Combination of antibody-drug conjugate and PARP inhibitor

Abstract

To provide a pharmaceutical composition comprising an antibody-drug conjugate for use in combination with a PARP Inhibitor.SOLUTION: Provided is a pharmaceutical composition for use in combination with a PARP inhibitor that is olaparib, rucaparib, niraparib, talazoparib, or veliparib, or a pharmacologically acceptable salt thereof, comprising an antibody-drug conjugate in which a drug linker represented by the following formula (where, A represents the binding position to the antibody) is bonded to the antibody via a thioether bond.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition characterized in that a specific antibody-drug conjugate and a PARP inhibitor are administered in combination, and / or a treatment method characterized in that a specific antibody-drug conjugate and a PARP inhibitor are administered in combination to an individual. [Background technology]

[0002] Single-stranded breaks and double-stranded breaks are known as types of DNA damage, and each type has its own repair mechanism. When the type of DNA damage is a single-stranded break, repair is performed by base excision repair, mainly by the action of PARP (polyadenosine 5' diphosphate (ADP) ribose polymerase). When the type of DNA damage is a double-stranded break, repair is performed by homologous recombination repair, mainly by the action of BRCA, ATM, RAD51, etc. (Non-Patent Document 1).

[0003] PARP inhibitors are drugs that inhibit PARP (particularly PARP-1 and PARP-2) and thus function to prevent the repair of single-strand breaks. It is known that some cancers, such as breast cancer and ovarian cancer, have abnormalities in the repair of double-strand breaks, and PARP inhibitors have been shown to have an antitumor effect by synthetic lethality against these cancers (Non-Patent Documents 2 to 5).

[0004] Known PARP inhibitors include Olaparib (Non-Patent Document 6), Rucaparib (Non-Patent Document 7), Niraparib (Non-Patent Document 8), and Talazoparib (Non-Patent Document 9).

[0005] It is also known that the combined use of PARP inhibitors with other anticancer drugs can produce an effect similar to synthetic lethality (Non-Patent Document 10). For example, the combined use of PARP inhibitors with topoisomerase I inhibitors is known to be effective against cancers with no abnormality in double-stranded break repair (Non-Patent Documents 11-16). However, clinical trials have reported that there are problems with the balance between tolerability and efficacy (Non-Patent Document 17), and it has not yet been established as a standard therapy.

[0006] Antibody-drug conjugates (ADCs), which combine a cytotoxic drug with an antibody that binds to an antigen expressed on the surface of cancer cells and can be internalized into the cells, are expected to be able to selectively deliver drugs to cancer cells, thereby accumulating the drugs within the cancer cells and killing the cancer cells (Non-Patent Documents 18 to 22).

[0007] As one type of antibody-drug conjugate, an antibody-drug conjugate containing as components an antibody and a derivative of exatecan, which is a topoisomerase I inhibitor, is known (Patent Documents 1 to 9, Non-Patent Documents 23 to 27).

[0008] There are no known test results showing the combined effect of the above antibody-drug conjugates and PARP inhibitors, nor any scientific evidence suggesting such test results. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2014 / 057687 [Patent Document 2] International Publication No. 2014 / 061277 [Patent Document 3] International Publication No. 2015 / 098099 [Patent Document 4] International Publication No. 2015 / 115091 [Patent Document 5] International Publication No. 2015 / 146132 [Patent Document 6] International Publication No. 2015 / 155976 [Patent Document 7] International Publication No. 2015 / 155998 [Patent Document 8] International Publication No. 2018 / 135501 [Patent Document 9] International Publication No. 2018 / 212136

Non-licensed documents

[0010]

Non-patent document 1

Non-patent document 2

Non-patent document 3

Non-patent document 4

Non-patent document 5

Non-patent document 6

Non-patent document 7

Non-patent document 8

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

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Non-licensed Document 17

Non-licensed Document 18

Non-licensed Document 19

Non-Patent Document 20

Non-Patent Document 21

Non-Patent Document 22

Non-Patent Document 23

Non-Patent Document 24

Non-Patent Document 25

Non-Patent Document 26

Non-Patent Document 27

Summary of the Invention

Problems to be Solved by the Invention

[0011] The antibody-drug conjugate used in the present invention (antibody-drug conjugate containing an exatecan derivative as a component) has been confirmed to exhibit excellent antitumor effects even as a single agent. However, it is desirable to obtain a treatment method that can suppress the proliferation of cancer cells in a complex manner and exhibit a more excellent antitumor effect by using it in combination with other anticancer drugs with different mechanisms of action.

[0012] An objective of the present invention is to provide a pharmaceutical composition characterized in that a specific antibody-drug conjugate and a PARP inhibitor are administered in combination, and / or a treatment method characterized in that a specific antibody-drug conjugate and a PARP inhibitor are administered in combination to an individual. [Means for solving the problem]

[0013] The present inventors conducted intensive studies to solve the above problems and discovered that administering a specific antibody-drug conjugate in combination with a PARP inhibitor exhibits excellent combined effects, thereby completing the present invention.

[0014] That is, the present invention provides the following [1] to

[0368] . [1] A pharmaceutical composition comprising an antibody-drug conjugate and a PARP inhibitor administered in combination, The antibody-drug conjugate has the formula

[0015] [ka]

[0016] (wherein A represents the binding site to the antibody) and an antibody via a thioether bond. [2] The pharmaceutical composition according to [1], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody. [3] The pharmaceutical composition described in [2], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody. [4] The pharmaceutical composition according to [3], wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 having the amino acid sequence set forth in amino acid numbers 26 to 33 of SEQ ID NO: 1, CDRH2 having the amino acid sequence set forth in amino acid numbers 51 to 58 of SEQ ID NO: 1, and CDRH3 having the amino acid sequence set forth in amino acid numbers 97 to 109 of SEQ ID NO: 1, and a light chain comprising CDRL1 having the amino acid sequence set forth in amino acid numbers 27 to 32 of SEQ ID NO: 2, CDRL2 having the amino acid sequence set forth in amino acid numbers 50 to 52 of SEQ ID NO: 2, and CDRL3 having the amino acid sequence set forth in amino acid numbers 89 to 97 of SEQ ID NO: 2.

[0017] [5] The pharmaceutical composition described in [3], wherein the anti-HER2 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of the amino acid sequence set forth in amino acid numbers 1 to 120 of SEQ ID NO: 1, and a light chain having a light chain variable region consisting of the amino acid sequence set forth in amino acid numbers 1 to 107 of SEQ ID NO: 2. [6] The pharmaceutical composition described in [3], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2. [7] The pharmaceutical composition described in [3], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO: 2. [8] The pharmaceutical composition according to any one of [3] to [7], wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8. [9] The pharmaceutical composition described in [2], wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[10] The pharmaceutical composition described in [9], wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 4.

[0018]

[11] The pharmaceutical composition described in

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

[12] The pharmaceutical composition according to any one of [9] to

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

[13] The pharmaceutical composition described in [2], wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[14] The pharmaceutical composition according to

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

[15] The pharmaceutical composition according to

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

[0019]

[16] The pharmaceutical composition according to any one of

[13] to

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

[17] The pharmaceutical composition according to [2], wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[18] The pharmaceutical composition according to

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

[19] The pharmaceutical composition according to

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

[20] The pharmaceutical composition according to any one of

[17] to

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

[0020] [twenty one] The pharmaceutical composition according to [2], wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody. [twenty two] The pharmaceutical composition described in

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

[22] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-GPR20 antibody is deleted. [twenty four] The pharmaceutical composition according to any one of

[21] to

[23] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8. [twenty five] The pharmaceutical composition described in [2], wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[0021]

[26] The pharmaceutical composition described in

[25] , 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.

[27] The pharmaceutical composition described in

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

[28] The pharmaceutical composition according to any one of

[25] to

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

[29] The pharmaceutical composition according to any one of [1] to

[28] , wherein the PARP inhibitor is olaparib, rucaparib, niraparib, talazoparib, or veliparib, or a pharmacologically acceptable salt thereof.

[30] The pharmaceutical composition according to

[29] , wherein the PARP inhibitor is olaparib or a pharmacologically acceptable salt thereof.

[0022]

[31] The pharmaceutical composition according to

[29] , wherein the PARP inhibitor is rucaparib or a pharmacologically acceptable salt thereof.

[32] The pharmaceutical composition according to

[29] , wherein the PARP inhibitor is niraparib or a pharmacologically acceptable salt thereof.

[33] The pharmaceutical composition according to

[29] , wherein the PARP inhibitor is talazoparib or a pharmacologically acceptable salt thereof.

[34] The pharmaceutical composition according to

[29] , wherein the PARP inhibitor is veliparib or a pharmacologically acceptable salt thereof.

[35] The pharmaceutical composition according to any one of [1] to

[34] , wherein the antibody-drug conjugate and the PARP inhibitor are contained as active ingredients in separate formulations and are administered simultaneously or at different times.

[0023]

[36] The pharmaceutical composition according to any one of [1] to

[35] , for the treatment of at least one cancer selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, uterine carcinosarcoma, gastrointestinal stromal tumor, renal cancer, and sarcoma.

[37] The pharmaceutical composition described in

[36] for the treatment of breast cancer.

[38] The pharmaceutical composition described in

[37] for the treatment of HER2 low-expressing breast cancer.

[39] The pharmaceutical composition described in

[36] for the treatment of gastric cancer.

[40] The pharmaceutical composition described in

[36] for the treatment of ovarian cancer.

[0024]

[41] The pharmaceutical composition described in

[36] for the treatment of lung cancer.

[42] The pharmaceutical composition described in

[36] for the treatment of pancreatic cancer.

[43] A method of treatment comprising administering to an individual in need of treatment a combination of an antibody-drug conjugate and a PARP inhibitor, The antibody-drug conjugate has the formula

[0025] [ka]

[0026] (wherein A represents the binding site to the antibody) and an antibody-drug conjugate in which the drug linker represented by the formula:

[44] The treatment method according to

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

[45] The treatment method described in

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

[0027]

[46] The treatment method described in

[45] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 having the amino acid sequence set forth in amino acid numbers 26 to 33 of SEQ ID NO: 1, CDRH2 having the amino acid sequence set forth in amino acid numbers 51 to 58 of SEQ ID NO: 1, and CDRH3 having the amino acid sequence set forth in amino acid numbers 97 to 109 of SEQ ID NO: 1, and a light chain comprising CDRL1 having the amino acid sequence set forth in amino acid numbers 27 to 32 of SEQ ID NO: 2, CDRL2 having the amino acid sequence set forth in amino acid numbers 50 to 52 of SEQ ID NO: 2, and CDRL3 having the amino acid sequence set forth in amino acid numbers 89 to 97 of SEQ ID NO: 2.

[47] The treatment method described in

[45] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of the amino acid sequence set forth in amino acid numbers 1 to 120 of SEQ ID NO: 1, and a light chain having a light chain variable region consisting of the amino acid sequence set forth in amino acid numbers 1 to 107 of SEQ ID NO: 2.

[48] The treatment method described in

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

[49] The treatment method described in

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

[50] The treatment method according to any one of

[45] to

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

[0028]

[51] The treatment method described in

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

[52] The treatment method described in

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

[53] The treatment method described in

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

[54] The treatment method according to any one of

[51] to

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

[55] The treatment method described in

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

[0029]

[56] The treatment method described in

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

[57] The treatment method described in

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

[58] The treatment method according to any one of

[55] to

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

[59] The therapeutic method according to

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

[60] The treatment method described in

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

[0030]

[61] The therapeutic method according to

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

[62] The treatment method according to any one of

[59] to

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

[63] The therapeutic method described in

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

[64] The treatment method described in

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

[65] The treatment method described in

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

[0031]

[66] The treatment method according to any one of

[63] to

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

[67] The therapeutic method described in

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

[68] The treatment method described in

[67] , 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.

[69] The therapeutic method described in

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

[70] The treatment method according to any one of

[67] to

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

[0032]

[71] The treatment method according to any one of

[43] to

[70] , wherein the PARP inhibitor is olaparib, rucaparib, niraparib, talazoparib, or veliparib, or a pharmacologically acceptable salt thereof.

[72] The method of treatment according to

[71] , wherein the PARP inhibitor is olaparib or a pharmacologically acceptable salt thereof.

[73] The treatment method according to

[71] , wherein the PARP inhibitor is rucaparib or a pharmacologically acceptable salt thereof.

[74] The treatment method according to

[71] , wherein the PARP inhibitor is niraparib or a pharmacologically acceptable salt thereof.

[75] The method of treatment according to

[71] , wherein the PARP inhibitor is talazoparib or a pharmacologically acceptable salt thereof.

[0033]

[76] The treatment method according to

[71] , wherein the PARP inhibitor is veliparib or a pharmacologically acceptable salt thereof.

[77] The treatment method according to any one of

[43] to

[76] , wherein the antibody-drug conjugate and the PARP inhibitor are contained as active ingredients in separate formulations and administered simultaneously or at different times.

[78] The method for treating at least one cancer selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, uterine carcinosarcoma, gastrointestinal stromal tumor, renal cancer, and sarcoma, according to any one of

[43] to

[77] .

[79] A therapeutic method as described in

[78] for the treatment of breast cancer.

[80] The therapeutic method described in

[79] for the treatment of HER2 low-expressing breast cancer.

[0034]

[81] A therapeutic method described in

[78] for the treatment of gastric cancer.

[82] The therapeutic method described in

[78] for the treatment of ovarian cancer.

[83] A therapeutic method described in

[78] for treating lung cancer.

[84] A therapeutic method described in

[78] for the treatment of pancreatic cancer.

[85] and administering in combination with a PARP inhibitor to treat a disease. formula

[0035] [ka]

[0036] (wherein A represents the binding site to the antibody) An antibody-drug conjugate in which a drug linker represented by the formula:

[0037]

[86] The antibody-drug conjugate according to

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

[87] The antibody-drug conjugate according to

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

[88] The antibody-drug conjugate according to

[87] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 having the amino acid sequence set forth in amino acid numbers 26 to 33 of SEQ ID NO: 1, CDRH2 having the amino acid sequence set forth in amino acid numbers 51 to 58 of SEQ ID NO: 1, and CDRH3 having the amino acid sequence set forth in amino acid numbers 97 to 109 of SEQ ID NO: 1, and a light chain comprising CDRL1 having the amino acid sequence set forth in amino acid numbers 27 to 32 of SEQ ID NO: 2, CDRL2 having the amino acid sequence set forth in amino acid numbers 50 to 52 of SEQ ID NO: 2, and CDRL3 having the amino acid sequence set forth in amino acid numbers 89 to 97 of SEQ ID NO: 2.

[89] The antibody-drug conjugate described in

[87] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of the amino acid sequence set forth in amino acid numbers 1 to 120 of SEQ ID NO: 1, and a light chain having a light chain variable region consisting of the amino acid sequence set forth in amino acid numbers 1 to 107 of SEQ ID NO: 2.

[90] The antibody-drug conjugate described in

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

[0038]

[91] The antibody-drug conjugate described in

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

[92] The antibody-drug conjugate according to any one of

[87] to

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

[93] The antibody-drug conjugate according to

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

[94] The antibody-drug conjugate described in

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

[95] An antibody-drug conjugate according to

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

[0039]

[96] The antibody-drug conjugate according to any one of

[93] to

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

[97] The antibody-drug conjugate according to

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

[98] The antibody-drug conjugate described in

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

[99] The antibody-drug conjugate described in

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

[0100] The antibody-drug conjugate according to any one of

[97] to

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

[0040]

[0101] The antibody-drug conjugate according to

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

[0102] The antibody-drug conjugate described in

[0101] , wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence described in amino acid numbers 20 to 471 of SEQ ID NO: 7 and a light chain consisting of the amino acid sequence described in amino acid numbers 21 to 233 of SEQ ID NO: 8.

[0103] An antibody-drug conjugate described in

[0102] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted.

[0104] An antibody-drug conjugate described in any one of

[0101] to

[0103] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[0105] The antibody-drug conjugate according to

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

[0041]

[0106] The antibody-drug conjugate described in

[0105] , wherein the anti-GPR20 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 472 in SEQ ID NO: 9 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 10.

[0107] An antibody-drug conjugate described in

[0106] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-GPR20 antibody is deleted.

[0108] An antibody-drug conjugate described in any one of

[0105] to

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

[0109] The antibody-drug conjugate according to

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

[0110] The antibody-drug conjugate described in

[0109] , 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.

[0042]

[0111] An antibody-drug conjugate described in

[0110] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.

[0112] An antibody-drug conjugate described in any one of

[0109] to

[0111] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0113] The antibody-drug conjugate described in any one of

[85] to

[0112] , wherein the PARP inhibitor is olaparib, rucaparib, niraparib, talazoparib, or veliparib, or a pharmacologically acceptable salt thereof.

[0114] The antibody-drug conjugate described in

[0113] , wherein the PARP inhibitor is olaparib or a pharmacologically acceptable salt thereof.

[0115] The antibody-drug conjugate described in

[0113] , wherein the PARP inhibitor is rucaparib or a pharmacologically acceptable salt thereof.

[0043]

[0116] The antibody-drug conjugate described in

[0113] , wherein the PARP inhibitor is niraparib or a pharmacologically acceptable salt thereof.

[0117] The antibody-drug conjugate described in

[0113] , wherein the PARP inhibitor is talazoparib or a pharmacologically acceptable salt thereof.

[0118] The antibody-drug conjugate described in

[0113] , wherein the PARP inhibitor is veliparib or a pharmacologically acceptable salt thereof.

[0119] The antibody-drug conjugate described in any one of

[85] to

[0118] , characterized in that the antibody-drug conjugate and the PARP inhibitor are contained as active ingredients in separate formulations and are administered simultaneously or at different times.

