Treatment of metastatic brain tumor by administration of antibody-drug conjugate

Abstract

To provide a therapeutic agent for metastatic brain tumor.SOLUTION: A therapeutic agent for metastatic brain tumor, comprising, as an active ingredient, an antibody-drug conjugate in which a drug linker represented by the following formula (wherein A represents a binding site to an antibody) is bound to an antibody via a thioether bond, and / or a method for treating metastatic brain tumor, comprising administering the antibody-drug conjugate to an individual in need of treatment of 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 or a method for treating metastatic brain tumors, characterized by administering a specific antibody-drug conjugate to an individual. This invention relates to a method of treating [Background technology]

[0002] Metastatic brain tumors are diseases that occur when primary cancer metastasizes to the brain. It is known that this occurs in 20-40% of cases. Cancer metastasis to the brain has a significant impact on prognosis. Not only does this cause serious problems, but it also leads to a significant decline in quality of life. There is a need for further development (Non-patent documents 1 and 2).

[0003] Primary cancers of metastatic brain tumors include lung cancer, breast cancer, melanoma, renal cell carcinoma, and kidney cancer , colon cancer, stomach cancer, head and neck cancer, hepatocellular carcinoma, liver cancer, ovarian cancer, prostate cancer, bladder cancer Cancer, pancreatic cancer, endometrial cancer, thyroid cancer, malignant lymphoma, and sarcoma are some of the cancers that can be seen. Among these, metastatic brain tumors caused by primary cancers such as lung cancer, breast cancer, and melanoma are particularly It is known that a high proportion of patients with rheumatoid arthritis have tumors (Non-Patent Documents 1 and 2).

[0004] As a treatment for metastatic brain tumors from primary lung cancer, epidermal growth factor receptor (EGFR) ) Gefitinib, a tyrosine kinase inhibitor (Non-Patent Document 3) , erlotinib (Non-Patent Document 4), afatinib ib) (Non-Patent Document 5), and osimertinib (Non-Patent Document 6) and the ALK inhibitor crizotinib (Non-patent Document 7), etc. Clinical studies using this method are known.

[0005] Trastuzumab, an anti-HER2 antibody, is used to treat metastatic brain tumors from primary breast cancer. Trastuzumab (Non-patent Document 8) and human epidermal growth factor receptor 2 (H Lapatinib, a tyrosine kinase inhibitor (ER2) (non-patent literature 9) and other clinical studies are known.

[0006] For the treatment of metastatic brain tumors from primary melanoma, the BRAF inhibitor BEMT is used. Clinical studies using rafenib (Vemurafenib) (Non-patent Document 10) and the like are known. are.

[0007] However, such drug therapy has not been established as a standard treatment, and radiation therapy and surgery are not yet available. Law is considered the first option.

[0008] Antibodies that bind to antigens expressed on the surface of cancer cells and can be internalized into the cells are used to treat cancer. Antibody-drug conjugates (Antibody-Drug Conjugates) ADCs (anti-cancer drug delivery systems) are effective in treating cancer by selectively delivering drugs to cancer cells. It is expected that drugs will accumulate inside cells and kill cancer cells (Non-Patent Documents 11-1 5).

[0009] One example of an antibody-drug conjugate is a conjugate of an antibody and a topoisomerase I inhibitor. Antibody-drug conjugates containing derivatives of exatecan as building blocks are known (Patent These antibody-drug conjugates have excellent anti- Because it has antitumor effects and is safe, clinical trials are currently underway.

[0010] Antibody-drug conjugates for the treatment of metastatic brain tumors include tubulin inhibitors. Trastuzumab, an anti-HER2 antibody-drug conjugate comprising DM1, Trastuzumab emtansine is a treatment for breast cancer Preclinical and clinical studies are known regarding the treatment of metastatic brain tumors caused by cancer (non-patented References 20-23). [Prior art documents] [Patent documents]

[0011] [Patent Document 1] International Publication No. 2014 / 057687 [Patent Document 2] International Publication No. 2015 / 098099 [Patent Document 3] International Publication No. 2015 / 115091 [Patent Document 4] International Publication No. 2015 / 155998 [Patent Document 5] International Publication No. 2018 / 066626 [Non-patent literature]

[0012] [Non-Patent Document 1] Lorenzo R., et al., Ther Adv Med Oncol. 2017 Dec; 9(12): 781-796. [Non-patent document 2] Rahmathulla G., et al., Journal of Oncology 2012, Article ID 723541. [Non-patent document 3] Kim JE., et al., Lung Cancer 2009; 65: 351-354. [Non-patent document 4] Iuchi T., et al., Cancer 2013; 82: 282-287.

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

[0013] Low molecular weight compounds and antibodies are used as cancer treatment drugs, but these usually penetrate the blood and brain. It is difficult to cross the blood-brain barrier (BBB) In particular, antibodies have a very large molecular weight, so it is almost impossible to expect them to pass through the blood-brain barrier. (Bendell JC., et al., Cancer 2003;97(12):2972-7). On the other hand, metastatic brain tumors There have also been reports that antibodies administered intravenously for the treatment of tumors have crossed the blood-brain barrier (Tamu ra K., et al., J. Nucl. Med. 2013;54(11):1869-75). The reason for this is that brain metastasis This is thought to be because the blood-brain barrier was destroyed by the tumor, which relatively increased the ability of the antibody to penetrate into the brain. It is thought that...

[0014] However, even when the brain concentrations of low-molecular-weight compounds or antibodies are at a considerable level, There are also reports that the expected therapeutic effect was not achieved. Drug resistance (e.g., genetic mutations affecting downstream signaling or drug excretion mechanisms such as P-glycoprotein) This is thought to be due to the acquisition of a specific structure (Saunus JM., et al., J. Pathol. 2015;237:36 3-78, Brastianos PK., et al., Cancer Discov. 2015;5:1164-77).

[0015] In addition, a blood-tumor barrier (BTB) was established between the metastatic tumor and normal tissue in the brain. It is also known that the formation of a barrier to the blood vessels (BTB) leads to drug resistance (Quai l DF. et al., Cancer Cell 2017;31:326-41).

[0016] The present invention provides specific antibody-drug conjugates that contain derivatives of exatecan. Whether or not the compound crosses the blood-brain barrier and whether or not it exerts the desired anti-tumor effect on metastatic brain tumors that have acquired drug resistance. The objective of the present invention is to verify whether the antibody-drug conjugate exhibits antitumor effects. and / or administering the antibody-drug conjugate to an individual. The present invention aims to provide a method for treating metastatic brain tumors, which is characterized by: [Means for solving the problem]

[0017] The present inventors have conducted extensive research to solve the above problems, and have discovered a derivative of exatecan. A specific antibody-drug conjugate comprising the above component has demonstrated excellent antitumor activity against metastatic brain tumors. The present invention was completed based on the discovery that the anti-tumor effect of the present invention is also exhibited.

[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 in which the antibody is bound to a drug linker represented by the formula: A therapeutic agent for metastatic brain tumors containing jugate as an active ingredient. [2] Primary cancers of metastatic brain tumors include breast cancer, lung cancer, melanoma, renal cell carcinoma, kidney cancer, and large intestine cancer. Intestinal cancer, stomach 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. The therapeutic agent according to [1], wherein the therapeutic agent is at least one of the following: [3] The primary cancer of the metastatic brain tumor is selected from the group consisting of breast cancer, lung cancer, and melanoma. The therapeutic agent according to [1], wherein the therapeutic agent is at least one of the following: [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 antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TR antibody, or OP2 antibody, anti-B7-H3 antibody, anti-GPR20 antibody, or anti-CDH6 antibody.[1] A therapeutic agent according to any one of [6] to [6]. [8] The therapeutic agent according to [7], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody. Therapeutic agent. [9] The anti-HER2 antibody comprises an amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1. a heavy chain consisting of a sequence of amino acids 1 to 214 in SEQ ID NO: 2; The therapeutic agent according to [8], wherein the antibody comprises a light chain consisting of:

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

[0021]

[11] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to The therapeutic agent according to any one of [8] to

[10] , wherein the number of the active ingredients is in the range of 8.

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

[13] The anti-HER3 antibody comprises a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 3 and a The therapeutic agent according to

[12] , which is an antibody comprising a light chain having the amino acid sequence described above.

[14] The anti-HER3 antibody lacks the lysine residue at the carboxyl terminus of the heavy chain, as described in

[13] . Therapeutic agents listed above.

[15] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to The therapeutic agent according to any one of

[12] to

[14] , wherein the number of the active ingredient is in the range of 8.

[16] [7] The antibody in the antibody-drug conjugate is an anti-TROP2 antibody. Therapeutic agent.

[17] The anti-TROP2 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO:5. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 6; The therapeutic agent according to

[16] , which is an antibody comprising a light chain consisting of an amino acid sequence.

[18] The anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain

[17] . The therapeutic agent described.

[19] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5 The therapeutic agent according to any one of

[16] to

[18] , wherein the range is from 1 to 4.5.

[20] [7] The antibody in the antibody-drug conjugate is an anti-B7-H3 antibody. Therapeutic agent.

[0022] [twenty one] The anti-B7-H3 antibody is selected from the group consisting of amino acids 20 to 471 in SEQ ID NO:7. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 8; The therapeutic agent according to

[20] , which is an antibody comprising a light chain consisting of an amino acid sequence. [twenty two] The anti-B7-H3 antibody lacks the lysine residue at the carboxyl terminus of the heavy chain

[21] . The therapeutic agent described. [twenty three] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5 The therapeutic agent according to any one of

[20] to

[22] , wherein the number of serotonin receptors is in the range of 1 to 4.5. [twenty four] [7] The antibody in the antibody-drug conjugate is an anti-GPR20 antibody. Therapeutic agent. [twenty five] The anti-GPR20 antibody is a polypeptide comprising the amino acids 20 to 472 of SEQ ID NO: 9. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 10; The therapeutic agent according to

[24] , which is an antibody comprising a light chain consisting of an amino acid sequence.

[26] The anti-GPR20 antibody lacks the lysine residue at the carboxyl terminus of the heavy chain

[25] . The therapeutic agent described.

[27] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to The therapeutic agent according to any one of

[24] to

[26] , wherein the number of the active ingredient is in the range of 8.

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

[29] The anti-CDH6 antibody is a nucleotide sequence selected from the group consisting of amino acids 20 to 471 in SEQ ID NO: 11. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 12; The therapeutic agent according to

[28] , which is an antibody comprising a light chain consisting of an amino acid sequence.

[30] The anti-CDH6 antibody lacks the lysine residue at the carboxyl terminus of the heavy chain, as described in

[29] . Therapeutic agents listed above.

[0023]

[31] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to The therapeutic agent according to any one of

[28] to

[30] , wherein the number of the active ingredients is in the range of 8.

