Methods of treatment for low drug-sensitive cancers by administration of anti-MUC1 antibody-drug conjugates

Abstract

Provided are a therapeutic agent and a treatment method for cancer having low sensitivity to existing anti-cancer agents, comprising an anti-MUC1 antibody-drug conjugate as an active ingredient.

Description

Technical Field

[0001] This invention relates to therapeutic agents and methods for treating cancers with low sensitivity to existing anticancer agents, including the administration of anti-MUC1 antibody-drug conjugates. Background Technology

[0002] Antibody-drug conjugates (ADCs) are a therapeutic approach that delivers drugs in a cancer-specific manner, potentially offering a wider safety margin and greater efficacy than traditional anticancer agents. For example, the anti-stem protein-4 antibody-drug conjugate enfortumab vedotin (INN: PADCEV(R)) and the anti-TROP2 antibody-drug conjugate sacituzumab govitecan (INN: TRODELVY(R)) have been approved as standard treatments for urothelial carcinoma, and the anti-HER2 antibody-drug conjugate trastuzumab deruxtecan (INN: ENHERTU(R)) and TRODELVY(R) have been approved as standard treatments for breast cancer (Patent Literature 1-3). However, many cases do not respond to standard chemotherapy drugs including these ADCs, or become unresponsive to these chemotherapy drugs after acquiring resistance following a temporary response. Because subsequent treatment options were limited, new treatment methods were needed.

[0003] Human mucin-1 (MUC1) is a highly glycosylated protein that is expressed on the apical membrane side of the epithelial layer in normal human tissues and forms a mucosal barrier. However, in tumor tissues, MUC1 loses its expression polarity and becomes expressed throughout the cell membrane or even the cytoplasm (Non-Patent Reference 1). Overexpression of MUC1 has been found in various clinical cancer types (Non-Patent Reference 1) and has been reported to lead to a poorer prognosis in patients with high expression compared to those with low expression, such as in bladder cancer (Non-Patent Reference 2). In tumors, a novel epitope of MUC1 with exposed glycosylation, known as tumor-associated MUC1 (TA-MUC1), becomes expressed through changes in the expression of sialyltransferases associated with glycan modification (Non-Patent Reference 1).

[0004] An ADC (Advanced Drug-Contractor) conjugated with an antibody that recognizes TA-MUC1 expressed on the surface of cancer cells and exhibits internalization activity can selectively deliver the drug to cancer cells, and thus is expected to cause drug accumulation within the cancer cells and kill them. The extracellular domain of MUC1 contains approximately 25-120 tandem repeat sequences of 20 amino acids each (Non-Patent Documents 3 and 4), and multiple antibodies can bind to a single MUC1 molecule. In other words, this ADC delivers more drug than conventional ADCs, and is therefore expected to exhibit stronger drug efficacy against tumors that do not respond to previous standard treatments.

[0005] Antibody-drug conjugates containing anti-MUC1 antibody and topoisomerase 1 inhibitor exatecan as components are called anti-MUC1 antibody-drug conjugates (Patent Document 4).

[0006] Reference List Patent documents Patent Document 1: International Publication No. WO 2010 / 093395 Patent Document 2: US Patent No. 7999083 Patent Document 3: International Publication No. WO 2015 / 115091 Patent Document 4: International Publication No. WO 2019 / 219891 Non-patent literature Non-patent literature 1: Nath S, Mukherjee P., Trends Mol Med. 2014; 20(6):332-42 Non-patent literature 2: Qing L, Li Q, Yang Y et al., BMC Urol. 2022; 22(1):114 Non-patent literature 3: Gendler SJ, Lancaster CA, Taylor-Papadimitriou J et al., J Biol Chem. 1990; 265(25):15286-93 Non-patent literature 4: Hanisch FG, Muller S. Glycobiology. 2000; 10(5):439-49 Summary of the Invention

[0007] Technical issues The purpose of this invention is to provide therapeutic agents and methods for treating tumors that are unresponsive to existing anticancer agents.

[0008] Solution to the problem The inventors have discovered that anti-MUC1 antibody-drug conjugates exhibit excellent antitumor activity against tumors that do not respond to existing anticancer agents.

[0009] Specifically, the present invention relates to the following.

[0010] [1] A therapeutic agent for cancers with low sensitivity to existing anticancer agents, comprising an anti-MUC1 antibody-drug conjugate as the active ingredient.

