to an antibody via a thioether bond.

[0262] The antibody-drug conjugate described in

[0261] , wherein the metastatic cancer is at least one selected from the group consisting of metastatic brain tumor, metastatic bone tumor, metastatic lung tumor, and metastatic liver cancer.

[0263] An antibody-drug conjugate described in

[0262] , wherein the metastatic cancer is a metastatic bone tumor.

[0264] For the treatment of metastatic cancer, formula

[0071] [ka]

[0072] (wherein the formula, the drug linker is bound to the antibody via a thioether bond, and n represents the average number of drug linkers bound per antibody). The antibody-drug conjugate shown in

[0265] The antibody-drug conjugate described in

[0264] , wherein the metastatic cancer is at least one selected from the group consisting of metastatic brain tumor, metastatic bone tumor, metastatic lung tumor, and metastatic liver cancer.

[0266] An antibody-drug conjugate described in

[0265] , wherein the metastatic cancer is a metastatic bone tumor.

[0267] for the manufacture of a medicament for the treatment of metastatic cancer, formula

[0073] [ka]

[0074] (wherein A represents the binding site to the antibody) and an antibody-drug conjugate in which the drug linker represented by the formula (I) is linked to the antibody via a thioether bond.

[0268] The use described in

[0267] , wherein the metastatic cancer is at least one selected from the group consisting of metastatic brain tumor, metastatic bone tumor, metastatic lung tumor, and metastatic liver cancer.

[0269] The use described in

[0268] , wherein the metastatic cancer is a metastatic bone tumor.

[0270] for the manufacture of a medicament for the treatment of metastatic cancer, formula

[0075] [ka]

[0076] (wherein the formula, the drug linker is bound to the antibody via a thioether bond, and n represents the average number of drug linkers bound per antibody). The use of an antibody-drug conjugate as shown in

[0077]

[0271] The use described in

[0270] , wherein the metastatic cancer is at least one selected from the group consisting of metastatic brain tumor, metastatic bone tumor, metastatic lung tumor, and metastatic liver cancer.

[0272] The use described in

[0271] , wherein the metastatic cancer is a metastatic bone tumor. [Effects of the Invention]

[0078] The present invention can provide a therapeutic agent for metastatic brain tumors containing a specific antibody-drug conjugate, and / or a method for treating metastatic brain tumors, which is characterized by administering a specific antibody-drug conjugate to an individual. [Brief explanation of the drawings]

[0079] [Figure 1] FIG. 1 shows the amino acid sequence of the anti-HER2 antibody heavy chain (SEQ ID NO: 1). [Figure 2] FIG. 1 shows the amino acid sequence of the anti-HER2 antibody light chain (SEQ ID NO: 2). [Figure 3] FIG. 1 shows the amino acid sequence of the anti-HER3 antibody heavy chain (SEQ ID NO: 3). [Figure 4] FIG. 1 shows the amino acid sequence of the anti-HER3 antibody light chain (SEQ ID NO: 4). [Figure 5] FIG. 1 shows the amino acid sequence of the anti-TROP2 antibody heavy chain (SEQ ID NO: 5). [Figure 6] FIG. 1 shows the amino acid sequence of the anti-TROP2 antibody light chain (SEQ ID NO: 6). [Figure 7] FIG. 1 shows the amino acid sequence of the anti-B7-H3 antibody heavy chain (SEQ ID NO: 7). [Figure 8]FIG. 1 shows the amino acid sequence of the anti-B7-H3 antibody light chain (SEQ ID NO: 8). [Figure 9] FIG. 1 shows the survival-prolonging effect of antibody-drug conjugate (1) in mice into which KPL-4-Luc was intracerebrally transplanted. [Figure 10] 1 shows the antitumor effect of antibody-drug conjugate (1) in mice into which KPL-4-Luc was intracerebrally transplanted. The tumor burden was confirmed by the luminescence intensity of KPL-4-Luc. [Figure 11] These are hematoxylin-eosin stained pathological images of the brains of mice in the vehicle-treated group (No. 1 and No. 2). The center shows the overall pathological image, and the left and right show enlarged pathological images. Tumor masses are observed in the areas surrounded by dotted lines or indicated by arrows. [Figure 12] FIG. 1 shows the amino acid sequence of the anti-GPR20 antibody heavy chain (SEQ ID NO: 9). [Figure 13] FIG. 1 shows the amino acid sequence of the anti-GPR20 antibody light chain (SEQ ID NO: 10). [Figure 14] FIG. 1 shows the amino acid sequence of the anti-CDH6 antibody heavy chain (SEQ ID NO: 11). [Figure 15] FIG. 1 shows the amino acid sequence of the anti-CDH6 antibody light chain (SEQ ID NO: 12). DETAILED DESCRIPTION OF THE INVENTION

[0080] Preferred embodiments for carrying out the present invention will be described below. Note that the embodiment described below shows one example of a typical embodiment of the present invention, and the scope of the present invention should not be construed as being narrow.

[0081] 1. Metastatic brain tumors In the present invention, "metastatic brain tumor" refers to a tumor that develops when a cancer (primary cancer) that originates in a biological tissue other than the brain metastasizes to the brain. Metastatic brain tumors in the present invention include not only tumors that metastasize to the brain parenchyma, but also tumors that infiltrate the pia mater or arachnoid mater (meningeal carcinomatosis). The site of metastasis may be single or multiple. Furthermore, metastatic brain tumors are often discovered after symptoms of the primary cancer appear, but they may also be discovered before symptoms of the primary cancer appear.

[0082] Symptoms of metastatic brain tumors include headache, vomiting, visual disturbance, impaired consciousness, seizures, paralysis, speech disorders, etc. These symptoms are thought to be caused by direct damage to brain tissue by the tumor or increased intracranial pressure.

[0083] Examination of metastatic brain tumors can be performed using, for example, CT (Computed Tomography), PET (Positron Emission Tomography), MRI (Magnetic Resonance Imaging), and the like.