[32] formula

[0024] [ka]

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

[33] Primary cancers of metastatic brain tumors include breast cancer, lung cancer, melanoma, renal cell carcinoma, kidney cancer, and large intestine cancer. Intestinal cancer, stomach 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. The therapeutic agent according to

[32] , wherein the therapeutic agent is at least one of the following:

[34] The primary cancer of the metastatic brain tumor is selected from the group consisting of breast cancer, lung cancer, and melanoma. The therapeutic agent according to

[32] , wherein the therapeutic agent comprises at least one of the following:

[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 antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TR antibody, or The therapeutic agent according to any one of

[0032] to

[37] , which is an OP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[39]

[38] The antibody in the antibody-drug conjugate is an anti-HER2 antibody. Therapeutic agent.

[40] The anti-HER2 antibody comprises an amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1. a heavy chain consisting of a sequence of amino acids 1 to 214 in SEQ ID NO: 2; The therapeutic agent according to

[39] , wherein the antibody comprises a light chain consisting of:

[0026]

[41] The anti-HER2 antibody comprises a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a The therapeutic agent according to

[39] , which is an antibody comprising a light chain having the amino acid sequence described above.

[42] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to The therapeutic agent according to any one of

[39] to

[41] , wherein the number of the active ingredient is in the range of 8.

[43]

[38] The antibody in the antibody-drug conjugate is an anti-HER3 antibody. Therapeutic agent.

[44] The anti-HER3 antibody comprises a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 3 and a The therapeutic agent according to

[43] , which is an antibody comprising a light chain consisting of the amino acid sequence described above.

[45] The anti-HER3 antibody lacks the lysine residue at the carboxyl terminus of the heavy chain, as described in

[44] . Therapeutic agents listed above.

[46] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to The therapeutic agent according to any one of

[43] to

[45] , wherein the number of the active ingredient is in the range of 8.

[47]

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

[48] The anti-TROP2 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO:5. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 6; The therapeutic agent according to

[47] , which is an antibody comprising a light chain consisting of an amino acid sequence.

[49] The anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain

[48] . The therapeutic agent described.

[50] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5 The therapeutic agent according to any one of

[47] to

[49] , wherein the number of serotonin receptors is in the range of 1 to 4.5.

[0027]

[51]

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

[52] The anti-B7-H3 antibody is selected from the group consisting of amino acids 20 to 471 in SEQ ID NO:7. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 8; The therapeutic agent according to

[51] , which is an antibody comprising a light chain consisting of an amino acid sequence.

[53] The anti-B7-H3 antibody lacks the lysine residue at the carboxyl terminus of the heavy chain

[52] . The therapeutic agent described.

[54] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5 The therapeutic agent according to any one of

[51] to

[53] , wherein the range is from 1 to 4.5.

[55]

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

[56] The anti-GPR20 antibody is a polypeptide comprising the amino acids 20 to 472 of SEQ ID NO: 9. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 10; The therapeutic agent according to

[55] , which is an antibody comprising a light chain consisting of an amino acid sequence.

[57] The anti-GPR20 antibody lacks the lysine residue at the carboxyl terminus of the heavy chain

[56] . The therapeutic agent described.

[58] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to The therapeutic agent according to any one of

[55] to

[57] , wherein the number of the active ingredients is in the range of 8.

[59]

[38] The antibody in the antibody-drug conjugate is an anti-CDH6 antibody. Therapeutic agent.

[60] The anti-CDH6 antibody is a nucleotide sequence selected from the group consisting of amino acids 20 to 471 in SEQ ID NO: 11. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 12; The therapeutic agent according to

[59] , which is an antibody comprising a light chain consisting of an amino acid sequence.

[0028]

[61] The anti-CDH6 antibody lacks the lysine residue at the carboxyl terminus of the heavy chain, as described in

[60] . Therapeutic agents listed above.

[62] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to The therapeutic agent according to any one of

[59] to

[61] , wherein the number of the active ingredients is in the range of 8.

[63] formula

[0029] [ka]

[0030] (wherein A represents the binding site to the antibody) and an antibody-drug conjugate in which the antibody is bound to a drug linker represented by the formula: 2. A method for treating metastatic brain tumors, comprising administering a medicament to an individual in need thereof. Brain tumor treatment methods.

[64] Primary cancers of metastatic brain tumors include breast cancer, lung cancer, melanoma, renal cell carcinoma, kidney cancer, and large intestine cancer. Intestinal cancer, stomach 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. The method for treatment according to

[63] , wherein the method comprises at least one of the following:

[65] The primary cancer of the metastatic brain tumor is selected from the group consisting of breast cancer, lung cancer, and melanoma. The method for treatment according to

[63] , wherein the method comprises at least one of the following:

[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 antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TR antibody, or The therapeutic method according to any one of

[0063] to

[68] , wherein the antibody is an OP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[70]

[69] The antibody in the antibody-drug conjugate is an anti-HER2 antibody. Treatment method.

[0031]

[71] The anti-HER2 antibody comprises an amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1. a heavy chain consisting of a sequence of amino acids 1 to 214 in SEQ ID NO: 2; The therapeutic method according to

[70] , wherein the antibody comprises a light chain consisting of:

[72] The anti-HER2 antibody comprises a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a The therapeutic method according to

[70] , wherein the antibody comprises a light chain having the amino acid sequence described above.

[73] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to The method for treatment according to any one of

[70] to

[72] , wherein the number of the active ingredients is in the range of 8.

[74]

[69] The antibody in the antibody-drug conjugate is an anti-HER3 antibody. Treatment method.

[75] The anti-HER3 antibody comprises a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 3 and a The therapeutic method according to

[74] , wherein the antibody comprises a light chain having the amino acid sequence described above.

[76] The anti-HER3 antibody lacks the lysine residue at the carboxyl terminus of the heavy chain, as described in

[75] . The treatment methods listed above.

[77] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to The method for treatment according to any one of

[74] to

[76] , wherein the number of the active ingredients is in the range of 8.

[78]

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

[79] The anti-TROP2 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO:5. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 6; The therapeutic method according to

[78] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[80] The anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain

[79] . The described method of treatment.

[0032]

[81] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5 The method of any one of

[78] to

[80] , wherein the number of serotonin receptors is in the range of 1 to 4.5.

[82]

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

[83] The anti-B7-H3 antibody is selected from the group consisting of amino acids 20 to 471 in SEQ ID NO:7. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 8; The therapeutic method according to

[82] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[84] The anti-B7-H3 antibody lacks the lysine residue at the carboxyl terminus of the heavy chain

[83] . The described method of treatment.

[85] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5 The method of any one of

[82] to

[84] , wherein the number of serotonin receptors is in the range of 1 to 4.5.

[86]

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

[87] The anti-GPR20 antibody is a polypeptide comprising the amino acids 20 to 472 of SEQ ID NO: 9. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 10; The therapeutic method according to

[86] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[88] The anti-GPR20 antibody lacks the lysine residue at the carboxyl terminus of the heavy chain

[87] . The described method of treatment.

[89] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to A treatment method according to any one of

[86] to

[88] , wherein the number of the active ingredients is in the range of 8.

[90]

[69] The antibody in the antibody-drug conjugate is an anti-CDH6 antibody. Treatment method.

[0033]

[91] The anti-CDH6 antibody is a nucleotide sequence selected from the group consisting of amino acids 20 to 471 in SEQ ID NO: 11. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 12; The therapeutic method according to

[90] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[92] The anti-CDH6 antibody lacks the lysine residue at the carboxyl terminus of the heavy chain, as described in

[91] . The treatment methods listed above.

[93] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to A treatment method according to any one of

[90] to

[92] , wherein the number of the active ingredients is in the range of 8.

[94] formula

[0034] [ka]

[0035] (wherein the formula, the drug linker is bonded to the antibody via a thioether bond, and n is the number of antibodies per (The average number of drug linkers per to an individual in need of treatment for metastatic brain tumors. A method for treating metastatic brain tumors, comprising:

[95] Primary cancers of metastatic brain tumors include breast cancer, lung cancer, melanoma, renal cell carcinoma, kidney cancer, and large intestine cancer. Intestinal cancer, stomach 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. The method for treatment according to

[94] , wherein the method comprises at least one of the following:

[96] The primary cancer of the metastatic brain tumor is selected from the group consisting of breast cancer, lung cancer, and melanoma. The method for treatment according to

[94] , wherein the method comprises at least one of the following:

[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 antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TR antibody, or The therapeutic method according to any one of

[0094] to

[99] , wherein the antibody is an OP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[0036]

[0101]

[0100] The antibody in the antibody-drug conjugate is an anti-HER2 antibody. Treatment methods.

[0102] The anti-HER2 antibody comprises an amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1. a heavy chain consisting of a sequence of amino acids 1 to 214 in SEQ ID NO: 2; A therapeutic method described in

[0101] , wherein the antibody comprises a light chain consisting of:

[0103] The anti-HER2 antibody comprises a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a A therapeutic method described in

[0101] , wherein the antibody comprises a light chain having the amino acid sequence described above.

[0104] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to A treatment method described in any one of

[0101] to

[0103] , wherein the number of the active ingredient is in the range of 8.

[0105]

[0100] The antibody in the antibody-drug conjugate is an anti-HER3 antibody. Treatment methods.

[0106] The anti-HER3 antibody comprises a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 3 and a A therapeutic method described in

[0105] , wherein the antibody comprises a light chain having the amino acid sequence described above.

[0107] The anti-HER3 antibody lacks the lysine residue at the carboxyl terminus of the heavy chain. The described method of treatment.

[0108] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to A treatment method described in any one of

[0105] to

[0107] , wherein the number of patients is in the range of 8.

[0109]

[0100] wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody. The treatment methods listed above.

[0110] The anti-TROP2 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO:5. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 6; A therapeutic method described in

[0109] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[0037]

[0111] The anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain. The treatment method described above.

[0112] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5

[0109] to

[0111] , wherein the range is from 1 to 4.5. .

[0113]

[0100] wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody. The treatment methods listed above.

[0114] The anti-B7-H3 antibody is selected from the group consisting of amino acids 20 to 471 in SEQ ID NO:7. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 8; A therapeutic method described in

[0113] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[0115] The anti-B7-H3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain. The treatment method described above.

[0116] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5

[0113] to

[0115] , wherein the range is from 1 to 4.5. .

[0117]

[0100] wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody. The treatment methods listed above.

[0118] The anti-GPR20 antibody is a polypeptide comprising the amino acids 20 to 472 of SEQ ID NO: 9. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 10; A therapeutic method described in

[0117] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[0119] An anti-GPR20 antibody lacking a lysine residue at the carboxyl terminus of the heavy chain. The treatment method described above.