[0011] [2] The therapeutic agent according to [1], wherein the anticancer agent is an alkylating agent, a platinum-containing drug, an antifolate agent, a pyridine metabolism inhibitor, a purine metabolism inhibitor, a ribonucleotide reductase inhibitor, a nucleotide analog, a topoisomerase inhibitor, a microtubule polymerization inhibitor, a microtubule depolymerization inhibitor, an antitumor antibiotic, an antihormonal agent, an EGFR inhibitor, a BTK inhibitor, a BCR-ABL inhibitor, an ALK inhibitor, a HER2 inhibitor, an angiogenesis inhibitor, a PARP inhibitor, an mTOR inhibitor, a membrane differentiation antigen-targeting drug, or an antibody-drug conjugate.

[0012] [3] The therapeutic agent according to [1], wherein the anticancer agent is an antibody-drug conjugate.

[0013] [4] The therapeutic agent according to [3], wherein the antibody-drug conjugate is an anti-TROP2 antibody-drug conjugate, an anti-stem protein-4 antibody-drug conjugate or an anti-HER2 antibody-drug conjugate.

[0014] [5] The therapeutic agent according to [4], wherein the antibody-drug conjugate is veentumumab, gosatuzumab, datopotamab deruxtecan, trastuzumab emtansine or dextuzumab.

[0015] [6] The therapeutic agent according to any one of [1] to [5], wherein the cancer expresses TA-MUC1.

[0016] [7] The therapeutic agent according to [6], wherein the cancer is selected from ovarian cancer, breast cancer, pancreatic cancer, lung cancer, colon cancer, gastric cancer, liver cancer, kidney cancer, blood cancer, endometrial cancer, thyroid cancer, leukemia, seminoma, melanoma, carcinoma, teratoma, lymphoma, sarcoma, mesothelioma, neuroblastoma, glioma, rectal cancer, adrenal cancer, skin cancer, brain cancer, cervical cancer, intestinal cancer, bowel cancer, head and neck cancer, digestive tract cancer, lymph node cancer, esophageal cancer, colorectal cancer, ear, nose and throat (ENT) cancer, prostate cancer, bladder cancer, uterine cancer, biliary tract cancer and their metastases.

[0017] [8] The therapeutic agent according to [6], wherein the cancer is breast cancer, lung cancer or bladder cancer.

[0018] [9] The therapeutic agent according to any one of [1] to [8], wherein the anti-MUC1 antibody is an anti-TA-MUC1 antibody.

[0019]

[10] The therapeutic agent according to any one of [1] to [9], wherein the anti-MUC1 antibody-drug conjugate is an anti-MUC1 antibody-drug conjugate, wherein the drug-linker represented by the following formula is conjugated to the anti-MUC1 antibody via a thioether bond: [Chem.1] Where A represents the binding site with the anti-MUC1 antibody.

[0020]

[11] The therapeutic agent according to any one of [1] to

[10] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain and a light chain, the heavy chain comprising CDRH1 consisting of the amino acid sequence shown in SEQ ID NO:1, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO:2 or SEQ ID NO:7, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO:3, and the light chain comprising CDRL1 consisting of the amino acid sequence shown in SEQ ID NO:4, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO:5, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO:6.

[0021]

[12] The therapeutic agent according to any one of [1] to

[10] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain and a light chain, the heavy chain comprising CDRH1 consisting of the amino acid sequence shown in SEQ ID NO:1, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO:2 and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO:3, and the light chain comprising CDRL1 consisting of the amino acid sequence shown in SEQ ID NO:4, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO:5 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO:6.

[0022]

[13] The therapeutic agent according to any one of [1] to

[10] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain and a light chain, the heavy chain comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO:8 or SEQ ID NO:10, and the light chain comprising a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO:9.

[0023]

[14] The therapeutic agent according to any one of [1] to

[10] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain and a light chain, the heavy chain comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO:8, and the light chain comprising a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO:9.

[0024]

[15] The therapeutic agent according to any one of [1] to

[10] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO:11 or SEQ ID NO:13 and a light chain consisting of the amino acid sequence shown in SEQ ID NO:12.

[0025]

[16] The therapeutic agent according to any one of [1] to

[10] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO:11 and a light chain consisting of the amino acid sequence shown in SEQ ID NO:12.

[0026]

[17] The therapeutic agent according to

[15] or

[16] wherein the lysine residue at the carboxyl terminus of the anti-MUC1 antibody heavy chain is deleted.

[0027]

[18] The therapeutic agent according to any one of [1] to

[17] , wherein the average number of drug-connector units conjugated to each antibody molecule in the anti-MUC1 antibody-drug conjugate is in the range of 7 to 8.

[0028]

[19] The therapeutic agent according to any one of [1] to

[17] , wherein the average number of drug-connector units conjugated to each antibody molecule in the anti-MUC1 antibody-drug conjugate is in the range of 7.5 to 8.

[0029]

[20] A method for treating cancers with low sensitivity to existing anticancer agents, comprising administering an anti-MUC1 antibody-drug conjugate.

