Combination of Antibody-Drug Conjugates with EZH1 and / or EZH2 Inhibitors

Abstract

A pharmaceutical product comprising an antibody-drug conjugate in which a drug linker represented by the following formula (wherein A represents the position of connection to the antibody) is conjugated to the antibody via a thioether bond, and an inhibitor selected from the group consisting of an EZH1 inhibitor, an EZH2 inhibitor, and an EZH1 / 2 dual inhibitor, administered in combination; and / or a method for treatment in which the antibody-drug conjugate and the inhibitor are administered in combination to a subject. JPEG2025513620000118.jpg62144

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical product in which a particular antibody-drug conjugate is administered in combination with an inhibitor selected from the group consisting of an EZH1 inhibitor, an EZH2 inhibitor, and an EZH1 / 2 dual inhibitor, and / or a method for treatment in which a particular antibody-drug conjugate is administered in combination with an inhibitor selected from the group consisting of an EZH1 inhibitor, an EZH2 inhibitor, and an EZH1 / 2 dual inhibitor to a subject. [Background technology]

[0002] The polycomb family negatively regulates gene expression through chromatin control mediated by histone modifications. Enhancer of zeste homolog 1 / 2 (EZH1 / 2) is the active center of polycomb repressive complex 2 (PRC2), which trimethylates histone H3K27. EZH1 and EZH2 complement each other's functions to maintain the epigenome in cells. Inhibition of EZH2 reduces the methylation level of H3K27 throughout the cell, but the effect is limited by the complementary effect of EZH1. Simultaneous inhibition of EZH1 and EZH2 more effectively removes methylation (Non-Patent Document 1). Abnormalities in the components of PRC2 cause cancer and abnormal function of stem cells. In particular, abnormalities in the EZH2 gene and its increased expression induce the accumulation of methylated H3K27me3, which has been identified in many cancers. EZH2 has attracted attention as a new molecular target for cancer, and research has been actively conducted (Non-Patent Documents 2, 3).

[0003] Known examples of compounds having EZH1 inhibitory activity and / or EZH2 inhibitory activity include the EZH1 / 2 dual inhibitor, (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide, and pharma- ceutical acceptable salts thereof (Patent Document 1).

[0004] Schlafen 11 (SLFN11), a putative DNA / RNA helicase that is recruited to stressed replication forks and irreversibly induces replication arrest and cell death, has emerged as a promising predictor of sensitivity to cytotoxic chemotherapy, particularly DNA damaging agents (DDAs) such as topoisomerase I and TOPII (irinotecan and etoposide, respectively), DNA synthesis inhibitors (e.g., gemcitabine), and DNA cross-linking agents, and alkylating agents (e.g., cisplatin) (Non-Patent Document 4).

[0005] One study found that EZH1 / 2 inhibitors could reverse the epigenetic mechanism of acquired chemotherapy resistance caused by epigenetic silencing of SLFN11. In this situation, inhibition of EZH1 / 2 could restore SLFN11 expression and synergize with various DNA damaging agents in vitro and in vivo (Non-Patent Document 5).

[0006] In terms of cancer therapy, it is known that a combination of multiple anticancer drugs is effective, and various studies (on combination therapy) are being actively conducted. For example, a patent application discloses that a combination drug containing a combination of an EZH1 / 2 dual inhibitor and another drug exerts excellent anticancer effects (Patent Document 12). In addition, a phase I and phase II clinical trial (NCT03879798) is ongoing to evaluate the safety and tolerability of valemetostat (DS-3201b), a potent dual EZH1 / 2 inhibitor, in combination with irinotecan in patients with recurrent SCLC.

[0007] Antibody-drug conjugates (ADCs), which have a cytotoxic drug conjugated to an antibody capable of binding to an antigen expressed on the surface of a cancer cell and being internalized by the cell, are expected to selectively deliver the drug to cancer cells, thus causing accumulation of the drug within the cancer cells and killing the cancer cells (Non-Patent Documents 6 to 10).

[0008] One such antibody-drug conjugate is known to contain an antibody and a derivative of exatecan, a topoisomerase I inhibitor, as its components (Patent Documents 2 to 10, Non-Patent Documents 11 to 15). Furthermore, a patent application discloses that a subject to be administered with a medicine containing an anti-hTROP2 antibody can be more accurately identified by combining the expression levels of the hTROP2 gene and the SLFN11 gene at the mRNA level (Patent Document 11).

[0009] However, none of the documents describe any test results showing the combined effect of the above-mentioned antibody-drug conjugate and an EZH1 inhibitor and / or an EZH2 inhibitor, nor any scientific evidence suggesting such test results. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] International Publication No. 2015 / 141616 Brochure [Patent Document 2] International Publication No. 2014 / 057687 Brochure [Patent Document 3] International Publication No. 2014 / 061277 Brochure [Patent Document 4] International Publication No. 2015 / 098099 Brochure [Patent Document 5] International Publication No. 2015 / 115091 Brochure [Patent Document 6] International Publication No. 2015 / 146132 Brochure [Patent Document 7] International Publication No. 2015 / 155976 Brochure [Patent Document 8] International Publication No. 2015 / 155998 Brochure [Patent Document 9] International Publication No. 2018 / 135501 Brochure [Patent Document 10] International Publication No. 2018 / 212136 Brochure [Patent Document 11] International Publication No. 2020 / 040245 Brochure [Patent Document 12] International Publication No. 2020 / 111234 Brochure [Non-patent literature]

[0011] [Non-Patent Document 1] Shen, X. et al., Mol Cell 2008;32(4):491-502 [Non-Patent Document 2] Sparmann A, van Lohuizen M., Nat Rev Cancer 2006;6:846 [Non-Patent Document 3] Lund, Adams, Copland. Leukemia 2014;28(1):44-9. [Non-Patent Document 4] Coleman, N. et al., British Journal of Cancer. (2021) 124: 857-859 [Non-Patent Document 5] Poirier, JT et al., Journal of Thoracic Oncology (2020) Vol. 15, No. 4: 520-540 [Non-Patent Document 6] Ducry, L. et al., Bioconjugate Chem. (2010) 21, 5-13 [Non-Patent Document 7] Alley, S.C. et al., Current Opinion in Chemical Biology (2010), Vol. 14, pp. 529-537 [Non-Patent Document 8] Damle NKExpert Opin.Biol.Ther.(2004) Volume 4, Pages 1445-1452 [Non-Patent Document 9] Senter PD et al., Nature Biotechnology (2012) 30, 631-637 [Non-Patent Document 10] Burris HA et al., J. Clin. Oncol. (2011) Volume 29 (No. 4): pp. 398-405 [Non-Patent Document 11] Ogitani Y. et al., Clinical Cancer Research (2016) Vol. 22 (No. 20), pp. 5097-5108 [Non-Patent Document 12] Ogitani Y. et al., Cancer Science (2016) 107, 1039-1046 [Non-Patent Document 13] Doi T et al., Lancet Oncol. (2017) vol. 18, pp. 1512-22 [Non-Patent Document 14] Takegawa N et al., Int. J. Cancer (2017) 141, 1682-1689 [Non-Patent Document 15] Yonesaka K et al., Oncogene (2019) 38:1398-1409 Summary of the Invention [Problem to be solved by the invention]

[0012] It has been confirmed that the antibody-drug conjugate used in the present invention (antibody-drug conjugate containing an exatecan derivative as a component) exerts an excellent antitumor effect even when used alone. However, there is a demand for a method of treatment that can suppress the proliferation of cancer cells in multiple ways and exert an even more excellent antitumor effect by using the antibody-drug conjugate in combination with another anticancer drug having a different mechanism of action.

[0013] The object of the present invention is to provide a pharmaceutical product for administering a specific antibody-drug conjugate in combination with an inhibitor selected from the group consisting of an EZH1 inhibitor, an EZH2 inhibitor, and an EZH1 / 2 dual inhibitor, and / or a therapeutic use and method of administering a specific antibody-drug conjugate in combination with an inhibitor selected from the group consisting of an EZH1 inhibitor, an EZH2 inhibitor, and an EZH1 / 2 dual inhibitor to a subject. [Means for solving the problem]

[0014] As a result of extensive research to solve the above problems, the inventors have found that the combined administration of a specific antibody-drug conjugate with an inhibitor selected from the group consisting of an EZH1 inhibitor, an EZH2 inhibitor, and an EZH1 / 2 dual inhibitor exerts an excellent combination effect, thereby completing the present invention.

[0015] Therefore, the present invention provides the following [1] to

[0261] .

[0016] [1] A pharmaceutical product for combined administration comprising an antibody-drug conjugate and an inhibitor selected from the group consisting of an EZH1 inhibitor, an EZH2 inhibitor, and an EZH1 / 2 dual inhibitor, The antibody-drug conjugate has the following formula:

[0017] [ka] (wherein A represents the attachment site to the antibody) The pharmaceutical product is an antibody-drug conjugate in which a drug-linker represented by the formula: is conjugated to the antibody via a thioether bond.

[0018] [2] The pharmaceutical product 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, an anti-CDH6 antibody, or an anti-MUC1 antibody.

[0019] [3] The pharmaceutical product described in [2], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[0020] [4] The pharmaceutical product according to [3], wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 having an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 having an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 having an amino acid sequence consisting of amino acid residues 97 to 109 of SEQ ID NO: 1, and a light chain comprising CDRL1 having an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 having an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 having an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2.

[0021] [5] The pharmaceutical product according to [3], wherein the anti-HER2 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 120 of SEQ ID NO: 1, and a light chain having a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 107 of SEQ ID NO: 2.

[0022] [6] The pharmaceutical product described in [3], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 1 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 2.

[0023] [7] The pharmaceutical product described in [3], wherein the anti-HER2 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1, and a light chain having an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2.

[0024] [8] The antibody-drug conjugate has the following formula:

[0025] [ka] wherein "antibody" represents an anti-HER2 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. The pharmaceutical product according to any one of [3] to [7].

[0026] [9] The pharmaceutical product described in [2], wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[0027]

[10] The pharmaceutical product described in [9], wherein the anti-HER3 antibody is an antibody comprising a heavy chain having the amino acid sequence represented by SEQ ID NO: 3 and a light chain having the amino acid sequence represented by SEQ ID NO: 4.

[0028]

[11] The pharmaceutical product described in

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

[0029]

[12] The antibody-drug conjugate has the following formula:

[0030] [ka] wherein "antibody" represents an anti-HER3 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. The pharmaceutical product according to any one of [9] to

[11] .

[0031]

[13] The pharmaceutical product according to [2], wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[0032]

[14] The pharmaceutical product according to

[13] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain comprising CDRH1 having an amino acid sequence consisting of amino acid residues 50 to 54 of SEQ ID NO: 5, CDRH2 having an amino acid sequence consisting of amino acid residues 69 to 85 of SEQ ID NO: 5, and CDRH3 having an amino acid sequence consisting of amino acid residues 118 to 129 of SEQ ID NO: 5, and a light chain comprising CDRL1 having an amino acid sequence consisting of amino acid residues 44 to 54 of SEQ ID NO: 6, CDRL2 having an amino acid sequence consisting of amino acid residues 70 to 76 of SEQ ID NO: 6, and CDRL3 having an amino acid sequence consisting of amino acid residues 109 to 117 of SEQ ID NO: 6.

[0033]

[15] The pharmaceutical product according to

[13] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 140 of SEQ ID NO: 5, and a light chain having a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 129 of SEQ ID NO: 6.

[0034]

[16] The pharmaceutical product according to

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

[0035]

[17] The pharmaceutical product described in

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

[0036]

[18] The antibody-drug conjugate has the following formula:

[0037] [ka] wherein "antibody" represents an anti-TROP2 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 3.5 to 4.5. The pharmaceutical product according to any one of

[13] to

[17] .

[0038]

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

[0039]

[20] The pharmaceutical product described in

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

[0040]

[21] The pharmaceutical product described in

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

[0041]

[22] The antibody-drug conjugate has the following formula:

[0042] [ka] wherein "antibody" represents an anti-B7-H3 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 3.5 to 4.5. The pharmaceutical product according to any one of

[19] to

[21] .

[0043]

[23] The pharmaceutical product described in [2], wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[0044]

[24] The pharmaceutical product described in

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

[0045]

[25] The pharmaceutical product described in

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

[0046]

[26] The antibody-drug conjugate has the following formula:

[0047] [ka] wherein "antibody" represents an anti-GPR20 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. The pharmaceutical product according to any one of

[23] to

[25] .

[0048]

[27] The pharmaceutical product described in [2], wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[0049]

[28] The pharmaceutical product described in

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

[0050]

[29] The pharmaceutical product described in

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

[0051]

[30] The antibody-drug conjugate may have the following formula:

[0052] [ka] wherein "antibody" represents an anti-CDH6 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. The pharmaceutical product according to any one of

[27] to

[29] .

[0053]

[31] The pharmaceutical product according to [2], wherein the antibody in the antibody-drug conjugate is an anti-MUC1 antibody.

[0054]

[32] The pharmaceutical product described in

[31] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain having the amino acid sequence represented by SEQ ID NO: 13 and a light chain having the amino acid sequence represented by SEQ ID NO: 15.

[0055]

[33] The pharmaceutical product of

[32] , wherein the anti-MUC1 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0056]

[34] The pharmaceutical product described in

[31] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain having the amino acid sequence represented by SEQ ID NO: 14 and a light chain having the amino acid sequence represented by SEQ ID NO: 15.

[0057]

[35] The pharmaceutical product of

[34] , wherein the anti-MUC1 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0058]

[36] The antibody-drug conjugate may have the following formula:

[0059] [ka] wherein "antibody" represents an anti-MUC1 antibody conjugated to a drug-linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. The pharmaceutical product according to any one of

[31] to

[35] .

[0060]

[37] The pharmaceutical product according to any one of [1] to [8], wherein the antibody-drug conjugate is trastuzumab deruxtecan (DS-8201a).

[0061]

[38] The pharmaceutical product according to any one of [1] to [2] and

[13] to

[18] , wherein the antibody-drug conjugate is datopotamab deruxtecan (DS-1062).

[0062]

[39] The pharmaceutical product according to any one of [1] to

[38] , wherein the inhibitor is an EZH2 inhibitor.

[0063]

[40] The pharmaceutical product according to

[39] , wherein the inhibitor is tazemetostat or a pharma- ceutically acceptable salt thereof.

[0064]

[41] The pharmaceutical product according to any one of [1] to

[38] , wherein the inhibitor is an EZH1 / 2 inhibitor.

[0065]

[42] The pharmaceutical product according to

[41] , wherein the inhibitor is valemetostat or a pharma- ceutically acceptable salt thereof.

[0066]

[43] The pharmaceutical product according to

[41] or

[42] , wherein the inhibitor is valemetostat tosylate.

[0067]

[44] The pharmaceutical product described in any one of [1] to

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

[0068]

[45] The pharmaceutical product according to any one of [1] to

[44] and

[0257] , which is for use in 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.

[0069]

[46] The pharmaceutical product according to

[45] , which is for use in the treatment of breast cancer.

[0070]

[47] The pharmaceutical product of

[46] , which is for use in the treatment of triple-negative breast cancer.

[0071]

[48] ​​The pharmaceutical product according to

[45] , which is for use in the treatment of gastric cancer.

[0072]

[49] The pharmaceutical product described in

[45] , which is for use in the treatment of ovarian cancer.

[0073]

[50] The pharmaceutical product described in

[45] , which is for use in the treatment of lung cancer.

[0074]

[51] The pharmaceutical product described in

[45] , which is for use in the treatment of pancreatic cancer.

[0075]

[52] A method for treatment, comprising administering to a subject in need of treatment an antibody-drug conjugate in combination with an inhibitor selected from the group consisting of an EZH1 inhibitor, an EZH2 inhibitor, and an EZH1 / 2 dual inhibitor, wherein the antibody-drug conjugate has the following formula:

[0076] [ka] (wherein A represents the attachment site to the antibody) The method for treatment, wherein the drug-linker represented by the formula: is an antibody-drug conjugate in which the drug-linker is conjugated to the antibody via a thioether bond.

[0077]

[53] The method for treatment according to

[52] , 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, an anti-CDH6 antibody, or an anti-MUC1 antibody.

[0078]

[54] The method for treatment according to

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

[0079] The method for treatment described in

[54] , wherein the anti-HER2 antibody "55" is an antibody comprising a heavy chain including CDRH1 having an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 having an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 having an amino acid sequence consisting of amino acid residues 97 to 109 of SEQ ID NO: 1, and a light chain including CDRL1 having an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 having an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 having an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2.

[0080]

[56] The method for treatment described in

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

[0081]

[57] The method for treatment described in

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

[0082]

[58] The method for treatment described in

[54] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by amino acid residues 1 to 449 of SEQ ID NO: 1, and a light chain consisting of an amino acid sequence represented by amino acid residues 1 to 214 of SEQ ID NO: 2.

[0083]

[59] The antibody-drug conjugate may have the following formula:

[0084] [ka] wherein "antibody" represents an anti-HER2 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

[0085]

[60] The method for treatment described in

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

[0086]

[61] The method for treatment described in

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

[0087]

[62] The method for treatment described in

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

[0088]

[63] The antibody-drug conjugate may have the following formula:

[0089] [ka] wherein "antibody" represents an anti-HER3 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

[0090]

[64] The method for treatment described in

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

[0091]

[65] The method for treatment described in

[64] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence of amino acid residues 50 to 54 of SEQ ID NO: 5, CDRH2 consisting of the amino acid sequence of amino acid residues 69 to 85 of SEQ ID NO: 5, and CDRH3 consisting of the amino acid sequence of amino acid residues 118 to 129 of SEQ ID NO: 5, and a light chain comprising CDRL1 consisting of the amino acid sequence of amino acid residues 44 to 54 of SEQ ID NO: 6, CDRL2 consisting of the amino acid sequence of amino acid residues 70 to 76 of SEQ ID NO: 6, and CDRL3 consisting of the amino acid sequence of amino acid residues 109 to 117 of SEQ ID NO: 6.

[0092]

[66] The method for treatment described in

[64] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 140 of SEQ ID NO: 5, and a light chain having a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 129 of SEQ ID NO: 6.

[0093]

[67] The method for treatment described in

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

[0094]

[68] The method for treatment described in

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

[0095]

[69] The antibody-drug conjugate may have the following formula:

[0096] [ka] wherein "antibody" represents an anti-TROP2 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 3.5 to 4.5.

[0097]

[70] The method for treatment described in

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

[0098]

[71] The method for treatment described in

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

[0099]

[72] The method for treatment according to

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

[0100]

[73] The antibody-drug conjugate may have the following formula:

[0101] [ka] wherein "antibody" represents an anti-B7-H3 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 3.5 to 4.5.

[0102]

[74] The method for treatment described in

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

[0103]

[75] The method for treatment described in

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

[0104]

[76] The method for treatment described in

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

[0105]

[77] The antibody-drug conjugate may have the following formula:

[0106] [ka] wherein "antibody" represents an anti-GPR20 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

[0107]

[78] The method for treatment described in

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

[0108]

[79] The method for treatment described in

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

[0109]

[80] The method for treatment described in

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

[0110]

[81] The antibody-drug conjugate may have the following formula:

[0111] [ka] wherein "antibody" represents an anti-CDH6 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

[0112]

[82] The method according to

[53] , wherein the antibody in the antibody-drug conjugate is an anti-MUC1 antibody.

[0113]

[83] The method according to

[82] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 13 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 15.

[0114]

[84] The method of

[83] , wherein the anti-MUC1 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0115]

[85] The method according to

[82] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 14 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 15.

[0116]

[86] The method of

[85] , wherein the anti-MUC1 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0117]

[87] The antibody-drug conjugate may have the following formula:

[0118] [ka] wherein "antibody" represents an anti-MUC1 antibody conjugated to a drug-linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

[0119]

[88] The method for treatment described in any one of

[52] to

[59] , wherein the antibody-drug conjugate is trastuzumab deruxtecan (DS-8201a).

[0120]

[89] The method for treatment described in any one of

[52] to

[53] and

[64] to

[69] , wherein the antibody-drug conjugate is datopotamab deruxtecan (DS-1062).

[0121]

[90] The method for treatment described in any one of

[52] to

[89] , wherein the inhibitor is an EZH2 inhibitor.

[0122]

[91] The method for treatment according to

[90] , wherein the inhibitor is tazemetostat or a pharma- ceutically acceptable salt thereof.

[0123]

[92] The method for treatment described in any one of

[52] to

[89] , wherein the inhibitor is an EZH1 / 2 dual inhibitor.

[0124]

[93] The method for treatment according to

[92] , wherein the inhibitor is valemetostat or a pharma- ceutically acceptable salt thereof.

[0125]

[94] The method for treatment according to

[92] or

[93] , wherein the inhibitor is valemetostat tosylate.

[0126]

[95] A method for treatment described in any one of

[52] to

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

[0127]

[96] The method for treatment described in any one of

[52] to

[95] and

[0258] , which is for treating 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.

[0128]

[97] The method for treatment described in

[96] , which is for treating breast cancer.

[0129]

[98] The method for treatment described in

[97] , which is for treating triple-negative breast cancer.

[0130]

[99] The method for treatment described in

[96] , which is for treating gastric cancer.

[0131]

[0100] The method for treatment described in

[96] , which is for treating ovarian cancer.

[0132]

[0101] The method for treatment described in

[96] , which is for treating lung cancer.

[0133]

[0102] The method for treatment described in

[96] , which is for treating pancreatic cancer.

[0134] An antibody-drug conjugate for use in a method for treating a disease, the method comprising administering the antibody-drug conjugate in combination with an inhibitor selected from the group consisting of an EZH1 inhibitor, an EZH2 inhibitor, and an EZH1 / 2 dual inhibitor, wherein the antibody-drug conjugate has the following formula:

[0135] [ka] (wherein A represents the attachment site to the antibody) An antibody-drug conjugate, wherein the drug-linker represented by the formula:

[0136]

[0104] An antibody-drug conjugate for use according to the invention, 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, an anti-CDH6 antibody, or an anti-MUC1 antibody.

[0137]

[0105] An antibody-drug conjugate for use according to

[0104] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[0138]

[0106] An antibody-drug conjugate for use as described in

[0105] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain including CDRH1 having an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 having an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 having an amino acid sequence consisting of amino acid residues 97 to 109 of SEQ ID NO: 1, and a light chain including CDRL1 having an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 having an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 having an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2.

[0139]

[0107] An antibody-drug conjugate for use as described in

[0105] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 120 of SEQ ID NO: 1, and a light chain having a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 107 of SEQ ID NO: 2.

[0140]

[0108] An antibody-drug conjugate for use as described in

[0105] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 1, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 2.

[0141]

[0109] An antibody-drug conjugate for use as described in

[0105] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1, and a light chain having an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2.

[0142]

[0110] The antibody-drug conjugate has the following formula:

[0143] [ka] wherein "antibody" represents an anti-HER2 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

[0144]

[0111] An antibody-drug conjugate for use according to

[0104] , wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[0145]

[0112] An antibody-drug conjugate for use as described in

[0111] , wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 3, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 4.

[0146]

[0113] An antibody-drug conjugate for use as described in

[0112] , wherein the anti-HER3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0147] The antibody-drug conjugate has the following formula:

[0148] [ka] wherein "antibody" represents an anti-HER3 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

[0149]

[0115] An antibody-drug conjugate for use as described in

[0104] , wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[0150]

[0116] An antibody-drug conjugate for use as described in

[0115] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain including CDRH1 having an amino acid sequence consisting of amino acid residues 50 to 54 of SEQ ID NO: 5, CDRH2 having an amino acid sequence consisting of amino acid residues 69 to 85 of SEQ ID NO: 5, and CDRH3 having an amino acid sequence consisting of amino acid residues 118 to 129 of SEQ ID NO: 5, and a light chain including CDRL1 having an amino acid sequence consisting of amino acid residues 44 to 54 of SEQ ID NO: 6, CDRL2 having an amino acid sequence consisting of amino acid residues 70 to 76 of SEQ ID NO: 6, and CDRL3 having an amino acid sequence consisting of amino acid residues 109 to 117 of SEQ ID NO: 6.

[0151]

[0117] An antibody-drug conjugate for use as described in

[0115] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 140 of SEQ ID NO: 5, and a light chain having a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 129 of SEQ ID NO: 6.

[0152]

[0118] An antibody-drug conjugate for use as described in

[0115] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 5, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 6.

[0153]

[0119] An antibody-drug conjugate for use as described in

[0118] , wherein the anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0154] The antibody-drug conjugate has the following formula:

[0155] [ka] wherein "antibody" represents an anti-TROP2 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 3.5 to 4.5.

[0156]

[0121] An antibody-drug conjugate for use according to

[0104] , wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[0157]

[0122] An antibody-drug conjugate for use as described in

[0121] , wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 7, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 8.