[0084] Examples of primary cancers for metastatic brain tumors include lung cancer, breast cancer, melanoma, renal cell carcinoma, kidney cancer, colon cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, liver cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, endometrial cancer, thyroid cancer, malignant lymphoma, and sarcoma. Of these, lung cancer, breast cancer, and melanoma are particularly prevalent as primary cancers for metastatic brain tumors.

[0085] 2. Antibody-drug conjugates The antibody-drug conjugate used in the present invention is formula

[0086] [ka]

[0087] (wherein A represents the binding site to the antibody) and an antibody via a thioether bond.

[0088] In the present invention, the partial structure of an antibody-drug conjugate consisting of a linker and a drug is referred to as a "drug linker." This drug linker is bound to a thiol group (in other words, the sulfur atom of a cysteine ​​residue) generated at the interchain disulfide bond sites of the antibody (two heavy-heavy chain and two heavy-light chain disulfide bond sites).

[0089] The drug linker of the present invention is based on the topoisomerase I inhibitor exatecan (IUPAC name: (1S,9S)-1-amino-9-ethyl-5-fluoro-1,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione, (chemical name: (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione)). formula

[0090] [ka]

[0091] It is a camptothecin derivative having an antitumor effect, represented by the formula:

[0092] The antibody-drug conjugate used in the present invention is formula

[0093] [ka]

[0094] It can also be expressed as

[0095] Here, the drug linker is bound to the antibody via a thioether bond, and n is synonymous with the so-called average number of drug linkers bound (DAR; Drug-to-Antibody Ratio), which indicates the average number of drug linkers bound per antibody.

[0096] The antibody-drug conjugate used in the present invention, after being transported into cancer cells, formula

[0097] [ka]

[0098] The compound represented by the formula (I) is released, thereby exerting an antitumor effect.

[0099] The above compound is believed to be the basis of the antitumor activity of the antibody-drug conjugate used in the present invention, and has been confirmed to have topoisomerase I inhibitory activity (Ogitani Y. et al., Clinical Cancer Research, 2016, Oct 15;22(20):5097-5108, Epub 2016 Mar 29).

[0100] The antibody-drug conjugate used in the present invention is also known to have a bystander effect (Ogitani Y. et al., Cancer Science (2016) 107, 1039-1046). This bystander effect is exerted when the antibody-drug conjugate used in the present invention is internalized into target-expressing cancer cells, and the compound is then released and exerts an antitumor effect on nearby cancer cells that do not express the target.

[0101] 3. Antibodies in antibody-drug conjugates The antibody in the antibody-drug conjugate used in the present invention may be derived from any species, but is preferably derived from human, rat, mouse, or rabbit. When the antibody is derived from a species other than human, it is preferably chimerized or humanized using well-known techniques. The antibody of the present invention may be a polyclonal antibody or a monoclonal antibody, but is preferably a monoclonal antibody.

[0102] The antibody in the antibody-drug conjugate used in the present invention preferably has the property of being able to target cancer cells, and preferably has the ability to recognize cancer cells, the ability to bind to cancer cells, the ability to be taken up and internalized within cancer cells, and / or cytocidal activity against cancer cells.

[0103] Antibody binding to cancer cells can be confirmed using flow cytometry. Antibody uptake into cancer cells can be confirmed using (1) an assay in which a fluorescently labeled secondary antibody that binds to the therapeutic antibody is used to visualize the antibody uptake by the cell using a fluorescence microscope (Cell Death and Differentiation (2008) 15, 751-761), (2) an assay in which a fluorescently labeled secondary antibody that binds to the therapeutic antibody is used to measure the amount of fluorescence uptake by the cell (Molecular Biology of the Cell Vol. 15, 5268-5282, December 2004), or (3) the Mab-ZAP assay in which an immunotoxin that binds to the therapeutic antibody is released upon intracellular uptake, inhibiting cell proliferation (BioTechniques 28:162-165, January 2000). A recombinant complex protein consisting of the catalytic domain of diphtheria toxin and protein G can also be used as an immunotoxin.

[0104] The antitumor activity of an antibody can be confirmed in vitro by measuring its inhibitory activity against cell proliferation. For example, a cancer cell line overexpressing the antibody's target protein is cultured, and the antibody is added to the culture system at various concentrations to measure its inhibitory activity against focus formation, colony formation, and spheroid growth. In vivo, antitumor activity can be confirmed by administering the antibody to nude mice transplanted with a cancer cell line overexpressing the target protein and measuring changes in the cancer cells.

[0105] Although it is preferable for the antibody itself to have antitumor activity, the antibody-drug conjugate is not necessarily antitumor because it is bound to a compound that exerts antitumor activity. However, for the purpose of specifically and selectively exerting the cytotoxicity of the antitumor compound on cancer cells, it is important and preferable for the antibody to have the property of being internalized and transported into cancer cells.

[0106] The antibody in the antibody-drug conjugate used in the present invention can be obtained by known means. For example, it can be obtained by immunizing an animal with a polypeptide antigen and collecting and purifying the antibody produced in the body using methods commonly used in this field. The origin of the antigen is not limited to humans; animals can also be immunized with antigens derived from animals other than humans, such as mice or rats. In this case, antibodies applicable to human diseases can be selected by testing the cross-reactivity of the obtained antibody that binds to the heterologous antigen with human antigens.

[0107] Alternatively, a monoclonal antibody can be obtained by fusing antibody-producing cells that produce an antibody against an antigen with myeloma cells to establish a hybridoma according to known methods (e.g., Kohler and Milstein, Nature (1975) 256, pp. 495-497; Kennet, R. ed., Monoclonal Antibodies, pp. 365-367, Plenum Press, NY (1980)).

[0108] Antigens can be obtained by genetically engineering a gene encoding an antigen protein in a host cell to produce it. Specifically, a vector capable of expressing the antigen gene is prepared, introduced into a host cell to express the gene, and the expressed antigen is purified. Antibodies can also be obtained by immunizing an animal with the above-mentioned genetically engineered antigen-expressing cells or a cell line expressing the antigen.

[0109] The antibody in the antibody-drug conjugate used in the present invention is preferably a genetically engineered antibody that has been artificially modified for the purpose of reducing heterologous antigenicity to humans, such as a chimeric antibody or a humanized antibody, or is preferably an antibody having only the genetic sequence of a human-derived antibody, i.e., a human antibody. These antibodies can be produced using known methods.