[0030]

[21] According to the treatment method described in

[20] , the anticancer agent is an alkylating agent, a platinum-containing drug, an antifolate agent, a pyridine metabolism inhibitor, a purine metabolism inhibitor, a ribonucleotide reductase inhibitor, a nucleotide analog, a topoisomerase inhibitor, a microtubule polymerization inhibitor, a microtubule depolymerization inhibitor, an antitumor antibiotic, an antihormonal agent, an EGFR inhibitor, a BTK inhibitor, a BCR-ABL inhibitor, an ALK inhibitor, a HER2 inhibitor, an angiogenesis inhibitor, a PARP inhibitor, an mTOR inhibitor, a membrane differentiation antigen-targeting drug, or an antibody-drug conjugate.

[0031]

[22] The treatment method according to

[20] , wherein the anticancer agent is an antibody-drug conjugate.

[0032]

[23] The treatment method according to

[22] , wherein the antibody-drug conjugate is an anti-TROP2 antibody-drug conjugate, an anti-stem protein-4 antibody-drug conjugate or an anti-HER2 antibody-drug conjugate.

[0033]

[24] The treatment method according to

[22] , wherein the antibody-drug conjugate is veentumumab, gosatuzumab, dedabrotuzumab, trastuzumab emtansine or detrastuzumab.

[0034]

[25] The treatment method according to any one of

[20] to

[24] , wherein the cancer expresses TA-MUC1.

[0035]

[26] According to the treatment method described in

[25] , the cancer is selected from ovarian cancer, breast cancer, pancreatic cancer, lung cancer, colon cancer, gastric cancer, liver cancer, kidney cancer, blood cancer, endometrial cancer, thyroid cancer, leukemia, seminoma, melanoma, carcinoma, teratoma, lymphoma, sarcoma, mesothelioma, neuroblastoma, glioma, rectal cancer, adrenal cancer, skin cancer, brain cancer, cervical cancer, intestinal cancer, bowel cancer, head and neck cancer, digestive tract cancer, lymph node cancer, esophageal cancer, colorectal cancer, ear, nose and throat (ENT) cancer, prostate cancer, bladder cancer, uterine cancer, biliary tract cancer and their metastases.

[0036]

[27] The treatment method described in

[25] is breast cancer, lung cancer or bladder cancer.

[0037]

[28] The treatment method according to any one of

[20] to

[27] , wherein the anti-MUC1 antibody is an anti-TA-MUC1 antibody.

[0038]

[29] The treatment method according to any one of

[20] to

[28] , wherein the anti-MUC1 antibody-drug conjugate is an anti-MUC1 antibody-drug conjugate, wherein the drug-linker represented by the following formula is conjugated to the anti-MUC1 antibody via a thioether bond: [Chem.2] Where A represents the binding site with the anti-MUC1 antibody.

[0039]

[30] The treatment method according to any one of

[20] to

[29] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain and a light chain, the heavy chain comprising CDRH1 consisting of the amino acid sequence shown in SEQ ID NO:1, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO:2 or SEQ ID NO:7, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO:3, and the light chain comprising CDRL1 consisting of the amino acid sequence shown in SEQ ID NO:4, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO:5, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO:6.

[0040]

[31] The treatment method according to any one of

[20] to

[29] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain and a light chain, the heavy chain comprising CDRH1 consisting of the amino acid sequence shown in SEQ ID NO:1, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO:2 and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO:3, and the light chain comprising CDRL1 consisting of the amino acid sequence shown in SEQ ID NO:4, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO:5 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO:6.

[0041]

[32] The treatment method according to any one of

[20] to

[29] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain and a light chain, the heavy chain comprising a heavy chain variable region consisting of an amino acid sequence shown in SEQ ID NO:8 or SEQ ID NO:10, and the light chain comprising a light chain variable region consisting of an amino acid sequence shown in SEQ ID NO:9.

[0042]

[33] The treatment method according to any one of

[20] to

[29] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain and a light chain, the heavy chain comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO:8, and the light chain comprising a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO:9.

[0043]

[34] The treatment method according to any one of

[20] to

[29] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO:11 or SEQ ID NO:13 and a light chain consisting of the amino acid sequence shown in SEQ ID NO:12.

[0044]

[35] The treatment method according to any one of

[20] to

[29] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO:11 and a light chain consisting of the amino acid sequence shown in SEQ ID NO:12.

[0045]

[36] The treatment method described in

[34] or

[35] wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-MUC1 antibody is deleted.

[0046]

[37] The treatment method according to any one of

[20] to

[36] , wherein the average number of drug-connector units conjugated to each antibody molecule in the anti-MUC1 antibody-drug conjugate is in the range of 7 to 8.