[0158]

[0123] An antibody-drug conjugate for use as described in

[0122] , wherein the anti-B7-H3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0159] The antibody-drug conjugate has the following formula:

[0160] [ka] wherein "antibody" represents an anti-B7-H3 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 3.5 to 4.5.

[0161]

[0125] An antibody-drug conjugate for use according to the invention, wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[0162]

[0126] An antibody-drug conjugate for use as described in

[0125] , wherein the anti-GPR20 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 472 of SEQ ID NO: 9, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 10.

[0163]

[0127] An antibody-drug conjugate for use as described in

[0126] , wherein the anti-GPR20 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0164] The antibody-drug conjugate has the following formula:

[0165] [ka] wherein "antibody" represents an anti-GPR20 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. An antibody-drug conjugate for use according to any one of claims

[0125] to

[0127] .

[0166]

[0129] An antibody-drug conjugate for use according to the invention described in

[0104] , wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[0167]

[0130] An antibody-drug conjugate for use as described in

[0129] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 11, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 12.

[0168]

[0131] An antibody-drug conjugate for use as described in

[0130] , wherein the anti-CDH6 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0169] The antibody-drug conjugate has the following formula:

[0170] [ka] wherein "antibody" represents an anti-CDH6 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

[0171]

[0133] An antibody-drug conjugate for use according to

[0104] , wherein the antibody in the antibody-drug conjugate is an anti-MUC1 antibody.

[0172]

[0134] An antibody-drug conjugate for use as described in

[0133] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 13, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 15.

[0173]

[0135] An antibody-drug conjugate for use as described in

[0134] , wherein the anti-MUC1 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0174]

[0136] An antibody-drug conjugate for use as described in

[0133] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 14, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 15.

[0175]

[0137] An antibody-drug conjugate for use as described in

[0136] , wherein the anti-MUC1 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0176] The antibody-drug conjugate has the following formula:

[0177] [ka] wherein "antibody" represents an anti-MUC1 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

[0178]

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

[0103] to

[0110] , wherein the antibody-drug conjugate is trastuzumab deruxtecan (DS-8201a).

[0179]

[0140] An antibody-drug conjugate for use according to any one of

[0103] to

[0104] and

[0115] to

[0120] , wherein the antibody-drug conjugate is datopotamab deruxtecan (DS-1062).

[0180]

[0141] An antibody-drug conjugate for use according to any one of

[0103] to

[0140] , wherein the inhibitor is an EZH2 inhibitor.

[0181]

[0142] The antibody-drug conjugate for use according to

[0141] , wherein the inhibitor is tazemetostat or a pharma- ceutically acceptable salt thereof.

[0182]

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

[0103] to

[0140] , wherein the inhibitor is an EZH1 / 2 dual inhibitor.

[0183]

[0144] The antibody-drug conjugate for use according to

[0143] , wherein the inhibitor is valemetostat or a pharma- ceutically acceptable salt thereof.

[0184]

[0145] An antibody-drug conjugate for use according to

[0143] or

[0144] , wherein the inhibitor is valemetostat tosylate.

[0185]

[0146] An antibody-drug conjugate for use according to any one of

[0103] to

[0145] , wherein the antibody-drug conjugate and the inhibitor are contained separately in different formulations as active ingredients and are administered simultaneously or at different times.

[0186]

[0147] The antibody-drug conjugate for use described in any one of

[0103] to

[0146] and

[0259] , wherein the disease is 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.

[0187]

[0148] The antibody-drug conjugate for use according to

[0147] , wherein the disease is breast cancer.

[0188]

[0149] The antibody-drug conjugate for use according to

[0148] , wherein the disease is triple-negative breast cancer.

[0189]

[0150] The antibody-drug conjugate for use according to

[0147] , wherein the disease is gastric cancer.

[0190]

[0151] The antibody-drug conjugate for use according to

[0147] , wherein the disease is ovarian cancer.

[0191]

[0152] The antibody-drug conjugate for use according to

[0147] , wherein the disease is lung cancer.

[0192]

[0153] An antibody-drug conjugate for use as described in

[0147] , wherein the disease is pancreatic cancer.

[0193]

[0154] Use of an antibody-drug conjugate or an inhibitor selected from the group consisting of an EZH1 inhibitor, an EZH2 inhibitor, and an EZH1 / 2 dual inhibitor, for the manufacture of a medicament for treating a disease by administering the antibody-drug conjugate and the inhibitor in combination, wherein the antibody-drug conjugate has the following formula:

[0194] [ka] (wherein A represents the attachment site to the antibody) The use of an antibody-drug conjugate, wherein the drug-linker represented by the formula:

[0195]

[0155] The use described in

[0154] , 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, an anti-CDH6 antibody, or an anti-MUC1 antibody.

[0196]

[0156] The use described in

[0155] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[0197]

[0157] The anti-HER2 antibody is an antibody comprising a heavy chain including CDRH1 having an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 having an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 having an amino acid sequence consisting of amino acid residues 97 to 109 of SEQ ID NO: 1, and a light chain including CDRL1 having an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 having an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 having an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2, as described in

[0156] .

[0198]

[0158] The use described in

[0156] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 120 of SEQ ID NO: 1, and a light chain having a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 107 of SEQ ID NO: 2.

[0199]

[0159] The use described in

[0156] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by sequence number 1, and a light chain consisting of the amino acid sequence represented by sequence number 2.

[0200]

[0160] The use described in

[0156] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1, and a light chain having an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2.

[0201]

[0161] The antibody-drug conjugate has the following formula:

[0202] [ka] wherein "antibody" represents an anti-HER2 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. The use described in any one of

[0156] to

[0160] .

[0203]

[0162] The use described in

[0155] , wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[0204]

[0163] The use described in

[0162] , wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 3, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 4.

[0205]

[0164] The use described in

[0163] , wherein the anti-HER3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0206] The antibody-drug conjugate has the following formula:

[0207] [ka] wherein "antibody" represents an anti-HER3 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. The use described in any one of

[0162] to

[0164] .

[0208]

[0166] The use described in

[0155] , wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[0209]

[0167] The anti-TROP2 antibody is an antibody comprising a heavy chain including CDRH1 having an amino acid sequence consisting of amino acid residues 50 to 54 of SEQ ID NO: 5, CDRH2 having an amino acid sequence consisting of amino acid residues 69 to 85 of SEQ ID NO: 5, and CDRH3 having an amino acid sequence consisting of amino acid residues 118 to 129 of SEQ ID NO: 5, and a light chain including CDRL1 having an amino acid sequence consisting of amino acid residues 44 to 54 of SEQ ID NO: 6, CDRL2 having an amino acid sequence consisting of amino acid residues 70 to 76 of SEQ ID NO: 6, and CDRL3 having an amino acid sequence consisting of amino acid residues 109 to 117 of SEQ ID NO: 6, as described in

[0166] .

[0210]

[0168] The use described in

[0166] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 140 of SEQ ID NO: 5, and a light chain having a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 129 of SEQ ID NO: 6.

[0211]

[0169] The use described in

[0166] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 5, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 6.

[0212]

[0170] The use described in

[0169] , wherein the anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0213]

[0171] The antibody-drug conjugate has the following formula:

[0214] [ka] wherein "antibody" represents an anti-TROP2 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 3.5 to 4.5.

[0215]

[0172] The use described in

[0155] , wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[0216]

[0173] The use described in

[0172] , wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 7, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 8.

[0217]

[0174] The use described in

[0173] , wherein the anti-B7-H3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0218] The antibody-drug conjugate has the following formula:

[0219] [ka] wherein "antibody" represents an anti-B7-H3 antibody conjugated to a drug-linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 3.5 to 4.5.

[0220]

[0176] The use described in

[0155] , wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[0221]

[0177] The use described in

[0176] , wherein the anti-GPR20 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 472 of SEQ ID NO: 9, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 10.

[0222]

[0178] The use described in

[0177] , wherein the anti-GPR20 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0223] The antibody-drug conjugate has the following formula:

[0224] [ka] wherein "antibody" represents an anti-GPR20 antibody conjugated to a drug-linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. The use described in any one of

[0176] to

[0178] .

[0225]

[0180] The use described in

[0155] , wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[0226]

[0181] The use described in

[0180] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 11, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 12.

[0227]

[0182] The use described in

[0181] , wherein the anti-CDH6 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0228] The antibody-drug conjugate has the following formula:

[0229] [ka] wherein "antibody" represents an anti-CDH6 antibody conjugated to a drug-linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. The use described in any one of

[0180] to

[0182] .

[0230]

[0184] The use described in

[0155] , wherein the antibody in the antibody-drug conjugate is an anti-MUC1 antibody.

[0231]

[0185] The use described in

[0184] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 13, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 15.

[0232]

[0186] The use described in

[0185] , wherein the anti-MUC1 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0233]

[0187] The use described in

[0184] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 14, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 15.

[0234]

[0188] The use described in

[0188] , wherein the anti-MUC1 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0235] The antibody-drug conjugate has the following formula:

[0236] [ka] wherein "antibody" represents an anti-MUC1 antibody conjugated to a drug-linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

[0237]

[0190] The use described in any one of

[0154] to

[0161] , wherein the antibody-drug conjugate is trastuzumab deruxtecan (DS-8201a).

[0238]

[0191] The use described in any one of

[0154] to

[0155] and

[0166] to

[0171] , wherein the antibody-drug conjugate is datopotamab deruxtecan (DS-1062).

[0239]

[0192] The use described in any one of

[0154] to

[0191] , wherein the inhibitor is an EZH2 inhibitor.

[0240]

[0193] The use described in

[0192] , wherein the inhibitor is tazemetostat or a pharma- ceutically acceptable salt thereof.

[0241]

[0194] The use described in any one of

[0154] to

[0191] , wherein the inhibitor is an EZH1 / 2 dual inhibitor.

[0242]

[0195] The use described in

[0194] , wherein the inhibitor is valemetostat or a pharma- ceutically acceptable salt thereof.

[0243]

[0196] The use described in

[0194] or

[0195] , wherein the inhibitor is valemetostat tosylate.

[0244]

[0197] The use described in any one of

[0154] to

[0196] , wherein the antibody-drug conjugate and the inhibitor are contained separately in different formulations as active ingredients and are administered simultaneously or at different times.

[0245]

[0198] The use described in any one of

[0154] to

[0197] and

[0260] , wherein the disease is 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.

[0246]

[0199] The use described in

[0198] , wherein the disease is breast cancer.

[0247]

[0200] The use described in

[0199] , wherein the disease is triple-negative breast cancer.

[0248]

[0201] The use described in

[0198] , wherein the disease is gastric cancer.

[0249]

[0202] The use described in

[0198] , wherein the disease is ovarian cancer.

[0250]

[0203] The use described in

[0198] , wherein the disease is lung cancer.

[0251]

[0204] The use described in

[0198] , wherein the disease is pancreatic cancer.

[0252] An inhibitor selected from the group consisting of an EZH1 inhibitor, an EZH2 inhibitor, and an EZH1 / 2 dual inhibitor, for use in a method for treating a disease, the method comprising administering the inhibitor in combination with an antibody-drug conjugate, the antibody-drug conjugate having the following formula:

[0253] [ka] (wherein A represents the attachment site to the antibody) The inhibitor is an antibody-drug conjugate, wherein the drug-linker represented by the formula:

[0254]

[0206] An inhibitor for use according to

[0205] , 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, an anti-CDH6 antibody, or an anti-MUC1 antibody.

[0255]

[0207] An inhibitor for use according to

[0206] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[0256]

[0208] An inhibitor for use as described in

[0207] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain including CDRH1 having an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 having an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 having an amino acid sequence consisting of amino acid residues 97 to 109 of SEQ ID NO: 1, and a light chain including CDRL1 having an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 having an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 having an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2.

[0257]

[0209] The anti-HER2 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 120 of SEQ ID NO: 1, and a light chain having a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 107 of SEQ ID NO: 2, an inhibitor for use as described in

[0207] .

[0258]

[0210] An inhibitor for use as described in

[0207] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by sequence number 1, and a light chain consisting of the amino acid sequence represented by sequence number 2.

[0259]

[0211] An inhibitor for use as described in

[0207] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1, and a light chain having an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2.

[0260]

[0212] The antibody-drug conjugate has the following formula:

[0261] [ka] wherein "antibody" represents an anti-HER2 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

[0262]

[0213] An inhibitor for use according to

[0206] , wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[0263]

[0214] An inhibitor for use as described in

[0213] , wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 3, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 4.

[0264]

[0215] An inhibitor for use as described in

[0214] , wherein the anti-HER3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0265]

[0216] The antibody-drug conjugate has the following formula:

[0266] [ka] wherein "antibody" represents an anti-HER3 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

[0267]

[0217] An inhibitor for use as described in

[0206] , wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[0268]

[0218] The anti-TROP2 antibody is an inhibitor for use as described in

[0217] , which is an antibody comprising a heavy chain including CDRH1 having an amino acid sequence consisting of amino acid residues 50 to 54 of SEQ ID NO: 5, CDRH2 having an amino acid sequence consisting of amino acid residues 69 to 85 of SEQ ID NO: 5, and CDRH3 having an amino acid sequence consisting of amino acid residues 118 to 129 of SEQ ID NO: 5, and a light chain including CDRL1 having an amino acid sequence consisting of amino acid residues 44 to 54 of SEQ ID NO: 6, CDRL2 having an amino acid sequence consisting of amino acid residues 70 to 76 of SEQ ID NO: 6, and CDRL3 having an amino acid sequence consisting of amino acid residues 109 to 117 of SEQ ID NO: 6.

[0269]

[0219] An inhibitor for use as described in

[0217] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 140 of SEQ ID NO: 5, and a light chain having a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 129 of SEQ ID NO: 6.

[0270]

[0220] An inhibitor for use as described in

[0217] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 5, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 6.

[0271]

[0221] An inhibitor for use as described in

[0220] , wherein the anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0272]

[0222] The antibody-drug conjugate has the following formula:

[0273] [ka] wherein "antibody" represents an anti-TROP2 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 3.5 to 4.5.

[0274]

[0223] An inhibitor for use according to

[0206] , wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[0275]

[0224] An inhibitor for use as described in

[0223] , wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 7, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 8.

[0276]

[0225] An inhibitor for use according to

[0224] , wherein the anti-B7-H3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0277]

[0226] The antibody-drug conjugate has the following formula:

[0278] [ka] wherein "antibody" represents an anti-B7-H3 antibody conjugated to a drug-linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 3.5 to 4.5.

[0279]

[0227] An inhibitor for use according to

[0206] , wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[0280]

[0228] An inhibitor for use according to the invention described in

[0227] , wherein the anti-GPR20 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 472 of SEQ ID NO: 9, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 10.

[0281]

[0229] An inhibitor for use as described in

[0228] , wherein the anti-GPR20 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0282]

[0230] The antibody-drug conjugate has the following formula:

[0283] [ka] wherein "antibody" represents an anti-GPR20 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

[0284]

[0231] An inhibitor for use according to

[0206] , wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[0285]

[0232] An inhibitor for use according to the invention described in

[0231] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 11, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 12.

[0286]

[0233] An inhibitor for use as described in

[0232] , wherein the anti-CDH6 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0287]

[0234] The anti-CDH6 antibody-drug conjugate has the following formula:

[0288] [ka] wherein "antibody" represents an anti-CDH6 antibody conjugated to a drug-linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

[0289]

[0235] An inhibitor for use according to

[0206] , wherein the antibody in the antibody-drug conjugate is an anti-MUC1 antibody.

[0290]

[0236] An inhibitor for use according to the invention described in

[0235] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 13, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 15.

[0291]

[0237] An inhibitor for use as described in

[0236] , wherein the anti-MUC1 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0292]

[0238] An inhibitor for use according to the invention described in

[0235] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 14, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 15.

[0293]

[0239] An inhibitor for use as described in

[0238] , wherein the anti-MUC1 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0294]

[0240] The antibody-drug conjugate has the following formula:

[0295] [ka] wherein "antibody" represents an anti-MUC1 antibody conjugated to a drug-linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

[0296]

[0241] An inhibitor for use according to any one of

[0205] to

[0212] , wherein the antibody-drug conjugate is trastuzumab deruxtecan (DS-8201a).

[0297]

[0242] An inhibitor for use according to any one of

[0205] to

[0206] and

[0217] to

[0222] , wherein the antibody-drug conjugate is datopotamab deruxtecan (DS-1062).

[0298]

[0243] An inhibitor for use according to any one of

[0205] to

[0242] , wherein the inhibitor is an EZH2 inhibitor.

[0299]

[0244] The inhibitor for use according to

[0243] , wherein the inhibitor is tazemetostat or a pharma- ceutically acceptable salt thereof.

[0300]

[0245] An inhibitor for use according to any one of

[0205] to

[0242] , wherein the inhibitor is an EZH1 / 2 dual inhibitor.

[0301]

[0246] The inhibitor for use according to

[0245] , wherein the inhibitor is valemetostat or a pharma- ceutically acceptable salt thereof.

[0302]

[0247] An inhibitor for use according to

[0245] or

[0246] , wherein the inhibitor is valemetostat tosylate.

[0303]

[0248] An inhibitor for use described in any one of

[0205] to

[0247] , wherein the antibody-drug conjugate and the inhibitor are contained separately in different formulations as active ingredients and are administered simultaneously or at different times.

[0304]

[0249] An inhibitor for use according to any one of

[0205] to

[0248] and

[0261] , wherein the disease is 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.

[0305]

[0250] An inhibitor for use according to the invention, wherein the disease is breast cancer.

[0306]

[0251] An inhibitor for use according to the invention, wherein the disease is triple-negative breast cancer.

[0307]

[0252] An inhibitor for use according to the method of

[0249] , wherein the disease is gastric cancer.

[0308]

[0253] An inhibitor for use according to the method of

[0249] , wherein the disease is ovarian cancer.

[0309]

[0254] An inhibitor for use according to the invention, wherein the disease is lung cancer.

[0310]

[0255] An inhibitor for use according to the method of

[0249] , wherein the disease is pancreatic cancer.

[0311]

[0256] A pharmaceutical product described in any one of [1] to

[51] and

[0257] , which is a pharmaceutical composition.

[0312]

[0257] A pharmaceutical product described in any one of [1] to

[44] , which is for use in the treatment of cancer.

[0313]

[0258] A method for treatment described in any one of

[52] to

[95] , which is for treating cancer.

[0314]

[0259] An antibody-drug conjugate for use according to any one of

[0103] to

[0146] , wherein the disease is cancer.

[0315]

[0260] The use described in any one of

[0154] to

[0197] , wherein the disease is cancer.

[0316]

[0261] An inhibitor for use according to any one of

[0205] to

[0248] , wherein the disease is cancer.

[0317] Other embodiments of the invention are described below.

[0318] [1-1] A pharmaceutical product for combined administration comprising an antibody-drug conjugate and an inhibitor selected from the group consisting of an EZH1 inhibitor, an EZH2 inhibitor, and an EZH1 / 2 dual inhibitor, The antibody-drug conjugate has the following formula:

[0319] [ka] (wherein A represents the attachment site to the antibody) The pharmaceutical product is an antibody-drug conjugate in which a drug-linker represented by the formula: is conjugated to the antibody via a thioether bond.

[0320] [2-1] The pharmaceutical product described in [1-1], 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, an anti-CDH6 antibody, an anti-MUC1 antibody, or an anti-CD37 antibody.

[0321] [3-1] The pharmaceutical product described in [2-1], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[0322] [4-1] The pharmaceutical product described in [3-1], wherein the anti-HER2 antibody is an antibody comprising a heavy chain including CDRH1 having an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 having an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 having an amino acid sequence consisting of amino acid residues 97 to 109 of SEQ ID NO: 1, and a light chain including CDRL1 having an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 having an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 having an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2.

[0323] [5-1] The pharmaceutical product described in [3-1], wherein the anti-HER2 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 120 of SEQ ID NO: 1, and a light chain having a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 107 of SEQ ID NO: 2.

[0324] [6-1] The pharmaceutical product described in [3-1], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by sequence number 1 and a light chain consisting of the amino acid sequence represented by sequence number 2.

[0325] [7-1] The pharmaceutical product described in [3-1], wherein the anti-HER2 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1, and a light chain having an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2.

[0326] [8-1] The antibody-drug conjugate has the following formula:

[0327] [ka] wherein "antibody" represents an anti-HER2 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. The pharmaceutical product according to any one of [3-1] to [7-1].

[0328] [9-1] The pharmaceutical product described in [2-1], wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[0329] [A1] The pharmaceutical product according to [9-1], wherein the anti-HER3 antibody is an antibody comprising a heavy chain including CDRH1 having an amino acid sequence consisting of amino acid residues 26 to 35 of SEQ ID NO: 3, CDRH2 having an amino acid sequence consisting of amino acid residues 50 to 65 of SEQ ID NO: 3, and CDRH3 having an amino acid sequence consisting of amino acid residues 98 to 106 of SEQ ID NO: 3, and a light chain including CDRL1 having an amino acid sequence consisting of amino acid residues 24 to 39 of SEQ ID NO: 4, CDRL2 having an amino acid sequence consisting of amino acid residues 56 to 62 of SEQ ID NO: 4, and CDRL3 having an amino acid sequence consisting of amino acid residues 95 to 103 of SEQ ID NO: 4.

[0330] [A2] The pharmaceutical product described in [9-1], wherein the anti-HER3 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 117 of SEQ ID NO: 3, and a light chain having a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 113 of SEQ ID NO: 4.

[0331] [10-1] The pharmaceutical product described in [9-1], wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by sequence number 3 and a light chain consisting of the amino acid sequence represented by sequence number 4.

[0332] [11-1] A pharmaceutical product described in [10-1], in which the anti-HER3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0333] [12-1] The antibody-drug conjugate has the following formula:

[0334] [ka] wherein "antibody" represents an anti-HER3 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. The pharmaceutical product according to any one of [9-1] to [11-1] and [A1] to [A2].

[0335] [13-1] The pharmaceutical product described in [2-1], wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[0336] [14-1] The pharmaceutical product described in [13-1], wherein the anti-TROP2 antibody is an antibody comprising a heavy chain including CDRH1 having an amino acid sequence consisting of amino acid residues 50 to 54 of SEQ ID NO: 5, CDRH2 having an amino acid sequence consisting of amino acid residues 69 to 85 of SEQ ID NO: 5, and CDRH3 having an amino acid sequence consisting of amino acid residues 118 to 129 of SEQ ID NO: 5, and a light chain including CDRL1 having an amino acid sequence consisting of amino acid residues 44 to 54 of SEQ ID NO: 6, CDRL2 having an amino acid sequence consisting of amino acid residues 70 to 76 of SEQ ID NO: 6, and CDRL3 having an amino acid sequence consisting of amino acid residues 109 to 117 of SEQ ID NO: 6.

[0337] [15-1] The pharmaceutical product described in [13-1], wherein the anti-TROP2 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 140 of SEQ ID NO: 5, and a light chain having a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 129 of SEQ ID NO: 6.

[0338] [16-1] The pharmaceutical product described in [13-1], wherein the anti-TROP2 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 5, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 6.

[0339] [17-1] A pharmaceutical product described in [16-1], in which the anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0340] [18-1] The antibody-drug conjugate has the following formula:

[0341] [ka] wherein "antibody" represents an anti-TROP2 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 3.5 to 4.5. The pharmaceutical product according to any one of [13-1] to [17-1].

[0342] [19-1] A pharmaceutical product described in [2-1], wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[0343] [20-1] The pharmaceutical product described in [19-1], wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 7, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 8.

[0344] [21-1] A pharmaceutical product described in [20-1], in which the anti-B7-H3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0345] [22-1] The antibody-drug conjugate has the following formula:

[0346] [ka] The pharmaceutical product according to any one of [19-1] to [21-1], wherein "antibody" represents an anti-B7-H3 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 3.5 to 4.5.

[0347] [23-1] The pharmaceutical product described in [2-1], wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[0348] [24-1] The pharmaceutical product described in [23-1], wherein the anti-GPR20 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 472 of SEQ ID NO: 9, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 10.

[0349] [25-1] A pharmaceutical product described in [24-1], in which the anti-GPR20 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0350] [26-1] The antibody-drug conjugate has the following formula:

[0351] [ka] The pharmaceutical product described in any one of [23-1] to [25-1], wherein "antibody" represents an anti-GPR20 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

[0352] [27-1] The pharmaceutical product described in [2-1], wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[0353] [28-1] The pharmaceutical product described in [27-1], wherein the anti-CDH6 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 11, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 12.

[0354] [29-1] A pharmaceutical product described in [28-1], in which the anti-CDH6 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0355] [30-1] The antibody-drug conjugate has the following formula:

[0356] [ka] wherein "antibody" represents an anti-CDH6 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. The pharmaceutical product described in any one of [27-1] to [29-1].

[0357] [31-1] The pharmaceutical product described in [2-1], wherein the antibody in the antibody-drug conjugate is an anti-MUC1 antibody.