[0110] Chimeric antibodies include antibodies in which the variable and constant regions are of different species, such as chimeric antibodies in which the variable regions of a mouse- or rat-derived antibody are joined to the constant regions of a human-derived antibody (Proc. Natl. Acad. Sci. USA, 81, 6851-6855, (1984)).

[0111] Examples of humanized antibodies include antibodies in which only the complementarity determining region (CDR) of a heterologous antibody has been incorporated into a human-derived antibody (Nature (1986) 321, pp. 522-525), antibodies in which not only the CDR sequence of a heterologous antibody but also some framework amino acid residues of the heterologous antibody have been grafted onto a human antibody using a CDR grafting method (WO 90 / 07861), and antibodies humanized using a gene conversion mutagenesis strategy (U.S. Pat. No. 5,821,337).

[0112] Examples of human antibodies include antibodies produced using human antibody-producing mice carrying human chromosomal fragments containing the heavy and light chain genes of human antibodies (see, for example, Tomizuka, K. et al., Nature Genetics (1997) 16, pp. 133-143; Kuroiwa, Y. et al., Nucl. Acids Res. (1998) 26, pp. 3447-3448; Yoshida, H. et al., Animal Cell Technology: Basic and Applied Aspects vol. 10, pp. 69-73 (Kitagawa, Y., Matsuda, T. and Iijima, S. eds.), Kluwer Academic Publishers, 1999; Tomizuka, K. et al., Proc. Natl. Acad. Sci. USA (2000) 97, pp. 722-727). Alternatively, antibodies obtained by phage display selected from a human antibody library can also be used (see, for example, Wormstone, I. M. et al., Investigative Ophthalmology & Visual Science. (2002) 43 (7), pp. 2301-2308; Carmen, S. et al., Briefings in Functional Genomics and Proteomics (2002), 1 (2), pp. 189-203; Siriwardena, D. et al., Ophthalmology (2002) 109 (3), pp. 427-431).

[0113] The antibody in the antibody-drug conjugate used in the present invention also includes modified antibodies. The modified antibody refers to an antibody of the present invention that has been chemically or biologically modified. Chemical modifications include those having a chemical moiety attached to the amino acid backbone or an N- or O-linked carbohydrate chain. Biological modifications include those that have undergone post-translational modification (e.g., addition of an N- or O-linked sugar chain, N- or C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, etc.), and those in which a methionine residue has been added to the N-terminus by expression in a prokaryotic host cell. Also included within the meaning of such modified antibodies are those labeled to enable detection or isolation of the antibody or antigen of the present invention, such as enzyme-labeled, fluorescent-labeled, or affinity-labeled antibodies. Such modified antibodies of the present invention are useful for improving antibody stability and blood retention, reducing antigenicity, and detecting or isolating antibodies or antigens.

[0114] Furthermore, antibody-dependent cellular cytotoxicity can be enhanced by modulating the sugar chain modification (glycosylation, defucosylation, etc.) attached to the antibody of the present invention. Techniques for modulating antibody sugar chain modification are known, including, but not limited to, those described in International Publication Nos. 99 / 54342, 00 / 61739, 02 / 31140, 2007 / 133855, and 2013 / 120066. Antibodies of the present invention also include antibodies with modified sugar chain modifications.

[0115] It is known that antibodies produced in cultured mammalian cells lose the lysine residue at the carboxyl terminus of their heavy chains (Journal of Chromatography A, 705: 129-134 (1995)). It is also known that two amino acid residues, glycine and lysine, are deleted from the carboxyl terminus of the heavy chain, and a proline residue at the carboxyl terminus is newly amidated (Analytical Biochemistry, 360: 75-83 (2007)). However, these deletions and modifications of the heavy chain sequence do not affect the antigen-binding ability or effector functions (e.g., complement activation and antibody-dependent cellular cytotoxicity) of the antibody. Therefore, the antibodies of the present invention also include antibodies that have undergone such modifications and functional fragments of such antibodies, including deletions in which one or two amino acids are deleted from the carboxyl terminus of the heavy chain, and amidated deletions (e.g., heavy chains in which the proline residue at the carboxyl terminus is amidated). However, as long as the antigen-binding ability and effector function are maintained, the carboxyl-terminal deletions of the heavy chains of the antibody of the present invention are not limited to the above types. The two heavy chains constituting the antibody of the present invention may be any one type of heavy chain selected from the group consisting of full-length and the above-mentioned deletions, or a combination of any two types. The quantitative ratio of each deletion may be affected by the type and culture conditions of the cultured mammalian cells producing the antibody of the present invention, but preferred antibodies of the present invention include those in which one amino acid residue is deleted at the carboxyl terminus of each of the two heavy chains.

[0116] The isotype of the antibody according to the present invention can be, for example, IgG (IgG1, IgG2, IgG3, IgG4), and preferably IgG1 or IgG2.

[0117] The antibody in the antibody-drug conjugate used in the present invention is not particularly limited, and examples thereof include an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-CD3 antibody, an anti-CD30 antibody, an anti-CD33 antibody, an anti-CD37 antibody, an anti-CD56 antibody, an anti-CD98 antibody, an anti-DR5 antibody, an anti-EGFR antibody, an anti-EPHA2 antibody, an anti-FGFR2 antibody, an anti-FGFR4 antibody, an anti-FOLR1 antibody, an anti-VEGF antibody, an anti-CD20 antibody, an anti-CD22 antibody, an anti-CD70 antibody, an anti-PSMA antibody, an anti-CEA antibody, Examples of antibodies include anti-Mesothelin antibody, anti-A33 antibody, anti-CanAg antibody, anti-Cripto antibody, anti-G250 antibody, anti-MUC1 antibody, anti-GPNMB antibody, anti-Integrin antibody, anti-Tenascin-C antibody, anti-SLC44A4 antibody, anti-GPR20 antibody, and anti-CDH6 antibody, and preferred examples include anti-HER2 antibody, anti-HER3 antibody, anti-TROP2 antibody, anti-B7-H3 antibody, anti-GPR20 antibody, and anti-CDH6 antibody, and more preferred examples include anti-HER2 antibody.