[0120] The antibody-drug conjugate according to any one of

[85] to

[0119] , for the treatment of at least one cancer selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, uterine carcinosarcoma, gastrointestinal stromal tumor, renal cancer, and sarcoma.

[0044]

[0121] An antibody-drug conjugate described in

[0120] for the treatment of breast cancer.

[0122] An antibody-drug conjugate described in

[0121] for the treatment of HER2 low-expressing breast cancer.

[0123] An antibody-drug conjugate described in

[0120] for the treatment of gastric cancer.

[0124] An antibody-drug conjugate described in

[0120] for the treatment of ovarian cancer.

[0125] An antibody-drug conjugate described in

[0120] for the treatment of lung cancer.

[0045]

[0126] An antibody-drug conjugate described in

[0120] for the treatment of pancreatic cancer.

[0127] For the manufacture of a medicament for treating a disease by administering in combination with a PARP inhibitor. formula

[0046] [ka]

[0047] (wherein A represents the binding site to the antibody) and an antibody-drug conjugate in which the drug linker represented by the formula:

[0128] The use described in

[0127] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[0129] The use described in

[0128] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[0130] The use described in

[0129] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence set forth in amino acid numbers 26 to 33 in SEQ ID NO: 1, CDRH2 consisting of the amino acid sequence set forth in amino acid numbers 51 to 58 in SEQ ID NO: 1, and CDRH3 consisting of the amino acid sequence set forth in amino acid numbers 97 to 109 in SEQ ID NO: 1, and a light chain comprising CDRL1 consisting of the amino acid sequence set forth in amino acid numbers 27 to 32 in SEQ ID NO: 2, CDRL2 consisting of the amino acid sequence set forth in amino acid numbers 50 to 52 in SEQ ID NO: 2, and CDRL3 consisting of the amino acid sequence set forth in amino acid numbers 89 to 97 in SEQ ID NO: 2.

[0048]

[0131] The use described in

[0129] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain including a heavy chain variable region consisting of the amino acid sequence set forth in amino acid numbers 1 to 120 of SEQ ID NO: 1, and a light chain including a light chain variable region consisting of the amino acid sequence set forth in amino acid numbers 1 to 107 of SEQ ID NO: 2.

[0132] The use described in

[0129] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2.

[0133] The use described in

[0129] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO: 2.

[0134] The use described in any one of

[0129] to

[0133] , wherein the average number of drug linker bonds per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0135] The use described in

[0128] , wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[0049]

[0136] The use described in

[0135] , wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 4.

[0137] The use described in

[0136] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-HER3 antibody is deleted.

[0138] The use described in any one of

[0135] to

[0137] , wherein the average number of drug linker bonds per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0139] The use described in

[0128] , wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[0140] The use described in

[0139] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO: 5 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO: 6.

[0050]

[0141] The use described in

[0140] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-TROP2 antibody is deleted.

[0142] The use described in any one of

[0139] to

[0141] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[0143] The use described in

[0128] , wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[0144] The use described in

[0143] , wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO: 7 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 of SEQ ID NO: 8.

[0145] The use described in

[0144] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted.

[0051]

[0146] The use described in any one of

[0143] to

[0145] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[0147] The use described in

[0128] , wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[0148] The use described in

[0147] , wherein the anti-GPR20 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 472 in SEQ ID NO: 9 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 10.

[0149] The use described in

[0148] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-GPR20 antibody is deleted.

[0150] The use described in any one of

[0147] to

[0149] , wherein the average number of drug linker bonds per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0052]

[0151] The use described in

[0128] , wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[0152] The use described in

[0151] , 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.

[0153] The use described in

[0152] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.

[0154] The use described in any one of

[0151] to

[0153] , wherein the average number of drug linker bonds per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0155] The use described in any one of

[0127] to

[0154] , wherein the PARP inhibitor is olaparib, rucaparib, niraparib, talazoparib, or veliparib, or a pharmacologically acceptable salt thereof.

[0053]

[0156] The use described in

[0155] , wherein the PARP inhibitor is olaparib or a pharmacologically acceptable salt thereof.

[0157] The use described in

[0155] , wherein the PARP inhibitor is rucaparib or a pharmacologically acceptable salt thereof.

[0158] The use described in

[0155] , wherein the PARP inhibitor is niraparib or a pharmacologically acceptable salt thereof.

[0159] The use described in

[0155] , wherein the PARP inhibitor is talazoparib or a pharmacologically acceptable salt thereof.

[0160] The use described in

[0155] , wherein the PARP inhibitor is veliparib or a pharmacologically acceptable salt thereof.

[0054]

[0161] The use described in any one of

[0127] to

[0160] , characterized in that the antibody-drug conjugate and the PARP inhibitor are contained as active ingredients in separate formulations and are administered simultaneously or at different times.

[0162] The use described in any one of

[0127] to

[0161] for the treatment of at least one cancer selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, uterine carcinosarcoma, gastrointestinal stromal tumor, renal cancer, and sarcoma.

[0163] The use described in

[0162] for the treatment of breast cancer.

[0164] The use described in

[0163] for the treatment of HER2 low-expressing breast cancer.

[0165] The use described in

[0162] for the treatment of gastric cancer.

[0055]

[0166] The use described in

[0162] for the treatment of ovarian cancer.

[0167] The use described in

[0162] for the treatment of lung cancer.

[0168] The use described in

[0162] for the treatment of pancreatic cancer.

[0169] A pharmaceutical composition comprising an antibody-drug conjugate and a PARP inhibitor administered in combination, The antibody-drug conjugate has the formula

[0056] [ka]

[0057] (In the formula, the drug linker is bound to the antibody via a thioether bond, and n represents the average number of drug linkers bound per antibody.) A pharmaceutical composition comprising an antibody-drug conjugate represented by the formula:

[0170] The pharmaceutical composition described in

[0169] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[0058]

[0171] The pharmaceutical composition described in

[0170] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[0172] The pharmaceutical composition described in

[0171] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 having the amino acid sequence set forth in amino acid numbers 26 to 33 in SEQ ID NO: 1, CDRH2 having the amino acid sequence set forth in amino acid numbers 51 to 58 in SEQ ID NO: 1, and CDRH3 having the amino acid sequence set forth in amino acid numbers 97 to 109 in SEQ ID NO: 1, and a light chain comprising CDRL1 having the amino acid sequence set forth in amino acid numbers 27 to 32 in SEQ ID NO: 2, CDRL2 having the amino acid sequence set forth in amino acid numbers 50 to 52 in SEQ ID NO: 2, and CDRL3 having the amino acid sequence set forth in amino acid numbers 89 to 97 in SEQ ID NO: 2.

[0173] The pharmaceutical composition described in

[0171] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of the amino acid sequence set forth in amino acid numbers 1 to 120 of SEQ ID NO: 1, and a light chain having a light chain variable region consisting of the amino acid sequence set forth in amino acid numbers 1 to 107 of SEQ ID NO: 2.

[0174] The pharmaceutical composition described in

[0171] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2.

[0175] The pharmaceutical composition described in

[0171] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO: 2.

[0059]

[0176] A pharmaceutical composition described in any one of

[0171] to

[0175] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0177] The pharmaceutical composition described in

[0170] , wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[0178] The pharmaceutical composition described in

[0177] , wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 4.

[0179] The pharmaceutical composition described in

[0178] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-HER3 antibody is deleted.

[0180] A pharmaceutical composition described in any one of

[0177] to

[0179] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0060]

[0181] The pharmaceutical composition described in

[0170] , wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[0182] The pharmaceutical composition described in

[0181] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO: 5 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO: 6.

[0183] The pharmaceutical composition described in

[0182] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-TROP2 antibody is deleted.

[0184] A pharmaceutical composition described in any one of

[0181] to

[0183] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[0185] The pharmaceutical composition described in

[0170] , wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[0061]

[0186] The pharmaceutical composition described in

[0185] , wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO: 7 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 of SEQ ID NO: 8.

[0187] A pharmaceutical composition described in

[0186] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted.

[0188] A pharmaceutical composition described in any one of

[0185] to

[0187] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[0189] The pharmaceutical composition described in

[0170] , wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[0190] The pharmaceutical composition described in

[0189] , wherein the anti-GPR20 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 472 of SEQ ID NO: 9 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO: 10.

[0062]

[0191] The pharmaceutical composition described in

[0190] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-GPR20 antibody is deleted.

[0192] A pharmaceutical composition described in any one of

[0189] to

[0191] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0193] The pharmaceutical composition described in

[0170] , wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[0194] The pharmaceutical composition described in

[0193] , 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.

[0195] The pharmaceutical composition described in

[0194] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.

[0063]

[0196] A pharmaceutical composition described in any one of

[0193] to

[0195] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0197] A pharmaceutical composition described in any one of

[0169] to

[0196] , wherein the PARP inhibitor is olaparib, rucaparib, niraparib, talazoparib, or veliparib, or a pharmacologically acceptable salt thereof.

[0198] The pharmaceutical composition according to

[0197] , wherein the PARP inhibitor is olaparib or a pharmacologically acceptable salt thereof.

[0199] The pharmaceutical composition according to

[0197] , wherein the PARP inhibitor is rucaparib or a pharmacologically acceptable salt thereof.

[0200] The pharmaceutical composition according to

[0197] , wherein the PARP inhibitor is niraparib or a pharmacologically acceptable salt thereof.

[0064]

[0201] The pharmaceutical composition according to

[0197] , wherein the PARP inhibitor is talazoparib or a pharmacologically acceptable salt thereof.

[0202] The pharmaceutical composition according to

[0197] , wherein the PARP inhibitor is veliparib or a pharmacologically acceptable salt thereof.

[0203] A pharmaceutical composition described in any one of

[0169] to

[0202] , characterized in that the antibody-drug conjugate and the PARP inhibitor are contained as active ingredients in separate formulations and are administered simultaneously or at different times.

[0204] A pharmaceutical composition described in any one of

[0169] to

[0203] for the treatment of at least one cancer selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, uterine carcinosarcoma, gastrointestinal stromal tumor, renal cancer, and sarcoma.

[0205] A pharmaceutical composition described in

[0204] for the treatment of breast cancer.

[0065]

[0206] A pharmaceutical composition described in

[0205] for the treatment of HER2 low-expressing breast cancer.

[0207] A pharmaceutical composition described in

[0204] for the treatment of gastric cancer.

[0208] A pharmaceutical composition described in

[0204] for the treatment of ovarian cancer.

[0209] A pharmaceutical composition described in

[0204] for the treatment of lung cancer.

[0210] A pharmaceutical composition described in

[0204] for the treatment of pancreatic cancer.

[0066]

[0211] A method of treatment comprising administering to an individual in need of treatment a combination of an antibody-drug conjugate and a PARP inhibitor, The antibody-drug conjugate has the formula

[0067] [ka]

[0068] (In the formula, the drug linker is bound to the antibody via a thioether bond, and n represents the average number of drug linkers bound per antibody.) The therapeutic method comprises administering to the patient an antibody-drug conjugate as defined above.

[0212] The therapeutic method described in

[0211] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[0213] A therapeutic method described in

[0212] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[0214] The treatment method described in

[0213] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence set forth in amino acid numbers 26 to 33 in SEQ ID NO: 1, CDRH2 consisting of the amino acid sequence set forth in amino acid numbers 51 to 58 in SEQ ID NO: 1, and CDRH3 consisting of the amino acid sequence set forth in amino acid numbers 97 to 109 in SEQ ID NO: 1, and a light chain comprising CDRL1 consisting of the amino acid sequence set forth in amino acid numbers 27 to 32 in SEQ ID NO: 2, CDRL2 consisting of the amino acid sequence set forth in amino acid numbers 50 to 52 in SEQ ID NO: 2, and CDRL3 consisting of the amino acid sequence set forth in amino acid numbers 89 to 97 in SEQ ID NO: 2.

[0215] The treatment method described in

[0213] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of the amino acid sequence set forth in amino acid numbers 1 to 120 of SEQ ID NO: 1, and a light chain having a light chain variable region consisting of the amino acid sequence set forth in amino acid numbers 1 to 107 of SEQ ID NO: 2.

[0069]

[0216] The treatment method described in

[0213] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2.

[0217] The treatment method described in

[0213] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO: 2.

[0218] A therapeutic method described in any one of

[0213] to

[0217] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0219] A therapeutic method described in

[0212] , wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[0220] The treatment method described in

[0219] , wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 4.

[0070]

[0221] A therapeutic method described in

[0220] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-HER3 antibody is deleted.

[0222] A therapeutic method described in any one of

[0219] to

[0221] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0223] The therapeutic method described in

[0212] , wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[0224] The treatment method described in

[0223] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO: 5 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO: 6.

[0225] A therapeutic method described in

[0224] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-TROP2 antibody is deleted.

[0071]

[0226] A therapeutic method described in any one of

[0223] to

[0225] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[0227] A therapeutic method described in

[0212] , wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[0228] The treatment method described in

[0227] , wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence described in amino acid numbers 20 to 471 of SEQ ID NO: 7 and a light chain consisting of the amino acid sequence described in amino acid numbers 21 to 233 of SEQ ID NO: 8.

[0229] A therapeutic method described in

[0228] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted.

[0230] A therapeutic method described in any one of

[0227] to

[0229] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[0072]

[0231] The therapeutic method described in

[0212] , wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[0232] The treatment method described in

[0231] , wherein the anti-GPR20 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 472 in SEQ ID NO: 9 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 10.

[0233] A therapeutic method described in

[0232] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-GPR20 antibody is deleted.

[0234] A therapeutic method described in any one of

[0231] to

[0233] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0235] A therapeutic method described in

[0212] , wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[0073]

[0236] The treatment method described in

[0235] , 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.

[0237] A therapeutic method described in

[0236] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.

[0238] A therapeutic method described in any one of

[0235] to

[0237] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0239] A therapeutic method described in any one of

[0211] to

[0238] , wherein the PARP inhibitor is olaparib, rucaparib, niraparib, talazoparib, or veliparib, or a pharmacologically acceptable salt thereof.

[0240] The treatment method described in

[0239] , wherein the PARP inhibitor is olaparib or a pharmacologically acceptable salt thereof.

[0074]

[0241] The treatment method described in

[0239] , wherein the PARP inhibitor is rucaparib or a pharmacologically acceptable salt thereof.

[0242] The treatment method described in

[0239] , wherein the PARP inhibitor is niraparib or a pharmacologically acceptable salt thereof.

[0243] The treatment method according to

[0239] , wherein the PARP inhibitor is talazoparib or a pharmacologically acceptable salt thereof.

[0244] The pharmaceutical composition described in

[0239] , wherein the PARP inhibitor is veliparib or a pharmacologically acceptable salt thereof.

[0245] A therapeutic method described in any one of

[0211] to

[0244] , characterized in that the antibody-drug conjugate and the PARP inhibitor are contained as active ingredients in separate formulations and administered simultaneously or at different times.

[0075]

[0246] A therapeutic method described in any one of

[0211] to

[0245] for treating at least one cancer selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, uterine carcinosarcoma, gastrointestinal stromal tumor, renal cancer, and sarcoma.

[0247] A therapeutic method described in

[0246] for treating breast cancer.

[0248] A therapeutic method described in

[0247] for treating HER2 low-expressing breast cancer.

[0249] A therapeutic method described in

[0246] for treating gastric cancer.

[0250] A therapeutic method described in

[0246] for treating ovarian cancer.

[0076]

[0251] A therapeutic method described in

[0246] for treating lung cancer.

[0252] A therapeutic method described in

[0246] for the treatment of pancreatic cancer.

[0253] and administering in combination with a PARP inhibitor to treat a disease. formula

[0077] [ka]

[0078] (In the formula, the drug linker is bound to the antibody via a thioether bond, and n represents the average number of drug linkers bound per antibody.) The antibody-drug conjugate shown in FIG.

[0254] The antibody-drug conjugate described in

[0253] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[0255] An antibody-drug conjugate described in

[0254] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[0079]

[0256] The antibody-drug conjugate described in

[0255] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 having the amino acid sequence set forth in amino acid numbers 26 to 33 in SEQ ID NO: 1, CDRH2 having the amino acid sequence set forth in amino acid numbers 51 to 58 in SEQ ID NO: 1, and CDRH3 having the amino acid sequence set forth in amino acid numbers 97 to 109 in SEQ ID NO: 1, and a light chain comprising CDRL1 having the amino acid sequence set forth in amino acid numbers 27 to 32 in SEQ ID NO: 2, CDRL2 having the amino acid sequence set forth in amino acid numbers 50 to 52 in SEQ ID NO: 2, and CDRL3 having the amino acid sequence set forth in amino acid numbers 89 to 97 in SEQ ID NO: 2.

[0257] The antibody-drug conjugate described in

[0255] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of the amino acid sequence set forth in amino acid numbers 1 to 120 of SEQ ID NO: 1, and a light chain having a light chain variable region consisting of the amino acid sequence set forth in amino acid numbers 1 to 107 of SEQ ID NO: 2.

[0258] The antibody-drug conjugate described in

[0255] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence described in SEQ ID NO: 2.

[0259] The antibody-drug conjugate described in

[0255] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO: 2.

[0260] An antibody-drug conjugate described in any one of

[0255] to

[0259] , wherein the average number of drug linker bonds per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0080]

[0261] An antibody-drug conjugate described in

[0254] , wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[0262] The antibody-drug conjugate described in

[0261] , wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 3 and a light chain consisting of the amino acid sequence described in SEQ ID NO: 4.

[0263] An antibody-drug conjugate described in

[0262] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-HER3 antibody is deleted.

[0264] An antibody-drug conjugate described in any one of

[0261] to

[0263] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0265] The antibody-drug conjugate described in

[0254] , wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[0081]

[0266] The antibody-drug conjugate described in

[0265] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO: 5 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO: 6.