[0358] [32-1] The pharmaceutical product described in [31-1], wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 13 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 15.

[0359] [33-1] A pharmaceutical product described in [32-1], wherein the anti-MUC1 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0360] [34-1] The pharmaceutical product described in [31-1], wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by sequence number 14 and a light chain consisting of the amino acid sequence represented by sequence number 15.

[0361] [35-1] A pharmaceutical product described in [34-1], wherein the anti-MUC1 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0362] [36-1] The antibody-drug conjugate has the following formula:

[0363] [ka] wherein "antibody" represents an anti-MUC1 antibody conjugated to a drug-linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. The pharmaceutical product according to any one of [31-1] to [35-1].

[0364] [B1] The pharmaceutical product according to [2-1], wherein the antibody in the antibody-drug conjugate is an anti-CD37 antibody.

[0365] [B2] Anti-CD37 antibody (a) an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 138 of SEQ ID NO: 16, and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 128 of SEQ ID NO: 19; (b) an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 138 of SEQ ID NO: 17, and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 128 of SEQ ID NO: 19; and (c) an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 138 of SEQ ID NO: 18, and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 128 of SEQ ID NO: 19. The pharmaceutical product according to [B1], wherein the antibody is selected from the group consisting of:

[0366] [B3] Anti-CD37 antibody (d) an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 16, and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19; (e) an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 17, and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19, and (f) an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 18, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19. The pharmaceutical product according to [B1], wherein the antibody is selected from the group consisting of:

[0367] [B4] The pharmaceutical product according to [B1], wherein the anti-CD37 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 16, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19.

[0368] [B5] A pharmaceutical product according to [B4], wherein the anti-CD37 antibody lacks one or two amino acid residues at the carboxyl terminus of the heavy chain.

[0369] [B6] The pharmaceutical product according to [B4] or [B5], wherein the proline residue at the carboxyl terminus of the heavy chain is amidated.

[0370] [B7] The pharmaceutical product according to [B1], wherein the anti-CD37 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 17, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19.

[0371] [B8] The pharmaceutical product described in [B7], wherein the anti-CD37 antibody lacks one or two amino acid residues at the carboxyl terminus of the heavy chain.

[0372] [B9] The pharmaceutical product according to [B7] or [B8], wherein the proline residue at the carboxyl terminus of the heavy chain is amidated.

[0373] [B10] The pharmaceutical product according to [B1], wherein the anti-CD37 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 18, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19.

[0374] [B11] The pharmaceutical product according to [B10], wherein the anti-CD37 antibody lacks one or two amino acid residues at the carboxyl terminus of the heavy chain.

[0375] [B12] The pharmaceutical product according to [B10] or [B11], wherein the proline residue at the carboxyl terminus of the heavy chain is amidated.

[0376] [B13] The antibody-drug conjugate has the following formula:

[0377] [ka] wherein "antibody" represents an anti-CD37 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. The pharmaceutical product according to any one of [B1] to [B12].

[0378] [37-1] The pharmaceutical product described in any one of [1-1] to [8-1], wherein the antibody-drug conjugate is trastuzumab deruxtecan (DS-8201a). [38-1] A pharmaceutical product described in any one of [1-1] to [2-1] and [13-1] to [18-1], wherein the antibody-drug conjugate is datopotamab deruxtecan (DS-1062).

[0379] [39-1] The pharmaceutical product according to any one of [1-1] to [38-1], [A1] to [A2], and [B1] to [B13], wherein the inhibitor is an EZH2 inhibitor.

[0380] [40-1] The pharmaceutical product described in [39-1], wherein the inhibitor is tazemetostat or a pharma- ceutically acceptable salt thereof.

[0381] [41-1] The pharmaceutical product described in any one of [1-1] to [38-1], [A1] to [A2] and [B1] to [B13], wherein the inhibitor is an EZH1 / 2 inhibitor.

[0382] [42-1] The pharmaceutical product described in [41-1], wherein the inhibitor is valemetostat or a pharma- ceutical acceptable salt thereof.

[0383] [43-1] The pharmaceutical product according to [41-1] or [42-1], wherein the inhibitor is valemetostat tosylate.

[0384] [44-1] A pharmaceutical product described in any one of [1-1] to [43-1], [A1] to [A2] or [B1] to [B13], in which the antibody-drug conjugate and the inhibitor are separately contained in different formulations as active ingredients and are administered simultaneously or at different times.

[0385] [45-1] The pharmaceutical product described in any one of [1-1] to [44-1], [A1] to [A2] or [B1] to [B13], or [257-1], which is for use in 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.

[0386] [46-1] A pharmaceutical product described in [45-1], which is for use in the treatment of breast cancer.

[0387] [47-1] A pharmaceutical product described in [46-1], which is for use in the treatment of triple-negative breast cancer.

[0388] [48-1] A pharmaceutical product described in [45-1], which is for use in the treatment of gastric cancer.

[0389] [49-1] A pharmaceutical product described in [45-1], which is for use in the treatment of ovarian cancer.

[0390] [50-1] A pharmaceutical product described in [45-1], which is for use in the treatment of lung cancer.

[0391] [51-1] A pharmaceutical product described in [45-1], which is for use in the treatment of pancreatic cancer.

[0392] [52-1] A method for treatment, comprising administering to a subject in need of treatment an antibody-drug conjugate in combination with an inhibitor selected from the group consisting of an EZH1 inhibitor, an EZH2 inhibitor, and an EZH1 / 2 dual inhibitor, wherein the antibody-drug conjugate has the following formula:

[0393] [ka] (wherein A represents the attachment site to the antibody) The method for treatment, wherein the drug-linker represented by the formula: is an antibody-drug conjugate in which the drug-linker is conjugated to the antibody via a thioether bond.

[0394] [53-1] A method for treatment described in [52-1], 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, an anti-CDH6 antibody, an anti-MUC1 antibody, or an anti-CD37 antibody.

[0395] [54-1] A method for treatment described in [53-1], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[0396] The method for treatment described in [54-1], wherein the anti-HER2 antibody "55-1" is an antibody comprising a heavy chain including CDRH1 having an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 having an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 having an amino acid sequence consisting of amino acid residues 97 to 109 of SEQ ID NO: 1, and a light chain including CDRL1 having an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 having an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 having an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2.

[0397] [56-1] A method for treatment described in [54-1], wherein the anti-HER2 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 120 of SEQ ID NO: 1, and a light chain having a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 107 of SEQ ID NO: 2.

[0398] [57-1] A method for treatment described in [54-1], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by sequence number 1, and a light chain consisting of the amino acid sequence represented by sequence number 2.

[0399] [58-1] A method for treatment described in [54-1], wherein the anti-HER2 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1, and a light chain having an amino acid sequence represented by amino acid residues 1 to 214 of SEQ ID NO: 2.

[0400] [59-1] The antibody-drug conjugate has the following formula:

[0401] [ka] wherein "antibody" represents an anti-HER2 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

[0402] [60-1] The method for treatment described in [53-1], wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[0403] [C1] The method according to [60-1], wherein the anti-HER3 antibody comprises a heavy chain comprising CDRH1 consisting of the amino acid sequence of amino acid residues 26 to 35 of SEQ ID NO: 3, CDRH2 consisting of the amino acid sequence of amino acid residues 50 to 65 of SEQ ID NO: 3, and CDRH3 consisting of the amino acid sequence of amino acid residues 98 to 106 of SEQ ID NO: 3, and a light chain comprising CDRL1 consisting of the amino acid sequence of amino acid residues 24 to 39 of SEQ ID NO: 4, CDRL2 consisting of the amino acid sequence of amino acid residues 56 to 62 of SEQ ID NO: 4, and CDRL3 consisting of the amino acid sequence of amino acid residues 95 to 103 of SEQ ID NO: 4.

[0404] [C2] The method according to [60-1], wherein the anti-HER3 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 117 of SEQ ID NO: 3, and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 113 of SEQ ID NO: 4.

[0405] [61-1] A method for treatment described in [60-1], wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by sequence number 3, and a light chain consisting of the amino acid sequence represented by sequence number 4.

[0406] [62-1] A method for treatment described in [61-1], wherein the anti-HER3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0407] [63-1] The antibody-drug conjugate has the following formula:

[0408] [ka] wherein "antibody" represents an anti-HER3 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

[0409] [64-1] A method for treatment described in [53-1], wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[0410] [65-1] A method for treatment described in [64-1], wherein the anti-TROP2 antibody is an antibody comprising a heavy chain including CDRH1 having an amino acid sequence consisting of amino acid residues 50 to 54 of SEQ ID NO: 5, CDRH2 having an amino acid sequence consisting of amino acid residues 69 to 85 of SEQ ID NO: 5, and CDRH3 having an amino acid sequence consisting of amino acid residues 118 to 129 of SEQ ID NO: 5, and a light chain including CDRL1 having an amino acid sequence consisting of amino acid residues 44 to 54 of SEQ ID NO: 6, CDRL2 having an amino acid sequence consisting of amino acid residues 70 to 76 of SEQ ID NO: 6, and CDRL3 having an amino acid sequence consisting of amino acid residues 109 to 117 of SEQ ID NO: 6.

[0411] [66-1] A method for treatment described in [64-1], wherein the anti-TROP2 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 140 of SEQ ID NO: 5, and a light chain having a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 129 of SEQ ID NO: 6.

[0412] [67-1] A method for treatment described in [64-1], wherein the anti-TROP2 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 5, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 6.

[0413] [68-1] A method for treatment described in [67-1], wherein the anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0414] [69-1] The antibody-drug conjugate has the following formula:

[0415] [ka] wherein "antibody" represents an anti-TROP2 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 3.5 to 4.5.

[0416] [70-1] A method for treatment described in [53-1], wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[0417] [71-1] A method for treatment described in [70-1], wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 7, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 8.

[0418] [72-1] A method for treatment described in [71-1], wherein the anti-B7-H3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0419] [73-1] The antibody-drug conjugate has the following formula:

[0420] [ka] wherein "antibody" represents an anti-B7-H3 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 3.5 to 4.5.

[0421] [74-1] A method for treatment described in [53-1], wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[0422] [75-1] A method for treatment described in [74-1], wherein the anti-GPR20 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 472 of SEQ ID NO: 9, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 10.

[0423] [76-1] A method for treatment described in [75-1], wherein the anti-GPR20 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0424] [77-1] The antibody-drug conjugate has the following formula:

[0425] [ka] wherein "antibody" represents an anti-GPR20 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. A method for treatment according to any one of [74-1] to [76-1].

[0426] [78-1] A method for treatment described in [53-1], wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[0427] [79-1] A method for treatment described in [78-1], wherein the anti-CDH6 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 11, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 12.

[0428] [80-1] A method for treatment described in [79-1], wherein the anti-CDH6 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0429] [81-1] The antibody-drug conjugate has the following formula:

[0430] [ka] wherein "antibody" represents an anti-CDH6 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

[0431] [82-1] The method according to [53-1], wherein the antibody in the antibody-drug conjugate is an anti-MUC1 antibody.

[0432] [83-1] The method described in [82-1], wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 13, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 15.

[0433] [84-1] The method according to [83-1], wherein the anti-MUC1 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0434] [85-1] The method described in [82-1], wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 14 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 15.

[0435] [86-1] The method according to [85-1], wherein the anti-MUC1 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0436] [87-1] The antibody-drug conjugate has the following formula:

[0437] [ka] The method according to any one of [82-1] to [86-1], wherein "antibody" represents an anti-MUC1 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

[0438] [D1] The method according to [53-1], wherein the antibody in the antibody-drug conjugate is an anti-CD37 antibody.

[0439] [D2] Anti-CD37 antibody (a) an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 138 of SEQ ID NO: 16, and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 128 of SEQ ID NO: 19; (b) an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 138 of SEQ ID NO: 17, and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 128 of SEQ ID NO: 19; and (c) an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 138 of SEQ ID NO: 18, and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 128 of SEQ ID NO: 19. The method according to [D1], wherein the antibody is selected from the group consisting of:

[0440] [D3] Anti-CD37 antibody (d) an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 16, and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19; (e) an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 17, and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19, and (f) an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 18, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19. The method according to [D1], wherein the antibody is selected from the group consisting of:

[0441] [D4] The method according to [D1], wherein the anti-CD37 antibody comprises a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 16, and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19.

[0442] [D5] The method according to [D4], wherein the anti-CD37 antibody lacks one or two amino acid residues at the carboxyl terminus of the heavy chain.

[0443] [D6] The method according to [D4] or [D5], wherein the proline residue at the carboxyl terminus of the heavy chain is amidated.

[0444] [D7] The method according to [D1], wherein the anti-CD37 antibody comprises a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 17, and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19.

[0445] [D8] The method according to [D7], wherein the anti-CD37 antibody lacks one or two amino acid residues at the carboxyl terminus of the heavy chain.

[0446] [D9] The method according to [D7] or [D8], wherein the proline residue at the carboxyl terminus of the heavy chain is amidated.

[0447] [D10] The method according to [D1], wherein the anti-CD37 antibody comprises a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 18, and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19.

[0448] [D11] The method according to [D10], wherein the anti-CD37 antibody lacks one or two amino acid residues at the carboxyl terminus of the heavy chain.

[0449] [D12] The method according to [D10] or [D11], wherein the proline residue at the carboxyl terminus of the heavy chain is amidated.

[0450] [D13] The antibody-drug conjugate has the following formula:

[0451] [ka] wherein "antibody" represents an anti-CD37 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. The method according to any one of [D1] to [D12].

[0452] [88-1] A method for treatment described in any one of [52-1] to [59-1], wherein the antibody-drug conjugate is trastuzumab deruxtecan (DS-8201a).

[0453] [89-1] A method for treatment described in any one of [52-1] to [53-1] and [64-1] to [69-1], wherein the antibody-drug conjugate is datopotamab deruxtecan (DS-1062).

[0454] [90-1] The method according to any one of [52-1] to [89-1], or [C1] to [C2] and [D1] to [D13], wherein the inhibitor is an EZH2 inhibitor.

[0455] [91-1] The method according to [90-1], wherein the inhibitor is tazemetostat or a pharma- ceutically acceptable salt thereof.

[0456] [92-1] The method according to any one of [52-1] to [89-1], [C1] to [C2] and [D1] to [D13], wherein the inhibitor is an EZH1 / 2 dual inhibitor.

[0457] [93-1] The method according to [92-1], wherein the inhibitor is valemetostat or a pharma- ceutically acceptable salt thereof.

[0458] [94-1] The method according to [92-1] or [93-1], wherein the inhibitor is valemetostat tosylate.

[0459] [95-1] The method described in any one of [52-1] to [94-1], [C1] to [C2] and [D1] to [D13], wherein the antibody-drug conjugate and the inhibitor are separately contained in different formulations as active ingredients and are administered simultaneously or at different times.

[0460] [96-1] The method according to any one of [52-1] to [95-1], [C1] to [C2], [D1] to [D13], and [258-1], which is for use in treating 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.

[0461] [97-1] The method according to [96-1], which is for use in treating breast cancer.

[0462] [98-1] The method according to [97-1], which is for use in treating triple-negative breast cancer.

[0463] [99-1] The method according to [96-1], which is for use in treating gastric cancer.

[0464] [100-1] The method according to [96-1], which is for use in treating ovarian cancer.

[0465] [101-1] The method according to [96-1], which is for use in treating lung cancer.

[0466] [102-1] The method described in [96-1], which is for use in the treatment of pancreatic cancer.

[0467] [103-1] An antibody-drug conjugate for use in a method for treating a disease, the method comprising administering the antibody-drug conjugate in combination with an inhibitor selected from the group consisting of an EZH1 inhibitor, an EZH2 inhibitor, and an EZH1 / 2 dual inhibitor, the antibody-drug conjugate having the following formula:

[0468] [ka] (wherein A represents the attachment site to the antibody) An antibody-drug conjugate, wherein the drug-linker represented by the formula:

[0469] [104-1] An antibody-drug conjugate for use according to [103-1], 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, an anti-CDH6 antibody, an anti-MUC1 antibody, or an anti-CD37 antibody.

[0470]

[0105] An antibody-drug conjugate for use according to [104-1], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[0471] [106-1] An antibody-drug conjugate for use according to [105-1], wherein the anti-HER2 antibody comprises a heavy chain comprising CDRH1 having an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 having an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 having an amino acid sequence consisting of amino acid residues 97 to 109 of SEQ ID NO: 1, and a light chain comprising CDRL1 having an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 having an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 having an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2.

[0472] [107-1] An antibody-drug conjugate for use according to [105-1], wherein the anti-HER2 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 120 of SEQ ID NO: 1, and a light chain having a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 107 of SEQ ID NO: 2.

[0473] [108-1] An antibody-drug conjugate for use according to [105-1], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 1, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 2.

[0474] [109-1] An antibody-drug conjugate for use according to [105-1], wherein the anti-HER2 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1, and a light chain having an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2.

[0475] [110-1] The antibody-drug conjugate has the following formula:

[0476] [ka] wherein "antibody" represents an anti-HER2 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. An antibody-drug conjugate for use according to any one of [105-1] to [109-1].

[0477] [111-1] An antibody-drug conjugate for use according to [104-1], wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[0478] [E1] An antibody-drug conjugate for use according to [111-1], wherein the anti-HER3 antibody comprises a heavy chain comprising CDRH1 consisting of an amino acid sequence consisting of amino acid residues 26 to 35 of SEQ ID NO: 3, CDRH2 consisting of an amino acid sequence consisting of amino acid residues 50 to 65 of SEQ ID NO: 3, and CDRH3 consisting of an amino acid sequence consisting of amino acid residues 98 to 106 of SEQ ID NO: 3, and a light chain comprising CDRL1 consisting of an amino acid sequence consisting of amino acid residues 24 to 39 of SEQ ID NO: 4, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 56 to 62 of SEQ ID NO: 4, and CDRL3 consisting of an amino acid sequence consisting of amino acid residues 95 to 103 of SEQ ID NO: 4.

[0479] [E2] The antibody-drug conjugate for use according to [111-1], wherein the anti-HER3 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 117 of SEQ ID NO: 3, and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 113 of SEQ ID NO: 4.

[0480] [112-1] An antibody-drug conjugate for use according to [111-1], wherein the anti-HER3 antibody is an antibody comprising a heavy chain having the amino acid sequence represented by SEQ ID NO: 3 and a light chain having the amino acid sequence represented by SEQ ID NO: 4.

[0481] [113-1] An antibody-drug conjugate for use according to [112-1], wherein the anti-HER3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0482] [114-1] The antibody-drug conjugate has the following formula:

[0483] [ka] wherein "antibody" represents an anti-HER3 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. An antibody-drug conjugate for use according to any one of [111-1] to [113-1] or [E1] to [E2].

[0484] [115-1] An antibody-drug conjugate for use according to [104-1], wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[0485] [116-1] An antibody-drug conjugate for use according to [115-1], wherein the anti-TROP2 antibody comprises a heavy chain comprising CDRH1 having an amino acid sequence consisting of amino acid residues 50 to 54 of SEQ ID NO: 5, CDRH2 having an amino acid sequence consisting of amino acid residues 69 to 85 of SEQ ID NO: 5, and CDRH3 having an amino acid sequence consisting of amino acid residues 118 to 129 of SEQ ID NO: 5, and a light chain comprising CDRL1 having an amino acid sequence consisting of amino acid residues 44 to 54 of SEQ ID NO: 6, CDRL2 having an amino acid sequence consisting of amino acid residues 70 to 76 of SEQ ID NO: 6, and CDRL3 having an amino acid sequence consisting of amino acid residues 109 to 117 of SEQ ID NO: 6.

[0486] [117-1] An antibody-drug conjugate for use according to [115-1], wherein the anti-TROP2 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 140 of SEQ ID NO: 5, and a light chain having a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 129 of SEQ ID NO: 6.

[0487] [118-1] The antibody-drug conjugate for use according to [115-1], wherein the anti-TROP2 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 5, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 6.

[0488] [119-1] An antibody-drug conjugate for use according to [118-1], wherein the anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0489] [120-1] The antibody-drug conjugate has the following formula:

[0490] [ka] wherein "antibody" represents an anti-TROP2 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 3.5 to 4.5.

[0491] [121-1] An antibody-drug conjugate for use according to [104-1], wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[0492] [122-1] An antibody-drug conjugate for use according to [121-1], wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 7, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 8.

[0493] [123-1] An antibody-drug conjugate for use according to [122-1], wherein the anti-B7-H3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0494] [124-1] The antibody-drug conjugate has the following formula:

[0495] [ka] An antibody-drug conjugate for use according to any one of [121-1] to [123-1], wherein "antibody" represents an anti-B7-H3 antibody conjugated to a drug-linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 3.5 to 4.5.

[0496] [125-1] An antibody-drug conjugate for use according to [104-1], wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[0497] [126-1] The antibody-drug conjugate for use according to [125-1], wherein the anti-GPR20 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 472 of SEQ ID NO: 9, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 10.

[0498] [127-1] An antibody-drug conjugate for use according to [126-1], wherein the anti-GPR20 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0499] [128-1] The antibody-drug conjugate has the following formula:

[0500] [ka] An antibody-drug conjugate for use according to any one of [125-1] to [127-1], wherein "antibody" represents an anti-GPR20 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

[0501] [129-1] An antibody-drug conjugate for use according to [104-1], wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[0502] [130-1] The antibody-drug conjugate for use according to [129-1], wherein the anti-CDH6 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 11, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 12.

[0503] [131-1] The antibody-drug conjugate for use according to [130-1], wherein the anti-CDH6 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0504] [132-1] The antibody-drug conjugate has the following formula:

[0505] [ka] wherein "antibody" represents an anti-CDH6 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. An antibody-drug conjugate for use according to any one of [129-1] to [131-1].

[0506] [133-1] The antibody-drug conjugate for use according to [104-1], wherein the antibody in the antibody-drug conjugate is an anti-MUC1 antibody.

[0507] [134-1] An antibody-drug conjugate for use according to [133-1], wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 13, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 15.

[0508] [135-1] The antibody-drug conjugate for use according to [134-1], wherein the anti-MUC1 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0509] [136-1] The antibody-drug conjugate for use according to [133-1], wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 14, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 15.

[0510] [137-1] The antibody-drug conjugate for use according to [136-1], wherein the anti-MUC1 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0511] [138-1] The antibody-drug conjugate has the following formula:

[0512] [ka] wherein "antibody" represents an anti-MUC1 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, where n is in the range of 7 to 8.

[0513] [F1] An antibody-drug conjugate for use according to [104-1], wherein the antibody in the antibody-drug conjugate is an anti-CD37 antibody.

[0514] [F2] Anti-CD37 antibody (a) an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 138 of SEQ ID NO: 16, and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 128 of SEQ ID NO: 19; (b) an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 138 of SEQ ID NO: 17, and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 128 of SEQ ID NO: 19; and (c) an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 138 of SEQ ID NO: 18, and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 128 of SEQ ID NO: 19. The antibody-drug conjugate for use according to [F1], wherein the antibody is selected from the group consisting of:

[0515] [F3] Anti-CD37 antibody (d) an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 16, and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19; (e) an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 17, and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19, and (f) an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 18, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19. The antibody-drug conjugate for use according to [F1], wherein the antibody is selected from the group consisting of:

[0516] [F4] The antibody-drug conjugate for use according to [F1], wherein the anti-CD37 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 16, and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19.

[0517] [F5] An antibody-drug conjugate for use according to [F4], wherein the anti-CD37 antibody lacks one or two amino acid residues at the carboxyl terminus of the heavy chain.

[0518] [F6] An antibody-drug conjugate for use according to [F4] or [F5], wherein the proline residue at the carboxyl terminus of the heavy chain is amidated.

[0519] [F7] An antibody-drug conjugate for use according to [F1], wherein the anti-CD37 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 17, and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19.

[0520] [F8] An antibody-drug conjugate for use according to [F7], wherein the anti-CD37 antibody lacks one or two amino acid residues at the carboxyl terminus of the heavy chain.

[0521] [F9] An antibody-drug conjugate for use according to [F7] or [F8], wherein the proline residue at the carboxyl terminus of the heavy chain is amidated.

[0522] [F10] An antibody-drug conjugate for use according to [F1], wherein the anti-CD37 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 18, and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19.

[0523] [F11] An antibody-drug conjugate for use according to [F10], wherein the anti-CD37 antibody lacks one or two amino acid residues at the carboxyl terminus of the heavy chain.

[0524] [F12] An antibody-drug conjugate for use according to [F10] or [F11], wherein the proline residue at the carboxyl terminus of the heavy chain is amidated.

[0525] [F13] The antibody-drug conjugate has the following formula:

[0526] [ka] wherein "antibody" represents an anti-CD37 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. An antibody-drug conjugate for use according to any one of [F1] to [F12].

[0527] [139-1] The antibody-drug conjugate for use according to any one of [103-1] to [110-1], wherein the antibody-drug conjugate is trastuzumab deruxtecan (DS-8201a).