[0120] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to A treatment method described in any one of

[0117] to

[0119] , in which the number is in the range of 8.

[0038]

[0121]

[0100] The antibody in the antibody-drug conjugate is an anti-CDH6 antibody. Treatment methods.

[0122] The anti-CDH6 antibody is a nucleotide sequence selected from the group consisting of amino acids 20 to 471 in SEQ ID NO: 11. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 12; A therapeutic method described in

[0121] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[0123] The anti-CDH6 antibody lacks the lysine residue at the carboxyl terminus of the heavy chain. The described method of treatment.

[0124] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to A treatment method described in any one of

[0121] to

[0123] , in which the range is 8.

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

[0039] [ka]

[0040] (wherein A represents the binding site to the antibody) and an antibody-drug conjugate in which the antibody is bound to a drug linker represented by the formula: Jugate.

[0126] Primary cancers of metastatic brain tumors include breast cancer, lung cancer, melanoma, renal cell carcinoma, kidney cancer, and large intestine cancer. Intestinal cancer, stomach 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. The antibody-drug conjugate described in

[0125] is at least one of the following.

[0127] The primary cancer of the metastatic brain tumor is selected from the group consisting of breast cancer, lung cancer, and melanoma. An antibody-drug conjugate according to

[0125] , which is at least one of the following:

[0128] The antibody-drug conjugate according to

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

[0129] The antibody-drug conjugate according to

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

[0130] The antibody-drug conjugate according to

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

[0041]

[0131] The antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TR antibody, or An antibody-drug conjugate described in any one of

[0125] to

[0130] , which is an OP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[0132]

[0131] The antibody in the antibody-drug conjugate is an anti-HER2 antibody. Antibody-drug conjugates.

[0133] The anti-HER2 antibody comprises an amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1. a heavy chain consisting of a sequence of amino acids 1 to 214 in SEQ ID NO: 2; An antibody-drug conjugate according to

[0132] , which is an antibody comprising a light chain consisting of:

[0134] The anti-HER2 antibody comprises a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a The antibody-drug according to

[0132] , which is an antibody comprising a light chain having the amino acid sequence described above. Conjugates.

[0135] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to 8. The antibody-drug conjugate according to any one of

[0132] to

[0134] , gate.

[0136]

[0131] The antibody in the antibody-drug conjugate is an anti-HER3 antibody. Antibody-drug conjugates.

[0137] The anti-HER3 antibody comprises a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 3 and a The antibody-drug according to

[0136] , which is an antibody comprising a light chain having the amino acid sequence described above. Conjugates.

[0138] The anti-HER3 antibody lacks the lysine residue at the carboxyl terminus of the heavy chain. 1. The antibody-drug conjugate described herein.

[0139] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to 8. The antibody-drug conjugate according to any one of

[0136] to

[0138] , gate.

[0140]

[0131] wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody. The antibody-drug conjugates described above.

[0042]

[0141] The anti-TROP2 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO:5. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 6; The antibody-drug conjugate according to

[0140] , which is an antibody comprising a light chain consisting of an amino acid sequence. Route.

[0142] The anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain. The antibody-drug conjugate according to claim 1.

[0143] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5

[0140] to

[0142] , wherein the antibody-drug of any one of

[0140] to

[0142] has a molecular weight in the range of 1 to 4.5. Object conjugates.

[0144]

[0131] wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody. The antibody-drug conjugates described above.

[0145] The anti-B7-H3 antibody is selected from the group consisting of amino acids 20 to 471 in SEQ ID NO:7. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 8; The antibody-drug conjugate according to

[0144] , which is an antibody comprising a light chain consisting of an amino acid sequence. Route.

[0146] The anti-B7-H3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain. The antibody-drug conjugate according to claim 1.

[0147] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5

[0144] to

[0146] , wherein the antibody-drug of any one of

[0144] to

[0146] has a molecular weight in the range of 1 to 4.5. Object conjugates.

[0148]

[0131] wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody. The antibody-drug conjugates described above.

[0149] The anti-GPR20 antibody is a polypeptide comprising the amino acids 20 to 472 of SEQ ID NO: 9. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 10; The antibody-drug conjugate according to

[0148] , which is an antibody comprising a light chain consisting of the amino acid sequence gate.

[0150] An anti-GPR20 antibody lacking a lysine residue at the carboxyl terminus of the heavy chain. The antibody-drug conjugate according to claim 1.

[0043]

[0151] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to 8. The antibody-drug conjugate according to any one of

[0148] to

[0150] , ugate.

[0152]

[0131] The antibody in the antibody-drug conjugate is an anti-CDH6 antibody. Antibody-drug conjugates.

[0153] The anti-CDH6 antibody is a nucleotide sequence selected from the group consisting of amino acids 20 to 471 in SEQ ID NO: 11. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 12; The antibody-drug conjugate according to

[0152] , which is an antibody comprising a light chain consisting of the amino acid sequence gate.

[0154] The anti-CDH6 antibody lacks the lysine residue at the carboxyl terminus of the heavy chain. 1. The antibody-drug conjugate described herein.

[0155] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to 8. The antibody-drug conjugate according to any one of

[0152] to

[0154] , ugate.

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

[0044] [ka]

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

[0157] Primary cancers of metastatic brain tumors include breast cancer, lung cancer, melanoma, renal cell carcinoma, kidney cancer, and large intestine cancer. Intestinal cancer, stomach 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. The antibody-drug conjugate described in

[0156] , which is at least one of the following:

[0158] The primary cancer of the metastatic brain tumor is selected from the group consisting of breast cancer, lung cancer, and melanoma. An antibody-drug conjugate according to

[0156] , which is at least one of the following:

[0159] The antibody-drug conjugate according to

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

[0160] The antibody-drug conjugate according to

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

[0046]

[0161] The antibody-drug conjugate according to

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

[0162] The antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TR antibody, or An antibody-drug conjugate described in any one of

[0156] to

[0161] , which is an OP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[0163]

[0162] The antibody in the antibody-drug conjugate is an anti-HER2 antibody. Antibody-drug conjugates.

[0164] The anti-HER2 antibody comprises an amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1. a heavy chain consisting of a sequence of amino acids 1 to 214 in SEQ ID NO: 2; An antibody-drug conjugate according to

[0163] , which is an antibody comprising a light chain consisting of:

[0165] The anti-HER2 antibody comprises a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a The antibody-drug described in

[0163] is an antibody comprising a light chain having the amino acid sequence described above. Conjugates.

[0166] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to 8. The antibody-drug conjugate according to any one of

[0163] to

[0165] , gate.

[0167]

[0162] The antibody in the antibody-drug conjugate is an anti-HER3 antibody. Antibody-drug conjugates.

[0168] The anti-HER3 antibody comprises a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 3 and a The antibody-drug of

[0167] is an antibody comprising a light chain having the amino acid sequence described above. Conjugates.

[0169] The anti-HER3 antibody lacks the lysine residue at the carboxyl terminus of the heavy chain. 1. The antibody-drug conjugate described herein.

[0170] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to 8. The antibody-drug conjugate according to any one of

[0167] to

[0169] . gate.

[0047]

[0171]

[0162] wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody. The antibody-drug conjugates described above.

[0172] The anti-TROP2 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO:5. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 6; The antibody-drug conjugate according to

[0171] , which is an antibody comprising a light chain consisting of an amino acid sequence. Route.

[0173] An anti-TROP2 antibody lacking a lysine residue at the carboxyl terminus of the heavy chain. The antibody-drug conjugate according to claim 1.

[0174] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5

[0171] to

[0173] , wherein the antibody-drug of any one of

[0171] to

[0173] is in the range of 4.5 to 4.5. Object conjugates.

[0175]

[0162] wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody. The antibody-drug conjugates described above.

[0176] The anti-B7-H3 antibody is selected from the group consisting of amino acids 20 to 471 in SEQ ID NO:7. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 8; The antibody-drug conjugate according to

[0175] , which is an antibody comprising a light chain consisting of an amino acid sequence. Route.

[0177] The anti-B7-H3 antibody lacks the lysine residue at the carboxyl terminus of the heavy chain. The antibody-drug conjugate according to claim 1.

[0178] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5

[0175] to

[0177] , wherein the antibody-drug of any one of

[0175] to

[0177] is in the range of 4.5 to 4.5. Object conjugates.

[0179]

[0162] wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody. The antibody-drug conjugates described above.

[0180] The anti-GPR20 antibody is a polypeptide comprising the amino acids 20 to 472 of SEQ ID NO: 9. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 10; The antibody-drug conjugate according to

[0179] , which is an antibody comprising a light chain consisting of the amino acid sequence gate.

[0048]

[0181] An anti-GPR20 antibody lacking a lysine residue at the carboxyl terminus of the heavy chain. The antibody-drug conjugate according to claim 1.

[0182] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to 8. The antibody-drug conjugate according to any one of

[0179] to

[0181] , ugate.

[0183]

[0162] The antibody in the antibody-drug conjugate is an anti-CDH6 antibody. Antibody-drug conjugates.

[0184] The anti-CDH6 antibody is a nucleotide sequence selected from the group consisting of amino acids 20 to 471 in SEQ ID NO: 11. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 12; The antibody-drug conjugate according to

[0183] , which is an antibody comprising a light chain consisting of the amino acid sequence gate.

[0185] The anti-CDH6 antibody lacks the lysine residue at the carboxyl terminus of the heavy chain. 1. The antibody-drug conjugate described herein.

[0186] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to 8. The antibody-drug conjugate according to any one of

[0183] to

[0185] , ugate.

[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 antibody is bound to a drug linker represented by the formula: Use of Jugate.

[0188] Primary cancers of metastatic brain tumors include breast cancer, lung cancer, melanoma, renal cell carcinoma, kidney cancer, and large intestine cancer. Intestinal cancer, stomach 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. The use described in

[0187] , wherein the use is at least one of the following:

[0189] The primary cancer of the metastatic brain tumor is selected from the group consisting of breast cancer, lung cancer, and melanoma. The use described in

[0187] , wherein the use is at least one of the following:

[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 antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TR antibody, or The use described in any one of

[0187] to

[0192] , wherein the antibody is an OP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[0194]

[0193] The antibody in the antibody-drug conjugate is an anti-HER2 antibody. Use of.

[0195] The anti-HER2 antibody comprises an amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1. a heavy chain consisting of a sequence of amino acids 1 to 214 in SEQ ID NO: 2; The use described in

[0194] , wherein the antibody comprises a light chain consisting of:

[0196] The anti-HER2 antibody comprises a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a The use described in

[0194] , wherein the antibody comprises a light chain having the amino acid sequence described above.

[0197] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to The use described in any one of

[0194] to

[0196] , which is in the range of 8.

[0198]

[0193] The antibody in the antibody-drug conjugate is an anti-HER3 antibody. Use of.