[0267] An antibody-drug conjugate described in

[0266] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-TROP2 antibody is deleted.

[0268] An antibody-drug conjugate described in any one of

[0265] to

[0267] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[0269] An antibody-drug conjugate described in

[0254] , wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[0270] The antibody-drug conjugate described in

[0269] , wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence described in amino acid numbers 20 to 471 of SEQ ID NO: 7 and a light chain consisting of the amino acid sequence described in amino acid numbers 21 to 233 of SEQ ID NO: 8.

[0082]

[0271] An antibody-drug conjugate described in

[0270] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted.

[0272] An antibody-drug conjugate described in any one of

[0269] to

[0271] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[0273] An antibody-drug conjugate described in

[0254] , wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[0274] The antibody-drug conjugate described in

[0273] , wherein the anti-GPR20 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence described in amino acid numbers 20 to 472 of SEQ ID NO: 9 and a light chain consisting of the amino acid sequence described in amino acid numbers 21 to 234 of SEQ ID NO: 10.

[0275] An antibody-drug conjugate described in

[0274] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-GPR20 antibody is deleted.

[0083]

[0276] An antibody-drug conjugate described in any one of

[0273] to

[0275] , wherein the average number of drug linker bonds per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0277] An antibody-drug conjugate described in

[0254] , wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[0278] The antibody-drug conjugate described in

[0277] , 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.

[0279] An antibody-drug conjugate described in

[0278] , in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.

[0280] An antibody-drug conjugate described in any one of

[0277] to

[0279] , wherein the average number of drug linker bonds per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0084]

[0281] An antibody-drug conjugate described in any one of

[0253] to

[0280] , wherein the PARP inhibitor is olaparib, rucaparib, niraparib, talazoparib, or veliparib, or a pharmacologically acceptable salt thereof.

[0282] The antibody-drug conjugate described in

[0281] , wherein the PARP inhibitor is olaparib or a pharmacologically acceptable salt thereof.

[0283] The antibody-drug conjugate described in

[0281] , wherein the PARP inhibitor is rucaparib or a pharmacologically acceptable salt thereof.

[0284] The antibody-drug conjugate described in

[0281] , wherein the PARP inhibitor is niraparib or a pharmacologically acceptable salt thereof.

[0285] The antibody-drug conjugate described in

[0281] , wherein the PARP inhibitor is talazoparib or a pharmacologically acceptable salt thereof.

[0085]

[0286] The antibody-drug conjugate described in

[0281] , wherein the PARP inhibitor is veliparib or a pharmacologically acceptable salt thereof.

[0287] An antibody-drug conjugate described in any one of

[0253] to

[0286] , characterized in that the antibody-drug conjugate and the PARP inhibitor are contained as active ingredients in separate formulations and are administered simultaneously or at different times.

[0288] The antibody-drug conjugate described in any one of

[0253] to

[0287] for the treatment of at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, uterine carcinosarcoma, gastrointestinal stromal tumor, renal cancer, and sarcoma.

[0289] An antibody-drug conjugate described in

[0288] for the treatment of breast cancer.

[0290] An antibody-drug conjugate described in

[0289] for the treatment of HER2 low-expressing breast cancer.

[0086]

[0291] An antibody-drug conjugate described in

[0288] for the treatment of gastric cancer.

[0292] An antibody-drug conjugate described in

[0288] for the treatment of ovarian cancer.

[0293] An antibody-drug conjugate described in

[0288] for the treatment of lung cancer.

[0294] An antibody-drug conjugate described in

[0288] for the treatment of pancreatic cancer.

[0295] For the manufacture of a medicament for treating a disease by administering in combination with a PARP inhibitor. formula

[0087] [ka]

[0088] (In the formula, the drug linker is bound to the antibody via a thioether bond, and n represents the average number of drug linkers bound per antibody.) The use of an antibody-drug conjugate as shown in

[0089]

[0296] The use described in

[0295] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[0297] The use described in

[0296] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[0298] The use described in

[0297] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence set forth in amino acid numbers 26 to 33 in SEQ ID NO: 1, CDRH2 consisting of the amino acid sequence set forth in amino acid numbers 51 to 58 in SEQ ID NO: 1, and CDRH3 consisting of the amino acid sequence set forth in amino acid numbers 97 to 109 in SEQ ID NO: 1, and a light chain comprising CDRL1 consisting of the amino acid sequence set forth in amino acid numbers 27 to 32 in SEQ ID NO: 2, CDRL2 consisting of the amino acid sequence set forth in amino acid numbers 50 to 52 in SEQ ID NO: 2, and CDRL3 consisting of the amino acid sequence set forth in amino acid numbers 89 to 97 in SEQ ID NO: 2.

[0299] The use described in

[0297] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain including a heavy chain variable region consisting of the amino acid sequence set forth in amino acid numbers 1 to 120 of SEQ ID NO: 1, and a light chain including a light chain variable region consisting of the amino acid sequence set forth in amino acid numbers 1 to 107 of SEQ ID NO: 2.

[0300] The use described in

[0297] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2.

[0090]

[0301] The use described in

[0297] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO: 2.

[0302] The use described in any one of

[0297] to

[0301] , wherein the average number of drug linker bonds per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0303] The use described in

[0296] , wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[0304] The use described in

[0303] , wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 4.

[0305] The use described in

[0304] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-HER3 antibody is deleted.

[0091]

[0306] The use described in any one of

[0303] to

[0305] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0307] The use described in

[0296] , wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[0308] The use described in

[0307] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO: 5 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO: 6.

[0309] The use described in

[0308] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-TROP2 antibody is deleted.

[0310] The use described in any one of

[0307] to

[0309] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[0092]

[0311] The use described in

[0296] , wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[0312] The use described in

[0311] , wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO: 7 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 of SEQ ID NO: 8.

[0313] The use described in

[0312] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted.

[0314] The use described in any one of

[0311] to

[0313] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[0315] The use described in

[0296] , wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[0093]

[0316] The use described in

[0315] , wherein the anti-GPR20 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 472 in SEQ ID NO: 9 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 10.

[0317] The use described in

[0316] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-GPR20 antibody is deleted.

[0318] The use described in any one of

[0315] to

[0317] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0319] The use described in

[0296] , wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[0320] The use described in

[0319] , 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.

[0094]

[0321] The use described in

[0320] , wherein the lysine residue at the carboxyl terminus of the heavy chain of an anti-CDH6 antibody is deleted.

[0322] The use described in any one of

[0319] to

[0321] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0323] The use described in any one of

[0295] to

[0322] , wherein the PARP inhibitor is olaparib, rucaparib, niraparib, talazoparib, or veliparib, or a pharmacologically acceptable salt thereof.

[0324] The use described in

[0323] , wherein the PARP inhibitor is olaparib or a pharmacologically acceptable salt thereof.

[0325] The use described in

[0323] , wherein the PARP inhibitor is rucaparib or a pharmacologically acceptable salt thereof.

[0095]

[0326] The use described in

[0323] , wherein the PARP inhibitor is niraparib or a pharmacologically acceptable salt thereof.

[0327] The use described in

[0323] , wherein the PARP inhibitor is talazoparib or a pharmacologically acceptable salt thereof.

[0328] The use described in

[0323] , wherein the PARP inhibitor is veliparib or a pharmacologically acceptable salt thereof.

[0329] The use described in any one of

[0295] to

[0328] , characterized in that the antibody-drug conjugate and the PARP inhibitor are contained as active ingredients in separate formulations and are administered simultaneously or at different times.

[0330] The use described in any one of

[0295] to

[0329] for the treatment of at least one cancer selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, uterine carcinosarcoma, gastrointestinal stromal tumor, renal cancer, and sarcoma.

[0096]

[0331] The use described in

[0330] for the treatment of breast cancer.

[0332] Use described in

[0331] for the treatment of HER2 low-expressing breast cancer.

[0333] The use described in

[0330] for the treatment of gastric cancer.

[0334] The use described in

[0330] for the treatment of ovarian cancer.

[0335] The use described in

[0330] for the treatment of lung cancer.

[0097]

[0336] The use described in

[0330] for the treatment of pancreatic cancer.

[0337] formula

[0098] [ka]

[0099] A pharmaceutical composition comprising a PARP inhibitor administered in combination with an anticancer agent which releases a drug represented by the formula (I) in a tumor.

[0338] The pharmaceutical composition described in

[0337] , wherein the PARP inhibitor is olaparib, rucaparib, niraparib, talazoparib, or veliparib, or a pharmacologically acceptable salt thereof.

[0339] The pharmaceutical composition described in

[0338] , wherein the PARP inhibitor is olaparib or a pharmacologically acceptable salt thereof.

[0340] The pharmaceutical composition described in

[0338] , wherein the PARP inhibitor is rucaparib or a pharmacologically acceptable salt thereof.

[0100]

[0341] The pharmaceutical composition described in

[0338] , wherein the PARP inhibitor is niraparib or a pharmacologically acceptable salt thereof.

[0342] The pharmaceutical composition described in

[0338] , wherein the PARP inhibitor is talazoparib or a pharmacologically acceptable salt thereof.

[0343] The pharmaceutical composition described in

[0338] , wherein the PARP inhibitor is veliparib or a pharmacologically acceptable salt thereof.

[0344] A pharmaceutical composition described in any one of

[0337] to

[0343] for the treatment of at least one cancer selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, uterine carcinosarcoma, gastrointestinal stromal tumor, renal cancer, and sarcoma.

[0345] formula

[0101] [ka]

[0102] A therapeutic method comprising administering to an individual in need of treatment a combination of an anticancer agent which releases a drug represented by the formula (I) in a tumor and a PARP inhibitor.

[0103]

[0346] The treatment method described in

[0345] , wherein the PARP inhibitor is olaparib, rucaparib, niraparib, talazoparib, or veliparib, or a pharmacologically acceptable salt thereof.

[0347] The treatment method described in

[0346] , wherein the PARP inhibitor is olaparib or a pharmacologically acceptable salt thereof.

[0348] The treatment method described in

[0346] , wherein the PARP inhibitor is rucaparib or a pharmacologically acceptable salt thereof.

[0349] The treatment method described in

[0346] , wherein the PARP inhibitor is niraparib or a pharmacologically acceptable salt thereof.

[0350] The treatment method described in

[0346] , wherein the PARP inhibitor is talazoparib or a pharmacologically acceptable salt thereof.

[0104]

[0351] The treatment method described in

[0346] , wherein the PARP inhibitor is veliparib or a pharmacologically acceptable salt thereof.

[0352] A therapeutic method described in any one of

[0345] to

[0351] for treating at least one cancer selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, uterine carcinosarcoma, gastrointestinal stromal tumor, renal cancer, and sarcoma.

[0353] and administering in combination with a PARP inhibitor to treat a disease. formula

[0105] [ka]

[0106] 1. An anticancer agent characterized by releasing a drug represented by the formula:

[0354] The anticancer agent described in

[0353] , wherein the PARP inhibitor is olaparib, rucaparib, niraparib, talazoparib, or veliparib, or a pharmacologically acceptable salt thereof.

[0355] The anticancer agent described in

[0354] , wherein the PARP inhibitor is olaparib or a pharmacologically acceptable salt thereof.

[0107]

[0356] The anticancer agent described in

[0354] , wherein the PARP inhibitor is rucaparib or a pharmacologically acceptable salt thereof.

[0357] The anticancer agent described in

[0354] , wherein the PARP inhibitor is niraparib or a pharmacologically acceptable salt thereof.

[0358] The anticancer agent described in

[0354] , wherein the PARP inhibitor is talazoparib or a pharmacologically acceptable salt thereof.

[0359] The anticancer agent described in

[0354] , wherein the PARP inhibitor is veliparib or a pharmacologically acceptable salt thereof.

[0360] The anticancer agent described in any one of

[0353] to

[0359] for the treatment of at least one cancer selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, uterine carcinosarcoma, gastrointestinal stromal tumor, renal cancer, and sarcoma.

[0108]

[0361] For the manufacture of a medicament for treating a disease by administering in combination with a PARP inhibitor. formula

[0109] [ka]

[0110] 2. Use of an anticancer agent which is characterized by releasing a drug represented by the formula:

[0362] The use described in

[0361] , wherein the PARP inhibitor is olaparib, rucaparib, niraparib, talazoparib, or veliparib, or a pharmacologically acceptable salt thereof.

[0363] The use described in

[0362] , wherein the PARP inhibitor is olaparib or a pharmacologically acceptable salt thereof.

[0364] The use described in

[0362] , wherein the PARP inhibitor is rucaparib or a pharmacologically acceptable salt thereof.

[0365] The use described in

[0362] , wherein the PARP inhibitor is niraparib or a pharmacologically acceptable salt thereof.

[0111]

[0366] The use described in

[0362] , wherein the PARP inhibitor is talazoparib or a pharmacologically acceptable salt thereof.

[0367] The use described in

[0362] , wherein the PARP inhibitor is veliparib or a pharmacologically acceptable salt thereof.

[0368] The use described in any one of

[0361] to

[0367] for the treatment of at least one cancer selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, uterine carcinosarcoma, gastrointestinal stromal tumor, renal cancer, and sarcoma. Effect of the Invention

[0112] The present invention can provide a pharmaceutical composition characterized in that a specific antibody-drug conjugate and a PARP inhibitor are administered in combination, and / or a treatment method characterized in that a specific antibody-drug conjugate and a PARP inhibitor are administered in combination to an individual. [Brief description of the drawings]

[0113] [Figure 1] FIG. 1 shows the amino acid sequence of the anti-HER2 antibody heavy chain (SEQ ID NO:1). [Diagram 2] FIG. 2 shows the amino acid sequence of the anti-HER2 antibody light chain (SEQ ID NO:2). [Diagram 3] FIG. 2 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). [Diagram 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. 7 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 amino acid sequence of the anti-GPR20 antibody heavy chain (SEQ ID NO: 9). [Figure 10] FIG. 1 shows the amino acid sequence of the anti-GPR20 antibody light chain (SEQ ID NO: 10). [Figure 11] FIG. 1 shows the amino acid sequence of the anti-CDH6 antibody heavy chain (SEQ ID NO: 11). [Figure 12] FIG. 1 shows the amino acid sequence of the anti-CDH6 antibody light chain (SEQ ID NO: 12). [Figure 13] FIG. 13 shows the tumor growth inhibitory effects of the HER2-ADC(1) and olaparib single-agent administration groups, and the HER2-ADC(1) and olaparib combined administration group in mice subcutaneously implanted with KPL-4 cells. [Figure 14] FIG. 13 shows the tumor growth inhibitory effects of the HER2-ADC(1) and talazoparib single-agent administration groups, and the HER2-ADC(1) and talazoparib combined administration group in mice subcutaneously implanted with KPL-4 cells. [Figure 15] FIG. 13 shows the tumor growth inhibitory effects of the HER2-ADC(1) and niraparib single-agent administration groups, and the HER2-ADC(1) and niraparib combined administration group in mice subcutaneously implanted with KPL-4 cells. [Figure 16] FIG. 13 shows the tumor growth inhibitory effects of the HER2-ADC(1) and rucaparib single-agent administration groups, and the HER2-ADC(1) and rucaparib combined administration group in mice subcutaneously implanted with KPL-4 cells. [Figure 17] This figure shows the tumor growth inhibitory effects of the HER2-ADC(1) and olaparib single-agent administration groups, as well as the combined administration group of HER2-ADC(1) and olaparib, in mice subcutaneously implanted with JIMT-1 cells. [Figure 18] This figure shows the tumor growth inhibitory effects of the HER2-ADC(1) and talazoparib single-agent administration groups, and the combined administration group of HER2-ADC(1) and talazoparib in mice subcutaneously implanted with JIMT-1 cells. [Figure 19] This figure shows the tumor growth inhibitory effects of the HER2-ADC(1) and rucaparib single-agent administration groups, as well as the combined administration group of HER2-ADC(1) and rucaparib, in mice subcutaneously implanted with JIMT-1 cells. [Figure 20] FIG. 13 shows the tumor growth inhibitory effects of the HER2-ADC(1) and olaparib single-agent administration groups, and the HER2-ADC(1) and olaparib combined administration group in mice subcutaneously implanted with NCI-N87 cells. [Figure 21] FIG. 13 shows the tumor growth inhibitory effects of the HER2-ADC(1) and talazoparib single-agent administration groups, and the HER2-ADC(1) and talazoparib combined administration group in mice subcutaneously implanted with NCI-N87 cells. [Figure 22] FIG. 13 shows the tumor growth inhibitory effects of the HER2-ADC(1) and olaparib single-agent administration groups, and the HER2-ADC(1) and olaparib combined administration group in mice subcutaneously implanted with SK-OV-3 cells. [Figure 23]FIG. 13 shows the tumor growth inhibitory effects of the HER2-ADC(1) and talazoparib single-agent administration groups, and the HER2-ADC(1) and talazoparib combined administration group in mice subcutaneously implanted with SK-OV-3 cells. [Figure 24] FIG. 13 shows the tumor growth inhibitory effects of the HER2-ADC(1) and olaparib single-agent administration groups, and the HER2-ADC(1) and olaparib combined administration group in mice subcutaneously implanted with MX-1 cells. [Diagram 25] FIG. 13 shows the tumor growth inhibitory effects of the HER2-ADC(1) and talazoparib single-agent administration groups, and the HER2-ADC(1) and talazoparib combined administration group in mice subcutaneously implanted with MX-1 cells. [Figure 26] FIG. 13 shows the tumor growth inhibitory effects of the HER3-ADC(1) and olaparib single-agent administration groups, and the HER3-ADC(1) and olaparib combined administration group in mice subcutaneously implanted with MX-1 cells. [Figure 27] FIG. 13 shows the tumor growth inhibitory effects of the HER3-ADC(1) and talazoparib single-agent administration groups, and the HER3-ADC(1) and talazoparib combined administration group in mice subcutaneously implanted with MX-1 cells. [Figure 28] FIG. 13 shows the tumor growth inhibitory effects of the HER3-ADC(1) and olaparib single-agent administration groups, and the HER3-ADC(1) and olaparib combined administration group in mice subcutaneously implanted with HCC70 cells. [Figure 29] FIG. 13 shows the tumor growth inhibitory effects of the HER3-ADC(1) and talazoparib single-agent administration groups, and the HER3-ADC(1) and talazoparib combined administration group in mice subcutaneously implanted with HCC70 cells. [Diagram 30] FIG. 13 shows the tumor growth inhibitory effects of the groups administered TROP2-ADC(1) or olaparib alone, and the group administered TROP2-ADC(1) and olaparib in combination, in mice subcutaneously implanted with HCC1806 cells. [Diagram 31]FIG. 13 shows the tumor growth inhibitory effects of the groups administered TROP2-ADC(1) or rucaparib alone, and the group administered TROP2-ADC(1) in combination with rucaparib, in mice subcutaneously implanted with HCC1806 cells. [Diagram 32] FIG. 13 shows the tumor growth inhibitory effects of the groups administered TROP2-ADC(1) or talazoparib alone, and the group administered TROP2-ADC(1) in combination with talazoparib, in mice subcutaneously implanted with HCC1806 cells. [Diagram 33] FIG. 13 shows the tumor growth inhibitory effects of the CDH6-ADC(1) and talazoparib single-agent administration groups, and the CDH6-ADC(1) and talazoparib combined administration group in mice subcutaneously implanted with OV-90 cells. [Diagram 34] FIG. 13 shows the tumor growth inhibitory effects of the CDH6-ADC(1) and rucaparib single-agent administration groups, and the CDH6-ADC(1) and rucaparib combined administration group in mice subcutaneously implanted with OV-90 cells. [Diagram 35] FIG. 13 shows the tumor growth inhibitory effects of the CDH6-ADC(1) and niraparib single-agent administration groups, and the CDH6-ADC(1) and niraparib combined administration group in mice subcutaneously implanted with OV-90 cells. [Diagram 36] FIG. 13 shows the tumor growth inhibitory effects of the CDH6-ADC(1) and veliparib single-agent administration groups, and the CDH6-ADC(1) and veliparib combined administration group in mice subcutaneously implanted with OV-90 cells. [Figure 37] FIG. 13 shows the tumor growth inhibitory effects of the CDH6-ADC(1) and olaparib single-agent administration groups, and the CDH6-ADC(1) and olaparib combined administration group in mice subcutaneously implanted with OV-90 cells. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0114] A preferred embodiment for carrying out the present invention will be described below. Note that the embodiment described below shows one example of a typical embodiment of the present invention, and the scope of the present invention is not to be interpreted narrowly by this embodiment.