[0528] [140-1] The antibody-drug conjugate for use according to any one of [103-1] to [104-1] and [115-1] to [120-1], wherein the antibody-drug conjugate is datopotamab deruxtecan (DS-1062).

[0529] [141-1] The antibody-drug conjugate for use according to any one of [103-1] to [140-1], [E1] to [E2] and [F1] to [F13], wherein the inhibitor is an EZH2 inhibitor.

[0530] [142-1] The antibody-drug conjugate for use according to [141-1], wherein the inhibitor is tazemetostat or a pharma- ceutically acceptable salt thereof.

[0531] The antibody-drug conjugate for use according to any one of [103-1] to [140-1], [E1] to [E2] and [F1] to [F13], wherein the [143-1] inhibitor is an EZH1 / 2 dual inhibitor.

[0532] [144-1] The antibody-drug conjugate for use according to [143-1], wherein the inhibitor is valemetostat or a pharma- ceutically acceptable salt thereof.

[0533] [145-1] The antibody-drug conjugate for use according to [143-1] or [144-1], wherein the inhibitor is valemetostat tosylate.

[0534] [146-1] An antibody-drug conjugate for use according to any one of [103-1] to [145-1], [E1] to [E2] and [F1] to [F13], wherein the antibody-drug conjugate and the inhibitor are contained separately as active ingredients in different formulations and administered simultaneously or at different times.

[0535] [147-1] The antibody-drug conjugate for use according to any one of [103-1] to [146-1], [E1] to [E2], [F1] to [F13] and [259-1], wherein the disease is 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, kidney cancer, and sarcoma.

[0536] [148-1] The antibody-drug conjugate for use according to [147-1], wherein the disease is breast cancer.

[0537] [149-1] The antibody-drug conjugate for use according to [148-1], wherein the disease is triple-negative breast cancer.

[0538] [150-1] The antibody-drug conjugate for use according to [147-1], wherein the disease is gastric cancer.

[0539] [151-1] The antibody-drug conjugate for use according to [147-1], wherein the disease is ovarian cancer.

[0540] [152-1] The antibody-drug conjugate for use according to [147-1], wherein the disease is lung cancer.

[0541] [153-1] The antibody-drug conjugate for use according to [147-1], wherein the disease is pancreatic cancer.

[0542] [154-1] Use of an antibody-drug conjugate or an inhibitor selected from the group consisting of an EZH1 inhibitor, an EZH2 inhibitor, and an EZH1 / 2 dual inhibitor, for the manufacture of a medicament for treating a disease by administering the antibody-drug conjugate and the inhibitor in combination, wherein the antibody-drug conjugate has the following formula:

[0543] [ka] (wherein A represents the attachment site to the antibody) The use of an antibody-drug conjugate, wherein the drug-linker represented by the formula:

[0544] [155-1] The use according to [154-1], 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, an anti-CDH6 antibody, an anti-MUC1 antibody, or an anti-CD37 antibody.

[0545] [156-1] The use according to [155-1], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[0546] [157-1] The use according to [156-1], wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 having an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 having an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 having an amino acid sequence consisting of amino acid residues 97 to 109 of SEQ ID NO: 1, and a light chain comprising CDRL1 having an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 having an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 having an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2.

[0547] [158-1] The use described in [156-1], wherein the anti-HER2 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 120 of SEQ ID NO: 1, and a light chain having a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 107 of SEQ ID NO: 2.

[0548] [159-1] The use according to [156-1], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 1, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 2.

[0549] [160-1] The use according to [156-1], wherein the anti-HER2 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1, and a light chain having an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2.

[0550] [161-1] The antibody-drug conjugate has the following formula:

[0551] [ka] wherein "antibody" represents an anti-HER2 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. The use described in any one of [156-1] to [160-1].

[0552] [162-1] The use according to [155-1], wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[0553] [G1] The use described in [162-1], wherein the anti-HER3 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence of amino acid residues 26 to 35 of SEQ ID NO: 3, CDRH2 consisting of the amino acid sequence of amino acid residues 50 to 65 of SEQ ID NO: 3, and CDRH3 consisting of the amino acid sequence of amino acid residues 98 to 106 of SEQ ID NO: 3, and a light chain comprising CDRL1 consisting of the amino acid sequence of amino acid residues 24 to 39 of SEQ ID NO: 4, CDRL2 consisting of the amino acid sequence of amino acid residues 56 to 62 of SEQ ID NO: 4, and CDRL3 consisting of the amino acid sequence of amino acid residues 95 to 103 of SEQ ID NO: 4.

[0554] [G2] The use described in [162-1], wherein the anti-HER3 antibody is an antibody comprising a heavy chain including a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 117 of SEQ ID NO: 3, and a light chain including a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 113 of SEQ ID NO: 4.

[0555] [163-1] The use described in [162-1], wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 3, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 4.

[0556] [164-1] The use described in [163-1], wherein the anti-HER3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0557] [165-1] The antibody-drug conjugate has the following formula:

[0558] [ka] wherein "antibody" represents an anti-HER3 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. The use described in any one of [162-1] to [164-1] and [G1] to [G2].

[0559] [166-1] The use according to [155-1], wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[0560] [167-1] The use of the anti-TROP2 antibody described in [166-1], which is an antibody comprising a heavy chain including CDRH1 having an amino acid sequence consisting of amino acid residues 50 to 54 of SEQ ID NO: 5, CDRH2 having an amino acid sequence consisting of amino acid residues 69 to 85 of SEQ ID NO: 5, and CDRH3 having an amino acid sequence consisting of amino acid residues 118 to 129 of SEQ ID NO: 5, and a light chain including CDRL1 having an amino acid sequence consisting of amino acid residues 44 to 54 of SEQ ID NO: 6, CDRL2 having an amino acid sequence consisting of amino acid residues 70 to 76 of SEQ ID NO: 6, and CDRL3 having an amino acid sequence consisting of amino acid residues 109 to 117 of SEQ ID NO: 6.

[0561] [168-1] The use described in [166-1], wherein the anti-TROP2 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 140 of SEQ ID NO: 5, and a light chain having a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 129 of SEQ ID NO: 6.

[0562] [169-1] The use described in [166-1], wherein the anti-TROP2 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 5, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 6.

[0563] [170-1] The use described in [169-1], wherein the anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0564]

[0171] The antibody-drug conjugate has the following formula:

[0565] [ka] wherein "antibody" represents an anti-TROP2 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 3.5 to 4.5.

[0566] [172-1] The use according to [155-1], wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[0567] [173-1] The use according to [172-1], wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 7, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 8.

[0568] [174-1] The use according to [173-1], wherein the anti-B7-H3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0569] [175-1] The antibody-drug conjugate has the following formula:

[0570] [ka] The use described in any one of [172-1] to [174-1], wherein "antibody" represents an anti-B7-H3 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 3.5 to 4.5.

[0571] [176-1] The use according to [155-1], wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[0572] [177-1] The use according to [176-1], wherein the anti-GPR20 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 472 of SEQ ID NO: 9, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 10.

[0573] [178-1] The use according to [177-1], wherein the anti-GPR20 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0574] [179-1] The antibody-drug conjugate has the following formula:

[0575] [ka] The use described in any one of [176-1] to [178-1], wherein "antibody" represents an anti-GPR20 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

[0576] [180-1] The use according to [155-1], wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[0577] [181-1] The use according to [180-1], wherein the anti-CDH6 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 11, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 12.

[0578] [182-1] The use described in [181-1], wherein the anti-CDH6 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0579] [183-1] The antibody-drug conjugate has the following formula:

[0580] [ka] wherein "antibody" represents an anti-CDH6 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. The use according to any one of [180-1] to [182-1].

[0581] [184-1] The use according to [155-1], wherein the antibody in the antibody-drug conjugate is an anti-MUC1 antibody.

[0582] [185-1] The use according to [184-1], wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 13, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 15.

[0583] [186-1] The use according to [185-1], wherein the anti-MUC1 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0584] [187-1] The use according to [184-1], wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 14, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 15.

[0585] [188-1] The use according to [187-1], wherein the anti-MUC1 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0586] [189-1] The antibody-drug conjugate has the following formula:

[0587] [ka] wherein "antibody" represents an anti-MUC1 antibody conjugated to a drug-linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. The use according to any one of [184-1] to [188-1].

[0588] [H1] The use according to [155-1], wherein the antibody in the antibody-drug conjugate is an anti-CD37 antibody.

[0589] [H2] Anti-CD37 antibody (a) an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 138 of SEQ ID NO: 16, and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 128 of SEQ ID NO: 19; (b) an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 138 of SEQ ID NO: 17, and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 128 of SEQ ID NO: 19; and (c) an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 138 of SEQ ID NO: 18, and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 128 of SEQ ID NO: 19. The use according to [H1], wherein the antibody is selected from the group consisting of:

[0590] [H3] Anti-CD37 antibody (d) an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 16, and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19; (e) an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 17, and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19, and (f) an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 18, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19. The use according to [H1], wherein the antibody is selected from the group consisting of:

[0591] [H4] The use according to [H1], wherein the anti-CD37 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 16, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19.

[0592] [H5] The use according to [H4], wherein the anti-CD37 antibody lacks one or two amino acid residues at the carboxyl terminus of the heavy chain.

[0593] [H6] The use according to [H4] or [H5], wherein the proline residue at the carboxyl terminus of the heavy chain is amidated.

[0594] [H7] The use according to [H1], wherein the anti-CD37 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 17, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19.

[0595] [H8] The use according to [H7], wherein the anti-CD37 antibody lacks one or two amino acid residues at the carboxyl terminus of the heavy chain.

[0596] [H9] The use according to [H7] or [H8], wherein the proline residue at the carboxyl terminus of the heavy chain is amidated.

[0597] [H10] The use according to [H1], wherein the anti-CD37 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 18, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19.

[0598] [H11] The use according to [H10], wherein the anti-CD37 antibody lacks one or two amino acid residues at the carboxyl terminus of the heavy chain.

[0599] [H12] The use according to [H10] or [H11], wherein the proline residue at the carboxyl terminus of the heavy chain is amidated.

[0600] [H13] The antibody-drug conjugate has the following formula:

[0601] [ka] wherein "antibody" represents an anti-CD37 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. The use according to any one of [H1] to [H12].

[0602] [190-1] The use according to any one of [154-1] to [161-1], wherein the antibody-drug conjugate is trastuzumab deruxtecan (DS-8201a).

[0603] [191-1] The use according to any one of [154-1] to [155-1] and [166-1] to [171-1], wherein the antibody-drug conjugate is datopotamab deruxtecan (DS-1062).

[0604] The use according to any one of [154-1] to [191-1], [G1] to [G2] and [H1] to [H13], wherein the [192-1] inhibitor is an EZH2 inhibitor.

[0605] [193-1] The use according to [192-1], wherein the inhibitor is tazemetostat or a pharma- ceutically acceptable salt thereof.

[0606] The use according to any one of [154-1] to [191-1], [G1] to [G2] and [H1] to [H13], wherein the [194-1] inhibitor is an EZH1 / 2 dual inhibitor.

[0607] [195-1] The use according to [194-1], wherein the inhibitor is valemetostat or a pharma- ceutically acceptable salt thereof.

[0608] [196-1] The use according to [194-1] or [195-1], wherein the inhibitor is valemetostat tosylate.

[0609] [197-1] The use described in any one of [154-1] to [196-1], [G1] to [G2] and [H1] to [H13], wherein the antibody-drug conjugate and the inhibitor are contained separately as active ingredients in different formulations and are administered simultaneously or at different times.

[0610] [198-1] The use according to any one of [154-1] to [197-1], [G1] to [G2], [H1] to [H13], and [260-1], wherein the disease is 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, kidney cancer, and sarcoma.

[0611] [199-1] The use described in [198-1], wherein the disease is breast cancer.

[0612] [200-1] The use described in [199-1], wherein the disease is triple-negative breast cancer.

[0613] [201-1] The use according to [198-1], wherein the disease is gastric cancer.

[0614] [202-1] The use described in [198-1], wherein the disease is ovarian cancer.

[0615] [203-1] The use described in [198-1], wherein the disease is lung cancer.

[0616] [204-1] The use described in [198-1], wherein the disease is pancreatic cancer.

[0617] [205-1] An inhibitor selected from the group consisting of an EZH1 inhibitor, an EZH2 inhibitor, and an EZH1 / 2 dual inhibitor, for use in a method for treating a disease, the method comprising administering the inhibitor in combination with an antibody-drug conjugate, the antibody-drug conjugate having the following formula:

[0618] [ka] (wherein A represents the attachment site to the antibody) The inhibitor is an antibody-drug conjugate, wherein the drug-linker represented by the formula:

[0619] [206-1] The inhibitor for use according to [205-1], 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, an anti-CDH6 antibody, an anti-MUC1 antibody, or an anti-CD37 antibody.

[0620] [207-1] The inhibitor for use according to [206-1], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[0621] [208-1] The anti-HER2 antibody is an antibody comprising a heavy chain including CDRH1 having an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 having an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 having an amino acid sequence consisting of amino acid residues 97 to 109 of SEQ ID NO: 1, and a light chain including CDRL1 having an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 having an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 having an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2, an inhibitor for use according to [207-1].

[0622] [209-1] An inhibitor for use according to [207-1], wherein the anti-HER2 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 120 of SEQ ID NO: 1, and a light chain having a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 107 of SEQ ID NO: 2.

[0623] [210-1] An inhibitor for use according to [207-1], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 1, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 2.

[0624] [211-1] The inhibitor for use according to [207-1], wherein the anti-HER2 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1, and a light chain having an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2.

[0625] [212-1] The antibody-drug conjugate has the following formula:

[0626] [ka] wherein "antibody" represents an anti-HER2 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

[0627] [213-1] The inhibitor for use according to [206-1], wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[0628] [I1] The inhibitor for use according to [213-1], wherein the anti-HER3 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence of amino acid residues 26 to 35 of SEQ ID NO: 3, CDRH2 consisting of the amino acid sequence of amino acid residues 50 to 65 of SEQ ID NO: 3, and CDRH3 consisting of the amino acid sequence of amino acid residues 98 to 106 of SEQ ID NO: 3, and a light chain comprising CDRL1 consisting of the amino acid sequence of amino acid residues 24 to 39 of SEQ ID NO: 4, CDRL2 consisting of the amino acid sequence of amino acid residues 56 to 62 of SEQ ID NO: 4, and CDRL3 consisting of the amino acid sequence of amino acid residues 95 to 103 of SEQ ID NO: 4.

[0629] [I2] The inhibitor for use according to [213-1], wherein the anti-HER3 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 117 of SEQ ID NO: 3, and a light chain having a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 113 of SEQ ID NO: 4.

[0630] [214-1] The inhibitor for use according to [213-1], wherein the anti-HER3 antibody is an antibody comprising a heavy chain having the amino acid sequence represented by SEQ ID NO: 3 and a light chain having the amino acid sequence represented by SEQ ID NO: 4.

[0631] [215-1] An inhibitor for use according to [214-1], wherein the anti-HER3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0632] [216-1] The antibody-drug conjugate has the following formula:

[0633] [ka] wherein "antibody" represents an anti-HER3 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

[0634] [217-1] The inhibitor for use according to [206-1], wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[0635] [218-1] The anti-TROP2 antibody is an inhibitor for use according to [217-1], which is an antibody comprising a heavy chain comprising CDRH1 having an amino acid sequence consisting of amino acid residues 50 to 54 of SEQ ID NO: 5, CDRH2 having an amino acid sequence consisting of amino acid residues 69 to 85 of SEQ ID NO: 5, and CDRH3 having an amino acid sequence consisting of amino acid residues 118 to 129 of SEQ ID NO: 5, and a light chain comprising CDRL1 having an amino acid sequence consisting of amino acid residues 44 to 54 of SEQ ID NO: 6, CDRL2 having an amino acid sequence consisting of amino acid residues 70 to 76 of SEQ ID NO: 6, and CDRL3 having an amino acid sequence consisting of amino acid residues 109 to 117 of SEQ ID NO: 6.

[0636] [219-1] The anti-TROP2 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 140 of SEQ ID NO: 5, and a light chain having a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 129 of SEQ ID NO: 6, as an inhibitor for use according to [217-1].

[0637] [220-1] The inhibitor for use according to [217-1], wherein the anti-TROP2 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 5, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 6.

[0638] [221-1] An inhibitor for use according to [220-1], wherein the anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0639] [222-1] The antibody-drug conjugate has the following formula:

[0640] [ka] wherein "antibody" represents an anti-TROP2 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 3.5 to 4.5.

[0641] [223-1] The inhibitor for use according to [206-1], wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[0642] [224-1] The inhibitor for use according to [223-1], wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 7, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 8.

[0643] [225-1] An inhibitor for use according to [224-1], wherein the anti-B7-H3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0644] [226-1] The antibody-drug conjugate has the following formula:

[0645] [ka] wherein "antibody" represents an anti-B7-H3 antibody conjugated to a drug-linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 3.5 to 4.5.

[0646] [227-1] The inhibitor for use according to [206-1], wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[0647] [228-1] The inhibitor for use according to [227-1], wherein the anti-GPR20 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 472 of SEQ ID NO: 9, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 10.

[0648] [229-1] An inhibitor for use according to [228-1], wherein the anti-GPR20 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0649] [230-1] The antibody-drug conjugate has the following formula:

[0650] [ka] wherein "antibody" represents an anti-GPR20 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. An inhibitor for use according to any one of [227-1] to [229-1].

[0651] [231-1] The inhibitor for use according to [206-1], wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[0652] [232-1] The inhibitor for use according to [231-1], wherein the anti-CDH6 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 11, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 12.

[0653] [233-1] An inhibitor for use according to [232-1], wherein the anti-CDH6 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0654] [234-1] The antibody-drug conjugate has the following formula:

[0655] [ka] wherein "antibody" represents an anti-CDH6 antibody conjugated to a drug-linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8. An inhibitor for use according to any one of [231-1] to [233-1].

[0656] [235-1] The inhibitor for use according to [206-1], wherein the antibody in the antibody-drug conjugate is an anti-MUC1 antibody.

[0657] [236-1] The inhibitor for use according to [235-1], wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 13, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 15.

[0658] [237-1] An inhibitor for use according to [236-1], wherein the anti-MUC1 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0659] [238-1] The inhibitor for use according to [235-1], wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 14, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 15.

[0660] [239-1] An inhibitor for use according to [238-1], wherein the anti-MUC1 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0661] [240-1] The antibody-drug conjugate has the following formula:

[0662] [ka] wherein "antibody" represents an anti-MUC1 antibody conjugated to a drug-linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

[0663] [J1] The inhibitor for use according to [206-1], wherein the antibody in the antibody-drug conjugate is an anti-CD37 antibody.

[0664] [J2] Anti-CD37 antibody, (a) an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 138 of SEQ ID NO: 16, and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 128 of SEQ ID NO: 19; (b) an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 138 of SEQ ID NO: 17, and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 128 of SEQ ID NO: 19; and (c) an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 138 of SEQ ID NO: 18, and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 128 of SEQ ID NO: 19. The inhibitor for use according to [J1], which is an antibody selected from the group consisting of:

[0665] [J3] Anti-CD37 antibody, (d) an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 16, and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19; (e) an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 17, and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19, and (f) an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 18, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19. The inhibitor for use according to [J1], which is an antibody selected from the group consisting of:

[0666] [J4] The inhibitor for use according to [J1], wherein the anti-CD37 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 16, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19.

[0667] [J5] An inhibitor for use according to [J4], wherein the anti-CD37 antibody lacks one or two amino acid residues at the carboxyl terminus of the heavy chain.

[0668] [J6] An inhibitor for use according to [J4] or [J5], wherein the proline residue at the carboxyl terminus of the heavy chain is amidated.

[0669] [J7] The inhibitor for use according to [J1], wherein the anti-CD37 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 17, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19.

[0670] [J8] An inhibitor for use according to [J7], wherein the anti-CD37 antibody lacks one or two amino acid residues at the carboxyl terminus of the heavy chain.

[0671] [J9] An inhibitor for use according to [J7] or [J8], wherein the proline residue at the carboxyl terminus of the heavy chain is amidated.

[0672] [J10] The inhibitor for use according to [J1], wherein the anti-CD37 antibody is an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 18, and a light chain having an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19.

[0673] [J11] An inhibitor for use according to [J10], wherein the anti-CD37 antibody lacks one or two amino acid residues at the carboxyl terminus of the heavy chain.

[0674] [J12] An inhibitor for use according to [J10] or [J11], wherein the proline residue at the carboxyl terminus of the heavy chain is amidated.

[0675] [J13] The antibody-drug conjugate has the following formula:

[0676] [ka] wherein "antibody" represents an anti-CD37 antibody conjugated to a drug linker via a thioether bond, and n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

[0677] [241-1] The inhibitor for use according to any one of [205-1] to [212-1], wherein the antibody-drug conjugate is trastuzumab deruxtecan (DS-8201a).

[0678] [242-1] The inhibitor for use according to any one of [205-1] to [206-1] and [217-1] to [222-1], wherein the antibody-drug conjugate is datopotamab deruxtecan (DS-1062).

[0679] [243-1] The inhibitor for use according to any one of [205-1] to [242-1], [I1] to [I2] and [J1] to [J13], wherein the inhibitor is an EZH2 inhibitor.

[0680] [244-1] The inhibitor for use according to [243-1], wherein the inhibitor is tazemetostat or a pharma- ceutically acceptable salt thereof.

[0681] The inhibitor for use according to any one of [205-1] to [242-1], [I1] to [I2] and [J1] to [J13], wherein the [245-1] inhibitor is an EZH1 / 2 dual inhibitor.

[0682] [246-1] The inhibitor for use according to [245-1], wherein the inhibitor is valemetostat or a pharma- ceutically acceptable salt thereof.

[0683] [247-1] The inhibitor for use according to [245-1] or [246-1], wherein the inhibitor is valemetostat tosylate.

[0684] [248-1] An inhibitor for use according to any one of [205-1] to [247-1], [I1] to [I2] and [J1] to [J13], wherein the antibody-drug conjugate and the inhibitor are separately contained as active ingredients in different formulations and administered simultaneously or at different times.

[0685] [249-1] The inhibitor for use according to any one of [205-1] to [248-1], [I1] to [I2], [J1] to [J13] and [261-1], wherein the disease is 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, kidney cancer, and sarcoma.

[0686] [250-1] The inhibitor for use according to [249-1], wherein the disease is breast cancer.

[0687] [251-1] The inhibitor for use according to [250-1], wherein the disease is triple-negative breast cancer.

[0688] [252-1] The inhibitor for use according to [249-1], wherein the disease is gastric cancer.

[0689] [253-1] The inhibitor for use according to [249-1], wherein the disease is ovarian cancer.

[0690] [254-1] The inhibitor for use according to [249-1], wherein the disease is lung cancer.

[0691] [255-1] The inhibitor for use according to [249-1], wherein the disease is pancreatic cancer.

[0692] [256-1] A pharmaceutical product described in any one of [1-1] to [51-1], [A1] to [A2], [B1] to [B13] and [257-1], which is a pharmaceutical composition.

[0693] [257-1] A pharmaceutical product described in any one of [1-1] to [44-1], [A1] to [A2] and [B1] to [B13], which is for use in the treatment of cancer.

[0694] [258-1] A method for treatment described in any one of [52-1] to [95-1], [C1] to [C2] and [D1] to [D13], which is for treating cancer.

[0695] [259-1] The antibody-drug conjugate for use according to any one of [103-1] to [146-1], [E1] to [E2] and [F1] to [F13], wherein the disease is cancer.

[0696] [260-1] The use described in any one of [154-1] to [197-1], [G1] to [G2] and [H1] to [H13], wherein the disease is cancer.