[0118] In the present invention, the term "anti-HER2 antibody" refers to an antibody that specifically binds to HER2 (Human Epidermal Growth Factor Receptor Type 2; ErbB-2), and preferably has the activity of being internalized into HER2-expressing cells upon binding to HER2.

[0119] Examples of anti-HER2 antibodies include trastuzumab (US Pat. No. 5,821,337) and pertuzumab (WO 01 / 00245), with trastuzumab being preferred.

[0120] In the present invention, the term "anti-HER3 antibody" refers to an antibody that specifically binds to HER3 (Human Epidermal Growth Factor Receptor Type 3; ErbB-3), and preferably has the activity of being internalized into HER3-expressing cells upon binding to HER3.

[0121] Examples of anti-HER3 antibodies include patritumab (U3-1287), U1-59 (WO 2007 / 077028), MM-121 (Seribantumab), the anti-ERBB3 antibodies described in WO 2008 / 100624, RG-7116 (Lumretuzumab), and LJM-716 (Elgemtumab), and preferred examples include patritumab and U1-59.

[0122] In the present invention, the term "anti-TROP2 antibody" refers to an antibody that specifically binds to TROP2 (Tumor-associated calcium signal transducer 2 (TACSTD2); EGP-1), and preferably has the activity of being internalized into TROP2-expressing cells upon binding to TROP2.

[0123] An example of an anti-TROP2 antibody is hTINA1-H1L1 (WO 2015 / 098099).

[0124] In the present invention, the term "anti-B7-H3 antibody" refers to an antibody that specifically binds to B7-H3 (B cell antigen #7 homolog 3; PD-L3; CD276), and preferably has the activity of being internalized into B7-H3-expressing cells upon binding to B7-H3.

[0125] An example of an anti-B7-H3 antibody is M30-H1-L4 (WO 2014 / 057687).

[0126] In the present invention, the term "anti-GPR20 antibody" refers to an antibody that specifically binds to GPR20 (G protein-coupled receptor 20), and preferably has the activity of being internalized into GPR20-expressing cells upon binding to GPR20.

[0127] An example of an anti-GPR20 antibody is h046-H4e / L7 (WO 2018 / 135501).

[0128] In the present invention, the term "anti-CDH6 antibody" refers to an antibody that specifically binds to CDH6 (Cadherin-6), and preferably has the activity of being internalized into CDH6-expressing cells upon binding to CDH6.

[0129] An example of an anti-CDH6 antibody is H01L02 (WO 2018 / 212136).

[0130] 4. Antibody-drug Conjugate Preparation The drug linker intermediate used in the preparation of the antibody-drug conjugates used in the present invention is represented by the following formula:

[0131] [ka]

[0132] The drug linker intermediate shown above is N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]glycylglycyl-L-phenylalanyl-N-[(2-{[(1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4': [6,7]indolizino[1,2-b]quinolin-1-yl]amino}-2-oxoethoxy)methyl]glycinamide, and can be produced with reference to the descriptions in WO 2014 / 057687, WO 2015 / 098099, WO 2015 / 115091, WO 2015 / 155998, WO 2019 / 044947, and the like.

[0133] The antibody-drug conjugate used in the present invention can be produced by reacting the aforementioned drug linker intermediate with an antibody having a thiol group (also called a sulfhydryl group).

[0134] Antibodies having sulfhydryl groups can be obtained by methods well known to those skilled in the art (Hermanson, G. T., Bioconjugate Techniques, pp. 56-136, pp. 456-493, Academic Press (1996)). For example, antibodies having sulfhydryl groups in which intra-chain disulfides have been partially or completely reduced can be obtained by reacting an antibody with a reducing agent such as tris(2-carboxyethyl)phosphine hydrochloride (TCEP) in an amount of 0.3 to 3 molar equivalents per intra-chain disulfide in the antibody in a buffer containing a chelating agent such as ethylenediaminetetraacetic acid (EDTA).

[0135] Furthermore, 2 to 20 molar equivalents of drug linker intermediate can be used per antibody having a sulfhydryl group to produce antibody-drug conjugates with 2 to 8 drugs bound per antibody.

[0136] The average number of drugs bound per antibody molecule in the produced antibody-drug conjugate can be calculated, for example, by a method in which the UV absorbance of the anti-HER2 antibody-drug conjugate and its conjugation precursor is measured at two wavelengths, 280 nm and 370 nm (UV method), or by a method in which the antibody-drug conjugate is treated with a reducing agent, and each of the resulting fragments is quantified by HPLC measurement and then calculated (HPLC method).

[0137] Conjugation of an antibody and a drug linker intermediate, and calculation of the average number of drugs bound per antibody molecule in an antibody-drug conjugate can be carried out with reference to the descriptions in WO 2014 / 057687, WO 2015 / 098099, WO 2015 / 115091, WO 2015 / 155998, WO 2018 / 135501, WO 2018 / 212136, and the like.

[0138] In the present invention, the term "anti-HER2 antibody-drug conjugate" refers to an antibody-drug conjugate according to the present invention in which the antibody is an anti-HER2 antibody.

[0139] The anti-HER2 antibody is preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 of SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 of SEQ ID NO: 2, or an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2.

[0140] The average number of drug linkers bound per antibody in the anti-HER2 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 8, even more preferably 7 to 8, even more preferably 7.5 to 8, and even more preferably about 8.

[0141] Anti-HER2 antibody-drug conjugates can be produced with reference to the descriptions in WO 2015 / 115091 and the like.

[0142] In the present invention, the term "anti-HER3 antibody-drug conjugate" refers to an antibody-drug conjugate according to the present invention in which the antibody is an anti-HER3 antibody.