[0199] The anti-HER3 antibody comprises a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 3 and a The use described in

[0198] , wherein the antibody comprises a light chain having the amino acid sequence described above.

[0200] The anti-HER3 antibody lacks the lysine residue at the carboxyl terminus of the heavy chain. Use as described.

[0052]

[0201] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to The use described in any one of

[0198] to

[0200] , which is in the range of 8.

[0202]

[0193] wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody. Use of the above.

[0203] The anti-TROP2 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO:5. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 6; The use described in

[0202] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[0204] An anti-TROP2 antibody lacking a lysine residue at the carboxyl terminus of the heavy chain. Use as described in.

[0205] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5 The use described in any one of

[0202] to

[0204] , wherein the range is from 1 to 4.5.

[0206]

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

[0207] The anti-B7-H3 antibody is selected from the group consisting of amino acids 20 to 471 in SEQ ID NO:7. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 8; The use described in

[0206] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[0208] The anti-B7-H3 antibody lacks the lysine residue at the carboxyl terminus of the heavy chain. Use as described in.

[0209] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5 The use described in any one of

[0206] to

[0208] , wherein the range is from 1 to 4.5.

[0210]

[0193] wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody. Use of the above.

[0053]

[0211] The anti-GPR20 antibody is a polypeptide comprising the amino acids 20 to 472 of SEQ ID NO: 9. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 10; The use described in

[0210] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[0212] An anti-GPR20 antibody lacking a lysine residue at the carboxyl terminus of the heavy chain. Use as described in.

[0213] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to The use described in any one of

[0210] to

[0212] , which is in the range of 8.

[0214]

[0193] The antibody in the antibody-drug conjugate is an anti-CDH6 antibody. Use of.

[0215] The anti-CDH6 antibody is a nucleotide sequence selected from the group consisting of amino acids 20 to 471 in SEQ ID NO: 11. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 12; The use described in

[0214] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[0216] The anti-CDH6 antibody lacks the lysine residue at the carboxyl terminus of the heavy chain. Use as described.

[0217] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to The use described in any one of

[0214] to

[0216] , which is in the range of 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 bonded to the antibody via a thioether bond, and n is the number of antibodies per (The average number of drug linkers per The use of an antibody-drug conjugate as shown in

[0219] Primary cancers of metastatic brain tumors include breast cancer, lung cancer, melanoma, renal cell carcinoma, kidney cancer, and large intestine cancer. Intestinal cancer, stomach 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. The use described in

[0218] , wherein the use is at least one of the following:

[0220] The primary cancer of the metastatic brain tumor is selected from the group consisting of breast cancer, lung cancer, and melanoma. The use described in

[0218] , wherein the use is at least one of the following.

[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 antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TR antibody, or The use described in any one of

[0218] to

[0223] , wherein the antibody is an OP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[0225]

[0224] The antibody in the antibody-drug conjugate is an anti-HER2 antibody. Use of.

[0226] The anti-HER2 antibody comprises an amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1. a heavy chain consisting of a sequence of amino acids 1 to 214 in SEQ ID NO: 2; The use described in

[0225] , wherein the antibody comprises a light chain consisting of:

[0227] The anti-HER2 antibody comprises a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a The use described in

[0225] , wherein the antibody comprises a light chain having the amino acid sequence described above.

[0228] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to The use described in any one of

[0225] to

[0227] , which is in the range of 8.

[0229]

[0224] The antibody in the antibody-drug conjugate is an anti-HER3 antibody. Use of.

[0230] The anti-HER3 antibody comprises a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 3 and a The use described in

[0229] , wherein the antibody comprises a light chain having the amino acid sequence described above.

[0057]

[0231] The anti-HER3 antibody lacks the lysine residue at the carboxyl terminus of the heavy chain. Use as described.

[0232] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to The use described in any one of

[0229] to

[0231] , which is in the range of 8.

[0233]

[0224] wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody. Use of the above.

[0234] The anti-TROP2 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO:5. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 6; The use described in

[0233] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[0235] An anti-TROP2 antibody lacking a lysine residue at the carboxyl terminus of the heavy chain. Use as described in.

[0236] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5 The use described in any one of

[0233] to

[0235] , wherein the range is from 1 to 4.5.

[0237]

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

[0238] The anti-B7-H3 antibody is selected from the group consisting of amino acids 20 to 471 in SEQ ID NO:7. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 8; The use described in

[0237] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[0239] The anti-B7-H3 antibody lacks the lysine residue at the carboxyl terminus of the heavy chain. Use as described in.

[0240] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5 The use described in any one of

[0237] to

[0239] , wherein the range is from 1 to 4.5.

[0058]

[0241]

[0224] wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody. Use of the above.

[0242] The anti-GPR20 antibody is a polypeptide comprising the amino acids 20 to 472 of SEQ ID NO: 9. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 10; The use described in

[0241] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[0243] An anti-GPR20 antibody lacking a lysine residue at the carboxyl terminus of the heavy chain. Use as described in.

[0244] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to The use described in any one of

[0241] to

[0243] , which is in the range of 8.

[0245]

[0244] The antibody in the antibody-drug conjugate is an anti-CDH6 antibody. Use of.

[0246] The anti-CDH6 antibody is a nucleotide sequence selected from the group consisting of amino acids 20 to 471 in SEQ ID NO: 11. a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 12; The use described in

[0245] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[0247] The anti-CDH6 antibody lacks the lysine residue at the carboxyl terminus of the heavy chain. Use as described.

[0248] The average number of drug linkers per antibody in antibody-drug conjugates ranges from 7 to The use described in any one of

[0245] to

[0247] , which is in the range of 8.

[0249] formula

[0059] [ka]

[0060] (wherein A represents the binding site to the antibody) and an antibody-drug conjugate in which the antibody is bound to a drug linker represented by the formula: A treatment for metastatic cancer containing jugate as an active ingredient.

[0250] Metastatic cancers range from metastatic brain tumors, metastatic bone tumors, metastatic lung tumors, and metastatic liver cancer. The therapeutic agent described in

[0249] , which is at least one selected from the group consisting of:

[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 bonded to the antibody via a thioether bond, and n is the number of antibodies per (The average number of drug linkers per A therapeutic agent for metastatic cancer, comprising as an active ingredient an antibody-drug conjugate represented by the formula:

[0253] Metastatic cancers range from metastatic brain tumors, metastatic bone tumors, metastatic lung tumors, and metastatic liver cancer. The therapeutic agent described in

[0252] , which is at least one selected from the group consisting of:

[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-drug conjugate in which the antibody is bound to a drug linker represented by the formula: and administering a compound of formula (I) to an individual in need of treatment for metastatic cancer. Treatment methods for cancer.

[0256] Metastatic cancers range from metastatic brain tumors, metastatic bone tumors, metastatic lung tumors, and metastatic liver cancer. The treatment method described in

[0255] , which is at least one selected from the group consisting of:

[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 bonded to the antibody via a thioether bond, and n is the number of antibodies per (The average number of drug linkers per and administering the antibody-drug conjugate represented by the formula (I) to an individual in need of treatment for metastatic cancer. A method for treating metastatic cancer, comprising:

[0259] Metastatic cancers range from metastatic brain tumors, metastatic bone tumors, metastatic lung tumors, and metastatic liver cancer. The treatment method described in

[0258] , which is at least one selected from the group consisting of:

[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) and an antibody-drug conjugate in which the antibody is bound to a drug linker represented by the formula: Jugate.

[0262] Metastatic cancers range from metastatic brain tumors, metastatic bone tumors, metastatic lung tumors, and metastatic liver cancer. The antibody-drug conjugate according to

[0261] , which is at least one selected from the group consisting of: Route.

[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 bonded to the antibody via a thioether bond, and n is the number of antibodies per (The average number of drug linkers per The antibody-drug conjugate shown in

[0265] Metastatic cancers range from metastatic brain tumors, metastatic bone tumors, metastatic lung tumors, and metastatic liver cancer. The antibody-drug conjugate according to

[0264] , which is at least one selected from the group consisting of: Route.

[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 antibody is bound to a drug linker represented by the formula: Use of Jugate.

[0268] Metastatic cancers range from metastatic brain tumors, metastatic bone tumors, metastatic lung tumors, and metastatic liver cancer. The use described in

[0267] , which is at least one selected from the group consisting of:

[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 bonded to the antibody via a thioether bond, and n is the number of antibodies per (The average number of drug linkers per The use of an antibody-drug conjugate as shown in

[0077]

[0271] Metastatic cancers range from metastatic brain tumors, metastatic bone tumors, metastatic lung tumors, and metastatic liver cancer. The use described in

[0270] , which is at least one selected from the group consisting of:

[0272] The use described in

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

[0078] The present invention provides a therapeutic agent for metastatic brain tumors containing a specific antibody-drug conjugate, and and / or a specific antibody-drug conjugate, A method for treating tumors can be provided. [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] A preferred embodiment of the present invention will be described below. The embodiment shows an example of a typical embodiment of the present invention, and the present invention The scope will not be interpreted narrowly.

[0081] 1. Metastatic brain tumors In the present invention, "metastatic brain tumor" refers to cancer that has developed in a living tissue other than the brain (primary cancer ) to the brain. In the present invention, metastatic brain tumors are This includes not only tumors that have metastasized into the brain parenchyma, but also tumors that have invaded the pia mater and arachnoid mater (meningeal carcinomatosis). The site of metastasis may be single or multiple. Also, metastatic brain tumors may occur from the primary tumor. It is usually discovered after symptoms of cancer appear, but it can also occur when symptoms of the primary cancer are present. Sometimes it can be discovered before it happens.

[0082] Symptoms of metastatic brain tumors include headache, vomiting, visual disturbance, impaired consciousness, seizures, These symptoms include paralysis and speech disorders. It is thought to be caused by injury or increased pressure inside the skull.

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

[0084] Primary cancers of metastatic brain tumors include, for example, lung cancer, breast cancer, melanoma, and renal cell carcinoma. , kidney cancer, colon cancer, stomach cancer, head and neck cancer, hepatocellular carcinoma, liver cancer, ovarian cancer, prostate These include cancer, bladder cancer, pancreatic cancer, endometrial cancer, thyroid cancer, malignant lymphoma, and sarcoma. Among these, lung cancer, breast cancer, and melanoma are particularly prevalent, as are metastatic brain tumors. It has a high incidence as a primary cancer.

[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-drug conjugate in which the antibody is bound to a drug linker represented by the formula: It's Jugate.

[0088] In the present invention, the portion of the antibody-drug conjugate consisting of a linker and a drug The structure is called a "drug linker." This drug linker binds to the disulfide bond between the antibody chains. Thiol groups (in other words) generated at positions (two heavy chain-heavy chain interchains and two heavy chain-light chain interchains) In other words, it is bound to the sulfur atom of a cysteine ​​residue.