[0697] [261-1] The inhibitor for use according to any one of [205-1] to [248-1], [I1] to [I2] and [J1] to [J13], wherein the disease is cancer. Effect of the Invention

[0698] The present invention provides pharmaceutical products in which a particular antibody-drug conjugate is administered in combination with an inhibitor selected from the group consisting of an EZH1 inhibitor, an EZH2 inhibitor, and an EZH1 / 2 dual inhibitor, and / or methods of treatment in which a particular antibody-drug conjugate is administered in combination with an inhibitor selected from the group consisting of an EZH1 inhibitor, an EZH2 inhibitor, and an EZH1 / 2 dual inhibitor to a subject. [Brief description of the drawings]

[0699] [Figure 1] FIG. 1 shows the amino acid sequence of the heavy chain of an anti-HER2 antibody (SEQ ID NO:1). [Diagram 2] FIG. 2 shows the amino acid sequence of the light chain of an anti-HER2 antibody (SEQ ID NO:2). [Diagram 3] FIG. 2 shows the amino acid sequence of the heavy chain of an anti-HER3 antibody (SEQ ID NO: 3). [Figure 4] FIG. 4 shows the amino acid sequence of the light chain of an anti-HER3 antibody (SEQ ID NO: 4). [Diagram 5] FIG. 1 shows the amino acid sequence of the heavy chain of an anti-TROP2 antibody (SEQ ID NO: 5). [Figure 6] FIG. 1 shows the amino acid sequence of the light chain of an anti-TROP2 antibody (SEQ ID NO: 6). [Figure 7] FIG. 7 shows the amino acid sequence of the heavy chain of anti-B7-H3 antibody (SEQ ID NO:7). [Figure 8] FIG. 1 shows the amino acid sequence of the light chain of anti-B7-H3 antibody (SEQ ID NO: 8). [Figure 9] FIG. 1 shows the amino acid sequence of the heavy chain of an anti-GPR20 antibody (SEQ ID NO: 9). [Figure 10] FIG. 1 shows the amino acid sequence of the light chain of an anti-GPR20 antibody (SEQ ID NO: 10). [Figure 11] FIG. 1 shows the amino acid sequence of the heavy chain of the anti-CDH6 antibody (SEQ ID NO: 11). [Figure 12] FIG. 1 shows the amino acid sequence of the light chain of anti-CDH6 antibody (SEQ ID NO: 12). [Figure 13] FIG. 1 shows the amino acid sequence of the heavy chain of anti-MUC1 antibody (PM N54Q) (SEQ ID NO: 13). [Figure 14] FIG. 1 shows the amino acid sequence of the heavy chain of anti-MUC1 antibody (PankoMab) (SEQ ID NO: 14). [Figure 15] FIG. 1 shows the amino acid sequence (SEQ ID NO: 15) of the light chain of anti-MUC1 antibodies (PM N54Q and PankoMab). [Figure 16] 1 is a diagram showing the tumor growth inhibitory effect in mice subcutaneously implanted with NCI-N87 cells, in the groups administered HER2-ADC(1) and Compound A alone, and in the group administered a combination of HER2-ADC(1) and Compound A. [Figure 17] This is a diagram showing the tumor growth inhibitory effect in mice subcutaneously implanted with JIMT-1 cells, in the groups administered HER2-ADC(1) and compound A alone, and in the group administered a combination of HER2-ADC(1) and compound A. [Figure 18] 1 is a diagram showing the tumor growth inhibitory effect in mice subcutaneously implanted with MDA-MB-453 cells, in the groups administered HER2-ADC(1) and Compound A alone, and in the group administered a combination of HER2-ADC(1) and Compound A. [Figure 19] 1 is a diagram showing the tumor growth inhibitory effect in mice subcutaneously implanted with MX-1 cells, in the groups administered HER2-ADC(1) and Compound A alone, and in the group administered a combination of HER2-ADC(1) and Compound A. [Figure 20] FIG. 1 shows the amino acid sequence of the heavy chain of anti-CD37 antibody (hmAb-H541) (SEQ ID NO: 16). [Figure 21] FIG. 1 shows the amino acid sequence of the heavy chain of anti-CD37 antibody (hmAb-H551) (SEQ ID NO: 17). [Figure 22] FIG. 1 shows the amino acid sequence of the heavy chain of anti-CD37 antibody (hmAb-H11a) (SEQ ID NO: 18). [Diagram 23] FIG. 1 shows the amino acid sequence (SEQ ID NO: 19) of the light chain of anti-CD37 antibody (hmAb-L11). [Figure 24] 1 is a diagram showing the tumor growth inhibitory effect in mice subcutaneously implanted with ZR-75-1 cells, in the groups administered HER2-ADC(1) and Compound A alone, and in the group administered a combination of HER2-ADC(1) and Compound A. [Diagram 25] 1 is a diagram showing the tumor growth inhibitory effect in mice subcutaneously implanted with Calu-3 cells, in the groups administered HER2-ADC(1) and Compound A alone, and in the group administered a combination of HER2-ADC(1) and Compound A. [Figure 26] 1 is a diagram showing the tumor growth inhibitory effect in mice subcutaneously implanted with NCI-H358 cells in the groups administered TROP2-ADC(1) or Compound A alone, and in the group administered TROP2-ADC(1) and Compound A in combination. [Figure 27] This is a diagram showing the tumor growth inhibitory effect in mice subcutaneously implanted with JIMT-1 cells, in the groups administered HER3-ADC(1) and compound A alone, and in the group administered a combination of HER3-ADC(1) and compound A. [Figure 28] 1 is a diagram showing the tumor growth inhibitory effect in mice subcutaneously implanted with WSU-DLCL2 cells in groups administered CD37-ADC(1) or compound A alone, and in groups administered CD37-ADC(1) and compound A in combination. [Figure 29] 1 is a diagram showing the tumor growth inhibitory effect in mice subcutaneously implanted with NCI-H660 cells in groups administered B7-H3-ADC(1) or Compound A alone, and in groups administered B7-H3-ADC(1) and Compound A in combination. [Diagram 30] FIG. 1 shows the amino acid sequence of CDRH1 of the heavy chain of an anti-HER2 antibody. [Diagram 31] FIG. 2 shows the amino acid sequence of CDRH2 of the heavy chain of an anti-HER2 antibody. [Diagram 32] FIG. 1 shows the amino acid sequence of CDRH3 of the heavy chain of an anti-HER2 antibody. [Diagram 33] FIG. 1 shows the amino acid sequence of CDRL1 of the light chain of an anti-HER2 antibody. [Diagram 34] FIG. 1 shows the amino acid sequence of CDRL2 of the light chain of an anti-HER2 antibody. [Diagram 35] FIG. 1 shows the amino acid sequence of CDRL3 of the light chain of an anti-HER2 antibody. [Diagram 36] FIG. 1 shows the amino acid sequences of the heavy chain variable regions of anti-HER2 antibodies. [Figure 37] FIG. 1 shows the amino acid sequence of the light chain variable region of an anti-HER2 antibody. [Figure 38] FIG. 1 shows the amino acid sequence of CDRH1 of the heavy chain of an anti-TROP2 antibody. [Figure 39] FIG. 2 shows the amino acid sequence of CDRH2 of the heavy chain of an anti-TROP2 antibody. [Diagram 40] FIG. 1 shows the amino acid sequence of CDRH3 of the heavy chain of an anti-TROP2 antibody. [Diagram 41] FIG. 1 shows the amino acid sequence of CDRL1 of the light chain of an anti-TROP2 antibody. [Diagram 42] FIG. 1 shows the amino acid sequence of CDRL2 of the light chain of an anti-TROP2 antibody. [Diagram 43] FIG. 1 shows the amino acid sequence of CDRL3 of the light chain of an anti-TROP2 antibody. [Diagram 44] FIG. 2 shows the amino acid sequence of the heavy chain variable region of an anti-TROP2 antibody. [Diagram 45] FIG. 1 shows the amino acid sequence of the light chain variable region of an anti-TROP2 antibody. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0700] Hereinafter, preferred embodiments for carrying out the present invention will be described. The embodiments described below are merely provided to illustrate examples of typical embodiments of the present invention, and are not intended to limit the scope of the present invention.

[0701] 1. Antibody-drug conjugates The antibody-drug conjugate used in the present invention has the following formula:

[0702] [ka] (wherein A represents the attachment site to the antibody) is conjugated to the antibody via a thioether bond.

[0703] In the present invention, the partial structure consisting of a linker and a drug in an antibody-drug conjugate is called a "drug-linker". The drug-linker is connected to a thiol group (in other words, a sulfur atom of a cysteine ​​residue) formed at an interchain disulfide bond site of an antibody (two sites between heavy chains and two sites between a heavy chain and a light chain).

[0704] The drug-linker of the present invention comprises 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, also referred to as (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)) as a component. Exatecan is a camptothecin derivative having antitumor effects and is represented by the following formula:

[0705] [ka]

[0706] The antibody-drug conjugate used in the present invention has the following formula:

[0707] [ka] where the drug-linker is conjugated to the antibody via a thioether bond. The meaning of n is the same as that of the average number of conjugated drug molecules (DAR; drug-to-antibody ratio), which indicates the average number of drug linkers bound per antibody.

[0708] After migrating into cancer cells, the antibody-drug conjugate used in the present invention is cleaved at the linker moiety to release a compound represented by the following formula:

[0709] [ka]

[0710] The above-mentioned compounds are presumed to be the underlying source of the antitumor activity of the antibody-drug conjugates used in the present invention, and have been confirmed to have a topoisomerase I inhibitory effect (Ogitani Y. et al., Clinical Cancer Research, October 15, 2016; Vol. 22(20): pp. 5097-5108, Epub March 29, 2016).

[0711] The antibody-drug conjugate used in the present invention is also known to have a bystander effect (Ogitani Y. et al., Cancer Science (2016) Vol. 107, pp. 1039-1046).

[0712] The bystander effect is exerted through a process in which the antibody-drug conjugate used in the present invention is internalized by cancer cells expressing the target, the above-mentioned compound is released, and then the compound exerts an antitumor effect on surrounding cancer cells that do not express the target.

[0713] The bystander effect is exerted as an excellent antitumor effect when the antibody-drug conjugate according to the present invention is used in combination with an inhibitor selected from the group consisting of an EZH1 inhibitor, an EZH2 inhibitor, and an EZH1 / 2 dual inhibitor.

[0714] 2. Antibodies in antibody-drug conjugates The antibody in the antibody-drug conjugate used in the present invention can be from any species, but is preferably from human, rat, mouse or rabbit.If the antibody is from a species other than human, it is preferably chimerized or humanized using well-known techniques.The antibody of the present invention can be a polyclonal antibody or a monoclonal antibody, and is preferably a monoclonal antibody.

[0715] The antibody in the antibody-drug conjugate used in the present invention is preferably an antibody having the property of being able to target cancer cells, and preferably an antibody having, for example, the property of being able to recognize cancer cells, the property of being able to bind to cancer cells, the property of being internalized by cancer cells, and / or cytocidal activity against cancer cells.

[0716] The binding activity of the antibody to the cancer cells can be confirmed using flow cytometry. The internalization of the antibody into the tumor cells can be confirmed using (1) an assay in which the internalized antibody is visualized under a fluorescent microscope using a secondary antibody (with a fluorescent label) that binds to the therapeutic antibody (Cell Death and Differentiation (2008) vol. 15, pp. 751-761), (2) an assay in which the fluorescence intensity of the internalized antibody is measured using a secondary antibody (with a fluorescent label) that binds to the therapeutic antibody (Molecular Biology of the Cell, vol. 15, pp. 5268-5282, December 2004), or (3) a Mab-ZAP assay in which an immunotoxin that binds to the therapeutic antibody is used, and the toxin is released upon internalization and inhibits cell proliferation (Bio Techniques 28: pp. 162-165, January 2000). The immunotoxin can be a recombinant complex protein of the diphtheria toxin catalytic domain and protein G.

[0717] The antitumor activity of an antibody can be confirmed in vitro by determining 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 determine the inhibitory activity against foci formation, colony formation, and spheroid growth. The antitumor activity can be confirmed in vivo, for example, by administering the antibody to nude mice carrying transplanted cancer cell lines that highly express the target protein, and determining the changes in the cancer cells.

[0718] In order for the conjugated compound in the antibody-drug conjugate to exert an antitumor effect, it is preferable but not essential that the antibody itself should have an antitumor effect. In order to exert the cytotoxic activity of the antitumor compound specifically and selectively against cancer cells, it is important and preferable that the antibody should have the property of being internalized and migrating into the cancer cells.

[0719] The antibody in the antibody-drug conjugate used in the present invention can be obtained by a procedure known in the art.For example, the antibody of the present invention can be obtained by using a method commonly used in the art, including immunizing an animal with an antigenic polypeptide, and collecting and purifying the antibody produced in vivo.The source of the antigen is not limited to human, and animals can also be immunized with antigens derived from non-human animals such as mice and rats.In this case, the antibody that binds to the obtained heterologous antigen can be tested for cross-reactivity with human antigens to screen for antibodies that can be applied to human diseases.

[0720] Alternatively, antibody-producing cells that produce antibodies against an antigen can be fused with myeloma cells according to methods known in the art to establish hybridomas from which monoclonal antibodies can then be obtained (e.g., Kohler and Milstein, Nature (1975) vol. 256, pp. 495-497; Kennet, R., ed., Monoclonal Antibodies, pp. 365-367, Plenum Press, NY (1980)).

[0721] Antigens can be obtained by genetically engineering host cells to produce genes encoding antigenic proteins. In particular, vectors that allow the expression of antigen genes are prepared and then introduced into host cells to express the genes. The antigens thus expressed may be purified. Antibodies can also be obtained by immunizing animals with the genetically engineered antigen-expressing cells or cell lines expressing the antigens described above.

[0722] The antibody in the antibody-drug conjugate used in the present invention is preferably a recombinant antibody obtained by artificial modification for the purpose of reducing heterologous antigenicity to humans, such as a chimeric antibody or a humanized antibody, or preferably an antibody derived from a human, i.e., an antibody having only the gene sequence of a human antibody. Such an antibody can be produced using known methods.

[0723] An example of a chimeric antibody is an antibody whose variable and constant regions are derived from different species, for example, a chimeric antibody in which a mouse- or rat-derived antibody variable region is linked to a human-derived antibody constant region (Proc. Natl. Acad. Sci. USA, Vol. 81, 6851-6855 (1984)).

[0724] Examples of humanized antibodies include antibodies obtained by incorporating only the complementarity determining region (CDR) of a heterologous antibody into a human-derived antibody (Nature, 1986, vol. 321, pp. 522-525), antibodies obtained by grafting part of the amino acid residues of the framework of a heterologous antibody and the CDR sequence of the heterologous antibody into a human antibody by CDR grafting (WO 90 / 07861), and antibodies humanized using gene conversion mutagenesis (U.S. Pat. No. 5,821,337).

[0725] Examples of human antibodies include antibodies produced using a human antibody-producing mouse having a human chromosomal fragment containing the heavy and light chain genes of a human antibody (see, for example, Tomizuka, K. et al., Nature Genetics (1997) vol. 16, pp. 133-143; Kuroiwa, Y. et al., Nucl. Acids Res. (1998) vol. 26, pp. 3447-3448; Yoshida, H. et al., Animal Cell Technology: Basic and Applied Aspects vol. 10, pp. 69-73 (Kitagawa, Y., Matsuda, T., and Iijima, S., eds.), Kluwer Academic Publishers, 1999; Tomizuka, K. et al., Proc. Natl. Acad. Sci. USA (2000) vol. 97, pp. 722-727). Alternatively, examples include antibodies obtained by phage display and selected from a human antibody library (see, for example, Wormstone, I. M. et al., Investigative Ophthalmology & Visual Science. (2002) Vol. 43 (No. 7), pp. 2301-2308; Carmen, S. et al., Briefings in Functional Genomics and Proteomics (2002) Vol. 1 (No. 2), pp. 189-203; Siriwardena, D. et al., Ophthalmology (2002) Vol. 109 (No. 3), pp. 427-431).

[0726] The antibody in the antibody-drug conjugate used in the present invention also includes modified variants of the antibody. Modified variants refer to variants obtained by chemically or biologically modifying the antibody according to the present invention. Examples of chemically modified variants include variants that include a chemical moiety linked to the amino acid backbone, variants that include a chemical moiety linked to an N-linked or O-linked glycan, and the like. Examples of biologically modified variants include variants obtained by post-translational modification (such as N-linked or O-linked glycosylation, N- or C-terminal processing, deamidation, isomerization of aspartic acid, or oxidation of methionine), and variants in which a methionine residue has been added to the N-terminus by expression in a prokaryotic host cell. In addition, antibodies labeled to enable detection or isolation of the antibody or antigen according to the present invention, such as enzyme-labeled antibodies, fluorescent-labeled antibodies, and affinity-labeled antibodies, are also included in the meaning of modified variants. Such modified variants of the antibody according to the present invention are useful for improving the stability and blood retention of the antibody, reducing the antigenicity of the antibody, and detecting or isolating the antibody or antigen, and the like.

[0727] Furthermore, it is possible to enhance antibody-dependent cellular cytotoxicity by adjusting the modification (glycosylation, defucosylation, etc.) of the glycan linked to the antibody according to the present invention. Techniques for adjusting the glycan modification of an antibody are known, such as WO 99 / 54342, WO 00 / 61739, WO 02 / 31140, WO 2007 / 133855, and WO 2013 / 120066. However, the techniques are not limited thereto. The antibody according to the present invention also includes an antibody in which the modification of the glycan is adjusted.

[0728] It is known that antibodies produced in cultured mammalian cells lack a lysine residue at the carboxyl terminus of the heavy chain (Journal of Chromatography A, vol. 705: pp. 129-134 (1995)), and it is also known that antibodies produced in cultured mammalian cells lack two amino acid residues (glycine and lysine) at the carboxyl terminus of the heavy chain and amidate the newly placed proline residue at the carboxyl terminus (Analytical Biochemistry, vol. 360: pp. 75-83 (2007)). However, such deletions and modifications of the heavy chain sequence do not affect the antigen-binding affinity and effector functions (complement activation, antibody-dependent cellular cytotoxicity, etc.) of the antibody. Therefore, the antibody according to the present invention also includes such modified antibodies and functional fragments of antibodies, including deletion variants in which one or two amino acids are deleted from the carboxyl terminus of the heavy chain and variants obtained by amidation of the deletion variants (e.g., heavy chains in which the carboxyl-terminal proline residue is amidated). The type of deletion variant having a deletion at the carboxyl terminus of the heavy chain of the antibody according to the present invention is not limited to the above variants, so long as the antigen-binding affinity and effector function are preserved. The two heavy chains constituting the antibody according to the present invention may be one type selected from the group consisting of the full-length heavy chain and the deletion variants described above, or may be a combination of two types selected from them. The ratio of the amount of each deletion variant may be influenced by the type and culture conditions of the cultured mammalian cells producing the antibody according to the present invention, but a preferred example is an antibody in which one amino acid residue is deleted at the carboxyl terminus of both of the two heavy chains of the antibody according to the present invention.

[0729] Examples of the isotype of the antibody according to the present invention include IgG (IgG1, IgG2, IgG3, IgG4). Preferably, the isotype is IgG1 or IgG2.

[0730] Examples of antibodies in the antibody-drug conjugates used in the present invention include, but are not limited to, an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, an anti-CDH6 antibody, an anti-CD3 antibody, an anti-CD30 antibody, an anti-CD33 antibody, an anti-CD37 antibody, an anti-CD56 antibody, an anti-CD98 antibody, an anti-DR5 antibody, an anti-EGFR antibody, an anti-EPHA2 antibody, an anti-FGFR2 antibody, an anti-FGFR4 antibody, an anti-FOLR1 antibody, an anti-VEGF antibody, an anti-CD20 antibody, an anti-CD22 antibody, an anti-CD70 antibody, an anti-PSMA antibody, an anti-CEA antibody, an anti-mesothelin antibody, an anti-A33 antibody, an anti-CanAg antibody, an anti-crypto antibody, an anti-G250 antibody, an anti-MUC1 antibody, an anti-GPNMB antibody, an anti-integrin antibody, an anti-tenascin-C antibody, and an anti-SLC44A4 antibody. Further, preferred examples include anti-HER2 antibody, anti-HER3 antibody, anti-TROP2 antibody, anti-B7-H3 antibody, anti-GPR20 antibody, anti-CDH6 antibody, anti-MUC1 antibody, and anti-CD37 antibody. Further, preferred examples include anti-HER2 antibody, anti-HER3 antibody, anti-TROP2 antibody, anti-B7-H3 antibody, anti-GPR20 antibody, anti-CDH6 antibody, and anti-MUC1 antibody.

[0731] 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), preferably an antibody that has the activity of being internalized into HER2-expressing cells by binding to HER2.

[0732] Examples of anti-HER2 antibodies include trastuzumab (U.S. Pat. No. 5,821,337) and pertuzumab (International Publication No. WO 01 / 00245). Preferably, trastuzumab is used.

[0733] 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 by binding to HER3.

[0734] Examples of anti-HER3 antibodies include patritumab (U3-1287), U1-59 (International Publication No. WO 2007 / 077028), MM-121 (seribantumab), the anti-ERBB3 antibodies described in International Publication No. WO 2008 / 100624, RG-7116 (lumuletuzumab), and LJM-716 (elgemtumab).Preferably, patritumab and U1-59 can be exemplified.

[0735] In the present invention, the term "anti-TROP2 antibody" refers to an antibody that specifically binds to TROP2 (TACSTD2: tumor-associated calcium signaling substance; EGP-1), and preferably has the activity of being internalized into TROP2-expressing cells by binding to TROP2.

[0736] An example of an anti-TROP2 antibody is hTINA1-H1L1 (WO 2015 / 098099).

[0737] 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-13; CD276) and preferably has the activity of being internalized into B7-H3-expressing cells by binding to B7-H3.

[0738] An example of an anti-B7-H3 antibody is M30-H1-L4 (WO 2014 / 057687).

[0739] 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 by binding to GPR20.

[0740] An example of an anti-GPR20 antibody is h046-H4e / L7 (WO 2018 / 135501).

[0741] 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 by binding to CDH6.

[0742] An example of an anti-CDH6 antibody is H01L02 (International Publication No. 2018 / 212136).

[0743] In the present invention, the term "anti-MUC1 antibody" refers to an antibody that specifically binds to MUC1 (mucin 1) and preferably has the activity of being internalized into MUC1-expressing cells by binding to MUC1.

[0744] Examples of anti-MUC1 antibodies include PankoMab (Danielczyk, A. et al. (2006) Cancer Immunol. Immunother. Vol. 55, pp. 1337-1347) and the PankoMab variant (PM-N54Q) disclosed in WO 2019 / 21989.

[0745] In the present invention, the term "anti-CD37 antibody" refers to an antibody that specifically binds to CD37, and preferably has the activity of being internalized into CD37-expressing cells upon binding to CD37.

[0746] Examples of anti-CD37 antibodies include, but are not limited to, an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 16 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19; an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 17 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19; and an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 18 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19.

[0747] 3. Production of Antibody-drug Conjugates A drug-linker intermediate for use in producing an antibody-drug conjugate according to the invention is represented by the formula:

[0748] [ka]

[0749] The drug-linker intermediate has the chemical name: N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]glycylglycyl-L-phenylalanyl-N-[(2-{[(1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1, 2-b]quinolin-1-yl]amino}-2-oxoethoxy)methyl]glycinamide, and can be produced by referring to the descriptions in WO 2014 / 057687, WO 2015 / 098099, WO 2015 / 115091, WO 2015 / 155998, and WO 2019 / 044947.

[0750] The antibody-drug conjugates used in the present invention can be produced by reacting the drug-linker intermediates described above with an antibody bearing a thiol group (alternatively referred to as a sulfhydryl group).

[0751] An antibody having a sulfhydryl group can be obtained by a method well known in the art (Hermanson, GT, Bioconjugate Techniques, pp. 56-136, pp. 456-493, Academic Press (1996)). For example, an antibody having a sulfhydryl group in which the interchain disulfides in the antibody are partially or completely reduced can be obtained by reacting the antibody with a reducing agent such as tris(2-carboxyethyl)phosphine hydrochloride (TCEP) in an amount of 0.3 to 3 molar equivalents per interchain disulfide in the antibody in a buffer solution containing a chelating agent such as ethylenediaminetetraacetic acid (EDTA).

[0752] Furthermore, by using 2-20 molar equivalents of drug-linker intermediate per antibody bearing a sulfhydryl group, antibody-drug conjugates in which 2-8 drug molecules are conjugated per antibody molecule can be produced.

[0753] The average number of conjugated drug molecules per antibody molecule of the produced antibody-drug conjugate can be determined, for example, by a method based on calculation of the UV absorbance of the antibody-drug conjugate and its conjugate precursor at two wavelengths, 280 nm and 370 nm (UV method), or by a method based on quantification by HPLC measurement of fragments obtained by treating the antibody-drug conjugate with a reducing agent (HPLC method).

[0754] Conjugation of an antibody with a drug-linker intermediate and calculation of the average number of drug molecules conjugated per antibody molecule of an antibody-drug conjugate can be performed with reference to descriptions in WO 2014 / 057687, WO 2015 / 098099, WO 2015 / 115091, WO 2015 / 155998, WO 2018 / 135501, WO 2018 / 212136, and the like.

[0755] In the present invention, the term "anti-HER2 antibody-drug conjugate" refers to an antibody-drug conjugate, wherein the antibody in the antibody-drug conjugate according to the present invention is an anti-HER2 antibody.