[0143] The anti-HER3 antibody is preferably an antibody comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence set forth in amino acid numbers 26 to 35 of SEQ ID NO: 3, CDRH2 consisting of the amino acid sequence set forth in amino acid numbers 50 to 65 of SEQ ID NO: 3, and CDRH3 consisting of the amino acid sequence set forth in amino acid numbers 98 to 106 of SEQ ID NO: 3, and a light chain comprising CDRL1 consisting of the amino acid sequence set forth in amino acid numbers 24 to 39 of SEQ ID NO: 4, CDRL2 consisting of the amino acid sequence set forth in amino acid numbers 56 to 62 of SEQ ID NO: 4, and CDRL3 consisting of the amino acid sequence set forth in amino acid numbers 95 to 103 of SEQ ID NO: 4, More preferably, the antibody comprises a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence set forth in amino acid numbers 1 to 117 of SEQ ID NO: 3, and a light chain comprising a light chain variable region consisting of the amino acid sequence set forth in amino acid numbers 1 to 113 of SEQ ID NO: 4, Even more preferably, the antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 4, or an antibody in which the lysine residue at the carboxyl terminus of the heavy chain of the antibody is deleted.

[0144] The average number of drug linkers bound per antibody in the anti-HER3 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 8, even more preferably 7 to 8, even more preferably 7.5 to 8, and even more preferably about 8.

[0145] Anti-HER3 antibody-drug conjugates can be produced with reference to the descriptions in WO 2015 / 155998 and the like.

[0146] In the present invention, the term "anti-TROP2 antibody-drug conjugate" refers to an antibody-drug conjugate according to the present invention in which the antibody is an anti-TROP2 antibody.

[0147] The anti-TROP2 antibody is preferably an antibody comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence set forth in amino acid numbers 50 to 54 of SEQ ID NO: 5, CDRH2 consisting of the amino acid sequence set forth in amino acid numbers 69 to 85 of SEQ ID NO: 5, and CDRH3 consisting of the amino acid sequence set forth in amino acid numbers 118 to 129 of SEQ ID NO: 5, and a light chain comprising CDRL1 consisting of the amino acid sequence set forth in amino acid numbers 44 to 54 of SEQ ID NO: 6, CDRL2 consisting of the amino acid sequence set forth in amino acid numbers 70 to 76 of SEQ ID NO: 6, and CDRL3 consisting of the amino acid sequence set forth in amino acid numbers 109 to 117 of SEQ ID NO: 6, More preferably, the antibody comprises a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence set forth in amino acid numbers 20 to 140 of SEQ ID NO: 5, and a light chain comprising a light chain variable region consisting of the amino acid sequence set forth in amino acid numbers 21 to 129 of SEQ ID NO: 6, Even more preferably, the antibody comprises a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO: 5 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO: 6, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain of the antibody.

[0148] The average number of drug linkers bound per antibody in the anti-TROP2 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 5, even more preferably 3.5 to 4.5, and even more preferably about 4.

[0149] Anti-TROP2 antibody-drug conjugates can be produced with reference to the descriptions in WO 2015 / 098099 and the like.

[0150] In the present invention, the term "anti-B7-H3 antibody-drug conjugate" refers to an antibody-drug conjugate according to the present invention in which the antibody is an anti-B7-H3 antibody.

[0151] The anti-B7-H3 antibody is preferably an antibody comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence set forth in amino acid numbers 50 to 54 of SEQ ID NO: 7, CDRH2 consisting of the amino acid sequence set forth in amino acid numbers 69 to 85 of SEQ ID NO: 7, and CDRH3 consisting of the amino acid sequence set forth in amino acid numbers 118 to 130 of SEQ ID NO: 7, and a light chain comprising CDRL1 consisting of the amino acid sequence set forth in amino acid numbers 44 to 53 of SEQ ID NO: 8, CDRL2 consisting of the amino acid sequence set forth in amino acid numbers 69 to 75 of SEQ ID NO: 8, and CDRL3 consisting of the amino acid sequence set forth in amino acid numbers 108 to 116 of SEQ ID NO: 8; More preferably, the antibody comprises a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence set forth in amino acid numbers 20 to 141 of SEQ ID NO: 7, and a light chain comprising a light chain variable region consisting of the amino acid sequence set forth in amino acid numbers 21 to 128 of SEQ ID NO: 8, Even more preferably, the antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO: 7 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 of SEQ ID NO: 8, or an antibody in which the lysine residue at the carboxyl terminus of the heavy chain of the antibody is deleted.

[0152] The average number of drug linkers bound per antibody in the anti-B7-H3 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 5, even more preferably 3.5 to 4.5, and even more preferably about 4.

[0153] The anti-B7-H3 antibody-drug conjugate used in the present invention can be produced with reference to the descriptions in WO 2014 / 057687 and the like.

[0154] In the present invention, the term "anti-GPR20 antibody-drug conjugate" refers to an antibody-drug conjugate according to the present invention in which the antibody is an anti-GPR20 antibody.

[0155] The anti-GPR20 antibody is preferably an antibody comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence set forth in amino acid numbers 45 to 54 of SEQ ID NO: 9, CDRH2 consisting of the amino acid sequence set forth in amino acid numbers 69 to 78 of SEQ ID NO: 9, and CDRH3 consisting of the amino acid sequence set forth in amino acid numbers 118 to 131 of SEQ ID NO: 9, and a light chain comprising CDRL1 consisting of the amino acid sequence set forth in amino acid numbers 44 to 54 of SEQ ID NO: 10, CDRL2 consisting of the amino acid sequence set forth in amino acid numbers 70 to 76 of SEQ ID NO: 10, and CDRL3 consisting of the amino acid sequence set forth in amino acid numbers 109 to 117 of SEQ ID NO: 10, More preferably, the antibody comprises a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence set forth in amino acid numbers 20 to 142 of SEQ ID NO: 9, and a light chain comprising a light chain variable region consisting of the amino acid sequence set forth in amino acid numbers 21 to 129 of SEQ ID NO: 10, Even more preferably, the antibody comprises a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 472 of SEQ ID NO: 9 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO: 10, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain of the antibody.

[0156] The average number of drug linkers bound per antibody in the anti-GPR20 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 8, even more preferably 7 to 8, even more preferably 7.5 to 8, and even more preferably about 8.