[0089] The drug linker of the present invention is a 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]pi Lano[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 1H,12H-benzo[de]pyrano[3',4': 6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione and It can also be expressed as 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. The so-called average number of drug-antibody bindings (DAR; Drug-to-Antibody Ratio) It is synonymous with and 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 the basis of the antitumor activity of the antibody-drug conjugate used in the present invention. It is believed to have a topoisomerase I inhibitory effect (Ogitani Y. et al., Clinical Cancer Research, 2016, Oct 15;22(20):5097-5108, Epub 2016 Mar 29).

[0100] The antibody-drug conjugates used in the present invention may also have a bystander effect. It is known (Ogitani Y. et al., Cancer Science (2016) 107, 1039-1046). This bystander effect is due to the fact that the antibody-drug conjugates used in the present invention inhibit target expression. After being internalized by cancer cells, the compound is released and transported to nearby cancer cells that do not express the target. This is achieved by exerting an antitumor effect on tumors.

[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. The antibodies may be derived from any of various origins, but are preferably derived from humans, rats, mice, and rabbits. If derived from a species other than human, it is preferred to chimerize or humanize it using well-known techniques. The antibody of the present invention may be a polyclonal antibody or a monoclonal antibody. Although antibodies may be used, monoclonal antibodies are preferred.

[0102] The antibody in the antibody-drug conjugate used in the present invention preferably targets cancer cells. It has the property of being able to recognize cancer cells and bind to them. characteristics, ability to be taken up and internalized by cancer cells, and / or cytocidal activity against cancer cells It is preferable that the material has properties such as

[0103] The binding of antibodies to cancer cells can be confirmed using flow cytometry. Antibody uptake into the cell can be achieved by (1) using a secondary antibody (fluorescently labeled) that binds to the therapeutic antibody. Cell Death and Differentiation Assay (Cell Death and Differentiation Assay) on (2008) 15, 751-761), (2) using a secondary antibody (fluorescently labeled) that binds to the therapeutic antibody to detect the cells. Assay to measure the amount of fluorescence taken up into the vesicles (Molecular Biology of the Cell Vol. 1 5, 5268-5282, December 2004), or (3) using immunotoxins that bind to therapeutic antibodies. When taken up into cells, Mab-ZA releases toxins that inhibit cell proliferation. This can be confirmed using the P assay (BioTechniques 28:162-165, January 2000). The toxin is a recombinant complex of the catalytic domain of diphtheria toxin and protein G. Proteins can also be used.

[0104] Anti-tumor activity of antibodies can be assessed in vitro by measuring their ability to inhibit cell proliferation. For example, a cancer cell line that overexpresses the antibody's target protein can be cultured and Antibodies were added at various concentrations to the cells, and the effects on focus formation, colony formation, and spheroid growth were evaluated. In vivo, for example, the inhibitory activity of a target protein can be measured. The antibody is administered to nude mice transplanted with the cancer cell line expressing the antibody, and changes in the cancer cells are measured. By this, antitumor activity can be confirmed.

[0105] It is preferable that the antibody itself has an anti-tumor effect, but the antibody-drug conjugate may also have an anti-tumor effect. Since the antibody is bound to a compound that exerts an antitumor effect, the antibody itself does not necessarily have an antitumor effect. For the purpose of specifically and selectively exerting the cytotoxicity of antitumor compounds on cancer cells, It is important and preferred that the antibody has 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, antigenic polynucleotides can be prepared by a method commonly used in the art. It is obtained by immunizing an animal with the peptide and collecting and purifying the antibodies produced in the body. The origin of the antigen is not limited to humans, but can be derived from animals other than humans, such as mice and rats. In this case, the antigen that binds to the obtained heterologous antigen can be used to immunize animals. Antibodies applicable to human diseases are selected by testing their cross-reactivity with human antigens. can.

[0107] Also, known methods (e.g., Kohler and Milstein, Nature (1975) 256, pp. 495-497; Ke nnet, R. ed., Monoclonal Antibodies, p.365-367, Plenum Press, NY (1980)). By fusing antibody-producing cells that produce antibodies against antigens with myeloma cells, It is also possible to establish hybridomas and obtain monoclonal antibodies.

[0108] The antigen is produced by genetically manipulating the gene encoding the antigen protein in the host cell. Specifically, a vector capable of expressing an antigen gene is prepared. This can then be introduced into host cells to express the gene, and the expressed antigen can be purified. Immunizing animals with the antigen-expressing cells or cell lines expressing the antigens obtained by the above genetic manipulation. Antibodies can also be obtained by using the method.

[0109] The antibody in the antibody-drug conjugate used in the present invention is a heterologous antigen for humans. Recombinant antibodies that have been artificially modified to reduce their sensitivity, for example, Preferably, the antibody is a chimeric antibody or a humanized antibody. or an antibody having only the gene 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 of the antibody are heterologous, such as mouse antibodies. Examples of such antibodies include chimeric antibodies in which the variable regions of a mouse or rat-derived antibody are joined to constant regions of human origin. (Proc. Natl. Acad. Sci. USA, 81, 6851-6855, (1984)).

[0111] Humanized antibodies are characterized by the complementarity determining regions (CDRs) of heterologous antibodies. The antibody was developed by incorporating only the ity determining region (IL-1) into a human-derived antibody. (Nature (1986) 321, p. 522-525), the CDR sequence of a heterologous antibody is grafted by CDR grafting. In addition, some framework amino acid residues of the heterologous antibody are also transplanted into a human antibody ( WO 90 / 07861, gene conversion mutagenesis Antibodies humanized using a ion mutagenesis strategy (U.S. Patent No. 5,649,496) No. 821337).

[0112] Human antibodies include those derived from humans having human chromosome fragments containing the heavy and light chain genes of human antibodies. Antibodies generated using antibody-producing mice (Tomizuka, K. et al., Nature Genetics (1997) 1 6, p.133-143;Kuroiwa, Y. et. al., Nucl. Acids Res.(1998) 26, p.3447-3448;Yoshida , H. et. al., Animal Cell Technology:Basic and Applied Aspects vol.10, p.69-73(K itagawa, Y., Matsuda, T. and Iijima, S. eds.), Kluwer Academic Publishers, 1999; (See Tomizuka, K. et al., Proc. Natl. Acad. Sci. USA (2000) 97, pp. 722-727, etc.) Alternatively, a phage display selected from a human antibody library can be used. The antibody obtained by the method (Wormstone, IM et al., Investigative Ophthalmology & Vis (2002)43 (7), p.2301-2308;Carmen, S. et. al., Briefings in Function al Genomics and Proteomics(2002), 1(2), p.189-203;Siriwardena, D. et. al., Ophth See, for example, Almology (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 is an antibody according to the present invention that has been chemically or biologically modified. Chemical modifications include attachment of chemical moieties to the amino acid backbone, N-bonds or O-bonds. - Chemical modifications include those with chemical moieties attached to the carbohydrate chain. The body contains post-translational modifications (e.g., addition of N-linked or O-linked glycosylation, N- or C-terminal processing, deamidation, isomerization of aspartic acid, oxidation of methionine, etc. By expressing this in a prokaryotic host cell, a methionine residue is added to the N-terminus. In addition, the present invention also includes those that enable the detection or isolation of the antibody or antigen of the present invention. Such modifications include those labeled with an enzyme label, a fluorescent label, and an affinity label. Such modified antibodies according to the present invention are included in the meaning of the term "antibody." The modified antibodies according to the present invention are intended to improve the stability and circulation of the antibodies. These are useful for improving the affinity, reducing the antigenicity, detecting or isolating antibodies or antigens, etc.

[0114] Furthermore, it is possible to regulate sugar chain modification (glycosylation, decarboxylation) of the antibody of the present invention. Antibody-dependent cellular cytotoxicity can be enhanced by glycosylation of antibodies. Techniques for controlling chain modification include those described in WO 99 / 54342 and WO 00 / 6173 9, WO 02 / 31140, WO 2007 / 133855, and WO 2007 / 133856. Publication No. 2013 / 120066 and the like are known, but are not limited to these. The antibodies according to the present invention also include antibodies in which the glycosylation has been regulated.

[0115] In addition, antibodies produced in mammalian cultured cells have a lysine residue at the carboxyl terminal of the heavy chain. It is known that the hydroxyl group is deleted (Journal of Chromatography A, 705: 129-134 (1995) ), and also, two amino acid residues, glycine and lysine, are deleted at the carboxyl terminal of the heavy chain. It is known that the proline residue at the carboxyl terminus is newly amidated ( Analytical Biochemistry, 360: 75-83(2007)). However, the deletion and Modifications affect the antigen-binding ability and effector functions of antibodies (complement activation and antibody-dependent cellular cytotoxicity). Therefore, the antibody of the present invention does not have any effect on the antibody's function (use, etc.). Also included are antibodies and functional fragments of such antibodies, which have one or two amino acids at the carboxyl terminus of the heavy chain. Deletions in which the acid is deleted and amidated deletions (e.g., carboxyl-terminal However, the antigen-binding ability and the effector - As long as the function is maintained, the carboxyl-terminal deletion of the heavy chain of the antibody according to the present invention can be carried out in the manner described above. The two heavy chains constituting the antibody of the present invention are not limited to the type. The heavy chain may be any one of heavy chains selected from the group consisting of α- and β-blockers, or a combination of any two of heavy chains. The ratio of the amounts of each deletion fragment is determined based on the mammalian culture medium producing the antibody of the present invention. Although the type of cultured cells and culture conditions may affect the antibody of the present invention, it is preferable to use two antibodies. List those in which one amino acid residue is deleted at the carboxyl terminus of both heavy chains. can be done.

[0116] The isotype of the antibody of the present invention may be, for example, IgG (IgG1, IgG2, Ig Examples of the antibody include IgG1 and IgG2. It is possible.

[0117] The antibody in the antibody-drug conjugate used in the present invention is not particularly limited, but examples thereof include: For example, anti-HER2 antibody, anti-HER3 antibody, anti-TROP2 antibody, anti-B7-H3 antibody, anti-CD 3 antibodies, anti-CD30 antibody, anti-CD33 antibody, anti-CD37 antibody, anti-CD56 antibody, anti-CD9 8 antibody, anti-DR5 antibody, anti-EGFR antibody, anti-EPHA2 antibody, anti-FGFR2 antibody, anti-FG FR4 antibody, anti-FOLR1 antibody, anti-VEGF antibody, anti-CD20 antibody, anti-CD22 antibody, anti- CD70 antibody, anti-PSMA antibody, anti-CEA antibody, anti-Mesothelin antibody, anti-A33 Antibodies, anti-CanAg antibody, anti-Cripto antibody, anti-G250 antibody, anti-MUC1 antibody, anti-G PNMB antibody, anti-Integrin antibody, anti-Tenascin-C antibody, anti-SLC44A Examples of antibodies include anti-HE4 antibody, anti-GPR20 antibody, and anti-CDH6 antibody, and preferably anti-HE R2 antibody, anti-HER3 antibody, anti-TROP2 antibody, anti-B7-H3 antibody, anti-GPR20 antibody, and anti-CDH6 antibodies, and more preferably anti-HER2 antibodies. can.