[0756] The anti-HER2 antibody preferably comprises a heavy chain including CDRH1 (SEQ ID NO: 20) consisting of an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 (SEQ ID NO: 21) consisting of an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 (SEQ ID NO: 22) consisting of an amino acid sequence consisting of amino acid residues 97 to 109 of SEQ ID NO: 1, and a CDR including CDRL1 (SEQ ID NO: 23) consisting of an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 (SEQ ID NO: 24) consisting of an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2, and an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2. An antibody having a light chain comprising L3 (SEQ ID NO: 25), more preferably an antibody having a heavy chain comprising a heavy chain variable region (SEQ ID NO: 26) consisting of amino acid residues 1 to 120 of SEQ ID NO: 1, and a light chain variable region (SEQ ID NO: 27) consisting of amino acid residues 1 to 107 of SEQ ID NO: 2, and even more preferably an antibody having a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 1 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 2, or an antibody having a heavy chain consisting of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1, and a light chain consisting of an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2.

[0757] The average number of drug linkers bound per antibody in the anti-HER2 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 8, even more preferably 7 to 8, even more preferably 7.5 to 8, and even more preferably about 8.

[0758] Anti-HER2 antibody-drug conjugates can be produced by referring to the descriptions in, for example, International Publication No. 2015 / 115091.

[0759] One such antibody-drug conjugate is trastuzumab deruxtecan (DS-8201a), which is composed of a HER2-targeting antibody and a derivative of exatecan. In particular, WO 2015 / 115091 provides a detailed description of exemplary HER2-targeting antibody-drug conjugates, including trastuzumab deruxtecan (DS-8201a).

[0760] In the present invention, the term "anti-HER3 antibody-drug conjugate" refers to an antibody-drug conjugate, wherein the antibody in the antibody-drug conjugate according to the present invention is an anti-HER3 antibody.

[0761] The anti-HER3 antibody is preferably an antibody comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence of amino acid residues 26 to 35 of SEQ ID NO: 3, CDRH2 consisting of the amino acid sequence of amino acid residues 50 to 65 of SEQ ID NO: 3, and CDRH3 consisting of the amino acid sequence of amino acid residues 98 to 106 of SEQ ID NO: 3, and a light chain comprising CDRL1 consisting of the amino acid sequence of amino acid residues 24 to 39 of SEQ ID NO: 4, CDRL2 consisting of the amino acid sequence of amino acid residues 56 to 62 of SEQ ID NO: 4, and CDRL3 consisting of the amino acid sequence of amino acid residues 95 to 103 of SEQ ID NO: 4; more preferably an antibody comprising a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence of amino acid residues 1 to 117 of SEQ ID NO: 3, and a light chain comprising a light chain variable region consisting of the amino acid sequence of amino acid residues 1 to 113 of SEQ ID NO: 4; and even more preferably an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 3, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 4, or a variant of an antibody in which a lysine residue at the carboxyl terminus of the heavy chain is deleted.

[0762] The average number of drug linkers bound per antibody in the anti-HER3 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 8, even more preferably 7 to 8, even more preferably 7.5 to 8, and even more preferably about 8.

[0763] Anti-HER3 antibody-drug conjugates can be produced by referring to the descriptions in, for example, International Publication No. 2015 / 155998.

[0764] In the present invention, the term "anti-TROP2 antibody-drug conjugate" refers to an antibody-drug conjugate in which the antibody in the antibody-drug conjugate according to the present invention is an anti-TROP2 antibody.

[0765] The anti-TROP2 antibody preferably comprises a heavy chain comprising CDRH1 (SEQ ID NO: 28) consisting of the amino acid sequence of amino acid residues 50 to 54 of SEQ ID NO: 5, CDRH2 (SEQ ID NO: 29) consisting of the amino acid sequence of amino acid residues 69 to 85 of SEQ ID NO: 5, and CDRH3 (SEQ ID NO: 30) consisting of the amino acid sequence of amino acid residues 118 to 129 of SEQ ID NO: 5, as well as CDRL1 (SEQ ID NO: 31) consisting of the amino acid sequence of amino acid residues 44 to 54 of SEQ ID NO: 6, CDRL2 (SEQ ID NO: 32) consisting of the amino acid sequence of amino acid residues 70 to 76 of SEQ ID NO: 6, and CDRH3 (SEQ ID NO: 33) consisting of the amino acid sequence of amino acid residues 109 to 117 of SEQ ID NO: 6. and more preferably an antibody comprising a heavy chain comprising a heavy chain variable region (SEQ ID NO: 34) consisting of amino acid residues 20 to 140 of SEQ ID NO: 5, and a light chain variable region (SEQ ID NO: 35) consisting of an amino acid sequence consisting of amino acid residues 21 to 129 of SEQ ID NO: 6, as well as an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 5, and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 6, or a variant of an antibody in which a lysine residue at the carboxyl terminus of the heavy chain is deleted.

[0766] The average number of drug linkers bound per antibody in the anti-TROP2 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 5, even more preferably 3.5 to 4.5, and even more preferably about 4.

[0767] Anti-TROP2 antibody-drug conjugates can be produced by referring to the descriptions in WO 2015 / 098099 and WO 2017 / 002776.

[0768] One such antibody-drug conjugate is datopotamab deruxtecan, which is composed of a TROP2-targeting antibody and a derivative of exatecan. In particular, WO 2015 / 098099 and WO 2020 / 240467 provide detailed descriptions of exemplary TROP2-targeting antibody-drug conjugates, including datopotamab deruxtecan (DS-1062).

[0769] In the present invention, the term "anti-B7-H3 antibody-drug conjugate" refers to an antibody-drug conjugate in which the antibody in the antibody-drug conjugate according to the present invention is an anti-B7-H3 antibody.

[0770] The anti-B7-H3 antibody preferably comprises a heavy chain comprising CDRH1 consisting of the amino acid sequence of amino acid residues 50 to 54 of SEQ ID NO: 7, CDRH2 consisting of the amino acid sequence of amino acid residues 69 to 85 of SEQ ID NO: 7, and CDRH3 consisting of the amino acid sequence of amino acid residues 118 to 130 of SEQ ID NO: 7, and a CDRL1 consisting of the amino acid sequence of amino acid residues 44 to 53 of SEQ ID NO: 8, CDRL2 consisting of the amino acid sequence of amino acid residues 69 to 75 of SEQ ID NO: 8, and CDRH3 consisting of the amino acid sequence of amino acid residues 108 to 116 of SEQ ID NO: 8. and more preferably, an antibody comprising a heavy chain comprising a heavy chain variable region consisting of amino acid residues 20 to 141 of SEQ ID NO: 7, and a light chain comprising a light chain variable region consisting of amino acid residues 21 to 128 of SEQ ID NO: 8, and even more preferably, an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 7, and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 8, or a variant of the antibody in which the lysine residue at the carboxyl terminus of the heavy chain is deleted.

[0771] The average number of drug linkers bound per antibody in the anti-B7-H3 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 5, even more preferably 3.5 to 4.5, and even more preferably 4.

[0772] The anti-B7-H3 antibody-drug conjugate used in the present invention can be produced by referring to the descriptions in WO 2014 / 057687 and WO 2017 / 002776.

[0773] In the present invention, the term "anti-GPR20 antibody-drug conjugate" refers to an antibody-drug conjugate in which the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[0774] The anti-GPR20 antibody preferably comprises a heavy chain comprising CDRH1 consisting of the amino acid sequence of amino acid residues 45 to 54 of SEQ ID NO: 9, CDRH2 consisting of the amino acid sequence of amino acid residues 69 to 78 of SEQ ID NO: 9, and CDRH3 consisting of the amino acid sequence of amino acid residues 118 to 131 of SEQ ID NO: 9, and a CDRH5 consisting of the amino acid sequence of amino acid residues 44 to 54 of SEQ ID NO: 10, CDRL2 consisting of the amino acid sequence of amino acid residues 70 to 76 of SEQ ID NO: 10, and a CDRH6 consisting of the amino acid sequence of amino acid residues 109 to 117 of SEQ ID NO: 10. more preferably, an antibody comprising a heavy chain comprising a heavy chain variable region consisting of amino acid residues 20 to 142 of SEQ ID NO: 9, and a light chain comprising a light chain variable region consisting of amino acid residues 21 to 129 of SEQ ID NO: 10; and even more preferably, an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 472 of SEQ ID NO: 9, and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 10, or a variant of an antibody in which a lysine residue at the carboxyl terminus of the heavy chain is deleted.

[0775] The average number of drug linkers bound 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.

[0776] The anti-GPR20 antibody-drug conjugate used in the present invention can be produced by referring to the descriptions in, for example, International Publication No. 2018 / 135501.

[0777] In the present invention, the term "anti-CDH6 antibody-drug conjugate" refers to an antibody-drug conjugate in which the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[0778] The anti-CDH6 antibody preferably comprises a heavy chain comprising CDRH1 consisting of the amino acid sequence of amino acid residues 45 to 54 of SEQ ID NO: 11, CDRH2 consisting of the amino acid sequence of amino acid residues 69 to 78 of SEQ ID NO: 11, and CDRH3 consisting of the amino acid sequence of amino acid residues 118 to 130 of SEQ ID NO: 11, and a CDRH5 consisting of the amino acid sequence of amino acid residues 44 to 54 of SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence of amino acid residues 70 to 76 of SEQ ID NO: 12, and a CDRH6 consisting of the amino acid sequence of amino acid residues 109 to 116 of SEQ ID NO: 12. more preferably, an antibody comprising a heavy chain comprising a heavy chain variable region consisting of amino acid residues 20 to 141 of SEQ ID NO: 11, and a light chain comprising a light chain variable region consisting of amino acid residues 21 to 128 of SEQ ID NO: 12; and even more preferably, an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 11, and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 12, or a variant of an antibody in which a lysine residue at the carboxyl terminus of the heavy chain is deleted.

[0779] The average number of drug linkers bound 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.

[0780] The anti-CDH6 antibody-drug conjugate used in the present invention can be produced by referring to the descriptions in, for example, International Publication No. 2018 / 212136.

[0781] In the present invention, the term "anti-MUC1 antibody-drug conjugate" refers to an antibody-drug conjugate in which the antibody in the antibody-drug conjugate according to the present invention is an anti-MUC1 antibody.

[0782] The anti-MUC1 antibody preferably comprises a heavy chain comprising CDRH1 consisting of the amino acid sequence of amino acid residues 31 to 35 of SEQ ID NO: 13, CDRH2 consisting of the amino acid sequence of amino acid residues 50 to 65 of SEQ ID NO: 13, and CDRH3 consisting of the amino acid sequence of amino acid residues 101 to 106 of SEQ ID NO: 13, and a heavy chain comprising CDRL1 consisting of the amino acid sequence of amino acid residues 24 to 39 of SEQ ID NO: 15, CDRL2 consisting of the amino acid sequence of amino acid residues 55 to 61 of SEQ ID NO: 15, and CDRH3 consisting of the amino acid sequence of amino acid residues 94 to 102 of SEQ ID NO: 15. more preferably, an antibody comprising a heavy chain comprising a heavy chain variable region consisting of amino acid residues 1 to 117 of SEQ ID NO: 13, and a light chain comprising a light chain variable region consisting of amino acid residues 1 to 113 of SEQ ID NO: 15; and even more preferably, an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 1 to 447 of SEQ ID NO: 13, and a light chain consisting of an amino acid sequence consisting of amino acid residues 1 to 219 of SEQ ID NO: 15, or a variant of an antibody in which a lysine residue at the carboxyl terminus of the heavy chain is deleted.

[0783] Alternatively, the anti-MUC1 antibody preferably comprises a heavy chain comprising a CDRH1 consisting of the amino acid sequence of amino acid residues 31 to 35 of SEQ ID NO: 14, a CDRH2 consisting of the amino acid sequence of amino acid residues 50 to 65 of SEQ ID NO: 14, and a CDRH3 consisting of the amino acid sequence of amino acid residues 101 to 106 of SEQ ID NO: 14, and a CDRL1 consisting of the amino acid sequence of amino acid residues 24 to 39 of SEQ ID NO: 15, a CDRL2 consisting of the amino acid sequence of amino acid residues 55 to 61 of SEQ ID NO: 15, and a CDRH3 consisting of the amino acid sequence of amino acid residues 94 to 102 of SEQ ID NO: 15. more preferably, an antibody comprising a heavy chain comprising a heavy chain variable region consisting of amino acid residues 1 to 117 of SEQ ID NO: 14, and a light chain comprising a light chain variable region consisting of amino acid residues 1 to 113 of SEQ ID NO: 15, and even more preferably, an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 1 to 447 of SEQ ID NO: 14 and a light chain consisting of an amino acid sequence consisting of amino acid residues 1 to 219 of SEQ ID NO: 15, or a variant of an antibody in which a lysine residue at the carboxyl terminus of the heavy chain is deleted.

[0784] The average number of drug linkers bound per antibody in the anti-MUC1 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.

[0785] Anti-MUC1 antibody-drug conjugates can be produced by referring to the descriptions in, for example, International Publication No. 2019 / 219891.

[0786] In the present invention, the term "anti-CD37 antibody-drug conjugate" refers to an antibody-drug conjugate, wherein the antibody in the antibody-drug conjugate according to the present invention is an anti-CD37 antibody.

[0787] The anti-CD37 antibody preferably comprises a heavy chain comprising CDRH1 consisting of the amino acid sequence of amino acid residues 45 to 54 of SEQ ID NO: 16, CDRH2 consisting of the amino acid sequence of amino acid residues 69 to 78 of SEQ ID NO: 16, and CDRH3 consisting of the amino acid sequence of amino acid residues 118 to 127 of SEQ ID NO: 16, and a CDRL1 consisting of the amino acid sequence of amino acid residues 44 to 54 of SEQ ID NO: 19, CDRL2 consisting of the amino acid sequence of amino acid residues 70 to 76 of SEQ ID NO: 19, and CDRH3 consisting of the amino acid sequence of amino acid residues 109 to 117 of SEQ ID NO: 19. more preferably, an antibody comprising a heavy chain comprising a heavy chain variable region consisting of amino acid residues 20 to 138 of SEQ ID NO: 16, and a light chain comprising a light chain variable region consisting of amino acid residues 21 to 128 of SEQ ID NO: 19; and even more preferably, an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 16, and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19, or a variant of an antibody in which a lysine residue at the carboxyl terminus of the heavy chain is deleted.

[0788] Alternatively, the anti-CD37 antibody preferably comprises a heavy chain comprising a CDRH1 consisting of the amino acid sequence of amino acid residues 45 to 54 of SEQ ID NO: 17, a CDRH2 consisting of the amino acid sequence of amino acid residues 69 to 78 of SEQ ID NO: 17, and a CDRH3 consisting of the amino acid sequence of amino acid residues 118 to 127 of SEQ ID NO: 17, and a CDRL1 consisting of the amino acid sequence of amino acid residues 44 to 54 of SEQ ID NO: 19, a CDRL2 consisting of the amino acid sequence of amino acid residues 70 to 76 of SEQ ID NO: 19, and a CDRH3 consisting of the amino acid sequence of amino acid residues 109 to 117 of SEQ ID NO: 19. more preferably, an antibody comprising a heavy chain comprising a heavy chain variable region consisting of amino acid residues 20 to 138 of SEQ ID NO: 17, and a light chain comprising a light chain variable region consisting of amino acid residues 21 to 128 of SEQ ID NO: 19; and even more preferably, an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 17, and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19, or a variant of an antibody in which a lysine residue at the carboxyl terminus of the heavy chain is deleted.

[0789] Furthermore, the anti-CD37 antibody preferably comprises a heavy chain comprising CDRH1 consisting of the amino acid sequence of amino acid residues 45 to 54 of SEQ ID NO: 18, CDRH2 consisting of the amino acid sequence of amino acid residues 69 to 78 of SEQ ID NO: 18, and CDRH3 consisting of the amino acid sequence of amino acid residues 118 to 127 of SEQ ID NO: 18, and a heavy chain comprising CDRL1 consisting of the amino acid sequence of amino acid residues 44 to 54 of SEQ ID NO: 19, CDRL2 consisting of the amino acid sequence of amino acid residues 70 to 76 of SEQ ID NO: 19, and CDRH3 consisting of the amino acid sequence of amino acid residues 109 to 117 of SEQ ID NO: 19. more preferably, an antibody comprising a heavy chain comprising a heavy chain variable region consisting of amino acid residues 20 to 138 of SEQ ID NO: 18, and a light chain comprising a light chain variable region consisting of amino acid residues 21 to 128 of SEQ ID NO: 19; and even more preferably, an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 18, and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19, or a variant of an antibody in which a lysine residue at the carboxyl terminus of the heavy chain is deleted.

[0790] The average number of drug linkers bound per antibody in the anti-CD37 antibody-drug conjugate is preferably 2 to 8, more preferably 5 to 8, even more preferably 7 to 8, even more preferably 7.5 to 8, and even more preferably about 8.

[0791] Anti-CD37 antibody-drug conjugates can be prepared by similar production methods to those described in the patent specifications referenced in the previous section for anti-HER2, anti-HER3, anti-TROP2, anti-B7-H3, anti-GPR20, anti-CDH6, and anti-MUC1 antibodies.

[0792] Anti-CD37 antibody-drug conjugates can be used to treat any cancer in which CD37 is expressed. Examples of cancer include, but are not limited to, B-cell non-Hodgkin's lymphoma (NHL) (e.g., diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL) and Burkitt's lymphoma (BL)), chronic lymphocytic leukemia (CLL), T-cell lymphoma (TCL) (e.g., peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL)), myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Other examples of cancer include, but are not limited to, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL).

[0793] 4. EZH1 inhibitors, EZH2 inhibitors, and dual EZH1 / 2 inhibitors In the present invention, an "EZH1 inhibitor" is a drug that has the function of inhibiting EZH1 (zeste homolog enhancer 1).

[0794] In one embodiment of the present invention, the EZH1 inhibitor has an inhibitory effect on the histone methyltransferase activity of human EZH1 and has an IC 50 may be 1 μM or lower, 500 nM or lower, 400 nM or lower, 300 nM or lower, 200 nM or lower, 150 nM or lower, 100 nM or lower, 90 nM or lower, 80 nM or lower, 70 nM or lower, 60 nM or lower, 50 nM or lower, 40 nM or lower, 30 nM or lower, 20 nM or lower, 15 nM or lower, or 10 nM or lower. 50The value can be determined, for example, based on the method described in Test Example 1 of WO 2015 / 141616, by detecting an inhibitory effect on the activity of EZH1 that transfers tritium-labeled S-adenosylmethionine to a peptide having an EZH1 target sequence (e.g., the sequence of amino acids 12 to 40 of human histone H3 protein; for the amino acid sequence of human histone H3 protein, see, for example, the sequence registered under GenBank registration number: CAB02546.1). The methyltransferase activity of EZH1 can be measured by using a PRC2-EZH1 complex.

[0795] Examples of EZH1 inhibitors that can be used in the present invention include, but are not limited to, (2R)-7-bromo-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide, valemetostat (IUPAC name: (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide, and pharma- ceutical acceptable salts thereof.

[0796] In the present invention, an "EZH2 inhibitor" is a drug that has the function of inhibiting EZH2.

[0797] In one embodiment of the present invention, the EZH2 inhibitor has an inhibitory effect on the histone methyltransferase activity of human EZH2 and has an IC 50may be 1 μM or lower, 500 nM or lower, 400 nM or lower, 300 nM or lower, 200 nM or lower, 150 nM or lower, 100 nM or lower, 90 nM or lower, 80 nM or lower, 70 nM or lower, 60 nM or lower, 50 nM or lower, 40 nM or lower, 30 nM or lower, 20 nM or lower, 15 nM or lower, or 10 nM or lower. 50 The value can be determined, for example, based on the method described in Test Example 2 of WO 2015 / 141616, by detecting an inhibitory effect on the activity of EZH2 that transfers tritium-labeled S-adenosylmethionine to a peptide having an EZH2 target sequence (e.g., the sequence of amino acids 12 to 40 of human histone H3 protein; for the amino acid sequence of human histone H3 protein, see, for example, the sequence registered under GenBank accession number: CAB02546.1). EZH2 methyltransferase activity can be measured by using a PRC2-EZH2 complex.

[0798] Examples of EZH2 inhibitors that can be used in the present invention include, but are not limited to, N-[(1,2-dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl]-3-methyl-1-[(1S)-1-methylpropyl]-6-[6-(1-piperazinyl)-3-pyridinyl]-1H-indole-4-carboxamide, N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-carboxamide, ( 2R)-7-bromo-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide, valemetostat (IUPAC name: (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide), and pharma- ceutical acceptable salts thereof.

[0799] Examples of EZH2 inhibitors that can be used in the present invention include (1S,2R,5R)-5-(4-aminoimidazo[4,5-c]pyridin-1-yl)-3-(hydroxymethyl)cyclopent-3-ene-1,2-diol and pharma- ceutical acceptable versions thereof.

[0800] Further examples of EZH2 inhibitors that can be used in the present invention include N-[(6-methyl-2-oxo-4-propyl-1H-pyridin-3-yl)methyl]-1-propan-2-yl-6-[6-(4-propan-2-ylpiperazin-1-yl)pyridin-3-yl]indazole-4-carboxamide and pharma- ceutical acceptable salts thereof.

[0801] Further examples of EZH2 inhibitors include tazemetostat (IUPAC name: N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-carboxamide) (E7438 or EPZ-6438) and pharma- ceutically acceptable salts thereof. This compound is disclosed in Example 44 of WO 2012 / 142504.

[0802] Further examples of EZH2 inhibitors include liramettostat (CPI-1205) and pharma- ceutically acceptable salts thereof.

[0803] Further examples of EZH2 inhibitors include N-[(1,2-dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl]-3-methyl-1-[(1S)-1-methylpropyl]-6-[6-(1-piperazinyl)-3-pyridinyl]-1H-indole-4-carboxamide (GSK126) and pharma- ceutically acceptable salts thereof, as disclosed in Example 270 of WO 2011 / 140324.

[0804] Further examples of EZH2 inhibitors that can be used in the present invention include N-[(1,2-dihydro-6-methyl-2-oxo-4-propyl-3-pyridinyl)methyl]-1-)1-methylethyl)-6-[2-(4-methyl-1-piperazinyl)-4-pyridinyl]-1H-indazole-4-carboxamide and pharma- ceutically acceptable salts thereof.

[0805] Further examples of EZH2 inhibitors that can be used in the present invention include various compounds described in Stazi, G. et al., Expert Opinion on Therapeutic Patents, Vol. 27:7, pp. 797-813, 2017. EZH2 inhibitors are known, and for example, the EZH2 inhibitors described in the following documents can be used in the present invention: WO 2014 / 100646, WO 2015 / 057859, WO 2015 / 057859, WO 2016 / 081523, WO 2014 / 144747, WO 2015 / 010078, WO 2015 / 010049, WO 2015 / 200650, WO 2015 / 132765, WO 2015 / 004618, and WO 2015 / 004618. FRET, WO 2016 / 066697, WO 2014 / 124418, WO 2015 / 023915, WO 2016 / 130396, WO 2015 / 077193, WO 2015 / 077194, WO 2015 / 193768, WO 2016 / 073956, WO 2016 / 073903, WO 2016 / 102493, WO 2016 / 089804, WO 2014 / 151369.

[0806] In the present invention, EZH2 inhibitor may also have EZH1 inhibitory effect, for example, it may be EZH1 / 2 dual inhibitor.For example, above-mentioned N-[(6-methyl-2-oxo-4-propyl-1H-pyridin-3-yl)methyl]-1-propan-2-yl-6-[6-(4-propan-2-ylpiperazin-1-yl)pyridin-3-yl]indazole-4-carboxamide and its pharmaceutical acceptable salt may be EZH1 / 2 dual inhibitor.

[0807] In one embodiment of the present invention, the EZH1 / 2 dual inhibitor has an inhibitory effect on the histone methyltransferase activity of human EZH1 and its IC 50 may be 1 μM or lower, may be 500 nM or lower, may be 400 nM or lower, may be 300 nM or lower, may be 200 nM or lower, may be 150 nM or lower, may be 100 nM or lower, may be 90 nM or lower, may be 80 nM or lower, may be 70 nM or lower, may be 60 nM or lower, may be 50 nM or lower, may be 40 nM or lower, may be 30 nM or lower, may be 20 nM or lower, may be 15 nM or lower, or may be 10 nM or lower, and has an inhibitory effect on the histone methyltransferase activity of human EZH2, and its IC 50 The IC of EZH1 and EZH2 may be 1 μM or lower, 500 nM or lower, 400 nM or lower, 300 nM or lower, 200 nM or lower, 150 nM or lower, 100 nM or lower, 90 nM or lower, 80 nM or lower, 70 nM or lower, 60 nM or lower, 50 nM or lower, 40 nM or lower, 30 nM or lower, 20 nM or lower, 15 nM or lower, or 10 nM or lower. 50 Each of the values ​​can be determined as mentioned above.

[0808] Examples of EZH1 / 2 dual inhibitors that can be used in the present invention include, but are not limited to, (2R)-7-bromo-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide, valemetostat (IUPAC name: (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide), and pharma- ceutical acceptable salts thereof.