[0115] 1. Antibody-drug conjugates The antibody-drug conjugate used in the present invention has the formula

[0116] [ka]

[0117] (wherein A represents the binding site to the antibody) and an antibody via a thioether bond.

[0118] In the present invention, a partial structure of an antibody-drug conjugate consisting of a linker and a drug is referred to as a "drug linker". This drug linker is bonded to a thiol group (in other words, a sulfur atom of a cysteine ​​residue) generated at disulfide bond sites between antibody chains (two sites between heavy chains and two sites between heavy chains and light chains).

[0119] The drug linker of the present invention is based on the topoisomerase I inhibitor exatecan (IUPAC name: (1S,9S)-1-amino-9-ethyl-5-fluoro-1,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione, (chemical name: (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione)). Exatecan has the formula

[0120] [ka]

[0121] It is a camptothecin derivative having an antitumor effect, represented by the following formula:

[0122] The antibody-drug conjugate used in the present invention may also be represented by the following formula:

[0123] [ka]

[0124] Here, the drug linker is bound to the antibody via a thioether bond, and n is synonymous with the so-called average drug binding number (DAR; Drug-to-Antibody Ratio), and indicates the average number of drug linkers bound per antibody. The antibody-drug conjugate used in the present invention is transported into cancer cells, and then the linker moiety is cleaved, formula

[0125] [ka]

[0126] This liberates a compound represented by the formula:

[0127] The above compound is considered to be the main component of the antitumor activity of the antibody-drug conjugate used in the present invention, and has been confirmed 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).

[0128] In addition, the antibody-drug conjugate used in the present invention is also known to have a bystander effect (Ogitani Y. et al., Cancer Science (2016) 107, 1039-1046).

[0129] This bystander effect is exerted when the antibody-drug conjugate used in the present invention is internalized into target-expressing cancer cells, and the compound is released and exerts an antitumor effect on nearby cancer cells that do not express the target.

[0130] This bystander effect is also exhibited as an excellent antitumor effect when the antibody-drug conjugate of the present invention is used in combination with a PARP inhibitor.

[0131] 2. Antibodies in antibody-drug conjugates The antibody in the antibody-drug conjugate used in the present invention may be derived from any species, but is preferably derived from human, rat, mouse, and rabbit. If the antibody is derived from a species other than human, it is preferably chimerized or humanized using well-known techniques. The antibody of the present invention may be a polyclonal antibody or a monoclonal antibody, but is preferably a monoclonal antibody.

[0132] The antibody in the antibody-drug conjugate used in the present invention preferably has the property of targeting cancer cells, and preferably has the property of recognizing cancer cells, the property of binding to cancer cells, the property of being taken up and internalized into cancer cells, and / or cytocidal activity against cancer cells.

[0133] The binding of the antibody to the cancer cells can be confirmed by flow cytometry. The uptake of the antibody into the cancer cells can be confirmed by (1) an assay in which the antibody taken up into the cells is visualized by a fluorescence microscope using a secondary antibody (fluorescently labeled) that binds to the therapeutic antibody (Cell Death and Differentiation (2008) 15, 751-761), (2) an assay in which the amount of fluorescence taken up into the cells is measured using a secondary antibody (fluorescently labeled) that binds to the therapeutic antibody (Molecular Biology of the Cell Vol. 15, 5268-5282, December 2004), or (3) a Mab-ZAP assay in which an immunotoxin that binds to the therapeutic antibody is released when the antibody is taken up into the cells, thereby suppressing cell proliferation (Bio Techniques 28:162-165, January 2000). A recombinant complex protein of the catalytic domain of diphtheria toxin and protein G can also be used as the immunotoxin.

[0134] The antitumor activity of an antibody can be confirmed in vitro by measuring the inhibitory activity against cell proliferation. For example, a cancer cell line that overexpresses the antibody's target protein is cultured, and the antibody is added to the culture system at various concentrations to measure the inhibitory activity against focus formation, colony formation, and spheroid proliferation. In vivo, the antitumor activity can be confirmed, for example, by administering the antibody to nude mice transplanted with a cancer cell line that highly expresses the target protein, and measuring the changes in the cancer cells.

[0135] It is preferable that the antibody itself has an antitumor effect, but since the antibody-drug conjugate is bound to a compound that exerts an antitumor effect, the antibody itself does not necessarily have an antitumor effect. For the purpose of exerting the cytotoxicity of the antitumor compound specifically and selectively in cancer cells, it is important and preferable that the antibody has the property of being internalized and transferred into the cancer cells.

[0136] The antibody in the antibody-drug conjugate used in the present invention can be obtained by known means. For example, it can be obtained by immunizing an animal with an antigenic polypeptide, and collecting and purifying the antibody produced in the body using a method commonly used in this field. The origin of the antigen is not limited to humans, and an animal can also be immunized with an antigen derived from an animal other than humans, such as a mouse or a rat. In this case, an antibody applicable to a human disease can be selected by testing the cross-reactivity of the obtained antibody that binds to a heterologous antigen with a human antigen.

[0137] Alternatively, a hybridoma can be established by fusing an antibody-producing cell that produces an antibody against an antigen with a myeloma cell according to known methods (e.g., Kohler and Milstein, Nature (1975) 256, p. 495-497; Kennet, R. ed., Monoclonal Antibodies, p. 365-367, Plenum Press, NY (1980)), thereby obtaining a monoclonal antibody.

[0138] The antigen can be obtained by genetically engineering a gene encoding an antigen protein in a host cell to produce it. Specifically, a vector capable of expressing an antigen gene is prepared, introduced into a host cell to express the gene, and the expressed antigen is purified. Antibodies can also be obtained by immunizing an animal with the above genetically engineered antigen-expressing cells or a cell line expressing the antigen.

[0139] The antibody in the antibody-drug conjugate used in the present invention is preferably a genetically engineered antibody that has been artificially modified for the purpose of reducing heterologous antigenicity against humans, such as a chimeric antibody or a humanized antibody, or is preferably an antibody having only the genetic sequence of an antibody derived from humans, i.e., a human antibody. These antibodies can be produced using known methods.

[0140] Chimeric antibodies include antibodies whose variable and constant regions are of different species, such as chimeric antibodies in which the variable region of an antibody derived from a mouse or rat is joined to a constant region derived from a human (Proc. Natl. Acad. Sci. USA, 81, 6851-6855, (1984)).

[0141] Examples of humanized antibodies include antibodies in which only the complementarity determining region (CDR) of a heterologous antibody has been incorporated into an antibody of human origin (Nature (1986) 321, p. 522-525), antibodies in which not only the CDR sequence of a heterologous antibody but also some framework amino acid residues of the heterologous antibody have been grafted onto a human antibody by CDR grafting (WO 90 / 07861), and antibodies humanized using a gene conversion mutagenesis strategy (U.S. Pat. No. 5,821,337).

[0142] Examples of human antibodies include antibodies produced using human antibody-producing mice having a human chromosome fragment containing the heavy and light chain genes of a human antibody (see, for example, Tomizuka, K. et al., Nature Genetics (1997) 16, 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 (Kitagawa, Y., Matsuda, T. and Iijima, S. eds.), Kluwer Academic Publishers, 1999; Tomizuka, K. et al., Proc. Natl. Acad. Sci. USA (2000) 97, p.722-727). Alternatively, antibodies obtained by phage display selected from a human antibody library can also be used (see, for example, Wormstone, IM et. al, Investigative Ophthalmology & Visual Science. (2002) 43 (7), p. 2301-2308; Carmen, S. et. al., Briefings in Functional Genomics and Proteomics (2002), 1 (2), p. 189-203; Siriwardena, D. et. al., Ophthalmology (2002) 109 (3), p. 427-431).

[0143] The antibody in the antibody-drug conjugate used in the present invention also includes modified antibodies. The modified antibody means an antibody according to the present invention that has been chemically or biologically modified. Chemical modifications include those having a chemical moiety bonded to the amino acid backbone, or a chemical moiety bonded to an N- or O-linked carbohydrate chain. Biological modifications include those that have been post-translationally modified (e.g., addition of an N- or O-linked sugar chain, processing of the N- or C-terminus, deamidation, isomerization of aspartic acid, oxidation of methionine, etc.), and those that have been expressed using a prokaryotic host cell to add a methionine residue to the N-terminus. In addition, those labeled to enable detection or isolation of the antibody or antigen according to the present invention, such as enzyme-labeled, fluorescent-labeled, and affinity-labeled, are also included in the meaning of such modified antibodies. Such modified antibodies according to the present invention are useful for improving the stability and blood retention of the antibody, reducing antigenicity, and detecting or isolating the antibody or antigen, etc.

[0144] In addition, antibody-dependent cellular cytotoxicity can be enhanced by regulating the sugar chain modification bound to the antibody of the present invention (glycosylation, defucosylation, etc.). Techniques for regulating the sugar chain modification of antibodies are known, including, but not limited to, International Publication Nos. WO 99 / 54342, WO 00 / 61739, WO 02 / 31140, WO 2007 / 133855, and WO 2013 / 120066. The antibody of the present invention also includes an antibody in which the sugar chain modification is regulated.

[0145] It is known that antibodies produced in cultured mammalian cells have a deletion of the lysine residue at the carboxyl terminus of their heavy chains (Journal of Chromatography A, 705: 129-134 (1995)), and also have a deletion of two amino acid residues, glycine and lysine, at the carboxyl terminus of the heavy chain, and amidation of the proline residue located at the carboxyl terminus (Analytical Biochemistry, 360: 75-83 (2007)). However, these deletions and modifications of the heavy chain sequence do not affect the antigen-binding ability and effector functions (complement activation, antibody-dependent cellular cytotoxicity, etc.) of the antibody. Therefore, the antibody according to the present invention also includes antibodies and functional fragments of the antibodies that have been modified in this way, and also includes deletion products in which one or two amino acids have been deleted at the carboxyl terminus of the heavy chain, and deletion products that have been amidated (for example, heavy chains in which the proline residue at the carboxyl terminus has been amidated). However, as long as the antigen-binding ability and effector function are maintained, the deletion of the carboxyl terminus of the heavy chain of the antibody according to the present invention is not limited to the above types. The two heavy chains constituting the antibody according to the present invention may be any one type of heavy chain selected from the group consisting of full-length and the above deletions, or may be a combination of any two types. The quantitative ratio of each deletion may be influenced by the type and culture conditions of the cultured mammalian cells producing the antibody according to the present invention, but the antibody according to the present invention is preferably one in which one amino acid residue is deleted at the carboxyl terminus of both of the two heavy chains.

[0146] The isotype of the antibody according to the present invention can be, for example, IgG (IgG1, IgG2, IgG3, IgG4), etc., and preferably IgG1 or IgG2.

[0147] The antibody in the antibody-drug conjugate used in the present invention is not particularly limited, and examples thereof include anti-HER2 antibody, anti-HER3 antibody, anti-TROP2 antibody, anti-B7-H3 antibody, anti-GPR20 antibody, anti-CDH6 antibody, anti-CD3 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD37 antibody, anti-CD56 antibody, anti-CD98 antibody, anti-DR5 antibody, anti-EGFR antibody, anti-EPHA2 antibody, anti-FGFR2 antibody, anti-FGFR4 antibody, anti-FOLR1 antibody, anti-VEGF antibody, anti-CD20 antibody, anti-C Examples of antibodies include D22 antibody, anti-CD70 antibody, anti-PSMA antibody, anti-CEA antibody, anti-Mesothelin antibody, anti-A33 antibody, anti-CanAg antibody, anti-Cripto antibody, anti-G250 antibody, anti-MUC1 antibody, anti-GPNMB antibody, anti-Integrin antibody, anti-Tenascin-C antibody, and anti-SLC44A4 antibody, and preferred examples include anti-HER2 antibody, anti-HER3 antibody, anti-TROP2 antibody, anti-B7-H3 antibody, anti-GPR20 antibody, and anti-CDH6 antibody.

[0148] In the present invention, the term "anti-HER2 antibody" refers to an antibody that specifically binds to HER2 (Human Epidermal Growth Factor Receptor Type 2; ErbB-2), and preferably has the activity of being internalized into HER2-expressing cells upon binding to HER2.

[0149] Examples of anti-HER2 antibodies include trastuzumab (US Pat. No. 5,821,337) and pertuzumab (International Publication No. WO 01 / 00245), and preferably trastuzumab.

[0150] In the present invention, the term "anti-HER3 antibody" refers to an antibody that specifically binds to HER3 (Human Epidermal Growth Factor Receptor Type 3; ErbB-3), and preferably has the activity of being internalized into HER3-expressing cells upon binding to HER3.

[0151] Examples of anti-HER3 antibodies include Patritumab (U3-1287), U1-59 (WO 2007 / 077028), MM-121 (Seribantumab), the anti-ERBB3 antibodies described in WO 2008 / 100624, RG-7116 (Lumretuzumab), and LJM-716 (Elgemtumab), and preferred examples include Patritumab and U1-59.

[0152] In the present invention, the term "anti-TROP2 antibody" refers to an antibody that specifically binds to TROP2 (TACSTD2: Tumor-associated calcium signal transducer 2; EGP-1), and preferably has the activity of being internalized into TROP2-expressing cells by binding to TROP2.

[0153] An example of an anti-TROP2 antibody is hTINA1-H1L1 (WO 2015 / 098099).

[0154] In the present invention, the term "anti-B7-H3 antibody" refers to an antibody that specifically binds to B7-H3 (B cell antigen #7 homolog 3; PD-L3; CD276), and preferably has the activity of being internalized into B7-H3-expressing cells through binding to B7-H3.

[0155] An example of an anti-B7-H3 antibody is M30-H1-L4 (WO 2014 / 057687).

[0156] In the present invention, the term "anti-GPR20 antibody" refers to an antibody that specifically binds to GPR20 (G protein-coupled receptor 20), and preferably has the activity of being internalized into GPR20-expressing cells through binding to GPR20.

[0157] An example of an anti-GPR20 antibody is h046-H4e / L7 (International Publication No. 2018 / 135501).

[0158] In the present invention, the term "anti-CDH6 antibody" refers to an antibody that specifically binds to CDH6 (Cadherin-6), and preferably has the activity of being internalized into CDH6-expressing cells through binding to CDH6.

[0159] An example of an anti-CDH6 antibody is H01L02 (International Publication No. 2018 / 212136).

[0160] 3. Preparation of Antibody-drug Conjugates The drug linker intermediate used in the preparation of the antibody-drug conjugate of the present invention is represented by the following formula:

[0161] [ka]

[0162] The drug linker intermediate shown above is N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]glycylglycyl-L-phenylalanyl-N-[(2-{[(1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4': It can be expressed by the chemical name, "6,7]indolizino[1,2-b]quinolin-1-yl]amino}-2-oxoethoxy)methyl]glycinamide," and can be produced with reference to the descriptions in WO 2014 / 057687, WO 2015 / 098099, WO 2015 / 115091, WO 2015 / 155998, and WO 2019 / 044947.