[0118] In the present invention, the term "anti-HER2 antibody" refers to an antibody against HER2 (Human Epidermal Growth Factor-2) l Growth Factor Receptor Type 2; ErbB-2) and preferably binds to HER2, thereby being internalized in HER2-expressing cells. The figures show antibodies with localizing activity.

[0119] Examples of anti-HER2 antibodies include trastuzumab (US Patent No. 5821337), Pertuzumab (International Publication No. 01 / No. 00245), and preferably trastuzumab.

[0120] In the present invention, the term "anti-HER3 antibody" refers to an antibody against HER3 (Human Epidermal Growth Factor-3) l Growth Factor Receptor Type 3; ErbB-3) and preferably binds to HER3, thereby being internalized in HER3-expressing cells. The figures show antibodies with localizing activity.

[0121] Examples of anti-HER3 antibodies include patritumab (U3-1 287), U1-59 (International Publication No. 2007 / 077028), MM-121 (Ser ibantumab), the anti-ERBB3 antibody described in WO 2008 / 100624, R G-7116 (Lumretuzumab) and LJM-716 (Elgemtumab) b) and preferably include patritumab and U1-59. do.

[0122] In the present invention, the term "anti-TROP2 antibody" refers to an antibody that specifically binds to TROP2 (TACSTD2: Tumor r-associated calcium signal transducer 2 ; EGP-1) and preferably binds to TROP2, thereby 1 shows antibodies that have the activity of being internalized into ROP2-expressing cells.

[0123] Examples of anti-TROP2 antibodies include hTINA1-H1L1 (International Publication No. 2015 / 003366). No. 098099).

[0124] In the present invention, the term "anti-B7-H3 antibody" refers to a B7-H3 (B cell antibody PD-L3; CD276) and specifically binds to Preferably, the antibody has the activity of being internalized into B7-H3-expressing cells by binding to B7-H3. The antibodies shown are:

[0125] Examples of anti-B7-H3 antibodies include M30-H1-L4 (International Publication No. 2014 / 05 No. 7687).

[0126] In the present invention, the term "anti-GPR20 antibody" refers to an antibody that binds to GPR20 (G Protein-coated Specifically binds to GPR20, preferably GPR20. The figures show antibodies that have the activity of being internalized into GPR20-expressing cells when combined with GPR20.

[0127] Examples of anti-GPR20 antibodies include h046-H4e / L7 (International Publication No. 2018 / 003366). No. 135501).

[0128] In the present invention, the term "anti-CDH6 antibody" refers to an antibody specific to CDH6 (Cadherin-6). and preferably binds to CDH6 and is internalized into CDH6-expressing cells. The antibodies shown have the activity.

[0129] Examples of anti-CDH6 antibodies include H01L02 (International Publication No. 2018 / 212136 No.) can be mentioned.

[0130] 4. Antibody-drug Conjugate Production Drug-linker intermediates used in the preparation of antibody-drug conjugates used in the present invention is expressed by the following equation:

[0131] [ka]

[0132] The drug linker intermediate shown above is N-[6-(2,5-dioxo-2,5-dihydro-1 H-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,12 H-Benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline -1-yl]amino}-2-oxoethoxy)methyl]glycinamide, and the like, which can be represented by International Publication No. 2014 / 057687 and International Publication No. 2015 / 0980 99, International Publication No. 2015 / 115091, International Publication No. 2015 / 155998, It can be produced by referring to the descriptions in International Publication No. 2019 / 044947 and the like.

[0133] The antibody-drug conjugate used in the present invention comprises the aforementioned drug linker intermediate and a thiol- It is produced by reacting an antibody having a hydroxyl group (also called a sulfhydryl group) with It is possible.

[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, a reducing agent such as tris(2-carboxyethyl)phosphine hydrochloride (TCEP) 0.3 to 3 molar equivalents per intra-chain disulfide of antibody are used, and ethylenediamine By reacting with the antibody in a buffer containing a chelating agent such as EDTA, Antibodies with partially or completely reduced interchain disulfides and sulfhydryl groups can be obtained.

[0135] Additionally, 2 to 20 molar equivalents of a drug linker per antibody having a sulfhydryl group are used. - Using the intermediate, antibody-drug conjugates with 2 to 8 drugs bound to each antibody can be prepared. Gates can be manufactured.

[0136] The average number of drugs bound per antibody molecule of the produced antibody-drug conjugate can be calculated using the following formula: For example, anti-HER2 antibody-drug conjugates at two wavelengths, 280 nm and 370 nm. and its conjugation precursor by measuring the UV absorbance (UV method), or antibody-drug conjugates were treated with a reducing agent and each fragment obtained was analyzed by HPLC. This can be done by a method of quantitatively measuring and calculating (HPLC method).

[0137] Conjugation of antibodies with drug linker intermediates and antibody-drug conjugates The average number of drugs bound per molecule was calculated according to the method described in WO 2014 / 057687 and WO 2014 / 057687. Publication No. 2015 / 098099, International Publication No. 2015 / 115091, International Publication No. 015 / 155998, WO 2018 / 135501, and WO 201 This can be done by referring to the descriptions in No. 8 / 212136 etc.

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

[0139] The anti-HER2 antibody preferably comprises the amino acid sequence set forth in amino acid numbers 1 to 449 of SEQ ID NO: 1. a heavy chain consisting of the amino acid sequence of SEQ ID NO: 2 and an amino acid sequence set forth in amino acid numbers 1 to 214; an antibody comprising a light 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, it is 2 to 8, more preferably 3 to 8, and even more preferably 7 to 8. and even more preferably between 7.5 and 8, and even more preferably about 8.

[0141] The anti-HER2 antibody-drug conjugate is described in WO 2015 / 115091 etc. The manufacturing method can be carried out with reference to the above.

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

[0143] The anti-HER3 antibody preferably comprises the amino acid sequence set forth in amino acid numbers 26 to 35 of SEQ ID NO: 3. CDRH1 consisting of the amino acid sequence set forth in amino acid numbers 50 to 65 in SEQ ID NO:3 and CDRH2 consisting of the amino acid sequence of amino acid numbers 98 to 10 in SEQ ID NO: 3. a heavy chain comprising a CDRH3 having the amino acid sequence set forth in SEQ ID NO: 4; CDRL1 consisting of the amino acid sequence set forth in amino acid numbers 24 to 39 in SEQ ID NO: 4 CDRL2 consisting of the amino acid sequence set forth in amino acid numbers 56 to 62, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 4 a light chain comprising a CDRL3 consisting of the amino acid sequence set forth in amino acid numbers 95 to 103 in , wherein the antibody comprises More preferably, the amino acid sequence of amino acid numbers 1 to 117 in SEQ ID NO: 3 and a heavy chain comprising a heavy chain variable region consisting of: a light chain comprising a light chain variable region consisting of the amino acid sequence set forth above, Even more preferably, a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 3 and a An antibody comprising a light chain consisting of the amino acid sequence set forth above, or the carboxyl terminal of the heavy chain of said antibody. It is an antibody in which the lysine residue is deleted.

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

[0145] The anti-HER3 antibody-drug conjugate is described in WO 2015 / 155998 etc. The manufacturing method can be carried out with reference to the above.

[0146] In the present invention, the term "anti-TROP2 antibody-drug conjugate" refers to the antibody of the present invention. -An antibody-drug conjugate, wherein the antibody in the drug conjugate is an anti-TROP2 antibody. Shows.

[0147] The anti-TROP2 antibody preferably comprises the amino acid sequence set forth in amino acids 50 to 54 of SEQ ID NO:5. CDRH1 consisting of the amino acid sequence shown in SEQ ID NO:5, which is represented by amino acid numbers 69 to 85. CDRH2 consisting of the amino acid sequence set forth above, and the amino acid sequences from amino acid number 118 to amino acid number 119 in SEQ ID NO: 5. 129, and a heavy chain comprising CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 6. CDRL1 consisting of the amino acid sequence set forth in amino acid numbers 44 to 54, and CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 6. CDRL2 consisting of the amino acid sequence set forth in amino acid numbers 70 to 76 in SEQ ID NO: 6, comprising a CDRL3 consisting of the amino acid sequence set forth in amino acid numbers 109 to 117. a light chain comprising a nucleotide sequence containing a nucleotide sequence of ... More preferably, the amino acid sequence set forth in amino acid numbers 20 to 140 in SEQ ID NO: 5 a heavy chain comprising a heavy chain variable region consisting of amino acid numbers 21 to 129 in SEQ ID NO: 6; an antibody comprising a light chain comprising a light chain variable region consisting of the amino acid sequence set forth in Even more preferably, the amino acids set forth in amino acid numbers 20 to 470 in SEQ ID NO:5 a heavy chain consisting of the sequence: or a lysine residue at the carboxyl terminus of the heavy chain of said antibody. It is an antibody that lacks

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

[0149] The anti-TROP2 antibody-drug conjugate may be any of the compounds described in WO 2015 / 098099, etc. The product can be produced by referring to the description.

[0150] In the present invention, the term "anti-B7-H3 antibody-drug conjugate" refers to the antibody of the present invention. -An antibody-drug conjugate, wherein the antibody in the drug conjugate is an anti-B7-H3 antibody Shows.

[0151] The anti-B7-H3 antibody preferably comprises the amino acid sequence set forth in amino acid numbers 50 to 54 of SEQ ID NO:7. CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 7, which is represented by amino acid numbers 69 to 85. CDRH2 consisting of the amino acid sequence set forth above, and the amino acid sequences from amino acid number 118 to amino acid number 119 in SEQ ID NO: 7. 130, and a heavy chain comprising CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 8. CDRL1 consisting of the amino acid sequence set forth in amino acid numbers 44 to 53, and CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 8. CDRL2 consisting of the amino acid sequence set forth in amino acid numbers 69 to 75 in SEQ ID NO: 8, which contains CDRL3 consisting of the amino acid sequence set forth in amino acid numbers 108 to 116. a light chain comprising a nucleotide sequence containing a nucleotide sequence of ... More preferably, the amino acid sequence set forth in amino acid numbers 20 to 141 in SEQ ID NO: 7 a heavy chain comprising a heavy chain variable region consisting of amino acid numbers 21 to 128 in SEQ ID NO: 8; an antibody comprising a light chain comprising a light chain variable region consisting of the amino acid sequence set forth in Even more preferably, the amino acids set forth in amino acid numbers 20 to 471 in SEQ ID NO:7 a heavy chain consisting of the sequence: or a lysine residue at the carboxyl terminus of the heavy chain of said antibody. It is an antibody that lacks

[0152] The average number of drug linkers per antibody in anti-B7-H3 antibody-drug conjugates is , preferably 2 to 8, more preferably 3 to 5, and 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 is The present invention can be produced by referring to the description in No. 14 / 057687.