[0157] Anti-GPR20 antibody-drug conjugates can be produced with reference to the descriptions in WO 2018 / 135501 and the like.

[0158] In the present invention, the term "anti-CDH6 antibody-drug conjugate" refers to an antibody-drug conjugate according to the present invention in which the antibody is an anti-CDH6 antibody.

[0159] The anti-CDH6 antibody is preferably an antibody comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence set forth in amino acid numbers 45 to 54 of SEQ ID NO: 11, CDRH2 consisting of the amino acid sequence set forth in amino acid numbers 69 to 78 of SEQ ID NO: 11, and CDRH3 consisting of the amino acid sequence set forth in amino acid numbers 118 to 130 of SEQ ID NO: 11, and a light chain comprising CDRL1 consisting of the amino acid sequence set forth in amino acid numbers 44 to 54 of SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence set forth in amino acid numbers 70 to 76 of SEQ ID NO: 12, and CDRL3 consisting of the amino acid sequence set forth in amino acid numbers 109 to 116 of SEQ ID NO: 12; More preferably, the antibody comprises a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence set forth in amino acid numbers 20 to 141 of SEQ ID NO: 11, and a light chain comprising a light chain variable region consisting of the amino acid sequence set forth in amino acid numbers 21 to 128 of SEQ ID NO: 12, Even more preferably, the antibody comprises a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO: 11 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 of SEQ ID NO: 12, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain of the antibody.

[0160] The average number of drug linkers bound per antibody in an anti-CDH6 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 8, even more preferably 7 to 8, even more preferably 7.5 to 8, and even more preferably about 8.

[0161] Anti-CDH6 antibody-drug conjugates can be produced with reference to the descriptions in WO 2018 / 212136 and the like.

[0162] 5. Therapeutic Agents and / or Treatment Methods The therapeutic agent of the present invention is characterized by containing the antibody-drug conjugate used in the present invention. Furthermore, the therapeutic method of the present invention is characterized by administering the antibody-drug conjugate used in the present invention. These therapeutic agents and therapeutic methods can be used for the treatment of metastatic brain tumors.

[0163] The primary cancer of a metastatic brain tumor for which the therapeutic agent and / or therapeutic method of the present invention can be used is not particularly limited as long as it is a cancer that has the potential to metastasize to the brain, and examples thereof include breast cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, renal cell carcinoma, kidney cancer, colon cancer (sometimes called colorectal cancer, including colon cancer and rectal cancer), gastric cancer (sometimes called gastric adenocarcinoma), head and neck cancer, hepatocellular carcinoma, liver cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, endometrial cancer, thyroid cancer, malignant lymphoma, and sarcoma, and preferred examples include breast cancer, lung cancer, and melanoma, more preferred examples include breast cancer and lung cancer, and even more preferred examples include breast cancer.

[0164] Among the antibody-drug conjugates used in the present invention, the antibody-drug conjugate having a particular antibody that is suitable can be determined by examining the properties of the primary cancer and tumor markers. For example, if the primary cancer is breast cancer or lung cancer and HER2 expression is confirmed, an anti-HER2 antibody-drug conjugate can be preferably used; if HER3 expression is confirmed, an anti-HER3 antibody-drug conjugate can be preferably used; if TROP2 expression is confirmed, an anti-TROP2 antibody-drug conjugate can be preferably used; and if B7-H3 expression is confirmed, an anti-B7-H3 antibody-drug conjugate can be preferably used. Furthermore, if the primary cancer is melanoma and HER3 expression is confirmed, an anti-HER3 antibody-drug conjugate can be preferably used; if TROP2 expression is confirmed, an anti-TROP2 antibody-drug conjugate can be preferably used; and if B7-H3 expression is confirmed, an anti-B7-H3 antibody-drug conjugate can be preferably used. Furthermore, when the primary cancer is renal cancer and CDH6 expression has been confirmed, an anti-CDH6 antibody-drug conjugate can be preferably used.

[0165] The presence or absence of HER2, HER3, TROP2, B7-H3, GPR20, CDH6, and other tumor markers can be confirmed, for example, by collecting tumor tissue from a cancer patient and examining the formalin-fixed, paraffin-embedded (FFPE) specimen at the gene product (protein) level using immunohistochemistry (IHC), flow cytometry, Western blot analysis, etc., or by examining the gene transcription level using in situ hybridization (ISH), quantitative PCR (q-PCR), microarray analysis, etc. Alternatively, cell-free circulating tumor DNA (ctDNA) can be collected from a cancer patient and confirmed by testing using methods such as next-generation sequencing (NGS).

[0166] The therapeutic agent and method of the present invention can be preferably used in mammals, and more preferably in humans.

[0167] The antitumor effect of the therapeutic agent and method of the present invention can be confirmed, for example, by preparing a model in which cancer cells derived from a primary cancer are transfected with a marker gene (e.g., a luciferase gene) and then transplanted into the brain of a test animal, and measuring the life-prolonging effect of administering the therapeutic agent or method of the present invention and the time course of the luminescence intensity of the marker by any imaging method. For example, when cells transfected with a luciferase gene are transplanted, luciferin is administered to examine the luminescence intensity, and if the luminescence intensity is reduced by administering the therapeutic agent or method of the present invention compared to the control, the therapeutic agent or method can be determined to have an antitumor effect.

[0168] The antitumor effects of the therapeutic agents and methods of the present invention can also be confirmed by preparing a model in which a biopsy from a patient with metastatic brain tumor is transplanted into a test animal (e.g., a PDX brain transplant model) and administering the therapeutic agents or methods of the present invention to a patient with metastatic brain tumor. The antitumor effects can be measured, for example, by using CT, PET, and / or MRI to confirm changes in tumor volume before and after administering the therapeutic agents or methods of the present invention.

[0169] Furthermore, the antitumor effect of the therapeutic agent and method of the present invention can be confirmed in clinical trials by the Response Evaluation Criteria in Solid Tumors (RECIST) evaluation method, the WHO evaluation method, the Macdonald evaluation method, body weight measurement, and other methods, and can be determined using indicators such as complete response (CR), partial response (PR), progressive disease (PD), objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS).