[0163] The antibody-drug conjugate used in the present invention can be prepared by reacting the above-mentioned drug linker intermediate with an antibody having a thiol group (also called a sulfhydryl group).

[0164] An antibody having a sulfhydryl group can be obtained by a method 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) can be used in an amount of 0.3 to 3 molar equivalents per antibody interchain disulfide, and reacted with the antibody in a buffer containing a chelating agent such as ethylenediaminetetraacetic acid (EDTA), to obtain an antibody having a sulfhydryl group in which the antibody interchain disulfide has been partially or completely reduced.

[0165] Additionally, 2-20 molar equivalents of drug linker intermediate can be used per antibody bearing a sulfhydryl group to produce antibody-drug conjugates with 2-8 drugs attached per antibody.

[0166] The average number of drugs bound per antibody molecule in the produced antibody-drug conjugate can be calculated, for example, by a method in which the UV absorbance of the antibody-drug conjugate and its conjugation precursor are measured at two wavelengths, 280 nm and 370 nm (UV method), or by a method in which the antibody-drug conjugate is treated with a reducing agent, and each of the resulting fragments is quantified by HPLC measurement and then calculated (HPLC method).

[0167] Conjugation of an antibody and a drug linker intermediate, and calculation of the average number of drugs bound per antibody molecule of an antibody-drug conjugate can be carried out with reference to the descriptions in WO 2014 / 057687, WO 2015 / 098099, WO 2015 / 115091, WO 2015 / 155998, WO 2018 / 135501, WO 2018 / 212136, etc.

[0168] In the present invention, the term "anti-HER2 antibody-drug conjugate" refers to an antibody-drug conjugate according to the present invention in which the antibody is an anti-HER2 antibody.

[0169] The anti-HER2 antibody is preferably an antibody comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence set forth in amino acid numbers 26 to 33 in SEQ ID NO: 1, CDRH2 consisting of the amino acid sequence set forth in amino acid numbers 51 to 58 in SEQ ID NO: 1, and CDRH3 consisting of the amino acid sequence set forth in amino acid numbers 97 to 109 in SEQ ID NO: 1, and a light chain comprising CDRL1 consisting of the amino acid sequence set forth in amino acid numbers 27 to 32 in SEQ ID NO: 2, CDRL2 consisting of the amino acid sequence set forth in amino acid numbers 50 to 52 in SEQ ID NO: 2, and CDRL3 consisting of the amino acid sequence set forth in amino acid numbers 89 to 97 in SEQ ID NO: 2, More preferably, the antibody comprises a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence set forth in amino acid numbers 1 to 120 of SEQ ID NO: 1, and a light chain comprising a light chain variable region consisting of the amino acid sequence set forth in amino acid numbers 1 to 107 of SEQ ID NO: 2, Even more preferably, it is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2, or an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO: 2.

[0170] The average number of drug linker bonds per antibody in the anti-HER2 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 8, even more preferably 7 to 8, even more preferably 7.5 to 8, and even more preferably about 8.

[0171] Anti-HER2 antibody-drug conjugates can be produced by referring to the descriptions in WO 2015 / 115091 and the like.

[0172] In the present invention, the term "anti-HER3 antibody-drug conjugate" refers to an antibody-drug conjugate according to the present invention in which the antibody is an anti-HER3 antibody.

[0173] The anti-HER3 antibody is preferably an antibody comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence set forth in amino acid numbers 26 to 35 of SEQ ID NO: 3, CDRH2 consisting of the amino acid sequence set forth in amino acid numbers 50 to 65 of SEQ ID NO: 3, and CDRH3 consisting of the amino acid sequence set forth in amino acid numbers 98 to 106 of SEQ ID NO: 3, and a light chain comprising CDRL1 consisting of the amino acid sequence set forth in amino acid numbers 24 to 39 of SEQ ID NO: 4, CDRL2 consisting of the amino acid sequence set forth in amino acid numbers 56 to 62 of SEQ ID NO: 4, and CDRL3 consisting of the amino acid sequence set forth in amino acid numbers 95 to 103 of SEQ ID NO: 4, More preferably, the antibody comprises a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence set forth in amino acid numbers 1 to 117 of SEQ ID NO: 3, and a light chain comprising a light chain variable region consisting of the amino acid sequence set forth in amino acid numbers 1 to 113 of SEQ ID NO: 4, Even more preferably, the antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 4, or an antibody in which the lysine residue at the carboxyl terminus of the heavy chain of the antibody is deleted.

[0174] The average number of drug linker bonds per antibody in the anti-HER3 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 8, even more preferably 7 to 8, even more preferably 7.5 to 8, and even more preferably about 8.

[0175] Anti-HER3 antibody-drug conjugates can be produced by referring to the descriptions in WO 2015 / 155998 and the like.

[0176] In the present invention, the term "anti-TROP2 antibody-drug conjugate" refers to an antibody-drug conjugate according to the present invention in which the antibody is an anti-TROP2 antibody.

[0177] The anti-TROP2 antibody is preferably an antibody comprising a heavy chain comprising a CDRH1 consisting of the amino acid sequence set forth in amino acid numbers 50 to 54 of SEQ ID NO:5, a CDRH2 consisting of the amino acid sequence set forth in amino acid numbers 69 to 85 of SEQ ID NO:5, and a CDRH3 consisting of the amino acid sequence set forth in amino acid numbers 118 to 129 of SEQ ID NO:5, and a light chain comprising a CDRL1 consisting of the amino acid sequence set forth in amino acid numbers 44 to 54 of SEQ ID NO:6, a CDRL2 consisting of the amino acid sequence set forth in amino acid numbers 70 to 76 of SEQ ID NO:6, and a CDRL3 consisting of the amino acid sequence set forth in amino acid numbers 109 to 117 of SEQ ID NO:6, More preferably, it is an antibody comprising a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence set forth in amino acid numbers 20 to 140 of SEQ ID NO:5, and a light chain comprising a light chain variable region consisting of the amino acid sequence set forth in amino acid numbers 21 to 129 of SEQ ID NO:6, Even more preferably, the antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO:5 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO:6, or an antibody in which the lysine residue at the carboxyl terminus of the heavy chain of the antibody is deleted.

[0178] The average number of drug linker bonds per antibody in the anti-TROP2 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 5, even more preferably 3.5 to 4.5, and even more preferably about 4.

[0179] Anti-TROP2 antibody-drug conjugates can be produced with reference to the descriptions in WO 2015 / 098099, WO 2017 / 002776, and the like.

[0180] In the present invention, the term "anti-B7-H3 antibody-drug conjugate" refers to an antibody-drug conjugate according to the present invention in which the antibody is an anti-B7-H3 antibody.

[0181] The anti-B7-H3 antibody is preferably an antibody comprising a heavy chain comprising a CDRH1 consisting of the amino acid sequence set forth in amino acid numbers 50 to 54 of SEQ ID NO: 7, a CDRH2 consisting of the amino acid sequence set forth in amino acid numbers 69 to 85 of SEQ ID NO: 7, and a CDRH3 consisting of the amino acid sequence set forth in amino acid numbers 118 to 130 of SEQ ID NO: 7, and a light chain comprising a CDRL1 consisting of the amino acid sequence set forth in amino acid numbers 44 to 53 of SEQ ID NO: 8, a CDRL2 consisting of the amino acid sequence set forth in amino acid numbers 69 to 75 of SEQ ID NO: 8, and a CDRL3 consisting of the amino acid sequence set forth in amino acid numbers 108 to 116 of SEQ ID NO: 8, More preferably, it is an antibody comprising a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence set forth in amino acid numbers 20 to 141 of SEQ ID NO: 7, and a light chain comprising a light chain variable region consisting of the amino acid sequence set forth in amino acid numbers 21 to 128 of SEQ ID NO: 8, Even more preferably, the antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO: 7 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 of SEQ ID NO: 8, or an antibody in which the lysine residue at the carboxyl terminus of the heavy chain of the antibody is deleted.

[0182] The average number of drug linker bonds per antibody in the anti-B7-H3 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 5, even more preferably 3.5 to 4.5, and even more preferably about 4.

[0183] The anti-B7-H3 antibody-drug conjugate used in the present invention can be produced with reference to the descriptions in WO 2014 / 057687, WO 2017 / 002776, and the like.

[0184] In the present invention, the term "anti-GPR20 antibody-drug conjugate" refers to an antibody-drug conjugate in which the antibody is an anti-GPR20 antibody.

[0185] The anti-GPR20 antibody is preferably an antibody comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence set forth in amino acid numbers 45 to 54 of SEQ ID NO: 9, CDRH2 consisting of the amino acid sequence set forth in amino acid numbers 69 to 78 of SEQ ID NO: 9, and CDRH3 consisting of the amino acid sequence set forth in amino acid numbers 118 to 131 of SEQ ID NO: 9, and a light chain comprising CDRL1 consisting of the amino acid sequence set forth in amino acid numbers 44 to 54 of SEQ ID NO: 10, CDRL2 consisting of the amino acid sequence set forth in amino acid numbers 70 to 76 of SEQ ID NO: 10, and CDRL3 consisting of the amino acid sequence set forth in amino acid numbers 109 to 117 of SEQ ID NO: 10, More preferably, it is an antibody comprising a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence set forth in amino acid numbers 20 to 142 of SEQ ID NO: 9, and a light chain comprising a light chain variable region consisting of the amino acid sequence set forth in amino acid numbers 21 to 129 of SEQ ID NO: 10, Even more preferably, the antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 472 of SEQ ID NO: 9 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO: 10, or an antibody in which the lysine residue at the carboxyl terminus of the heavy chain of the antibody is deleted.

[0186] The average number of drug linker bonds per antibody in the anti-GPR20 antibody-drug conjugate used in the present invention is preferably 2 to 8, more preferably 3 to 8, even more preferably 7 to 8, even more preferably 7.5 to 8, and even more preferably about 8.

[0187] The anti-GPR20 antibody-drug conjugate used in the present invention can be produced with reference to the descriptions in International Publication No. 2018 / 135501, etc.

[0188] In the present invention, the term "anti-CDH6 antibody-drug conjugate" refers to an antibody-drug conjugate in which the antibody is an anti-CDH6 antibody.

[0189] The anti-CDH6 antibody is preferably an antibody comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence set forth in amino acid numbers 45 to 54 in SEQ ID NO:11, CDRH2 consisting of the amino acid sequence set forth in amino acid numbers 69 to 78 in SEQ ID NO:11, and CDRH3 consisting of the amino acid sequence set forth in amino acid numbers 118 to 130 in SEQ ID NO:11, and a light chain comprising CDRL1 consisting of the amino acid sequence set forth in amino acid numbers 44 to 54 in SEQ ID NO:12, CDRL2 consisting of the amino acid sequence set forth in amino acid numbers 70 to 76 in SEQ ID NO:12, and CDRL3 consisting of the amino acid sequence set forth in amino acid numbers 109 to 116 in SEQ ID NO:12, More preferably, it is an antibody comprising a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence set forth in amino acid numbers 20 to 141 of SEQ ID NO: 11, and a light chain comprising a light chain variable region consisting of the amino acid sequence set forth in amino acid numbers 21 to 128 of SEQ ID NO: 12, Even more preferably, the antibody 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, or an antibody in which the lysine residue at the carboxyl terminus of the heavy chain of the antibody is deleted.

[0190] The average number of drug linker bonds per antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is preferably 2 to 8, more preferably 3 to 8, even more preferably 7 to 8, even more preferably 7.5 to 8, and even more preferably about 8.

[0191] The anti-CDH6 antibody-drug conjugate used in the present invention can be produced with reference to the descriptions in International Publication No. 2018 / 212136, etc.

[0192] 4. PARP inhibitors In the present invention, the "PARP inhibitor" refers to a drug that inhibits PARP (polyadenosine 5' diphosphate (ADP) ribose polymerase) and thereby prevents the repair of single-strand breaks (Benafif S, et al., Onco. Targets Ther. (2015) 8, 519-528.) (Fong PC, et al., N. Engl. J. Med. (2009) 361, 123-134.) (Gelmon KA, et al., Lancet Oncol. (2011) 12, 852-861.). There are multiple subtypes of PARP, and the PARP inhibitor in the present invention preferably inhibits PARP-1 and PARP-2. The PARP inhibitor in the present invention is not limited as long as it is a drug that has the function of inhibiting the repair of single-strand breaks by inhibiting PARP, but is preferably olaparib (Menear KA, et al., J. Med. Chem. (2008) 51, 6581-6591), rucaparib (Gillmore AT, et al., Org. Process Res. Dev. (2012) 16, 1897-1904), niraparib (Jones P, et al., J. Med. Chem. (2009) 52, 7170-7185), talazoparib (Shen Y, et al., Clin. Cancer Res. (2013) 19(18), 5003-15.), Veliparib, Pamiparib, and Fluzoparib, and pharmacologically acceptable salts thereof, and more preferably, Olaparib, Rucaparib, Niraparib, Talazoparib, and Veliparib, and pharmacologically acceptable salts thereof.

[0193] The "pharmacologically acceptable salt" of the PARP inhibitor in the present invention may be either an acid addition salt or a base addition salt, but is preferably an acid addition salt, and examples thereof include lower alkane sulfonate salts such as camsylate (camphorsulfonate), methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; arylsulfonate salts such as tosylate (p-toluenesulfonate) and benzenesulfonate; inorganic acid salts such as phosphate, nitrate, perchlorate, and sulfate; hydrohalide salts such as hydrochloride, hydrobromide, hydroiodide, and hydrofluoride; organic acid salts such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalate, and maleate; and amino acid salts such as ornithine, glutamate, and aspartate.

[0194] Furthermore, the PARP inhibitors and pharmacologically acceptable salts thereof may exist as solvates, and these solvates are also included in the PARP inhibitors and pharmacologically acceptable salts thereof of the present invention.

[0195] Furthermore, the PARP inhibitor or a pharmacologically acceptable salt thereof used in the present invention may exist as a solvate, and these solvates are also included in the PARP inhibitor or a pharmacologically acceptable salt thereof used in the present invention.

[0196] Olaparib is a

[0197] [ka]

[0198] It is a compound represented by the formula:

[0199] Rucaparib is a

[0200] [ka]

[0201] The pharmacologically acceptable salt of rucaparib is preferably a camsylate or a phosphate.

[0202] Niraparib is a

[0203] [ka]

[0204] It is a compound represented by the formula:

[0205] Talazoparib is a

[0206] [ka]

[0207] The pharmacologically acceptable salt of talazoparib is preferably a tosylate (also called talazoparib tosilate).

[0208] Veliparib is a

[0209] [ka]

[0210] The pharmacologically acceptable salt of veliparib is preferably the dihydrochloride salt (veliparib dihydrochloride).

[0211] 5. Pharmaceuticals Hereinafter, a pharmaceutical composition and a treatment method characterized in that the antibody-drug conjugate according to the present invention and a PARP inhibitor are administered in combination will be described.

[0212] The pharmaceutical composition and treatment method of the present invention may be characterized in that the antibody-drug conjugate and the PARP inhibitor are contained as active ingredients in separate formulations and administered simultaneously or at different times, or may be characterized in that the antibody-drug conjugate and the PARP inhibitor are contained as active ingredients in a single formulation and administered.

[0213] The pharmaceutical composition and treatment method of the present invention can be used for the treatment of cancer, and preferably, breast cancer (including triple-negative breast cancer and luminal breast cancer), gastric cancer (sometimes referred to as gastric adenocarcinoma), colon cancer (sometimes referred to as colorectal cancer, including colon cancer and rectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), esophageal cancer, head and neck cancer (including salivary gland cancer and pharyngeal cancer), gastroesophageal junction adenocarcinoma, biliary tract cancer (including bile duct cancer), Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, cervical cancer, and squamous cell carcinoma. The present invention can be used to treat at least one cancer selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, uterine carcinosarcoma, gastrointestinal stromal tumor, renal cancer, and sarcoma.

[0214] Among the antibody-drug conjugates used in the present invention, the antibody-drug conjugate having a particular antibody is suitable, which can be determined by examining the type of cancer and tumor marker. For example, when HER2 expression is confirmed in cancer, anti-HER2 antibody-drug conjugates can be preferably used, when HER3 expression is confirmed in cancer, anti-HER3 antibody-drug conjugates can be preferably used, when TROP2 expression is confirmed in cancer, anti-TROP2 antibody-drug conjugates can be preferably used, when B7-H3 expression is confirmed in cancer, anti-B7-H3 antibody-drug conjugates can be preferably used, when GPR20 expression is confirmed in cancer, anti-GPR20 antibody-drug conjugates can be preferably used, and when CDH6 expression is confirmed in cancer, anti-CDH6 antibody-drug conjugates can be preferably used.

[0215] The presence or absence of HER2, HER3, TROP2, B7-H3, GPR20, and CDH6, as well as other tumor markers, can be confirmed, for example, by collecting tumor tissue from a cancer patient and testing the formalin-fixed, paraffin-embedded (FFPE) specimen at the gene product (protein) level using immunohistochemistry (IHC), flow cytometry, western blot analysis, etc., or by testing at the gene transcription level using in situ hybridization (ISH), quantitative PCR (q-PCR), microarray analysis, etc. Alternatively, acellular circulating tumor DNA (ctDNA) can be collected from a cancer patient and confirmed by testing using a method such as next-generation sequencing (NGS).

[0216] In addition, when the antibody-drug conjugate used in the present invention is an anti-HER2 antibody-drug conjugate, the pharmaceutical composition and treatment method of the present invention can be suitably used not only for HER2-overexpressing cancers, but also for HER2-low expressing cancers and HER2-mutated cancers.