[0154] In the present invention, the term "anti-GPR20 antibody-drug conjugate" refers to the antibody of the present invention. -An antibody-drug conjugate, wherein the antibody in the drug conjugate is an anti-GPR20 antibody Shows.

[0155] The anti-GPR20 antibody preferably comprises the amino acid sequence set forth in amino acid numbers 45 to 54 of SEQ ID NO:9. CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 9, which is represented by amino acid numbers 69 to 78. CDRH2 consisting of the amino acid sequence set forth above, and the amino acid sequences from amino acid number 118 to amino acid number 119 in SEQ ID NO: 9. a heavy chain comprising a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 131; 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 in A CDRL consisting of the amino acid sequence set forth in amino acid numbers 109 to 117 in No. 10. a light chain comprising 3, More preferably, the amino acid sequence set forth in amino acid numbers 20 to 142 in SEQ ID NO: 9 a heavy chain comprising a heavy chain variable region consisting of amino acid numbers 21 to 12 in SEQ ID NO: 10; 9. A light chain comprising a light chain variable region consisting of the amino acid sequence of Even more preferably, the amino acids set forth in amino acid numbers 20 to 472 in SEQ ID NO:9 and a heavy chain consisting of the sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO: 10. an antibody comprising a light chain consisting of a lysine residue at the carboxyl terminus of a heavy chain of said antibody; It is an antibody in which the base is deleted.

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

[0157] The anti-GPR20 antibody-drug conjugate may be any of the compounds described in WO 2018 / 135501, etc. The product can be produced by referring to the description.

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

[0159] The anti-CDH6 antibody preferably comprises the sequence set forth in amino acids 45 to 54 of SEQ ID NO: 11. CDRH1 consisting of the amino acid sequence of amino acid numbers 69 to 78 in SEQ ID NO: 11 CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 11, and a heavy chain comprising a CDRH3 consisting of the amino acid sequence set forth in any one of SEQ ID NO: 12 to 130; CDRL1 consisting of the amino acid sequence set forth in amino acid numbers 44 to 54 in SEQ ID NO: CDRL2 consisting of the amino acid sequence set forth in amino acid numbers 70 to 76 in paragraph 12; and A CD44 comprising the amino acid sequence set forth in amino acid numbers 109 to 116 in SEQ ID NO: 12. a light chain comprising RL3, More preferably, the amino acid sequence set forth in amino acid numbers 20 to 141 in SEQ ID NO: 11 is a heavy chain comprising a heavy chain variable region consisting of amino acid numbers 21 to 1 in SEQ ID NO: 12; 28. A light chain comprising a light chain variable region consisting of the amino acid sequence of 29. Even more preferably, the amino acids set forth in SEQ ID NO: 11 at amino acid numbers 20 to 471 are a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 12; an antibody comprising a light chain consisting of the carboxyl-terminal lysine of said antibody heavy chain, It is an antibody in which residues are deleted.

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

[0161] The anti-CDH6 antibody-drug conjugate is described in WO 2018 / 212136 and the like. The manufacturing method can be carried out with reference to the above.

[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. The therapeutic method of the present invention also includes the step of administering to a subject the antibody-drug conjugate of the present invention. These therapeutic agents and methods are characterized by administering the therapeutic agent to a subject in need thereof for the treatment of metastatic brain tumors. can be used for.

[0163] Primary cancer of metastatic brain tumors for which the therapeutic agent and / or method of the present invention can be used and There are no particular limitations on cancers that can metastasize to the brain, but for example, 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), stomach cancer (stomach cancer) adenocarcinoma), head and neck cancer, hepatocellular carcinoma, liver cancer, ovarian cancer, and prostate cancer , bladder cancer, pancreatic cancer, endometrial cancer, thyroid cancer, malignant lymphoma, and sarcoma, etc. Suitable cancers include breast cancer, lung cancer, and melanoma, and more preferably Cancers that can be treated include breast cancer and lung cancer, and more preferably breast cancer. can be done.

[0164] Among the antibody-drug conjugates used in the present invention, what kind of antibody is particularly The suitability of the body-drug conjugate depends on the nature of the primary cancer and the tumor markers tested. For example, if the primary cancer is breast cancer or lung cancer and HE If R2 expression is confirmed, anti-HER2 antibody-drug conjugates are preferably used. If HER3 expression is confirmed, anti-HER3 antibody-drug conjugates If TROP2 expression is confirmed, an anti-TROP2 antibody can be preferably used. -When the drug conjugate can be used successfully and B7-H3 expression is confirmed In addition, anti-B7-H3 antibody-drug conjugates can be preferably used. If the cancer is melanoma and HER3 expression is confirmed, anti-HER3 antibody-drug combination therapy is recommended. If TROP2 expression is confirmed, anti-T conjugates can be used. ROP2 antibody-drug conjugates can be preferably used, and B7-H3 expression can be confirmed. If this is confirmed, anti-B7-H3 antibody-drug conjugates can be preferably used. Furthermore, if the primary cancer is renal cancer and CDH6 expression is confirmed, anti-CDH6 Antibody-drug conjugates can be preferably used.

[0165] HER2, HER3, TROP2, B7-H3, GPR20, and CDH6, and The presence or absence of other tumor markers can be determined, for example, by collecting tumor tissue from a cancer patient and fixing it in formalin. Paraffin-embedded specimens (FFPE) can be analyzed by immunohistochemistry (IHC) and flow cytometry. Testing at the gene product (protein) level using a meter, Western blot method, etc. Alternatively, in situ hybridization (ISH) or quantitative PCR (qPCR) CR), and can be confirmed by testing at the gene transcription level using microarray analysis, etc. Alternatively, cell-free circulating tumor DNA (ctDNA) can be collected from cancer patients and used for next-generation It can also be confirmed by testing using methods such as next-generation sequencing (NGS).

[0166] The therapeutic agent and method of the present invention can be suitably used for mammals, but More preferably, it can be used in humans.

[0167] The antitumor effect of the therapeutic agent and method of the present invention is exerted by, for example, the induction of myeloma in cancer cells derived from primary cancer. A gene carrying a marker gene (e.g., luciferase gene) is transplanted into the brain of the test animal. A model was created, and the life-prolonging effect and markers of the therapeutic agent or method of the present invention were investigated. The transition of the luminescence intensity can be confirmed by measuring it using any imaging method. For example, when cells transfected with luciferase gene are transplanted, luciferin can be produced. The luminescence intensity is examined by administering the therapeutic agent or method of the present invention. If the effect is attenuated compared to that of Trol, it can be determined that the antitumor effect is present.

[0168] Furthermore, the antitumor effects of the therapeutic agent and method of the present invention were confirmed by biopsy from patients with metastatic brain tumors. A model in which the PDX is transplanted into a test animal (for example, a PDX brain transplant model) is prepared, and the therapeutic agent or This can also be confirmed by administering the treatment, and furthermore, this The antitumor effect can also be confirmed by administering the therapeutic agent of the present invention or by carrying out the therapeutic method. The results can be measured using, for example, CT, PET, and / or MRI, etc. This can be done by confirming the change in tumor volume before and after the treatment method.

[0169] Furthermore, the antitumor effects of the therapeutic agent and method of the present invention have been demonstrated in clinical trials. se Evaluation Criteria in Solid Tumors(R ECIST evaluation method, WHO evaluation method, Macdonald evaluation method, weight measurement, and others This can be confirmed by the method of R), Partial response (PR), Progress ive disease (PD), objective response rate (ORR) ORR), duration of response (DoR), Progression-Free Survival (PFS), overall It can be judged by indicators such as overall survival (OS). Cut.

[0170] The above-mentioned method has been used to investigate the antitumor effects of the therapeutic agent and treatment method of the present invention on metastatic brain tumors. It is possible to confirm its superiority over existing anticancer drugs.

[0171] The therapeutic agent and method of the present invention not only have an antitumor effect on metastatic brain tumors, but also It can also show antitumor effects against metastatic cancers other than metastatic brain tumors. Examples of metastatic cancers other than those mentioned above include metastatic bone tumors, metastatic lung tumors, and metastatic liver cancers. Examples of tumors include metastatic bone tumors, and preferably metastatic brain tumors. Metastatic cancer may occur together with metastatic brain tumors or may occur separately from metastatic brain tumors. In either case, the therapeutic agent and method of the present invention exert an antitumor effect. It can be demonstrated.

[0172] The therapeutic agent and method of the present invention slow the growth of cancer cells, suppress their proliferation, and further prevent cancer These actions can reduce the severity of cancer-related symptoms in cancer patients. It is possible to achieve relief from symptoms and improve quality of life, and it is also possible to achieve therapeutic effects while preserving the lives of cancer patients. Even if it does not destroy cancer cells, it may suppress or control their proliferation. To achieve a higher quality of life and longer survival in cancer patients by can be done.

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

[0174] The therapeutic agent of the present invention is administered as a pharmaceutical composition containing one or more pharmaceutically compatible ingredients. The pharmaceutically compatible component is a component that is suitable for the administration of the antibody-drug conjugate used in the present invention. Depending on the dosage and administration concentration, appropriate additives are selected from those commonly used in this field. For example, the therapeutic agent of the present invention can be used in the presence of a buffer such as a histidine buffer, excipients such as sucrose or trehalose, and surfactants such as polysorbate 80 or 20 The composition may be administered as a pharmaceutical composition containing the active ingredient (hereinafter referred to as "the pharmaceutical composition of the present invention"). The pharmaceutical composition of the present invention can be preferably used as an injection, more preferably as an aqueous solution. The composition can be used as an injectable preparation or a freeze-dried injection, and more preferably as a freeze-dried injection. It can be used as a propellant.

[0175] When the pharmaceutical composition of the present invention is an aqueous injection, it is preferably diluted with a suitable diluent and then: It can be administered intravenously by drip infusion. Diluents include glucose solution, saline solution, etc. Examples of the solution include glucose solution, preferably 5% glucose solution, and more preferably 5% glucose solution. A sugar solution may be mentioned.

[0176] When the pharmaceutical composition of the present invention is a freeze-dried injection, it is preferably dissolved in water for injection. After that, the required amount can be diluted with an appropriate diluent and administered intravenously. Examples of the solution include a glucose solution and a physiological saline solution, and preferably a glucose solution. and more preferably, a 5% glucose solution.