[0170] By the above-mentioned method, it is possible to confirm the superiority of the therapeutic agent and method of the present invention in terms of the antitumor effect on metastatic brain tumors over existing anticancer agents.

[0171] The therapeutic agent and method of the present invention not only exhibit antitumor effects against metastatic brain tumors, but also against metastatic cancers other than metastatic brain tumors. Examples of metastatic cancers other than metastatic brain tumors include metastatic bone tumors, metastatic lung tumors, and metastatic liver cancers, with metastatic bone tumors being preferred. Metastatic cancers other than metastatic brain tumors may occur concomitantly with metastatic brain tumors or may develop separately from metastatic brain tumors, but in either case, the therapeutic agent and method of the present invention can exert antitumor effects.

[0172] The therapeutic agents and methods of the present invention can slow the growth of cancer cells, suppress their proliferation, and even destroy them. These actions can relieve cancer patients from cancer-related symptoms and improve their quality of life, thereby achieving therapeutic effects while preserving the lives of cancer patients. Even if cancer cells are not destroyed, the inhibition and control of cancer cell proliferation can enable cancer patients to achieve a higher quality of life and longer survival.

[0173] The therapeutic agent of the present invention can be applied to patients as a systemic therapy, and also can be applied locally to cancer tissues to be expected to have a therapeutic effect.

[0174] The therapeutic agent of the present invention can be administered as a pharmaceutical composition containing one or more pharmaceutically compatible ingredients. The pharmaceutically compatible ingredients can be appropriately selected from formulation additives and other ingredients commonly used in this field depending on the dose and administration concentration of the antibody-drug conjugate used in the present invention. For example, the therapeutic agent of the present invention can be administered as a pharmaceutical composition (hereinafter referred to as the "pharmaceutical composition of the present invention") containing a buffer such as a histidine buffer, an excipient such as sucrose or trehalose, and a surfactant such as polysorbate 80 or 20. The pharmaceutical composition of the present invention can be preferably used as an injection, more preferably as an aqueous injection or a lyophilized injection, and even more preferably as a lyophilized injection.

[0175] When the pharmaceutical composition of the present invention is an aqueous injection, it can be preferably administered intravenously after diluting with an appropriate diluent, such as a glucose solution or saline, preferably a glucose solution, and more preferably a 5% glucose solution.

[0176] When the pharmaceutical composition of the present invention is in the form of a lyophilized injection, it is preferably dissolved in water for injection, diluted with an appropriate diluent at a required amount, and then administered intravenously by infusion. The diluent may include a glucose solution or physiological saline, preferably a glucose solution, and more preferably a 5% glucose solution.

[0177] The pharmaceutical composition of the present invention can be administered via intravenous, intradermal, subcutaneous, intramuscular, or intraperitoneal routes, preferably via intravenous injection. The pharmaceutical composition of the present invention can also be administered via direct injection into the brain parenchyma, pia mater, or arachnoid membrane.

[0178] The antibody-drug conjugate used in the present invention can be administered to humans at intervals of once every 1 to 180 days, preferably once every 1, 2, 3, or 4 weeks, and even more preferably once every 3 weeks. The antibody-drug conjugate used in the present invention can be administered at a single dose of approximately 0.001 to 100 mg / kg, preferably at a single dose of 0.8 to 12.4 mg / kg. When the antibody-drug conjugate used in the present invention is an anti-ER2 antibody-drug conjugate, it can be preferably administered at a dose of 0.8 mg / kg, 1.6 mg / kg, 3.2 mg / kg, 5.4 mg / kg, 6.4 mg / kg, 7.4 mg / kg, or 8 mg / kg per dose, once every three weeks, more preferably at a dose of 5.4, 6.4, or 7.4 mg / kg per dose, once every three weeks, and even more preferably at a dose of 5.4 mg / kg or 6.4 mg / kg per dose, once every three weeks. When the antibody-drug conjugate used in the present invention is an anti-HER3 antibody-drug conjugate, it can be preferably administered at a single dose of 1.6 mg / kg, 3.2 mg / kg, 4.8 mg / kg, 5.6 mg / kg, 6.4 mg / kg, 8.0 mg / kg, 9.6 mg / kg, or 12.8 mg / kg once every three weeks, and more preferably at a single dose of 4.8 mg / kg, 5.6 mg / kg, or 6.4 mg / kg once every three weeks. When the antibody-drug conjugate used in the present invention is an anti-TROP2 antibody-drug conjugate, it can be preferably administered at a single dose of 0.27 mg / kg, 0.5 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 4.0 mg / kg, 6.0 mg / kg, or 8.0 mg / kg once every three weeks, and more preferably at a single dose of 4.0 mg / kg, 6.0 mg / kg, or 8.0 mg / kg once every three weeks.

[0179] The therapeutic agent of the present invention can also be administered in combination with a cancer therapeutic agent other than the antibody-drug conjugate used in the present invention, thereby enhancing the antitumor effect. The other cancer therapeutic agent used for such a purpose may be administered to an individual simultaneously with the therapeutic agent of the present invention, separately, or consecutively, or at different administration intervals.Such cancer therapeutic agents are not limited as long as they have antitumor activity, and examples thereof include irinotecan (CPT-11), cisplatin, carboplatin, oxaliplatin, fluorouracil (5-FU), gemcitabine, capecitabine, paclitaxel, docetaxel, doxorubicin, epirubicin, cyclophosphamide, mitomycin C, and the like. C), Tegafur / Gimeracil / Oteracil combination drug, Cetuximab, Panitumumab, Bevacizumab, Ramucirumab, Regorafenib, Trifluridine / Tipiracil combination drug, Gefitinib, Erlotinib nib, afatinib, methotrexate, pemetrexed, tamoxifen, toremifene, fulvestrant, leuprorelin, goserelin, letrozole, anastrozole, progesterone formulation, trastuzumab emtansine, trastuzumab, pertuzumab, and lapatinib.