[0217] In the present invention, the term "HER2-overexpressing cancer" is not particularly limited as long as it is recognized as a HER2-overexpressing cancer by those skilled in the art, but preferably includes cancer in which HER2 expression is determined to be 3+ by immunohistochemistry, or cancer in which HER2 expression is determined to be 2+ by immunohistochemistry and HER2 expression is determined to be positive by in situ hybridization. The in situ hybridization method of the present invention includes fluorescent in situ hybridization (FISH) and dual color in situ hybridization (DISH).

[0218] In the present invention, the term "HER2 low-expressing cancer" is not particularly limited as long as it is recognized as a HER2 low-expressing cancer by those skilled in the art, but preferably includes cancer in which HER2 expression is determined to be 2+ by immunohistochemistry and HER2 expression is determined to be negative by in situ hybridization, or cancer in which HER2 expression is determined to be 1+ by immunohistochemistry.

[0219] There are no particular limitations on the method for determining the degree of HER2 expression by immunohistochemistry, or the method for determining whether HER2 expression is positive or negative by in situ hybridization, as long as it is recognized by those skilled in the art. For example, the HER2 Testing Guide, Breast Cancer Edition, Fourth Edition (created by the Breast Cancer HER2 Testing Pathology Subcommittee) can be mentioned.

[0220] The HER2-low-expressing cancer for which the pharmaceutical composition and treatment method of the present invention can be used is preferably HER2-low-expressing breast cancer, HER2-low-expressing gastric cancer, HER2-low-expressing colon cancer, or HER2-low-expressing non-small cell lung cancer, and more preferably HER2-low-expressing breast cancer.

[0221] The pharmaceutical composition and treatment method of the present invention can be suitably used in mammals, and more suitably used in humans.

[0222] The antitumor effect of the pharmaceutical composition and treatment method of the present invention can be confirmed, for example, by preparing a model in which cancer cells are transplanted into a test animal and measuring the reduction in tumor volume and the life-prolonging effect caused by administering the pharmaceutical composition and treatment method of the present invention. The combined effect of the antibody-drug conjugate and the PARP inhibitor used in the present invention can be confirmed by comparing the antitumor effect with that of the antibody-drug conjugate and the PARP inhibitor used in the present invention when administered alone.

[0223] Furthermore, the antitumor effect of the pharmaceutical composition and treatment method of the present invention can be confirmed in clinical trials by the Response Evaluation Criteria in Solid Tumors (RECIST) evaluation method, the WHO evaluation method, the Macdonald evaluation method, body weight measurement, and other methods, and can be determined by indicators such as complete response (CR), partial response (PR), progressive disease (PD), objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), etc.

[0224] By the above-mentioned method, the superiority of the antitumor effect of the pharmaceutical composition and treatment method of the present invention over existing pharmaceutical compositions and treatment methods for cancer treatment can be confirmed.

[0225] The pharmaceutical composition and treatment method of the present invention can slow the growth of cancer cells, suppress their proliferation, and even destroy them. These actions can relieve cancer patients from symptoms caused by cancer and improve their QOL, and the therapeutic effect can be achieved while preserving the life of the cancer patient. Even if the destruction of cancer cells is not achieved, the inhibition and control of the proliferation of cancer cells can enable cancer patients to achieve a higher QOL and longer survival.

[0226] The pharmaceutical composition of the present invention can be applied to patients as a systemic therapy, and can also be applied locally to cancer tissues to be expected to have a therapeutic effect.

[0227] The pharmaceutical composition of the present invention may be administered containing one or more pharma- ceutical compatible components. The pharma-ceutical compatible components may be appropriately selected from formulation additives and others commonly used in this field depending on the dose and administration concentration of the antibody-drug conjugate and PARP inhibitor used in the present invention. For example, the antibody-drug conjugate used in the present invention may be administered as a pharmaceutical composition containing a buffer such as a histidine buffer, an excipient such as sucrose or trehalose, and a surfactant such as polysorbate 80 or 20. The pharmaceutical composition containing the antibody-drug conjugate used in the present invention may be preferably used as an injection, more preferably used as an aqueous injection or a lyophilized injection, and even more preferably used as a lyophilized injection.

[0228] When the pharmaceutical composition containing the antibody-drug conjugate used in the present invention is an aqueous injection, it can be preferably administered intravenously after diluting with a suitable diluent. The diluent can be a glucose solution, a physiological saline solution, etc., preferably a glucose solution, more preferably a 5% glucose solution.

[0229] When the pharmaceutical composition containing the antibody-drug conjugate used in the present invention is a lyophilized injection, it is preferably dissolved in water for injection, and then diluted with a required amount of an appropriate diluent, and then administered by intravenous drip infusion. The diluent may be a glucose solution, a physiological saline solution, etc., preferably a glucose solution, and more preferably a 5% glucose solution.

[0230] Examples of introduction routes that can be used to administer the pharmaceutical composition of the present invention include intravenous, intradermal, subcutaneous, intramuscular, and intraperitoneal routes, and preferably include the intravenous route.

[0231] The antibody-drug conjugate used in the present invention can be administered to humans at intervals of once every 1 to 180 days, preferably once every week, 2 weeks, 3 weeks, or 4 weeks, and more preferably once every 3 weeks. The antibody-drug conjugate used in the present invention can be administered at a dose of about 0.001 to 100 mg / kg per administration, preferably at a dose of 0.8 to 12.4 mg / kg per administration. When the antibody-drug conjugate used in the present invention is an anti-HER2 antibody-drug conjugate, it can be preferably administered at a dose of 0.8 mg / kg, 1.6 mg / kg, 3.2 mg / kg, 5.4 mg / kg, 6.4 mg / kg, 7.4 mg / kg, or 8 mg / kg per administration, at intervals of once every 3 weeks. When the antibody-drug conjugate used in the present invention is an anti-HER3 antibody-drug conjugate, it can be preferably administered at a dose of 1.6 mg / kg, 3.2 mg / kg, 4.8 mg / kg, 5.6 mg / kg, 6.4 mg / kg, 8.0 mg / kg, 9.6 mg / kg, or 12.8 mg / kg once every three weeks. When the antibody-drug conjugate used in the present invention is an anti-TROP2 antibody-drug conjugate, it can be preferably administered at a dose of 0.27 mg / kg, 0.5 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 4.0 mg / kg, 6.0 mg / kg, or 8.0 mg / kg once every three weeks.

[0232] The PARP inhibitor according to the present invention can be administered to humans at intervals of 1 to 2 times every 1 to 7 days, and preferably once a day or twice a day. The PARP inhibitor used in the present invention can be administered at a dose of 0.1 mg to 3000 mg per administration, and preferably at a dose of 0.25 mg to 600 mg per administration.

[0233] When the PARP inhibitor used in the present invention is olaparib or a pharmacologically acceptable salt thereof, it can be orally administered at a dose of 100 mg, 150 mg, 200 mg, or 300 mg per administration, preferably twice a day.

[0234] When the PARP inhibitor used in the present invention is rucaparib or a pharmacologically acceptable salt thereof, it can be orally administered at a dose of 200 mg, 250 mg, 300 mg, 400 mg, 500 mg or 600 mg per administration, preferably twice a day.

[0235] When the PARP inhibitor used in the present invention is niraparib or a pharmacologically acceptable salt thereof, it can be orally administered at a dose of 100 mg, 200 mg, or 300 mg per administration at intervals of once a day.

[0236] When the PARP inhibitor used in the present invention is talazoparib or a pharmacologically acceptable salt thereof, it can be orally administered at a dose of 0.25 mg, 0.5 mg, 0.75 mg, or 1 mg per administration, preferably at intervals of once a day.

[0237] The pharmaceutical composition and treatment method of the present invention may further contain a cancer therapeutic agent other than the antibody-drug conjugate and PARP inhibitor of the present invention. The pharmaceutical composition and treatment method of the present invention may be administered in combination with other cancer therapeutic agents, thereby enhancing the antitumor effect. The other cancer therapeutic agents used for such purposes may be administered to an individual simultaneously with the pharmaceutical composition of the present invention, separately, or consecutively, or may be administered at different administration intervals.Such cancer therapeutic agents are not limited as long as they have antitumor activity, and examples thereof include irinotecan (CPT-11), cisplatin, carboplatin, oxaliplatin, fluorouracil (5-FU), gemcitabine, capecitabine, paclitaxel, docetaxel, doxorubicin, epirubicin, cyclophosphamide, mitomycin C, and the like. C), Tegafur / Gimeracil / Oteracil combination drug, Cetuximab, Panitumumab, Bevacizumab, Ramucirumab, Regorafenib, Trifluridine / Tipiracil combination drug, Gefitinib, Erlotinib nib, Afatinib, Methotrexate, Pemetrexed, Tamoxifen, Toremifene, Fulvestrant, Leuprorelin, Goserelin, Letrozole, Anastrozole, Progesterone formulation, Trastuzumab, Pertuzumab, and Lapatinib may be mentioned as at least one selected from the group consisting of.

[0238] The pharmaceutical compositions and treatment methods of the present invention can also be used in combination with radiation therapy, for example, a cancer patient can receive radiation therapy before and / or after, or simultaneously with, treatment with the pharmaceutical composition of the present invention.

[0239] The pharmaceutical composition and treatment method of the present invention can also be used as adjuvant chemotherapy in combination with surgery. The pharmaceutical composition of the present invention may be administered before surgery to reduce tumor size (referred to as preoperative adjuvant chemotherapy, or neoadjuvant therapy), or after surgery to prevent tumor recurrence (referred to as postoperative adjuvant chemotherapy, or adjuvant therapy). EXAMPLES

[0240] The present invention will be specifically described with reference to the following examples, but the present invention is not limited thereto. Furthermore, the examples should not be construed as being limiting in any sense.

[0241] Example 1: Preparation of anti-HER2 antibody-drug conjugate (1) According to the production method described in WO 2015 / 115091, an anti-HER2 antibody (an antibody comprising a heavy chain having an amino acid sequence represented by amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain having an amino acid sequence represented by amino acid numbers 1 to 214 in SEQ ID NO: 2) is used to produce a HER2 antibody having the formula

[0242] [ka]

[0243] (wherein A represents the binding site to the antibody) An anti-HER2 antibody-drug conjugate (hereinafter referred to as "HER2-ADC(1)") was produced in which the drug linker represented by the formula: is linked to the anti-HER2 antibody via a thioether bond. The DAR of HER2-ADC(1) is 7.7 or 7.8.

[0244] Example 2: Preparation of anti-TROP2 antibody-drug conjugate (1) According to the production methods described in WO 2015 / 098099 and WO 2017 / 002776, an anti-TROP2 antibody (an antibody comprising a heavy chain having an amino acid sequence represented by amino acid numbers 20 to 470 in SEQ ID NO:5 and a light chain having an amino acid sequence represented by amino acid numbers 21 to 234 in SEQ ID NO:6) is used to produce a compound represented by the formula:

[0245] [ka]

[0246] (wherein A represents the binding site to the antibody) An anti-TROP2 antibody-drug conjugate (hereinafter referred to as "TROP2-ADC(1)") was produced in which the drug linker represented by the formula: was linked to the anti-TROP2 antibody via a thioether bond. The DAR of TROP2-ADC(1) is 3.5 to 4.5.

[0247] Example 3: Preparation of Compound (1) According to the method described in WO 2014 / 057687 and WO 2015 / 115091,

[0248] [ka]

[0249] A compound represented by the following formula (hereinafter referred to as “Compound (1)”) was produced.

[0250] Example 4: Cell proliferation inhibition test (1) The human gastric cancer cell line NCI-N87 obtained from ATCC (American Type Culture Collection) was used for the evaluation. Olaparib, talazoparib, rucaparib (phosphate), niraparib, or DMSO were added to a 1536-well cell culture plate at 2 mM, 400 μM, 80 μM, 16 μM, 3.2 μM, or 640 nM, respectively, at 25 nL / well. Compound (1) prepared at 60nM, 24nM, 9.6nM, 3.8nM, 1.5nM, 0.61nM in RPMI1640 Medium (Thermo Fisher Scientific) containing 10% fetal bovine serum (GE Healthcare), TROP2-ADC (1) prepared at 32nM, 11nM, 3.6nM, 1.2nM, 0.40nM, 0.13nM, or HER2-ADC (1) prepared at 8.0nM, 2.7nM, 0.89nM, 0.30nM, 0.10nM, 0.033nM, was added at 2.5μL / well. Next, 4×10 4 NCI-N87 cells suspended in 1000 cells / mL were seeded at 2.5 μL / well and cultured at 37°C under 5% CO2 for 6 days.

[0251] After incubation, CellTiter-Glo 2.0 Assay (Promega) was diluted with an equal volume of Glo Lysis buffer, 1× (Promega) and added at 2 μL / well. After incubation at room temperature for 1 hour, the luminescence intensity of each well was measured.

[0252] The cell proliferation inhibition rate (%) under each condition was calculated using the following formula. Cell proliferation inhibition rate (%) = 100 × (TB) / (CB)-100 T: Average luminescence intensity of each sample-added well B: Average luminescence intensity in wells with DMSO and medium added C: Average luminescence intensity in wells to which DMSO and cells were added

[0253] In addition, sigmoid fitting was performed using Genedata Screener Analyzer Version 14 (Genedata, hereinafter referred to as Screener) to examine the concentration-dependent changes in cell growth inhibition rate under each combination condition.

[0254] For the combined effect, the difference between the estimated additive effect by the Loewe model (Greco WR. et al., Pharmacol. Rev. 1995 Jun;47(2):331-85) and the sigmoidally fitted cell growth inhibition rate (%) was converted into a matrix, and the synergy score was calculated from the matrix components using the method described in the literature (Lehar J. et al., Nat Biotechnol. 2009 Jul;27(7):659-66). Note that a Synergy Score of 0 indicates an additive effect, a Synergy Score of >0 indicates a synergistic effect, and a Synergy Score of <0 indicates an antagonistic effect.

[0255] The Synergy Score for each combination is shown in Table 1. In cell proliferation inhibition tests against the NCI-N87 cell line, Compound (1), HER2-ADC (1), and TROP2-ADC (1) showed synergistic activity in all combinations with olaparib, talazoparib, rucaparib, and niraparib.

[0256] [Table 1]

[0257] Example 5: Cell proliferation inhibition test (2) The human breast cancer cell line KPL-4 (British Journal of Cancer, (1999) 79 (5 / 6). 707-717) obtained from Dr. Junichi Kurebayashi, Kawasaki Medical School, was used for the evaluation. Olaparib, talazoparib, rucaparib (phosphate), niraparib, or DMSO were added to a 1536-well cell culture plate at 2 mM, 400 μM, 80 μM, 16 μM, 3.2 μM, or 640 nM, respectively, at 25 nL / well. Compound (1) prepared at 36nM, 20nM, 11nM, 6.2nM, 3.4nM, 1.9nM in RPMI1640 Medium containing 10% fetal bovine serum, TROP2-ADC (1) prepared at 40nM, 13nM, 4.4nM, 1.5nM, 0.49nM, 0.16nM, or HER2-ADC (1) prepared at 3.7nM, 1.3nM, 0.48nM, 0.17nM, 0.061nM, 0.022nM, were added at 2.5μL / well. Next, 1×10 4 KPL-4 cells suspended in 1000 cells / mL were seeded at 2.5 μL / well and cultured at 37°C under 5% CO2 for 6 days. After culture, CellTiter-Glo 2.0 Assay was diluted with an equal amount of Glo Lysis buffer, 1×, and added at 2 μL / well. After incubation at room temperature for 1 hour, the luminescence intensity of each well was measured.

[0258] The cell proliferation inhibition rate (%) and the combined effect under each condition were analyzed in the same manner as in Example 4.

[0259] The Synergy Score for each combination is shown in Table 2. In cell proliferation inhibition tests against the KPL-4 cell line, Compound (1), HER2-ADC (1), and TROP2-ADC (1) showed synergistic activity in all combinations with olaparib, talazoparib, rucaparib, and niraparib.

[0260] [Table 2]

[0261] Example 6: Cell proliferation inhibition test (3) The human lung cancer cell line EBC-1 obtained from the Human Science Research Resources Bank (currently the Japanese Collection of Research Bioresources (JCRB) Cell Bank) was used for the evaluation. Olaparib, talazoparib, rucaparib (phosphate), niraparib, or DMSO were added to 1536-well cell culture plates at 2 mM, 400 μM, 80 μM, 16 μM, 3.2 μM, or 640 nM, respectively, at 25 nL / well. Compound (1) was prepared at 16 nM, 8.0 nM, 4.0 nM, 2.0 nM, 1.0 nM, or 0.50 nM in RPMI 1640 Medium containing 10% fetal bovine serum, or TROP2-ADC (1) was prepared at 40 nM, 13 nM, 4.4 nM, 1.5 nM, 0.49 nM, or 0.16 nM in RPMI 1640 Medium containing 10% fetal bovine serum, and then added at 2.5 μL / well. 4 EBC-1 cells suspended in 1000 cells / mL were seeded at 2.5 μL / well and cultured at 37℃ under 5% CO2 for 6 days. After culture, CellTiter-Glo 2.0 Assay was diluted with an equal amount of Glo Lysis buffer, 1×, and added at 2 μL / well. After incubation at room temperature for 1 hour, the luminescence intensity of each well was measured.

[0262] Analysis of the cell proliferation inhibition rate (%) and the combination effect under each condition was performed in the same manner as in Example 4. The synergy scores for each combination are shown in Table 3. In a cell proliferation inhibition test against the EBC-1 cell line, Compound (1) and TROP2-ADC (1) showed synergistic effects in all combinations with olaparib, talazoparib, rucaparib, and niraparib.