[0177] Routes of administration that can be used to administer the pharmaceutical compositions of the present invention include, for example, intravenous Intradermal, subcutaneous, intramuscular, and intraperitoneal routes are included, and preferably, intravenous routes. In addition, the pharmaceutical composition of the present invention can be administered by direct administration to the brain parenchyma, pia mater, or arachnoid membrane. It may also be administered by intravenous injection.

[0178] The antibody-drug conjugate used in the present invention can be administered to humans in a dose of 100 mg / day for 1 to 180 days. The dose can be administered at intervals of once every week, preferably once every 1, 2, 3, or 4 weeks. It can be administered at intervals of once every three weeks, and even more preferably at intervals of once every three weeks. The antibody-drug conjugate used in the present invention is administered in an amount of about 0.001 to 10 It can be administered at a dose of 0.0 mg / kg, preferably 0.8 to 12.4 mg per dose. The antibody-drug conjugates used in the present invention can be administered at a dose of 100 mg / kg. When the drug is an anti-ER2 antibody-drug conjugate, the amount is preferably 0.8 mg per dose. / kg, 1.6mg / kg, 3.2mg / kg, 5.4mg / kg, 6.4mg / kg, Doses of 7.4 mg / kg or 8 mg / kg can be administered every 3 weeks. More preferably, a single dose of 5.4, 6.4, or 7.4 mg / kg is administered every three weeks. and even more preferably at 5.4 mg / kg or 6 mg / kg per dose. A dose of 0.4 mg / kg can be administered at intervals of once every three weeks. When the antibody-drug conjugate is an anti-HER3 antibody-drug conjugate, it is preferably 1.6mg / kg, 3.2mg / kg, 4.8mg / kg, 5.6mg per dose / kg, 6.4mg / kg, 8.0mg / kg, 9.6mg / kg, or 12.8mg / The dose may be administered at intervals of once every three weeks, more preferably at a dose of 4 kg. 0.8mg / kg, 5.6mg / kg, or 6.4mg / kg every 3 weeks The antibody-drug conjugate used in the present invention can be administered in an amount of 100 mg / kg or less. In the case of an antibody-drug conjugate, the dose is preferably 0.27 mg / kg, 0 .5mg / kg, 1.0mg / kg, 2.0mg / kg, 4.0mg / kg, 6.0mg / kg or 8.0 mg / kg can be administered at intervals of once every 3 weeks, Preferably, the dose is 4.0 mg / kg, 6.0 mg / kg, or 8.0 mg / kg. Doses can be administered at intervals of once every three weeks.

[0179] The therapeutic agent of the present invention may be any cancer therapeutic agent other than the antibody-drug conjugate used in the present invention. They can also be administered in combination, which can enhance the antitumor effect. Other cancer therapeutic agents used for various purposes may be administered simultaneously, separately, or consecutively with the therapeutic agent of the present invention. The doses may be administered to an individual at different intervals, or may be administered at different administration intervals. The cancer therapeutic agent is not limited as long as it has antitumor activity, but examples thereof include , irinotecan (CPT-11), cisplatin (Cisplatin tin), carboplatin, oxaliplatin platin), fluorouracil (5-FU), gemcitabine Gemcitabine, Capecitabine, Paclitaxel, Docetaxel, Doxorubicin Doxorubicin, Epirubicin, Cyclophosphamide Cyclophosphamide, Mitomycin C in C), Tegafur, Gimeracil, Ote Oteracil combination drug, Cetuximab, Panitumumab Panitumumab, Bevacizumab, Ramucirumab Ramucirumab, Regorafenib, Trifluvial Trifluridine and Tipiracil combination drug, Gef Gefitinib, Erlotinib, Afatinib Afatinib, methotrexate, pemetrexed Pemetrexed, Tamoxifen, Toremifene Toremifene, Fulvestrant, Leuprorelat Leuprorelin, Goserelin, Letrozole Letrozole, Anastrozole, Progesterone Progesterone formulation, trastuzumab emtan Trastuzumab emtansine, Trastuzumab zumab, pertuzumab, and lapatinib nib) may be mentioned.

[0180] The therapeutic agent of the present invention can also be used in combination with radiation therapy. The patient may receive radiation therapy before and / or after, or simultaneously with, treatment with the therapeutic agent of the present invention. Radiation therapy is performed using a method such as whole brain irradiation. radiation therapy (WBRT) and stereotactic radiation therapy (Stereotac tic irradiation (STI), stereotactic surgical irradiation (STI), c radiosurgery; SRS).

[0181] The therapeutic agent of the present invention can also be used as adjuvant chemotherapy in combination with surgery. Surgery may be performed, for example, by physically removing all or part of a brain tumor. The therapeutic agents of the present invention may be administered prior to surgery with the aim of reducing the size of brain tumors ( Neoadjuvant chemotherapy (also called neoadjuvant therapy) is administered, and the recurrence of brain tumors after surgery is confirmed. It may also be administered to prevent the progression of the disease (called postoperative adjuvant chemotherapy, or adjuvant therapy). [Example]

[0182] The present invention will be described in detail with reference to the following examples, but the present invention is not limited to these examples. Furthermore, these should not be interpreted in any restrictive manner.

[0183] Example 1: Preparation of antibody-drug conjugates Humanized anti-HER2 antibodies were prepared according to the manufacturing method described in WO 2015 / 115091. 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. Using an antibody comprising formula

[0184] [ka]

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

[0186] Example 2: Life extension study Mice: 5-6 week old female BALB / c nude mice (Charles River Japan) It was used in the experiment.

[0187] The antibody-drug conjugate (1) was dissolved in ABS buffer (10 mM acetate buffer ( The solution was diluted with 10 mL / kg of 5% sorbitol (pH 5.5) and administered intravenously into the tail vein. Ta.

[0188] Professor Junichi Kurebayashi, Kawasaki Medical School (British Journal of Cancer, (1999) 79 (5 / 6). 707-71 7) We transfected the luciferase gene into KPL-4 cells, a human breast cancer cell line obtained from KPL-4-Luc was used. KPL-4-Luc was suspended in saline and diluted to 1 × 10 4 c Cells were transplanted intracerebrally into female nude mice, and randomized to groups 7 days after transplantation (Da Antibody-drug conjugate (1) was administered at a dose of 10 mg / kg on days 0 and 21. The control group received the solvent. Each group contained five mice. From the viewpoint of animal ethics, if the animals lost more than 30% of their body weight or showed abnormal behavior, the animals were observed to see if they were alive or not. If any abnormalities (circling movements, eating and drinking disorders, etc.) were observed, the animals were euthanized. On Day 1, tumor localization and tumor burden were confirmed using luciferase activity of -Luc as an indicator. On days 4, 21, and 28, each mouse was intraperitoneally injected with luciferin, and the in vivo I The luminescence of the head was measured using the IVIS (Integrated Vehicle Imaging System). A vehicle-administered group (2 animals) was also set up, and on Day 14, the heads of the mice were formalin-fixed and paraffin-embedded. Sections were prepared and stained with hematoxylin and eosin.

[0189] The results are shown in Figures 9 to 11. Death was observed in the control group from Day 14 onwards, and All patients died by Day 6. In contrast, the antibody-drug conjugate (1) administration group died by Day 2. All patients survived to 8 days (Figure 9). In the mice administered with Jugate (1), tumor growth was observed up to Day 21, but after the second administration One week after administration, on Day 28, a decrease in luminescence was observed, indicating that the antibody-drug conjugate was effective against the tumor in the brain. These results suggest that Jugate (1) is effective (Figure 10). Pathological image of the brain on Day 14 In 2 / 2 cases, tumors were found around the olfactory bulb, nasal turbinates, cerebral parenchyma, base of the brain, intraventricular spaces, and around the cerebellum. An ulcer was observed (Figure 11).

[0190] These results indicate that antibody-drug conjugate (1) is effective against metastatic brain tumors. It was suggested that this treatment has a life-prolonging effect. [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 (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-CDH6 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 lung cancer, renal cell carcinoma, kidney cancer, colon cancer, gastric cancer, head and neck cancer, ovarian cancer, and endometrial cancer.

4. The method of claim 1, wherein the primary cancer of the metastatic brain tumor is renal cell carcinoma.

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

6. The method of claim 1, wherein the primary cancer of the metastatic brain tumor is renal cancer.

7. The method of claim 1, wherein the primary cancer of the metastatic brain tumor is gastric cancer.

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

9. The method according to claim 1, wherein the primary cancer of the metastatic brain tumor is head and neck cancer.

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

11. The method of claim 1, wherein the primary cancer of the metastatic brain tumor is endometrial cancer.

12. The therapeutic agent according to any one of claims 1 to 11, wherein the anti-CDH6 antibody is an antibody comprising: a CDRH1 consisting of the amino acid sequence set forth in amino acid numbers 45 to 54 in SEQ ID NO: 11; a CDRH2 consisting of the amino acid sequence set forth in amino acid numbers 69 to 78 in SEQ ID NO: 11; and a CDRH3 consisting of the amino acid sequence set forth in amino acid numbers 118 to 130 in SEQ ID NO: 11; and a CDRL1 consisting of the amino acid sequence set forth in amino acid numbers 44 to 54 in SEQ ID NO: 12; a CDRL2 consisting of the amino acid sequence set forth in amino acid numbers 70 to 76 in SEQ ID NO: 12; and a CDRL3 consisting of the amino acid sequence set forth in amino acid numbers 109 to 116 in SEQ ID NO:

12.

13. The therapeutic agent according to any one of claims 1 to 11, wherein the anti-CDH6 antibody is an antibody 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 variable region consisting of the amino acid sequence set forth in amino acid numbers 21 to 128 of SEQ ID NO:

12.

14. The therapeutic agent according to any one of claims 1 to 11, 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.

15. The therapeutic agent according to any one of claims 1 to 11, 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 470 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.

16. The therapeutic agent according to any one of claims 1 to 15, wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 2 to 8.

17. The therapeutic agent according to claim 16, wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3 to 8.

18. The therapeutic agent according to claim 17, wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

19. The therapeutic agent according to claim 18, wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7.5 to 8.

20. The therapeutic agent according to claim 19, wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is 8.

21. The therapeutic agent according to any one of claims 1 to 15, wherein the antibody-drug conjugate is represented by the following formula: (wherein n represents the drug-to-antibody ratio)

22. The therapeutic agent of claim 21, wherein n is 2 to 8.

23. The therapeutic agent of claim 22, wherein n is 3 to 8.

24. The therapeutic agent of claim 23, wherein n is 7 to 8.

25. The therapeutic agent of claim 24, wherein n is 7.5 to 8.

26. The therapeutic agent of claim 25, wherein n is 8.

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