[0180] The therapeutic agent of the present invention can also be used in combination with radiation therapy. For example, a cancer patient may receive radiation therapy before and / or after, or simultaneously with, treatment with the therapeutic agent of the present invention. Examples of radiation therapy methods include whole brain radiation therapy (WBRT), stereotactic irradiation (STI), and stereotactic radiosurgery (SRS).

[0181] The therapeutic agent of the present invention can also be used as adjuvant chemotherapy in combination with surgery. Surgery is performed, for example, by physically removing all or part of a brain tumor. The therapeutic agent of the present invention may be administered before surgery to reduce the size of the brain tumor (referred to as preoperative adjuvant chemotherapy or neoadjuvant therapy), or after surgery to prevent the recurrence of the brain tumor (referred to as postoperative adjuvant chemotherapy or adjuvant therapy). [Example]

[0182] The present invention will be specifically described with reference to the following examples, but the present invention is not limited to these examples. Furthermore, these examples should not be construed as limiting in any sense.

[0183] Example 1: Preparation of antibody-drug conjugates According to the production method described in WO 2015 / 115091, a humanized anti-HER2 antibody (an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO: 2) is used, formula

[0184] [ka]

[0185] (wherein A represents the binding site to the antibody) An antibody-drug conjugate (hereinafter referred to as "antibody-drug conjugate (1)") was produced in which an anti-HER2 antibody was linked to a drug linker represented by the formula (I) via a thioether bond. The DAR of antibody-drug conjugate (1) is 7.8.

[0186] Example 2: Life extension study Mice: Five- to six-week-old female BALB / c nude mice (Charles River Japan) were used in the experiment.

[0187] The antibody-drug conjugate (1) was diluted with ABS buffer (10 mM acetate buffer (pH 5.5), 5% sorbitol) and administered into the tail vein at a volume of 10 mL / kg.

[0188] We used KPL-4-Luc, a human breast cancer cell line obtained from Professor Junichi Kurebayashi of Kawasaki Medical School (British Journal of Cancer, (1999) 79 (5 / 6). 707-717) in which the luciferase gene was introduced. KPL-4-Luc was suspended in saline and incubated at 1 × 10 4 KPL-4 cells were intracerebrally transplanted into female nude mice, and 7 days after transplantation, mice were randomly assigned to groups (Day 0). Antibody-drug conjugate (1) was administered intravenously at a dose of 10 mg / kg on Days 0 and 21. Vehicle was administered to the control group. Five mice per group were monitored for survival until Day 28. From an animal ethics perspective, mice were euthanized if they exhibited a 30% or greater weight loss or abnormal behavior (circling, difficulty eating or drinking, etc.). To confirm tumor localization and tumor burden using KPL-4-Luc luciferase activity, luciferin was administered intraperitoneally to each mouse on Days 14, 21, and 28, and luminescence in the head was measured using an In Vivo Imaging System (IVIS). A vehicle-treated group (2 mice) was also included. On Day 14, formalin-fixed, paraffin-embedded sections of the mouse heads were prepared and stained with hematoxylin and eosin.

[0189] The results are shown in Figures 9 to 11. Deaths were observed in the control group from Day 14 onwards, and all died by Day 26. In contrast, all mice in the antibody-drug conjugate (1)-administered group survived until Day 28 (Figure 9). In the KPL-4-Luc luminescence assay, tumor growth was observed in the antibody-drug conjugate (1)-administered group until Day 21, but luminescence attenuated on Day 28, one week after the second administration, suggesting that antibody-drug conjugate (1) was effective against intracerebral tumors (Figure 10). Pathological examination of the brain on Day 14 revealed tumor masses around the olfactory bulb, nasal turbinates, cerebral parenchyma, base of the brain, ventricles, and around the cerebellum in 2 / 2 mice (Figure 11).

[0190] These results suggest that antibody-drug conjugate (1) is effective against metastatic brain tumors and has a survival benefit. [Sequence List Free Text]

[0191] SEQ ID NO: 1: Amino acid sequence of the anti-HER2 antibody heavy chain SEQ ID NO: 2: Amino acid sequence of the anti-HER2 antibody light chain SEQ ID NO: 3: Amino acid sequence of the anti-HER3 antibody heavy chain SEQ ID NO: 4: Amino acid sequence of the anti-HER3 antibody light chain SEQ ID NO: 5: Amino acid sequence of the anti-TROP2 antibody heavy chain SEQ ID NO: 6: Amino acid sequence of the anti-TROP2 antibody light chain SEQ ID NO: 7: Amino acid sequence of the anti-B7-H3 antibody heavy chain SEQ ID NO: 8: Amino acid sequence of the anti-B7-H3 antibody light chain SEQ ID NO: 9: Amino acid sequence of the anti-GPR20 antibody heavy chain SEQ ID NO: 10: Amino acid sequence of the anti-GPR20 antibody light chain SEQ ID NO: 11: Amino acid sequence of the anti-CDH6 antibody heavy chain SEQ ID NO: 12: Amino acid sequence of the anti-CDH6 antibody light chain

Claims

1. formula 【Chemistry 1】 (wherein A represents the binding site to the antibody) and an antibody-drug conjugate, as an active ingredient, in which the antibody is bound to a drug linker represented by the formula: the antibody in the antibody-drug conjugate is an anti-TROP2 antibody; A treatment for metastatic brain tumors.

2. 2. The therapeutic agent according to claim 1, wherein the primary cancer of the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer, melanoma, renal cell carcinoma, kidney cancer, colon cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, liver cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, endometrial cancer, thyroid cancer, malignant lymphoma, and sarcoma.

3. The method of claim 1, wherein the primary cancer of the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer, and melanoma.

4. The therapeutic agent according to claim 1, wherein the primary cancer of the metastatic brain tumor is breast cancer.

5. The therapeutic agent according to claim 1, wherein the primary cancer of the metastatic brain tumor is lung cancer.

6. The therapeutic agent according to claim 5, wherein the primary cancer of the metastatic brain tumor is non-small cell lung cancer.

7. The therapeutic agent according to any one of claims 1 to 6, wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO: 5 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO:

6.

8. The therapeutic agent according to claim 7, wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-TROP2 antibody is deleted.

9. The therapeutic agent according to any one of claims 1 to 8, wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

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