[0263] [Table 3]

[0264] Example 7: Cell proliferation inhibition test (4) Human breast cancer cell line HCC70 obtained from ATCC was used for the evaluation. Olaparib, talazoparib, rucaparib (phosphate), niraparib, or DMSO were added to 1536-well cell culture plates at 2 mM, 400 μM, 80 μM, 16 μM, 3.2 μM, or 640 nM, respectively, at 25 nL / well. Compound (1) was added to 800 nM, 200 nM, 50 nM, 13 nM, 3.1 nM, or 0.78 nM, respectively, at 5.6 nM, 2.0 nM, 0.71 nM, 0.26 nM, 0.091 nM, or 0.033 nM, respectively, at 2.5 μL / well, respectively, at 10% fetal bovine serum-containing RPMI 1640 medium. Next, 4 × 10 4 HCC70 cells suspended in 1000 cells / mL were seeded at 2.5 μL / well and cultured at 37°C under 5% CO2 for 6 days. After culture, CellTiter-Glo 2.0 Assay was diluted with an equal amount of Glo Lysis buffer, 1×, and added at 2 μL / well. After incubation at room temperature for 1 hour, the luminescence intensity of each well was measured.

[0265] Analysis of the cell proliferation inhibition rate (%) and the combination effect under each condition was performed in the same manner as in Example 4. The synergy scores for each combination are shown in Table 4. In a cell proliferation inhibition test against HCC70 cell lines, Compound (1) and TROP2-ADC (1) showed synergistic effects in all combinations with olaparib, talazoparib, rucaparib, and niraparib.

[0266] [Table 4]

[0267] Example 8: Cell proliferation inhibition test (5) Human pancreatic cancer cell line BxPC-3 obtained from ATCC was used for the evaluation. Olaparib, talazoparib, rucaparib (phosphate), niraparib, or DMSO were added to 1536-well cell culture plates at 2 mM, 400 μM, 80 μM, 16 μM, 3.2 μM, or 640 nM, respectively, at 25 nL / well. Compound (1) was added to 80 nM, 32 nM, 13 nM, 5.1 nM, 2.0 nM, or 0.82 nM, respectively, at 2.5 μL / well, and TROP2-ADC (1) was added to 16 nM, 5.3 nM, 1.8 nM, 0.59 nM, 0.20 nM, or 0.066 nM, respectively, at 2.5 μL / well, respectively, at 2.5 μL / well, respectively, at 2.5 μL / well. Next, 4 × 10 4 BxPC-3 cells suspended in 1000 cells / mL were seeded at 2.5 μL / well and cultured at 37°C under 5% CO2 for 6 days. After culture, CellTiter-Glo 2.0 Assay (Promega) was diluted with an equal amount of Glo Lysis buffer, 1× (Promega) and added at 2 μL / well. After incubation at room temperature for 1 hour, the luminescence intensity of each well was measured.

[0268] Analysis of the cell proliferation inhibition rate (%) and the combination effect under each condition was performed in the same manner as in Example 4. The synergy scores for each combination are shown in Table 5. In a cell proliferation inhibition test against the BxPC-3 cell line, Compound (1) and TROP2-ADC (1) showed synergistic effects in all combinations with olaparib, talazoparib, rucaparib, and niraparib.

[0269] [Table 5]

[0270] Example 9: Antitumor Test (1) Mice: 5-6 week-old female BALB / c nude mice (Charles River Laboratories Japan) were used in the experiment.

[0271] Measurements and calculations: In all studies, the major and minor diameters of tumors were measured twice a week using an electronic digital caliper (CD-15CX, Mitutoyo Corp.), and tumor volumes (mm 3 ) was calculated using the following formula: Tumor volume (mm 3 ) = 1 / 2 x major axis (mm) x [minor axis (mm)] 2 HER2-ADC(1) was diluted with ABS buffer (10 mM acetate buffer (pH 5.5), 5% sorbitol) and administered intravenously at a volume of 10 mL / kg. Olaparib was dissolved in dimethyl sulfoxide (DMSO) and diluted with 10% 2-hydroxy-propyl-β-cyclodextrin / Dulbecco's Phosphate-Buffered Saline, and then administered intraperitoneally at a volume of 10 mL / kg. Talazoparib was dissolved in DMSO, diluted with 0.5% hydroxypropyl methylcellulose, and orally administered at a volume of 10 mL / kg. Rucaparib (camsylate) and niraparib were dissolved in DMSO, diluted with 0.5% methylcellulose, and orally administered at a volume of 10 mL / kg. The above method is common to Examples 9 to 12.

[0272] KPL-4 cells, a human breast cancer line obtained from Dr. Junichi Kurebayashi of Kawasaki Medical School (British Journal of Cancer, (1999) 79 (5 / 6). 707-717), were suspended in saline and incubated at 1.5 × 10 7 The cells were subcutaneously transplanted into the right flank of female nude mice, and randomized groups were assigned 17 days after transplantation (Day 0). HER2-ADC(1) was administered into the tail vein at a dose of 7.5 mg / kg on Day 0. PARP inhibitors were administered once daily, five times a week for two weeks, at doses of olaparib and niraparib at 50 mg / kg, talazoparib at 0.4 mg / kg, and rucaparib at 150 mg / kg. Each drug was administered alone or in combination, and a vehicle-administered control group was also included.

[0273] The results of the combination of HER2-ADC(1) and olaparib are shown in Figure 13. The tumor growth inhibition rate (Tumor Growth Inhibition, TGI) on the final day of the test for single-agent administration of olaparib was 21%. The TGI for single-agent administration of HER2-ADC(1) was 83%. On the other hand, the combination of HER2-ADC(1) and olaparib showed a significantly superior tumor growth inhibition effect than single-agent administration of olaparib (P<0.0001 (calculated by Dunnett's test. The same applies below)). In addition, the tumor growth inhibition rate was higher than that of single-agent administration of HER2-ADC(1) (TGI, 95%), and a strong combination effect was observed. In the figure, the horizontal axis indicates the number of days after cell transplantation, and the vertical axis indicates the tumor volume. In addition, no particularly noticeable findings such as weight loss were observed in any of the single-agent and combined administration groups. In addition, in the evaluation examples of the antitumor tests below, unless otherwise specified, the tests were conducted using the methods used in these evaluation examples.

[0274] The results of the combination of HER2-ADC(1) and talazoparib are shown in Figure 14. The TGI with talazoparib alone was 31%. The TGI with HER2-ADC(1) alone was 83%. On the other hand, the combination of HER2-ADC(1) and talazoparib showed a significantly better tumor growth inhibition effect than the combination of talazoparib alone (P<0.0001). In addition, the tumor growth inhibition rate was higher than that of the combination of HER2-ADC(1) alone (TGI, 99%), demonstrating a strong combination effect. No particularly noticeable findings such as weight loss were observed in any of the single-agent and combination administration groups.

[0275] The results of the combination of HER2-ADC(1) and niraparib are shown in Figure 15. The TGI with niraparib alone was 39%. The TGI with HER2-ADC(1) alone was 83%. On the other hand, the combination of HER2-ADC(1) and niraparib showed a significantly better tumor growth inhibition effect than the single-agent administration of niraparib (P = 0.0001). In addition, the tumor growth inhibition rate was higher than that of the single-agent administration of HER2-ADC(1) (TGI, 97%), and a strong combination effect was observed. No particularly noticeable findings such as weight loss were observed in any of the single-agent and combination administration groups.

[0276] The results of the combination of HER2-ADC(1) and rucaparib are shown in Figure 16. The TGI with rucaparib alone was 42%. The TGI with HER2-ADC(1) alone was 83%. On the other hand, the combination of HER2-ADC(1) and rucaparib showed a significantly superior tumor growth inhibition effect than the single-agent administration of rucaparib (P<0.0001). In addition, the tumor growth inhibition rate was higher (TGI, 100%) than the single-agent administration of HER2-ADC(1), demonstrating a strong combination effect. No particularly noticeable findings such as weight loss were observed in any of the single-agent or combination administration groups.

[0277] Example 10: Antitumor Test (2) Human breast cancer line JIMT-1 cells purchased from DSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH) were suspended in saline and diluted to 5 × 10 6 The cells were subcutaneously transplanted into the right flank of female nude mice, and 10 days after transplantation, the mice were randomly assigned to groups (Day 0). HER2-ADC(1) was administered into the tail vein at a dose of 10 mg / kg on Day 0. PARP inhibitors were administered once daily, five times a week for three weeks, at doses of olaparib 50 mg / kg, talazoparib 0.4 mg / kg, and rucaparib 150 mg / kg. Groups were administered each drug alone or in combination, and a vehicle-administered control group was also set up.

[0278] The results of the combination of HER2-ADC(1) and olaparib are shown in Figure 17. The TGI with olaparib alone was 26%. The TGI with HER2-ADC(1) alone was 80%. On the other hand, the combination of HER2-ADC(1) and olaparib showed a significantly superior tumor growth inhibition effect than the single-agent administration of olaparib (P<0.0001). In addition, the tumor growth inhibition rate was higher than that of the single-agent administration of HER2-ADC(1) (TGI, 84%). No particularly notable findings such as weight loss were observed in any of the single-agent and combination administration groups.

[0279] The results of the combination of HER2-ADC(1) and talazoparib are shown in Figure 18. The TGI with talazoparib alone was 13%. The TGI with HER2-ADC(1) alone was 80%. On the other hand, the combination of HER2-ADC(1) and talazoparib showed a significantly better tumor growth inhibition effect than the single-agent administration of talazoparib (P<0.0001). In addition, the tumor growth inhibition rate was higher than that of the single-agent administration of HER2-ADC(1) (TGI, 93%), and a strong combination effect was observed. No particularly noticeable findings such as weight loss were observed in any of the single-agent and combination administration groups.

[0280] The results of the combination of HER2-ADC(1) and rucaparib are shown in Figure 19. The TGI with rucaparib alone was 30%. The TGI with HER2-ADC(1) alone was 80%. On the other hand, the combination of HER2-ADC(1) and rucaparib showed a significantly superior tumor growth inhibition effect than the single-agent administration of rucaparib (P = 0.0002). In addition, the tumor growth inhibition rate was higher than that of the single-agent administration of HER2-ADC(1) (TGI, 84%). No particularly noticeable findings such as weight loss were observed in any of the single-agent and combination administration groups.

[0281] Example 11: Antitumor Test (3) Human gastric cancer line NCI-N87 cells purchased from ATCC (American Type Culture Collection) were suspended in saline at 1 × 10 7 The cells were subcutaneously transplanted into the right flank of female nude mice, and 6 days after transplantation, the mice were randomly assigned to groups (Day 0). HER2-ADC(1) was administered into the tail vein at a dose of 1 mg / kg on Day 0. PARP inhibitors were administered once a day, 5 times a week for 2 weeks, with olaparib at 50 mg / kg and talazoparib at 0.4 mg / kg. Each drug was administered alone or in combination, and a vehicle-administered control group was also included. No significant findings, such as weight loss, were observed in any of the single drug or combination administration groups.

[0282] The results of the combination of HER2-ADC(1) and olaparib are shown in Figure 20. The TGI with single-agent administration of olaparib was 26%. The TGI with single-agent administration of HER2-ADC(1) was 45%. On the other hand, the combined administration of HER2-ADC(1) and olaparib had a higher tumor growth inhibition rate (TGI, 48%) than the single-agent administration of olaparib or HER2-ADC(1). No particularly notable findings such as weight loss were observed in any of the single-agent or combined administration groups.

[0283] The results of the combination of HER2-ADC(1) and talazoparib are shown in Figure 21. The TGI with talazoparib alone was -2%. The TGI with HER2-ADC(1) alone was 45%. On the other hand, the combination of HER2-ADC(1) and talazoparib showed a significantly better tumor growth inhibition effect than the single administration of talazoparib (P<0.0001). In addition, the tumor growth inhibition rate was higher than that of the single administration of HER2-ADC(1) (TGI, 67%), and a significantly better combination effect was observed (P=0.0103). No particularly noticeable findings such as weight loss were observed in any of the single-agent and combination administration groups.

[0284] Example 12: Antitumor Test (4) Human ovarian cancer line SK-OV-3 cells purchased from ATCC (American Type Culture Collection) were maintained by nude mouse transplantation, and solid tumor fragments (3 × 3 × 3 mm) were subcutaneously transplanted into the right flank of female nude mice, and randomized groups were assigned 19 days after transplantation (Day 0). HER2-ADC(1) was administered into the tail vein at a dose of 3 mg / kg on Day 0 and Day 14. PARP inhibitors were administered once a day, five times a week for three weeks, with olaparib at 60 mg / kg and talazoparib at 0.4 mg / kg. Each drug was administered alone or in combination, and a solvent-administered group was used as a control group. No significant findings such as weight loss were observed in any of the single drug or combination administration groups.

[0285] The results of the combination of HER2-ADC(1) and olaparib are shown in Figure 22. The TGI with olaparib alone was 15%. The TGI with HER2-ADC(1) alone was 39%. On the other hand, the combination of HER2-ADC(1) and olaparib showed a significantly superior tumor growth inhibition effect than the single-agent administration of olaparib (P = 0.016). In addition, the tumor growth inhibition rate was higher than that of the single-agent administration of HER2-ADC(1) (TGI, 61%). No particularly noticeable findings such as weight loss were observed in any of the single-agent and combination administration groups.

[0286] The results of the combination of HER2-ADC(1) and talazoparib are shown in Figure 23. The TGI with talazoparib alone was 12%. The TGI with HER2-ADC(1) alone was 39%. On the other hand, the combination of HER2-ADC(1) and talazoparib showed a significantly superior tumor growth inhibition effect than the single administration of talazoparib (P = 0.0004). In addition, the tumor growth inhibition rate was higher (TGI, 88%) than the single administration of HER2-ADC(1), and a significantly superior combination effect was observed (P = 0.0136). No particularly noticeable findings such as weight loss were observed in any of the single-agent and combination administration groups.

[0287] Example 13: Preparation of anti-HER3 antibody-drug conjugate (1) According to the production method described in WO 2015 / 155998, an anti-HER3 antibody (an antibody comprising a heavy chain having the amino acid sequence set forth in SEQ ID NO: 3 and a light chain having the amino acid sequence set forth in SEQ ID NO: 4) is used to produce a HER3 antibody having the formula

[0288] [ka]

[0289] (wherein A represents the binding site to the antibody) An anti-HER3 antibody-drug conjugate (hereinafter referred to as "HER3-ADC (1)") was produced in which the drug linker represented by the formula (I) is linked to the anti-HER3 antibody via a thioether bond. The DAR of HER3-ADC (1) is 7.6.

[0290] Example 14: Preparation of anti-CDH6 antibody-drug conjugate (1) According to the production method described in WO 2018 / 212136, an anti-CDH6 antibody (an antibody comprising a heavy chain having an amino acid sequence represented by amino acid numbers 20 to 471 in SEQ ID NO: 11 and a light chain having an amino acid sequence represented by amino acid numbers 21 to 233 in SEQ ID NO: 12) is used to produce a CDH6 antibody having the formula

[0291] [ka]

[0292] (wherein A represents the binding site to the antibody) An anti-CDH6 antibody-drug conjugate (hereinafter referred to as "CDH6-ADC (1)") was produced in which the drug linker represented by the formula (I) is linked to the anti-CDH6 antibody via a thioether bond. The DAR of CDH6-ADC (1) is 7.8.

[0293] Example 15: Antitumor Test (5) In Examples 15 to 17, olaparib was suspended in 0.5% hydroxypropyl methylcellulose, 0.1% Tween 80 and orally administered at a volume of 10 mL / kg. Talazoparib was dissolved in dimethyl acetamide, diluted with 5% Kolliphor HS15 / Dulbecco's phosphate-buffered saline, and orally administered at a volume of 10 mL / kg.

[0294] Human breast cancer cell line MX-1 cells purchased from CLS (Cell Lines Service) were suspended in 50% Matrigel matrix at 5 × 10 6 The cells were subcutaneously transplanted into the right flank of female nude mice, and randomized groups were assigned 13 days after transplantation (Day 0). HER2-ADC(1) was administered into the tail vein at a dose of 3 mg / kg on Day 0. PARP inhibitors were administered once a day, five times a week for two weeks, with olaparib at 100 mg / kg and talazoparib at 0.4 mg / kg. Each drug was administered alone or in combination, and a vehicle-administered control group was also included.

[0295] The results of the combination of HER2-ADC (1) and olaparib are shown in Figure 24. The TGI with single-agent administration of olaparib was 44%. The TGI with single-agent administration of HER2-ADC (1) was 78%. On the other hand, the combination of HER2-ADC (1) and olaparib showed a significantly superior tumor growth inhibitory effect than single-agent administration of olaparib (P < 0.0001), and a significantly superior tumor growth inhibitory effect than single-agent administration of HER2-ADC (1) (P = 0.0001), with a TGI of 97%.

[0296] The results of the combination of HER2-ADC(1) and talazoparib are shown in Figure 25. The TGI with talazoparib alone was 47%. The TGI with HER2-ADC(1) alone was 78%. On the other hand, the combination of HER2-ADC(1) and talazoparib showed a significantly superior tumor growth inhibitory effect (P<0.0001) than the single-agent administration of talazoparib, and a significantly superior tumor growth inhibitory effect (P=0.0001) than the single-agent administration of HER2-ADC(1), with a TGI of 100%. No particularly notable findings such as weight loss were observed in any of the single-agent and combination administration groups.

[0297] Example 16: Antitumor Test (6) In Examples 16 to 17, HER3-ADC(1) was diluted with ABS buffer (10 mM acetate buffer (pH 5.5), 5% sorbitol) and administered into the tail vein at a volume of 10 mL / kg.