[0809] (2R)-7-Bromo-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide is disclosed in Example 15 of WO 2015 / 141616 and is a compound having the following structure.

[0810] [ka]

[0811] Valemetostat (IUPAC name: (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide) (DS-3201a) is disclosed in Example 35 of WO 2015 / 141616, and is a compound having the following structure.

[0812] [ka]

[0813] Valemetostat tosylate (IUPAC name: (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide p-toluenesulfonate) (DS-3201b) (also referred to as "Compound A" in this patent specification) is disclosed in Example 80 of WO 2015 / 141616. Compound A can be prepared with reference to the synthesis method disclosed in WO 2015 / 141616.

[0814] The inhibitor selected from the group consisting of EZH1 inhibitor, EZH2 inhibitor, and EZH1 / 2 dual inhibitor in the present invention may be in the form of pharmaceutically acceptable salt.Pharmaceutically acceptable salt includes either acid addition salt or salt with base, but is preferably acid addition salt, examples of which include lower alkane sulfonate such as camsilate (camphorsulfonate), methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; arylsulfonate such as tosilate (p-toluenesulfonate) and benzenesulfonate; inorganic acid salt such as phosphate, nitrate, perchlorate, and hydrosulfide; hydrohalide salt such as hydrochloride, hydrobromide, hydroiodide, and hydrofluoride; organic acid salt such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalate, and maleate; and amino acid salt such as ornithine, glutamate, and aspartate.

[0815] In addition, the inhibitor selected from the group consisting of EZH1 inhibitors, EZH2 inhibitors, and EZH1 / 2 dual inhibitors, and pharma- ceutically acceptable salts thereof, may also exist in the form of a solvate. For clarity, the solvate may be a solvate of a pharma-ceutically acceptable salt of the inhibitor selected from the group consisting of EZH1 inhibitors, EZH2 inhibitors, and EZH1 / 2 dual inhibitors.

[0816] 5. Pharmaceuticals The following describes pharmaceutical products and methods for treatment according to the present invention, in which an antibody-drug conjugate is administered in combination with an inhibitor selected from the group consisting of an EZH1 inhibitor, an EZH2 inhibitor, and an EZH1 / 2 dual inhibitor.

[0817] The pharmaceutical product and method for treatment of the present invention may be one in which the antibody-drug conjugate and the inhibitor selected from the group consisting of EZH1 inhibitors, EZH2 inhibitors, and EZH1 / 2 dual inhibitors are separately contained as active ingredients in different formulations and administered at the same time or at different times, or the antibody-drug conjugate and the inhibitor selected from the group consisting of EZH1 inhibitors, EZH2 inhibitors, and EZH1 / 2 dual inhibitors are separately contained as active ingredients in a single formulation and administered. The antibody-drug conjugate and the inhibitor selected from the group consisting of EZH1 inhibitors, EZH2 inhibitors, and EZH1 / 2 dual inhibitors can be administered at different intervals when the antibody-drug conjugate and the inhibitor selected from the group consisting of EZH1 inhibitors, EZH2 inhibitors, and EZH1 / 2 dual inhibitors are separately contained as active ingredients in different formulations.

[0818] The term "pharmaceutical product" refers to a preparation, either as a composition containing all of the active ingredients (in the case of simultaneous administration) or as a combination of separate compositions (combined preparations) each containing at least one but not all of the active ingredients (in the case of sequential or simultaneous administration), in a form that permits the biological activity of the active ingredients and does not contain additional ingredients that are unacceptably toxic to the subject to which the product is to be administered. Such products can be sterile.

[0819] The pharmaceutical products and methods for treatment of the present invention can be used to treat cancer, preferably breast cancer (including triple-negative breast cancer and luminal breast cancer), gastric cancer (also called gastric adenocarcinoma), colorectal cancer (also called colon and rectal 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, and rectal cancer. Bladder cancer, gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, endometrial cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, non-Hodgkin's lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Burkitt lymphoma (BL), chronic lymphocytic leukemia, T-cell lymphoma (TCL) (e.g., peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), acute myeloblastic leukemia ( and more preferably, it can be used to treat at least one disease 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, kidney cancer, and sarcoma, and more preferably, it can be used to treat at least one cancer selected from the group consisting of non-Hodgkin's lymphoma (e.g., diffuse large intestinal lymphoma ... It can be used to treat at least one cancer selected from the group consisting of large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Burkitt's lymphoma (BL), and chronic lymphocytic leukemia, and more preferably, it can be used to treat at least one cancer selected from the group consisting of T-cell lymphoma (TCL) (e.g., peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), and acute myeloblastic leukemia (AML).

[0820] In one embodiment, the pharmaceutical product and method for treatment of the present invention can be used to treat breast cancer.In another embodiment, the pharmaceutical product and method for treatment of the present invention can be used to treat triple negative breast cancer.In another embodiment, the pharmaceutical product and method for treatment of the present invention can be used to treat HER2 low expressing breast cancer.

[0821] In one embodiment, the pharmaceutical products and methods of treatment of the present invention can be used to treat lung cancer. In another embodiment, the pharmaceutical products and methods of treatment of the present invention can be used to treat non-small cell lung cancer.

[0822] In one embodiment, the pharmaceutical products and methods for treatment of the present invention can be used to treat non-Hodgkin's lymphoma. In another embodiment, the pharmaceutical products and methods for treatment of the present invention can be used to treat diffuse large B-cell lymphoma (DLBCL).

[0823] In one embodiment, the pharmaceutical products and methods for treatment of the present invention can be used to treat prostate cancer.

[0824] In one embodiment, the pharmaceutical products and methods for treatment of the present invention can be used to treat ovarian cancer.

[0825] Among the antibody-drug conjugates used in the present invention, which type of antibody is preferred for use in the antibody-drug conjugate can be determined by investigating the type of cancer and tumor marker.For example, when HER2 expression is found in cancer, preferably anti-HER2 antibody-drug conjugate can be used; when HER3 expression is found in cancer, preferably anti-HER3 antibody-drug conjugate can be used; when TROP2 expression is found in cancer, preferably anti-TROP2 antibody-drug conjugate can be used; when B7-H3 expression is found in cancer, preferably anti-B7-H3 antibody-drug conjugate can be used; when GPR20 expression is found in cancer, preferably anti-GPR20 antibody-drug conjugate can be used; when CDH6 expression is found in cancer, preferably anti-CDH6 antibody-drug conjugate can be used; when MUC1 expression is found in cancer, preferably anti-MUC1 antibody-drug conjugate can be used; when CD37 expression is found in cancer, preferably anti-CD37 antibody-drug conjugate can be used.

[0826] The presence or absence of HER2, HER3, TROP2, B7-H3, GPR20, CDH6, and MUC1, as well as other tumor markers, can be verified, for example, by collecting tumor tissue from a cancer patient and subjecting the formalin-fixed paraffin-embedded specimen (FFPE) to testing at the gene product (protein) level, such as immunohistochemistry (IHC), flow cytometry, Western blotting, or at the gene transcription level, such as in situ hybridization (ISH), quantitative PCR (q-PCR), or microarray analysis. Alternatively, cell-free circulating tumor DNA (ctDNA) can also be verified by collecting from a cancer patient and subjecting to testing using methods such as next-generation sequencing (NGS). Such methods can be applied to the presence or absence of CD37.

[0827] When the antibody-drug conjugate used in the present invention is an anti-HER2 antibody-drug conjugate, the pharmaceutical product and method for treatment of the present invention can be preferably used not only for HER2-overexpressing cancers, but also for HER2-low expressing cancers and HER2-mutated cancers.

[0828] In the present invention, the term "HER2-overexpressing cancer" is not particularly limited, as long as it is recognized by those skilled in the art as a HER2-overexpressing cancer. Preferred examples of HER2-overexpressing cancer include cancers whose HER2 expression score is determined to be 3+ by immunohistochemistry, and cancers whose HER2 expression score is determined to be 2+ by immunohistochemistry and whose HER2 expression is determined to be positive by in situ hybridization. Examples of the in situ hybridization method of the present invention include fluorescent in situ hybridization (FISH) and dual color in situ hybridization (DISH).

[0829] In the present invention, the term "HER2 low-expressing cancer" is not particularly limited, as long as it is recognized by those skilled in the art as a HER2 low-expressing cancer.Preferred examples of HER2 low-expressing cancer include cancers whose HER2 expression score is determined to be 2+ by immunohistochemistry and whose HER2 expression is determined to be negative by in situ hybridization, and cancers whose HER2 expression score is determined to be 1+ by immunohistochemistry.Another example of HER2 low-expressing cancer includes, but is not limited to, cancers whose HER2 expression score is determined to be >0 and <1+ by immunohistochemistry.

[0830] The method for scoring the degree of HER2 expression by immunohistochemical method, or the method for determining whether HER2 expression is positive or negative by in situ hybridization method is not particularly limited, as long as it is recognized by those skilled in the art.Examples of the method include the method described in the 4th edition of the HER2 test guideline for breast cancer (developed by the Japanese Pathology Board for Optimal Use of HER2 for Breast Cancer).

[0831] The HER2-low expressing cancer for which the pharmaceutical products and methods for treatment of the present invention can be used is preferably HER2-low expressing breast cancer, HER2-low expressing gastric cancer, HER2-low expressing colorectal cancer, or HER2-low expressing non-small cell lung cancer, more preferably HER2-low expressing breast cancer.

[0832] The pharmaceutical products and methods for treatment of the present invention can be used preferably on mammals, and more preferably on humans.

[0833] The pharmaceutical product and method for treatment of the present invention can be preferably used for maintenance therapy.The pharmaceutical product and method for treatment of the present invention can be used for the purpose of preventing tumor recurrence after initial chemotherapy.

[0834] In the present invention, the term "maintenance therapy" is used to mean a treatment administered to help prevent cancer recurrence after the cancer has disappeared after initial therapy. This term is defined based on "maintenance therapy" in the following literature:

[0835] NCI Dictionary, "Maintenance Therapy," NCI Cancer Glossary [online]. National Cancer Institute [accessed 2023-04-10].<cancer.gov / publications / dictionaries / cancer-terms / def / maintenance-therapy> Obtained from.

[0836] The antitumor effect of the pharmaceutical product and the method for treatment of the present invention can be confirmed, for example, by generating a model in which cancer cells are transplanted into a test animal, and measuring the reduction in tumor volume and the life-prolonging effect by applying the pharmaceutical product and the method for treatment of the present invention.Furthermore, by comparing the antitumor effect of the antibody-drug conjugate used in the present invention and the inhibitor selected from the group consisting of EZH1 inhibitor, EZH2 inhibitor, and EZH1 / 2 dual inhibitor, the combination effect of the antibody-drug conjugate used in the present invention and the inhibitor selected from the group consisting of EZH1 inhibitor, EZH2 inhibitor, and EZH1 / 2 dual inhibitor can be confirmed.

[0837] In addition, the antitumor effect of the pharmaceutical products and methods for treatment 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 McDonald evaluation method, weight measurement method, and other methods, and can be determined by indicators such as complete response rate (CR), partial response rate (PR), disease progression (PD), objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS).

[0838] The above-mentioned method can provide confirmation of the superiority of the pharmaceutical products and methods for treatment of the present invention in terms of anti-tumor effects compared to existing pharmaceutical products and methods for treatment for cancer therapy.

[0839] The pharmaceutical product and method for treatment of the present invention can slow down the proliferation of cancer cells, inhibit their proliferation, and even kill cancer cells. Such effects can enable cancer patients to be relieved from symptoms caused by cancer, or achieve an improvement in the quality of life of cancer patients, and can achieve a therapeutic effect by maintaining the life of cancer patients. Even if the pharmaceutical product and method for treatment do not achieve the death of cancer cells, they can achieve a longer survival while achieving a higher quality of life for cancer patients by inhibiting or controlling the proliferation of cancer cells. Furthermore, the pharmaceutical product and method for treatment of the present invention can show a sustained antitumor effect.

[0840] The pharmaceutical products and methods for treatment of the present invention do not involve severe weight loss.

[0841] The pharmaceutical product of the present invention can be expected to exert its therapeutic effect by application as a systemic therapy to the patient, and additionally by local application to the cancer tissue.

[0842] The pharmaceutical product of the present invention includes a pharmaceutical composition containing at least one pharma- ceutical suitable component. The pharma-ceutical suitable component can be suitably selected from formulation additives generally used in the art, etc., depending on the dosage or administration concentration of the antibody-drug conjugate used in the present invention and the inhibitor selected from the group consisting of EZH1 inhibitors, EZH2 inhibitors, and EZH1 / 2 dual inhibitors. For example, the antibody-drug conjugate used in the present invention can be administered as a pharmaceutical product 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 product containing the antibody-drug conjugate used in the present invention can be preferably used as an injection, more preferably as an aqueous injection or a lyophilized injection, and even more preferably as a lyophilized injection.

[0843] When the pharmaceutical product containing the antibody-drug conjugate used in the present invention is an aqueous injection, it can be preferably diluted with a suitable diluent and then administered as an intravenous infusion.The diluent can be exemplified by dextrose solution and saline, preferably dextrose solution, more preferably 5% dextrose solution.

[0844] When the pharmaceutical product containing the antibody-drug conjugate used in the present invention is a lyophilized injection, it can be preferably dissolved in water for injection, then diluted with a suitable diluent in the required amount, and then administered as an intravenous infusion.The diluent can be exemplified by dextrose solution and physiological saline, preferably dextrose solution, more preferably 5% dextrose solution.

[0845] Examples of routes of administration that can be used to administer the pharmaceutical products of the present invention include intravenous, intradermal, subcutaneous, intramuscular, and intraperitoneal routes, preferably the intravenous route.

[0846] The antibody-drug conjugate used in the present invention can be administered to humans once at intervals of 1 to 180 days, preferably once a week, once every 2 weeks, once every 3 weeks, or once every 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, preferably at a dose of 0.8 to 12.4 mg / kg. 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 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 once every three weeks 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. When the antibody-drug conjugate used in the present invention is an anti-TROP2 antibody-drug conjugate, it can be preferably administered once every three weeks 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.

[0847] The dosage of the inhibitor selected from the group consisting of EZH1 inhibitors, EZH2 inhibitors, and EZH1 / 2 dual inhibitors according to the present invention is not particularly limited as long as it is an amount effective for treating the target disease, and is appropriately selected according to the age, weight, symptoms, health condition, and disease progression of the patient. The frequency of administration is not particularly limited and can be appropriately selected according to the purpose. For example, the daily dosage is administered once a day, or divided into multiple doses and administered separately. When the drug of the present invention is administered to humans, the dosage of the active ingredient is in the range of about 0.01 mg / kg (body weight) to about 500 mg / kg (body weight), preferably about 0.1 mg / kg (body weight) to about 100 mg / kg (body weight). When administered to humans, the daily dosage is preferably administered once a day, or divided into 2 to 4 doses and administered separately at appropriate intervals.

[0848] The pharmaceutical product and method for treatment of the present invention may further comprise a cancer therapeutic agent other than the antibody-drug conjugate according to the present invention and an inhibitor selected from the group consisting of an EZH1 inhibitor, an EZH2 inhibitor, and an EZH1 / 2 dual inhibitor. The pharmaceutical product and method for treatment of the present invention may also be administered in combination with another cancer therapeutic agent, thereby enhancing the antitumor effect. The other cancer therapeutic agent used for such a purpose may be administered to a subject simultaneously, separately, or sequentially with the pharmaceutical composition of the present invention, or may be administered at different dosage intervals. Such a cancer therapeutic agent is not limited as long as it is an agent having antitumor activity, and may include irinotecan (CPT-11), cisplatin, carboplatin, oxaliplatin, fluorouracil (5-FU), gemcitabine, capecitabine, paclitaxel, docetaxel, doxorubicin, epirubicin, cyclophosphamide, mitomycin C, a combination of tegafur-gimeracil-oteracil, cetuximab, panitumumab, bevacizumab, cyclophosphamide ... The present invention can be exemplified by at least one selected from the group consisting of ramucirumab, regorafenib, a combination of trifluridine-tipiracil, gefitinib, erlotinib, afatinib, methotrexate, pemetrexed, tamoxifen, toremifene, fulvestrant, leuprorelin, goserelin, letrozole, anastrozole, a progesterone preparation, trastuzumab, pertuzumab, and lapatinib.

[0849] The pharmaceutical products and methods for treatment of the present invention can also be used in combination with radiation therapy. For example, cancer patients may receive radiation therapy before and / or after or at the same time as receiving therapy with the pharmaceutical products of the present invention.

[0850] The pharmaceutical product of the present invention and the method for treatment can also be used as adjuvant chemotherapy in combination with surgical procedure.The pharmaceutical product of the present invention can be administered before surgical procedure to reduce tumor size (called preoperative adjuvant chemotherapy or neoadjuvant therapy), or can be administered after surgical procedure to prevent tumor recurrence (called postoperative adjuvant chemotherapy or adjuvant therapy). EXAMPLES

[0851] The present invention will be described in detail in the light of the following examples. However, the present invention is not limited thereto. Moreover, the present invention should not be interpreted as being limited in any way. EXAMPLES

[0852] Production of anti-HER2 antibody-drug conjugate (1) In accordance with the production method described in WO 2015 / 115091, an anti-HER2 antibody (an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain having an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2) is used together with a compound represented by the following formula:

[0853] [ka] (wherein A represents the attachment site to the antibody) An anti-HER2 antibody-drug conjugate (hereinafter referred to as "HER2-ADC (1)" (trastuzumab deruxtecan / DS-8201a)) was produced in which the drug-linker represented by the formula (I) is conjugated to the anti-HER2 antibody via a thioether bond. The DAR of HER2-ADC (1) is 7.7 or 7.8. EXAMPLES

[0854] Production of anti-TROP2 antibody-drug conjugate (1) In accordance with the production methods described in WO 2015 / 098099 and WO 2017 / 002776, an anti-TROP2 antibody (an antibody comprising a heavy chain consisting of amino acid residues 20 to 470 of SEQ ID NO:5 and a light chain consisting of amino acid residues 21 to 234 of SEQ ID NO:6) is used together with a compound represented by the following formula:

[0855] [ka] (wherein A represents the attachment site to the antibody) An anti-TROP2 antibody-drug conjugate (hereinafter referred to as "TROP2-ADC(1)") was produced in which a drug-linker represented by the formula (I) is conjugated to an anti-TROP2 antibody via a thioether bond. The DAR of TROP2-ADC(1) is 3.5 to 4.5. EXAMPLES

[0856] Production of anti-HER3 antibody-drug conjugate (1) Using an anti-HER3 antibody (an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 3 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 4) in accordance with the production method described in WO 2015 / 115998,

[0857] [ka] (wherein A represents the attachment site to the antibody) An anti-HER3 antibody-drug conjugate (hereinafter referred to as "HER3-ADC (1)") was produced in which a drug-linker represented by the formula (I) is conjugated to an anti-HER3 antibody via a thioether bond. The DAR of HER3-ADC (1) is 7.6. EXAMPLES

[0858] Production of anti-CDH6 antibody-drug conjugate (1) In accordance with the production method described in WO 2018 / 212136, an anti-CDH6 antibody (an antibody comprising a heavy chain having an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 11 and a light chain having an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 12) is used together with a compound represented by the following formula:

[0859] [ka] (wherein A represents the attachment 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 conjugated to the anti-CDH6 antibody via a thioether bond. The DAR of CDH6-ADC (1) is 7.8. EXAMPLES

[0860] Antitumor Research (1) Measurements and calculations: In all studies, tumor major and minor diameters were measured weekly or twice weekly with electronic digital calipers, and estimated tumor volumes (mm 3 ) was calculated using the formula shown below. Estimated tumor volume (mm 3 ) = 1 / 2 x major axis (mm) x [minor axis (mm)] 2 Tumor growth inhibition (TGI) was calculated according to the following formula. Tumor growth inhibition (%) = 100 × (1-T / C) T: Mean estimated tumor volume of mice in the test substance administration group C: Mean estimated tumor volume of mice in the control group HER2-ADC(1) was diluted in ABS buffer (10 mM acetate buffer [pH 5.5], 5% sorbitol) and administered intravenously via the tail vein in a fluid volume of 10 mL / kg. Compound A was administered orally in a chow mix containing 0.3% Compound A. These methods are common to Examples 5 to 8 and Examples 11 to 16. In Examples 12 to 16, TROP2-ADC(1), HER3-ADC(1), CD37-ADC(1), or B7-H3-ADC(1) was used for evaluation. Furthermore, in Examples 12 to 16, Compound A was orally administered in a feed mix containing 0.25% Compound A.

[0861] Human gastric cancer cell line NCI-N87 purchased from ATCC (American Type Culture Collection) was suspended in DPBS (Dulbecco's phosphate-buffered saline) at 1 × 10 7 Cells were subcutaneously implanted into the right side of each female SCID (severe combined immunodeficiency) mouse (CLEA Japan, Inc.) (day 0). After 6 days, the mice were divided into groups based on the estimated tumor volume. Compound A was orally administered ad libitum in a food mix containing 0.3% compound A for 28 consecutive days from day 6 to day 34. HER2-ADC(1) was intravenously administered into the tail vein at a dose of 2 mg / kg on day 10. No notable findings such as severe weight loss were observed in either the single-administration group or the combination-administration group. The results of the combination of HER2-ADC(1) and compound A are shown in Figure 16. On day 63, single administration of compound A showed a TGI of 38%, and single administration of HER2-ADC(1) showed a TGI of 82%. Meanwhile, the combination administration of compound A and HER2-ADC(1) showed a TGI of 97%. Compared with HER2-ADC(1) alone and Compound A alone, the combination of HER2-ADC(1) and Compound A exerted durable and superior antitumor efficacy. EXAMPLES

[0862] Antitumor Research (2) Human breast cancer cell line JIMT-1 purchased from DSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH) was suspended in DPBS at 5 × 10 6Cells were subcutaneously implanted into the right side of each female SCID mouse (CLEA Japan, Inc.) (day 0). After 14 days, the mice were divided into groups based on the estimated tumor volume. Compound A was orally administered ad libitum in a food mix containing 0.3% compound A for 28 consecutive days from day 14 to day 42. HER2-ADC(1) was intravenously administered into the tail vein at a dose of 10 mg / kg on day 18. No notable findings such as severe weight loss were observed in either the single-administration group or the combination-administration group. The results of the combination of HER2-ADC(1) and compound A are shown in Figure 17. On day 52, single administration of compound A showed a TGI of 19%, and single administration of HER2-ADC(1) showed a TGI of 52%. Meanwhile, the combination administration of compound A and HER2-ADC(1) showed a TGI of 94%. Compared with HER2-ADC(1) alone and Compound A alone, the combination of HER2-ADC(1) and Compound A exerted durable and superior antitumor efficacy. EXAMPLES

[0863] Antitumor Research (3) Human breast cancer cell line MDA-MB-453 purchased from ATCC was suspended in 50% Matrigel matrix and 1 × 10 7Cells were subcutaneously implanted into the right side of each female SCID mouse (CLEA Japan, Inc.) (day 0). After 18 days, the mice were divided into groups based on the estimated tumor volume. Compound A was orally administered ad libitum in a food mix containing 0.3% compound A for 28 consecutive days from day 18 to day 46. HER2-ADC(1) was intravenously administered into the tail vein at a dose of 1 mg / kg on day 22. No notable findings, such as severe weight loss, were observed in either the single-administration group or the combination-administration group. The results of the combination of HER2-ADC(1) and compound A are shown in Figure 18. On day 74, single administration of compound A showed a TGI of 41%, and single administration of HER2-ADC(1) showed a TGI of 98%. Meanwhile, the combination administration of compound A and HER2-ADC(1) showed a TGI of 100%. Compared with HER2-ADC(1) alone and Compound A alone, the combination of HER2-ADC(1) and Compound A exerted durable and superior antitumor efficacy. EXAMPLES

[0864] Antitumor Research (4) Human breast cancer cell line MX-1 purchased from CLS (Cell Lines Service) was suspended in 50% Matrigel matrix and 5 × 10 6Cells were subcutaneously implanted into the right side of each female SCID mouse (CLEA Japan, Inc.) (day 0). After 13 days, the mice were divided into groups based on the estimated tumor volume. Compound A was orally administered ad libitum in a food mix containing 0.3% compound A for 28 consecutive days from day 13 to day 41. HER2-ADC(1) was intravenously administered into the tail vein at a dose of 3 mg / kg on day 17. No notable findings such as severe weight loss were observed in either the single-administration group or the combination-administration group. The results of the combination of HER2-ADC(1) and compound A are shown in Figure 19. On day 51, single administration of compound A showed a TGI of 9%, and single administration of HER2-ADC(1) showed a TGI of 70%. Meanwhile, the combination administration of compound A and HER2-ADC(1) showed a TGI of 85%. Compared with HER2-ADC(1) alone and Compound A alone, the combination of HER2-ADC(1) and Compound A exerted durable and superior antitumor efficacy. EXAMPLES

[0865] Production of anti-CD37 antibody-drug conjugate (1) Using an anti-CD37 antibody (an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 468 of SEQ ID NO: 16 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 19), a compound having the following formula:

[0866] [ka] (wherein A represents the attachment site to the antibody) An anti-CD37 antibody-drug conjugate (hereinafter referred to as "CD37-ADC (1)") was produced in which a drug-linker represented by the formula (I) is conjugated to an anti-CD37 antibody via a thioether bond. The DAR of CD37-ADC (1) is 7.8. EXAMPLES

[0867] Production of anti-B7-H3 antibody-drug conjugate (1) The anti-B7-H3 antibody (an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 7 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 8) was used in accordance with the production method described in WO 2014 / 057687, and the antibody was synthesized using the following formula:

[0868] [ka] (wherein A represents the attachment site to the antibody) An anti-B7-H3 antibody-drug conjugate (hereinafter referred to as "B7-H3-ADC (1)") was produced in which a drug-linker represented by the formula (I) is conjugated to an anti-B7-H3 antibody via a thioether bond. The DAR of B7-H3-ADC (1) is 4.0. EXAMPLES

[0869] Antitumor Research (5) Human breast cancer cell line ZR-75-1 purchased from ATCC (American Type Culture Collection) was suspended in Matrigel matrix at 1 × 10 7The cells were subcutaneously implanted (day 0) into the right side of each female NSG mouse (The Jackson Laboratory Japan, Inc.), and each of them was treated once a week with 0.02 mg of estradiol cypionate administered subcutaneously from day 0. After 14 days, the mice were divided into groups based on the estimated tumor volume. Compound A was orally administered ad libitum in a food mix containing 0.3% compound A for 28 consecutive days from day 14 to day 42. HER2-ADC(1) was intravenously administered into the tail vein at a dose of 5 mg / kg on day 14. No notable findings such as severe weight loss were observed in either the single-administration group or the combination-administration group. The results of the combination of HER2-ADC(1) and compound A are shown in Figure 24. On day 49, single administration of compound A showed a TGI of 53%, and single administration of HER2-ADC(1) showed a TGI of 61%. On the other hand, the combined administration of Compound A and HER2-ADC(1) showed a TGI of 76%. Compared with HER2-ADC(1) alone and Compound A alone, the combination of HER2-ADC(1) and Compound A demonstrated a sustained and superior antitumor effect. EXAMPLES

[0870] Antitumor Research (6) Human non-small lung cancer cell line Calu-3 purchased from ATCC (American Type Culture Collection) was suspended in Matrigel matrix at 3 × 10 6Cells were subcutaneously implanted into the right side of each female SCID mouse (The Jackson Laboratory Japan, Inc.) (day 0). After 14 days, the mice were divided into groups based on the estimated tumor volume. Compound A was orally administered ad libitum in a food mix containing 0.3% compound A for 28 consecutive days from day 14 to day 42. HER2-ADC(1) was intravenously administered into the tail vein at a dose of 1 mg / kg on day 14. No notable findings such as severe weight loss were observed in either the single-administration group or the combination-administration group. The results of the combination of HER2-ADC(1) and compound A are shown in Figure 25. On day 35, single administration of compound A showed a TGI of 20%, and single administration of HER2-ADC(1) showed a TGI of 76%. Meanwhile, the combination administration of compound A and HER2-ADC(1) showed a TGI of 95%. Compared with HER2-ADC(1) alone and Compound A alone, the combination of HER2-ADC(1) and Compound A exerted durable and superior antitumor efficacy. EXAMPLES

[0871] Antitumor Research (7) Human cells purchased from ATCC (American Type Culture Collection) Non-small lung cancer The cell line NCI-H358 was suspended in 50% Matrigel matrix at 3 × 10 6Cells were subcutaneously implanted into the right side of each female SCID mouse (CLEA Japan, Inc.) (day 0). After 24 days, the mice were divided into groups based on the estimated tumor volume. Compound A was orally administered ad libitum in a food mix containing 0.25% compound A for 42 consecutive days from day 24 to day 66. TROP2-ADC(1) was intravenously administered into the tail vein at a dose of 10 mg / kg on days 24 and 45. No notable findings such as severe weight loss were observed in either the single-administration group or the combination-administration group. The results of the combination of TROP2-ADC(1) and compound A are shown in Figure 26. On day 115, single administration of compound A showed a TGI of 20%, and single administration of TROP2-ADC(1) showed a TGI of 78%. Meanwhile, the combination administration of compound A and TROP2-ADC(1) showed a TGI of 93%. Compared with TROP2-ADC(1) alone and Compound A alone, the combination of TROP2-ADC(1) and Compound A exerted durable and superior antitumor effects. EXAMPLES

[0872] Antitumor Research (8) Human breast cancer cell line JIMT-1 purchased from DSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH) was suspended in saline and diluted to 5 × 10 6Cells were subcutaneously implanted into the right side of each female SCID mouse (CLEA Japan, Inc.) (day 0). After 11 days, the mice were divided into groups based on the estimated tumor volume. Compound A was orally administered ad libitum in a food mix containing 0.25% compound A for 28 consecutive days from day 11 to day 39. HER3-ADC(1) was intravenously administered into the tail vein at a dose of 10 mg / kg on day 11. No notable findings such as severe weight loss were observed in either the single-administration group or the combination-administration group. The results of the combination of HER3-ADC(1) and compound A are shown in Figure 27. On day 46, single administration of compound A showed a TGI of 41%, and single administration of HER3-ADC(1) showed a TGI of 66%. Meanwhile, the combination administration of compound A and HER3-ADC(1) showed a TGI of 77%. Compared with HER3-ADC(1) alone and Compound A alone, the combination of HER3-ADC(1) and Compound A exerted durable and superior antitumor efficacy. EXAMPLES

[0873] Antitumor Research (9) Human diffuse large B-cell lymphoma cell line WSU-DLCL2 purchased from DSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH) was suspended in DPBS and diluted to 1 × 10 7Cells were subcutaneously implanted into the right side of each female SCID mouse (CLEA Japan, Inc.) (day 0). After 16 days, the mice were divided into groups based on the estimated tumor volume. Compound A was orally administered ad libitum in a food mix containing 0.25% compound A for 28 consecutive days from day 16 to day 44. CD37-ADC(1) was intravenously administered into the tail vein at a dose of 1 mg / kg on day 16. No notable findings such as severe weight loss were observed in either the single-administration group or the combination-administration group. The results of the combination of CD37-ADC(1) and compound A are shown in Figure 28. On day 44, single administration of compound A showed a TGI of 31%, and single administration of CD37-ADC(1) showed a TGI of 43%. Meanwhile, the combination administration of compound A and CD37-ADC(1) showed a TGI of 78%. Compared with CD37-ADC(1) alone and Compound A alone, the combination of CD37-ADC(1) and Compound A exerted a durable and superior antitumor effect. EXAMPLES

[0874] Antitumor Research (10) Human neuroendocrine prostate cancer cell line NCI-H660 purchased from ATCC (American Type Culture Collection) was suspended in 50% Matrigel matrix at 2 × 10 6Cells were subcutaneously implanted into the right side of each castrated male SCID mouse (CLEA Japan, Inc.) (day 0). After 29 days, the mice were divided into groups based on the estimated tumor volume. Compound A was orally administered ad libitum in a food mix containing 0.25% compound A for 29 consecutive days from day 29 to day 58. B7-H3-ADC(1) was intravenously administered into the tail vein at a dose of 0.3 mg / kg on days 29 and 43. No notable findings, such as severe weight loss, were observed in either the single-administration group or the combination-administration group. The results of the combination of B7-H3-ADC(1) and compound A are shown in Figure 29. On day 58, single administration of compound A showed a TGI of 80%, and single administration of B7-H3-ADC(1) showed a TGI of 37%. Meanwhile, the combination administration of compound A and B7-H3-ADC(1) showed a TGI of 91%. Compared with B7-H3-ADC(1) alone and Compound A alone, the combination of B7-H3-ADC(1) and Compound A exerted a durable and superior antitumor effect.

[0875] Free text in sequence listing SEQ ID NO:1 - Amino acid sequence of the heavy chain of the anti-HER2 antibody SEQ ID NO:2 - Amino acid sequence of the light chain of the anti-HER2 antibody SEQ ID NO:3 - Amino acid sequence of the heavy chain of the anti-HER3 antibody SEQ ID NO:4 - Amino acid sequence of the light chain of the anti-HER3 antibody SEQ ID NO:5 - Amino acid sequence of the heavy chain of the anti-TROP2 antibody SEQ ID NO:6 - Amino acid sequence of the light chain of the anti-TROP2 antibody SEQ ID NO:7 - Amino acid sequence of the heavy chain of the anti-B7-H3 antibody SEQ ID NO:8 - Amino acid sequence of the light chain of anti-B7-H3 antibody SEQ ID NO:9 - Amino acid sequence of the heavy chain of an anti-GPR20 antibody SEQ ID NO:10 - Amino acid sequence of the light chain of an anti-GPR20 antibody SEQ ID NO:11 - Amino acid sequence of the heavy chain of anti-CDH6 antibody SEQ ID NO: 12 - Amino acid sequence of the light chain of anti-CDH6 antibody SEQ ID NO:13 - Amino acid sequence of the heavy chain of anti-MUC1 antibody (N54Q) SEQ ID NO: 14 - Amino acid sequence of the heavy chain of anti-MUC1 antibody (PankoMab) SEQ ID NO: 15 - Amino acid sequence of the light chain of anti-MUC1 antibodies (N54Q and PankoMab) SEQ ID NO: 16 - Amino acid sequence of the heavy chain of anti-CD37 antibody (hmAb-H541) SEQ ID NO: 17 - Amino acid sequence of the heavy chain of anti-CD37 antibody (hmAb-H551) SEQ ID NO: 18 - Amino acid sequence of the heavy chain of anti-CD37 antibody (hmAb-H11a) SEQ ID NO: 19 - Amino acid sequence of the light chain of anti-CD37 antibody (hmAb-L11) SEQ ID NO:20 - Amino acid sequence of CDRH1 of the heavy chain of the anti-HER2 antibody SEQ ID NO: 21 - Amino acid sequence of CDRH2 of the heavy chain of anti-HER2 antibody SEQ ID NO: 22 - Amino acid sequence of CDRH3 of the heavy chain of anti-HER2 antibody SEQ ID NO: 23 - Amino acid sequence of CDRL1 of the light chain of the anti-HER2 antibody SEQ ID NO: 24 - Amino acid sequence of CDRL2 of the light chain of anti-HER2 antibody SEQ ID NO: 25 - Amino acid sequence of CDRL3 of the light chain of anti-HER2 antibody SEQ ID NO: 26 - Amino acid sequence of the heavy chain variable region of an anti-HER2 antibody SEQ ID NO: 27 - Amino acid sequence of the light chain variable region of the anti-HER2 antibody SEQ ID NO:28 - Amino acid sequence of CDRH1 of the heavy chain of the TROP2 antibody SEQ ID NO: 29 - Amino acid sequence of CDRH2 of the heavy chain of the TROP2 antibody SEQ ID NO: 30 - Amino acid sequence of CDRH3 of the heavy chain of the TROP2 antibody SEQ ID NO: 31 - Amino acid sequence of CDRL1 of the light chain of anti-TROP2 antibody SEQ ID NO: 32 - Amino acid sequence of CDRL2 of the light chain of anti-TROP2 antibody SEQ ID NO: 33 - Amino acid sequence of CDRL3 of the light chain of anti-TROP2 antibody SEQ ID NO: 34 - Amino acid sequence of the heavy chain variable region of an anti-TROP2 antibody SEQ ID NO: 35 - Amino acid sequence of the light chain variable region of an anti-TROP2 antibody

Claims

1. The antibody-drug conjugate comprises an inhibitor selected from the group consisting of EZH1 inhibitors, EZH2 inhibitors, and EZH1 / 2 bi-inhibitors. A pharmaceutical product for combination administration of an antibody-drug conjugate and an inhibitor, The antibody-drug conjugate is expressed by the following formula: 【Chemistry 1】 (In the formula, A represents the connection point with the antibody.) A pharmaceutical product in which a drug-linker, represented by [the formula shown], is conjugated to an antibody via a thioether bond, forming an antibody-drug conjugate.

2. The pharmaceutical product according to 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, an anti-CDH6 antibody, an anti-MUC1 antibody, or an anti-CD37 antibody.

3. The antibody in the antibody-drug conjugate is an anti-HER2 antibody. The anti-HER2 antibody is an antibody comprising a heavy chain containing CDRH1, consisting of amino acid sequences of amino acid residues 26-33 of SEQ ID NO: 1; CDRH2, consisting of amino acid sequences of amino acid residues 51-58 of SEQ ID NO: 1; and CDRH3, consisting of amino acid sequences of amino acid residues 97-109 of SEQ ID NO: 1; and a light chain containing CDRL1, consisting of amino acid sequences of amino acid residues 27-32 of SEQ ID NO: 2; CDRL2, consisting of amino acid sequences of amino acid residues 50-52 of SEQ ID NO: 2; and CDRL3, consisting of amino acid sequences of amino acid residues 89-97 of SEQ ID NO:

2. The anti-HER2 antibody is an antibody that includes a heavy chain containing a heavy chain variable region consisting of amino acid residues 1 to 120 of SEQ ID NO: 1, and a light chain containing a light chain variable region consisting of amino acid residues 1 to 107 of SEQ ID NO:

2. The anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 1 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 2, or The anti-HER2 antibody is an antibody that contains a heavy chain consisting of amino acid residues 1 to 449 of SEQ ID NO: 1, and a light chain consisting of amino acid residues 1 to 214 of SEQ ID NO:

2. The pharmaceutical product according to claim 2.

4. The antibody-drug conjugate is expressed by the following formula: 【Chemistry 2】 The pharmaceutical product according to claim 3, wherein the formula is represented as follows, where "antibody" refers to an anti-HER2 antibody conjugated to a drug-linker via a thioether bond, n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

5. The antibody in the antibody-drug conjugate is an anti-HER3 antibody. The anti-HER3 antibody is an antibody comprising a heavy chain containing CDRH1, consisting of amino acid sequences of amino acid residues 26-35 of SEQ ID NO: 3; CDRH2, consisting of amino acid sequences of amino acid residues 50-65 of SEQ ID NO: 3; and CDRH3, consisting of amino acid sequences of amino acid residues 98-106 of SEQ ID NO: 3; and a light chain containing CDRL1, consisting of amino acid sequences of amino acid residues 24-39 of SEQ ID NO: 4; CDRL2, consisting of amino acid sequences of amino acid residues 56-62 of SEQ ID NO: 4; and CDRL3, consisting of amino acid sequences of amino acid residues 95-103 of SEQ ID NO:

4. The anti-HER3 antibody is an antibody that includes a heavy chain containing a heavy chain variable region consisting of amino acid residues 1 to 117 of SEQ ID NO: 3, and a light chain containing a light chain variable region consisting of amino acid residues 1 to 113 of SEQ ID NO:

4. The anti-HER3 antibody is an antibody that includes a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 3 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 4, or The anti-HER3 antibody is an antibody that contains a heavy chain consisting of amino acid residues 1 to 446 of SEQ ID NO: 3, and a light chain consisting of amino acid residues 1 to 220 of SEQ ID NO:

4. The pharmaceutical product according to claim 2.

6. The antibody-drug conjugate is expressed by the following formula: 【Transformation 3】 The pharmaceutical product according to claim 5, wherein the formula is represented as follows, where "antibody" refers to an anti-HER3 antibody conjugated to a drug-linker via a thioether bond, n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

7. The antibody in the antibody-drug conjugate is an anti-TROP2 antibody. The anti-TROP2 antibody is an antibody comprising a heavy chain containing CDRH1, consisting of amino acid sequences of amino acid residues 50-54 of SEQ ID NO: 5; CDRH2, consisting of amino acid sequences of amino acid residues 69-85 of SEQ ID NO: 5; and CDRH3, consisting of amino acid sequences of amino acid residues 118-129 of SEQ ID NO: 5; and a light chain containing CDRL1, consisting of amino acid sequences of amino acid residues 44-54 of SEQ ID NO: 6; CDRL2, consisting of amino acid sequences of amino acid residues 70-76 of SEQ ID NO: 6; and CDRL3, consisting of amino acid sequences of amino acid residues 109-117 of SEQ ID NO:

6. The anti-TROP2 antibody is an antibody that includes a heavy chain containing a heavy chain variable region consisting of amino acid residues 20-140 of SEQ ID NO: 5, and a light chain containing a light chain variable region consisting of amino acid residues 21-129 of SEQ ID NO:

6. The anti-TROP2 antibody is an antibody that includes a heavy chain consisting of amino acid residues 20-470 of SEQ ID NO: 5, and a light chain consisting of amino acid residues 21-234 of SEQ ID NO: 6, or The anti-TROP2 antibody is an antibody that contains a heavy chain consisting of amino acid residues 20-469 of SEQ ID NO: 5, and a light chain consisting of amino acid residues 21-234 of SEQ ID NO:

6. The pharmaceutical product according to claim 2.

8. The antibody-drug conjugate is expressed by the following formula: 【Chemistry 4】 The pharmaceutical product according to claim 7, wherein the formula is represented as follows, where “antibody” refers to an anti-TROP2 antibody conjugated to a drug-linker via a thioether bond, n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 3.5 to 4.

5.

9. The antibody in the antibody-drug conjugate is an anti-B7-H3 antibody. The anti-B7-H3 antibody is an antibody that includes a heavy chain consisting of amino acid residues 20-471 of SEQ ID NO: 7, and a light chain consisting of amino acid residues 21-233 of SEQ ID NO: 8, or The anti-B7-H3 antibody is an antibody that contains a heavy chain consisting of amino acid residues 20-470 of SEQ ID NO: 7, and a light chain consisting of amino acid residues 21-233 of SEQ ID NO:

8. The pharmaceutical product according to claim 2.

10. The antibody-drug conjugate is expressed by the following formula: 【Transformation 5】 The pharmaceutical product according to claim 9, wherein the formula is represented as, where "antibody" refers to an anti-B7-H3 antibody conjugated to a drug-linker via a thioether bond, n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 3.5 to 4.

5.

11. The antibody in the antibody-drug conjugate is an anti-GPR20 antibody. The anti-GPR20 antibody is an antibody that includes a heavy chain consisting of amino acid residues 20-472 of SEQ ID NO: 9 and a light chain consisting of amino acid residues 21-234 of SEQ ID NO: 10, or The anti-GPR20 antibody is an antibody that contains a heavy chain consisting of amino acid residues 20-471 of SEQ ID NO: 9, and a light chain consisting of amino acid residues 21-234 of SEQ ID NO:

10. The pharmaceutical product according to claim 2.

12. The antibody-drug conjugate is expressed by the following formula: 【Transformation 6】 The pharmaceutical product according to claim 11, wherein the formula is represented as follows, where “antibody” refers to an anti-GPR20 antibody conjugated to a drug-linker via a thioether bond, n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

13. The antibody in the antibody-drug conjugate is an anti-CDH6 antibody. The anti-CDH6 antibody is an antibody that includes a heavy chain consisting of amino acid residues 20-471 of SEQ ID NO: 11 and a light chain consisting of amino acid residues 21-233 of SEQ ID NO: 12, or The anti-CDH6 antibody is an antibody that includes a heavy chain consisting of amino acid residues 20-470 of SEQ ID NO: 11, and a light chain consisting of amino acid residues 21-233 of SEQ ID NO:

12. The pharmaceutical product according to claim 2.

14. The antibody-drug conjugate is expressed by the following formula: 【Transformation 7】 The pharmaceutical product according to claim 13, wherein the formula is represented as follows, where "antibody" refers to an anti-CDH6 antibody conjugated to a drug-linker via a thioether bond, n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

15. The antibody in the antibody-drug conjugate is an anti-MUC1 antibody. The anti-MUC1 antibody is an antibody that includes a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 13 and a light chain consisting of the amino acid sequence represented by SEQ ID NO:

15. The anti-MUC1 antibody is an antibody that includes a heavy chain consisting of amino acid residues 1 to 446 of SEQ ID NO: 13, and a light chain consisting of amino acid residues 1 to 219 of SEQ ID NO:

15. The anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 14 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 15, or The anti-MUC1 antibody is an antibody that includes a heavy chain consisting of amino acid residues 1 to 446 of SEQ ID NO: 14, and a light chain consisting of amino acid residues 1 to 219 of SEQ ID NO:

15. The pharmaceutical product according to claim 2.

16. The antibody-drug conjugate is expressed by the following formula: 【Transformation 8】 The pharmaceutical product according to claim 15, wherein the formula is represented as, where "antibody" refers to an anti-MUC1 antibody conjugated to a drug-linker via a thioether bond, n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

17. The antibody in the antibody-drug conjugate is an anti-CD37 antibody. Anti-CD37 antibody, (a) An antibody comprising a heavy chain containing a heavy chain variable region consisting of amino acid residues 20 to 138 of SEQ ID NO: 16, and a light chain containing a light chain variable region consisting of amino acid residues 21 to 128 of SEQ ID NO: 19, (b) An antibody comprising a heavy chain containing a heavy chain variable region consisting of amino acid residues 20 to 138 of SEQ ID NO: 17, and a light chain containing a light chain variable region consisting of amino acid residues 21 to 128 of SEQ ID NO: 19, (c) An antibody comprising a heavy chain containing a heavy chain variable region consisting of an amino acid sequence of amino acid residues 20 to 138 of SEQ ID NO: 18, and a light chain containing a light chain variable region consisting of an amino acid sequence of amino acid residues 21 to 128 of SEQ ID NO:

19. (d) An antibody comprising a heavy chain consisting of amino acid residues 20 to 468 of SEQ ID NO: 16, and a light chain consisting of amino acid residues 21 to 234 of SEQ ID NO: 19, (e) An antibody comprising a heavy chain consisting of amino acid residues 20 to 468 of SEQ ID NO: 17, and a light chain consisting of amino acid residues 21 to 234 of SEQ ID NO: 19, and (f) An antibody comprising a heavy chain consisting of amino acid residues 20-468 of SEQ ID NO: 18, and a light chain consisting of amino acid residues 21-234 of SEQ ID NO:

19. The antibody is selected from the group consisting of the following: The pharmaceutical product according to claim 2.

18. The pharmaceutical product according to claim 17, wherein the anti-CD37 antibody is deleting one or two amino acid residues at the carboxyl terminus of the heavy chain.

19. The pharmaceutical product according to claim 18, wherein the proline residue at the carboxyl terminus of the heavy chain is amidated.

20. The antibody-drug conjugate is expressed by the following formula: 【Chemistry 9】 The pharmaceutical product according to claim 17, wherein the formula is represented as follows, where "antibody" refers to an anti-CD37 antibody conjugated to a drug-linker via a thioether bond, n represents the average number of drug linkers bound per antibody in the antibody-drug conjugate, and n is in the range of 7 to 8.

21. The pharmaceutical product according to claim 4, wherein the antibody-drug conjugate is trastuzumab deruxtecan (DS-8201a).

22. The pharmaceutical product according to claim 8, wherein the antibody-drug conjugate is datopotamab deruxtecan (DS-1062).

23. The pharmaceutical product according to any one of claims 1 to 22, wherein the inhibitor is tazemetostat or a pharmaceutically acceptable salt thereof, valemetostat or a pharmaceutically acceptable salt thereof, or valemetostat tosylate.

24. A pharmaceutical product according to any one of claims 1 to 22, wherein an antibody-drug conjugate and an inhibitor are separately contained as active ingredients in different formulations and are administered simultaneously or at different time points.

25. A pharmaceutical product according to any one of claims 1 to 22, for use in 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, kidney cancer, and sarcoma.

26. The pharmaceutical product according to claim 25, for use in the treatment of triple-negative breast cancer.

27. An antibody-drug conjugate for disease treatment, administered in combination with an inhibitor selected from the group consisting of EZH1 inhibitors, EZH2 inhibitors, and EZH1 / 2 bi-inhibitors. The antibody-drug conjugate is given by the following formula: 【Chemistry 10】 (In the formula, A represents the connection point with the antibody.) An antibody-drug conjugate in which a drug-linker represented by is conjugated to an antibody via a thioether linkage in an antibody-drug conjugate.

28. The antibody-drug conjugate according to claim 27, wherein the antibody in the antibody-drug conjugate and the antibody-drug conjugate are as described in any one of claims 2 to 22.

29. The antibody-drug conjugate according to claim 27, wherein the inhibitor is as described in claim 23.

30. The antibody-drug conjugate according to claim 27, wherein the antibody-drug conjugate and the inhibitor are separately contained as active ingredients in different formulations and are administered simultaneously or at different time points.

31. The antibody-drug conjugate according to claim 27, wherein the disease is as described in claim 25 or 26.

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