[0298] Human breast cancer cell line MX-1 cells were suspended in 50% Matrigel matrix at 5 × 10 6 The cells were subcutaneously transplanted into the right flank of female nude mice, and randomized groups were assigned 13 days after transplantation (Day 0). HER3-ADC(1) was administered into the tail vein at a dose of 3 mg / kg on Days 0, 7, and 15. PARP inhibitors were administered once a day, five times a week for two weeks, with olaparib at 100 mg / kg and talazoparib at 0.4 mg / kg. Groups were administered each drug alone or in combination, and a vehicle-administered control group was also set up.

[0299] The results of the combination of HER3-ADC (1) and olaparib are shown in Figure 26. The TGI with olaparib alone was 23%. The TGI with HER3-ADC (1) alone was 59%. On the other hand, the combination of HER3-ADC (1) and olaparib showed a significantly superior tumor growth inhibitory effect than the single-agent administration of olaparib (P < 0.0001), and a significantly superior tumor growth inhibitory effect than the single-agent administration of HER3-ADC (1) (P = 0.0018), with a TGI of 94%.

[0300] The results of the combination of HER3-ADC(1) and talazoparib are shown in Figure 27. The TGI with talazoparib alone was 49%. The TGI with HER3-ADC(1) alone was 59%. On the other hand, the combination of HER3-ADC(1) and talazoparib showed a significantly superior tumor growth inhibitory effect (P<0.0001) than the single-agent administration of talazoparib, and a significantly superior tumor growth inhibitory effect (P<0.0001) than the single-agent administration of HER3-ADC(1), with a TGI of 99%. No particularly notable findings such as weight loss were observed in any of the single-agent and combination administration groups.

[0301] Example 17: Antitumor Test (7) Human breast cancer cell line HCC70 cells were suspended in saline at 1 × 10 7 The cells were subcutaneously transplanted into the right flank of female nude mice, and randomized groups were assigned 13 days after transplantation (Day 0). HER3-ADC(1) was administered into the tail vein at a dose of 10 mg / kg on Days 0, 7, and 14. PARP inhibitors were administered once a day, five times a week for two weeks, with olaparib at 100 mg / kg and talazoparib at 0.4 mg / kg. Groups were administered each drug alone or in combination, and a vehicle-administered control group was also set up.

[0302] The results of the combination of HER3-ADC(1) and olaparib are shown in Figure 28. The TGI with olaparib alone was 18%. The TGI with HER3-ADC(1) alone was 86%. On the other hand, the combination of HER3-ADC(1) and olaparib showed a significantly superior tumor growth inhibitory effect (P<0.0001) to the single-agent administration of olaparib, with a TGI of 97%.

[0303] The results of the combination of HER3-ADC(1) and talazoparib are shown in Figure 29. The TGI with talazoparib alone was 19%. The TGI with HER3-ADC(1) alone was 86%. On the other hand, the combination of HER3-ADC(1) and talazoparib showed a significantly superior tumor growth inhibitory effect (P<0.0001) to the combination of talazoparib alone, with a TGI of 97%. No particularly notable findings such as weight loss were observed in any of the single-agent and combination administration groups.

[0304] Example 18: Antitumor Test (8) Mice: 5-6 week-old female BALB / c nude mice (Charles River Laboratories Japan) were used in the experiment.

[0305] Measurements and calculations: In all studies, the major and minor diameters of tumors were measured twice a week using an electronic digital caliper (CD-15CX, Mitutoyo Corp.), and tumor volumes (mm 3 ) was calculated using the following formula: Tumor volume (mm 3 ) = 1 / 2 x major axis (mm) x [minor axis (mm)] 2 The tumor growth inhibition rate (TGI) was calculated according to the following formula. Tumor growth inhibition rate (%)=100×(1-T / C) T: Average tumor volume of mice administered the test substance C: Average tumor volume of control mice TROP2-ADC(1) was diluted with ABS buffer and administered intravenously at 10 mL / kg. Olaparib was dissolved in DMSO, diluted with 10% 2-hydroxy-propyl-β-cyclodextrin / Dulbecco's Phosphate-Buffered Saline, and administered intraperitoneally at 10 mL / kg. Rucaparib (camsylate) was dissolved in DMSO, diluted with saline, and administered orally at 10 mL / kg. Talazoparib was dissolved in DMSO, diluted with 10% N,N-Dimethylacetamide / 5% Kolliphor HS 15 / Dulbecco's Phosphate-Buffered Saline, and administered orally at 10 mL / kg.

[0306] Human breast cancer cell line HCC1806 cells purchased from ATCC were suspended in saline at 1 × 10 6 The cells were subcutaneously transplanted into the right flank of female nude mice, and randomized groups were assigned 10 days after transplantation (Day 0). TROP2-ADC(1) was administered at a dose of 3 mg / kg on Day 0. PARP inhibitors were administered once a day, 5 times a week for 2 weeks, at doses of olaparib 50 mg / kg, rucaparib 150 mg / kg, and talazoparib 0.8 mg / kg. Each drug was administered alone or in combination, and a vehicle-administered control group was set up, and the tumor growth inhibition rate (TGI) on Day 21 was calculated. No significant findings such as weight loss were observed in any of the single drug or combination administration groups.

[0307] The results of the combined use of TROP2-ADC(1) and olaparib are shown in Figure 30. The TGI with single-agent administration of olaparib was -9%, and the TGI with single-agent administration of TROP2-ADC(1) was 82%. On the other hand, the TGI with combined administration of TROP2-ADC(1) and olaparib was 93%, demonstrating a significantly superior tumor growth inhibitory effect than single-agent administration of olaparib (P<0.0001; calculated using Dunnett's test; the same applies below), and the tumor growth inhibition rate was higher than that of single-agent administration of TROP2-ADC(1).

[0308] The results of the combination of TROP2-ADC(1) and rucaparib are shown in Figure 31. The TGI with rucaparib alone was 9%, and the TGI with TROP2-ADC(1) alone was 82%. On the other hand, the TGI with the combination of HER2-ADC(1) and rucaparib was 97%, demonstrating a significantly superior tumor growth inhibition effect compared to the single-agent administration of rucaparib (P<0.0001), and a higher tumor growth inhibition rate than the single-agent administration of TROP2-ADC(1).

[0309] The results of the combination of TROP2-ADC(1) and talazoparib are shown in Figure 32. The TGI with talazoparib alone was 27%, and the TGI with TROP2-ADC(1) alone was 82%. On the other hand, the TGI with TROP2-ADC(1) and talazoparib combined was 98%, demonstrating a significantly superior tumor growth inhibitory effect than talazoparib alone (P<0.0001), and a significantly superior tumor inhibitory effect than TROP2-ADC(1) alone (P=0.0209).

[0310] Example 19: Antitumor Test (9) Mice: 5-6 week-old female BALB / c nude mice (Charles River Laboratories Japan) were used in the experiment.

[0311] Measurements and calculations: In all studies, the major and minor diameters of tumors were measured twice a week using an electronic digital caliper (CD-15CX, Mitutoyo Corp.), and tumor volumes (mm 3 ) was calculated using the following formula: Tumor volume (mm 3 ) = 1 / 2 x major axis (mm) x [minor axis (mm)] 2 The tumor growth inhibition rate (TGI) was calculated according to the following formula. Tumor growth inhibition rate (%)=100×(1-T / C) T: Average tumor volume of mice administered the test substance C: Average tumor volume of control mice

[0312] CDH6-ADC(1) was diluted with ABS buffer and administered intravenously at 10 mL / kg. Olaparib was dissolved in DMSO, diluted with 10% 2-hydroxypropyl-β-cyclodextrin / Dulbecco's Phosphate-Buffered Saline, and administered intraperitoneally at 10 mL / kg. Talazoparib was dissolved in DMSO, diluted with 0.5% hydroxypropyl methylcellulose, and administered orally at 10 mL / kg. Rucaparib (camsylate) and niraparib were dissolved in DMSO, diluted with 0.5% methylcellulose, and administered orally at 10 mL / kg. Veliparib was dissolved in 0.05 M CH3COOH solution, and administered orally at 10 mL / kg.

[0313] Human ovarian cancer line OV-90 cells purchased from ATCC were suspended in saline at 1 × 10 7 The cells were subcutaneously transplanted into the right flank of female nude mice, and 14 days after transplantation, mice were randomly assigned to groups (Day 0). CDH6-ADC(1) was administered into the tail vein at a dose of 1 mg / kg on Day 0. PARP inhibitors were administered once daily, five times a week for two weeks, at doses of olaparib 50 mg / kg, talazoparib 0.4 mg / kg, rucaparib 150 mg / kg, niraparib 50 mg / kg, and veliparib 100 mg / kg. Each drug was administered alone or in combination, and a vehicle-administered control group was also set up. The OV-90 model had a tumor size of 1500 mm 3 As a result, at day 17 after administration, 2 out of 6 mice in the control group, 1 out of 6 mice in the rucaparib monotherapy group, and 1 out of 6 mice in the niraparib monotherapy group were euthanized due to weight loss. No mice in the CDH6-ADC monotherapy or combination therapy groups lost weight or required euthanasia.

[0314] The results of the combined use of CDH6-ADC(1) and talazoparib are shown in Figure 33. The TGI with single-agent administration of talazoparib was 12%. The TGI with single-agent administration of CDH6-ADC(1) was 66%. On the other hand, the combined use of CDH6-ADC(1) and talazoparib showed a significantly superior tumor growth inhibition effect compared to single-agent administration of talazoparib (P = 0.0004; calculated using Dunnett's test. The same applies below.). In addition, the tumor growth inhibition rate was higher (TGI, 88%) than that of single-agent administration of CDH6-ADC(1), demonstrating a strong combined effect.

[0315] The results of the combination of CDH6-ADC(1) and rucaparib are shown in Figure 34. The TGI with single-agent administration of rucaparib was 6%. The TGI with single-agent administration of CDH6-ADC(1) was 66%. On the other hand, the combination of CDH6-ADC(1) and rucaparib showed a significantly superior tumor growth inhibition effect than the single-agent administration of rucaparib (P = 0.004). In addition, the tumor growth inhibition rate was higher (TGI, 83%) than the single-agent administration of CDH6-ADC(1), and a strong combination effect was observed.

[0316] The results of the combination of CDH6-ADC(1) and niraparib are shown in Figure 35. The TGI with niraparib alone was 10%. The TGI with CDH6-ADC(1) alone was 66%. On the other hand, the combination of CDH6-ADC(1) and niraparib showed a significantly better tumor growth inhibition effect than the single administration of niraparib (P = 0.0025). In addition, the tumor growth inhibition rate was higher (TGI, 76%) than the single administration of CDH6-ADC(1), and a strong combination effect was observed.

[0317] The results of the combination of CDH6-ADC(1) and veliparib are shown in Figure 36. The TGI with veliparib alone was 4.4%. The TGI with CDH6-ADC(1) alone was 66%. On the other hand, the combination of CDH6-ADC(1) and veliparib showed a significantly better tumor growth inhibition effect than the single administration of veliparib (P = 0.0013). In addition, the tumor growth inhibition rate was higher (TGI, 82%) than the single administration of CDH6-ADC(1), and a strong combination effect was observed.

[0318] The results of the combination of CDH6-ADC(1) and olaparib are shown in Figure 37. The TGI with single-agent administration of olaparib was 10%. The TGI with single-agent administration of CDH6-ADC(1) was 66%. On the other hand, the combination of CDH6-ADC(1) and olaparib showed a significantly superior tumor growth inhibition effect than the single-agent administration of olaparib (P = 0.0025). In addition, the tumor growth inhibition rate was higher (TGI, 79%) than that of single-agent administration of CDH6-ADC(1), and a strong combination effect was observed. [Sequence List Free Text]

[0319] 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. 1. A pharmaceutical composition comprising an antibody-drug conjugate for use in combination with a PARP inhibitor, comprising: The antibody-drug conjugate has the formula (In the formula, A represents the binding site with the antibody.) and an antibody-drug conjugate in which the drug linker represented by the formula: The PARP inhibitor is olaparib, rucaparib, niraparib, talazoparib, or veliparib, or a pharmacologically acceptable salt thereof; Pharmaceutical compositions.

2. The pharmaceutical composition of claim 1, wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

3. The pharmaceutical composition of claim 2, wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

4. The pharmaceutical composition of claim 3, wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising a CDRH1 having the amino acid sequence set forth in amino acid numbers 26 to 33 of SEQ ID NO: 1, a CDRH2 having the amino acid sequence set forth in amino acid numbers 51 to 58 of SEQ ID NO: 1, and a CDRH3 having the amino acid sequence set forth in amino acid numbers 97 to 109 of SEQ ID NO: 1, and a light chain comprising a CDRL1 having the amino acid sequence set forth in amino acid numbers 27 to 32 of SEQ ID NO: 2, a CDRL2 having the amino acid sequence set forth in amino acid numbers 50 to 52 of SEQ ID NO: 2, and a CDRL3 having the amino acid sequence set forth in amino acid numbers 89 to 97 of SEQ ID NO:

2.

5. The pharmaceutical composition according to claim 3, wherein the anti-HER2 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of the amino acid sequence set forth in amino acid numbers 1 to 120 of SEQ ID NO: 1, and a light chain having a light chain variable region consisting of the amino acid sequence set forth in amino acid numbers 1 to 107 of SEQ ID NO:

2.

6. The pharmaceutical composition according to claim 3 , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO:

2.

7. The pharmaceutical composition according to claim 3, wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO:

2.

8. The pharmaceutical composition according to any one of claims 3 to 7, wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

9. The pharmaceutical composition of claim 2, wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

10. The pharmaceutical composition according to claim 9 , wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO:

4.

11. The pharmaceutical composition of claim 10, wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-HER3 antibody is deleted.

12. The pharmaceutical composition according to any one of claims 9 to 11, wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

13. The pharmaceutical composition according to claim 2, wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

14. The pharmaceutical composition according to claim 13, wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO:5 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO:

6.

15. The pharmaceutical composition of claim 14 , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-TROP2 antibody is deleted.

16. The pharmaceutical composition according to any one of claims 13 to 15, wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.

5.

17. The pharmaceutical composition of claim 2, wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

18. The pharmaceutical composition according to claim 17, wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO: 7 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 of SEQ ID NO:

8.

19. The pharmaceutical composition of claim 18, wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted.

20. The pharmaceutical composition according to any one of claims 17 to 19, wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.

5.

21. The pharmaceutical composition of claim 2, wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

22. The pharmaceutical composition according to claim 21, wherein the anti-GPR20 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 472 of SEQ ID NO: 9 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO:

10.

23. The pharmaceutical composition of claim 22, wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-GPR20 antibody is deleted.

24. The pharmaceutical composition according to any one of claims 21 to 23, wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

25. The pharmaceutical composition according to claim 2, wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

26. The pharmaceutical composition according to claim 25, 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.

27. The pharmaceutical composition of claim 26, wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.

28. The pharmaceutical composition according to any one of claims 25 to 27, wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

29. 29. The pharmaceutical composition according to any one of claims 1 to 28, wherein the PARP inhibitor is olaparib, or a pharmacologically acceptable salt thereof.

30. 29. The pharmaceutical composition of any one of claims 1 to 28, wherein the PARP inhibitor is rucaparib, or a pharmacologically acceptable salt thereof.

31. 29. The pharmaceutical composition of any one of claims 1 to 28, wherein the PARP inhibitor is niraparib, or a pharmacologically acceptable salt thereof.

32. 29. The pharmaceutical composition according to any one of claims 1 to 28, wherein the PARP inhibitor is talazoparib, or a pharmacologically acceptable salt thereof.

33. 29. The pharmaceutical composition of any one of claims 1 to 28, wherein the PARP inhibitor is veliparib, or a pharmacologically acceptable salt thereof.

34. The pharmaceutical composition according to any one of claims 1 to 33, wherein the antibody-drug conjugate and the PARP inhibitor are contained as active ingredients in different formulations and are administered simultaneously or at different times.

35. The pharmaceutical composition according to any one of claims 1 to 33, wherein the antibody-drug conjugate and the PARP inhibitor are contained as active ingredients in a single formulation.

36. 36. The pharmaceutical composition of any one of claims 1 to 35, for the treatment of at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, uterine carcinosarcoma, gastrointestinal stromal tumor, renal cancer, and sarcoma.

37. 37. The pharmaceutical composition of claim 36 for the treatment of breast cancer.

38. 38. The pharmaceutical composition of claim 37 for the treatment of HER2 underexpressing breast cancer.

39. 37. The pharmaceutical composition of claim 36 for the treatment of gastric cancer.

40. 37. The pharmaceutical composition of claim 36 for the treatment of ovarian cancer.

41. 37. The pharmaceutical composition of claim 36 for the treatment of lung cancer.

42. 37. The pharmaceutical composition of claim 36 for the treatment of pancreatic cancer.

43. A pharmaceutical composition comprising an antibody-drug conjugate and a PARP inhibitor, The antibody-drug conjugate has the formula (In the formula, A represents the binding site with the antibody.) and an antibody-drug conjugate in which the drug linker represented by the formula: A pharmaceutical composition, wherein the PARP inhibitor is olaparib, rucaparib, niraparib, talazoparib, or veliparib, or a pharmacologically acceptable salt thereof.

44. The pharmaceutical composition of claim 43, wherein the antibody-drug conjugate is an antibody-drug conjugate according to any one of claims 2 to 28.

45. 45. The pharmaceutical composition of claim 43 or 44, wherein the PARP inhibitor is a PARP inhibitor according to any one of claims 29 to 33.

46. A pharmaceutical composition according to any one of claims 43 to 45 for the treatment of a cancer according to any one of claims 36 to 42.

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