[0047]

[38] The treatment method according to any one of

[20] to

[36] , wherein the average number of drug-connector units conjugated to each antibody molecule in the anti-MUC1 antibody-drug conjugate is in the range of 7.5 to 8.

[0048]

[39] Anti-MUC1 antibody-drug conjugates for the treatment of cancers with low sensitivity to existing anticancer agents.

[0049]

[40] According to the anti-MUC1 antibody-drug conjugate described in

[39] , the anticancer agent is an alkylating agent, a platinum-containing drug, an antifolate agent, a pyridine metabolism inhibitor, a purine metabolism inhibitor, a ribonucleotide reductase inhibitor, a nucleotide analog, a topoisomerase inhibitor, a microtubule polymerization inhibitor, a microtubule depolymerization inhibitor, an antitumor antibiotic, an antihormonal agent, an EGFR inhibitor, a BTK inhibitor, a BCR-ABL inhibitor, an ALK inhibitor, a HER2 inhibitor, an angiogenesis inhibitor, a PARP inhibitor, an mTOR inhibitor, a membrane differentiation antigen-targeting drug, or an antibody-drug conjugate.

[0050]

[41] The anti-MUC1 antibody-drug conjugate according to

[39] , wherein the anticancer agent is an antibody-drug conjugate.

[0051]

[42] The anti-MUC1 antibody-drug conjugate according to

[41] , wherein the antibody-drug conjugate is an anti-TROP2 antibody-drug conjugate, an anti-stem protein-4 antibody-drug conjugate or an anti-HER2 antibody-drug conjugate.

[0052]

[43] The anti-MUC1 antibody-drug conjugate according to

[41] , wherein the antibody-drug conjugate is veentumumab, gosatuzumab, dedabrotuzumab, trastuzumab emtansine or detrastuzumab.

[0053]

[44] The anti-MUC1 antibody-drug conjugate according to any one of

[39] to

[43] , wherein the cancer expresses TA-MUC1.

[0054]

[45] The anti-MUC1 antibody-drug conjugate according to

[44] , wherein the cancer is selected from ovarian cancer, breast cancer, pancreatic cancer, lung cancer, colon cancer, gastric cancer, liver cancer, kidney cancer, blood cancer, endometrial cancer, thyroid cancer, leukemia, seminoma, melanoma, carcinoma, teratoma, lymphoma, sarcoma, mesothelioma, neuroblastoma, glioma, rectal cancer, adrenal cancer, skin cancer, brain cancer, cervical cancer, intestinal cancer, bowel cancer, head and neck cancer, digestive tract cancer, lymph node cancer, esophageal cancer, colorectal cancer, ear, nose and throat (ENT) cancer, prostate cancer, bladder cancer, uterine cancer, biliary tract cancer and their metastases.

[0055]

[46] The anti-MUC1 antibody-drug conjugate according to

[44] , wherein the cancer is breast cancer, lung cancer or bladder cancer.

[0056]

[47] An anti-MUC1 antibody-drug conjugate according to any one of

[39] to

[46] , wherein the anti-MUC1 antibody is an anti-TA-MUC1 antibody.

[0057]

[48] ​​The anti-MUC1 antibody-drug conjugate according to any one of

[39] to

[47] , wherein the anti-MUC1 antibody-drug conjugate is an anti-MUC1 antibody-drug conjugate, wherein the drug-linker represented by the following formula is conjugated to the anti-MUC1 antibody via a thioether bond: [Chem.3] Where A represents the binding site with the anti-MUC1 antibody.

[0058]

[49] An anti-MUC1 antibody-drug conjugate according to any one of

[39] to

[48] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain and a light chain, the heavy chain comprising CDRH1 consisting of the amino acid sequence shown in SEQ ID NO:1, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO:2 or SEQ ID NO:7, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO:3, and the light chain comprising CDRL1 consisting of the amino acid sequence shown in SEQ ID NO:4, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO:5, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO:6.

[0059]

[50] An anti-MUC1 antibody-drug conjugate according to any one of

[39] to

[48] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain and a light chain, the heavy chain comprising CDRH1 consisting of the amino acid sequence shown in SEQ ID NO:1, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO:2, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO:3, and the light chain comprising CDRL1 consisting of the amino acid sequence shown in SEQ ID NO:4, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO:5, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO:6.

[0060]

[51] An anti-MUC1 antibody-drug conjugate according to any one of

[39] to

[48] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain and a light chain, the heavy chain comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO:8 or SEQ ID NO:10, and the light chain comprising a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO:9.

[0061]

[52] An anti-MUC1 antibody-drug conjugate according to any one of

[39] to

[48] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain and a light chain, the heavy chain comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO:8, and the light chain comprising a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO:9.

[0062]

[53] An anti-MUC1 antibody-drug conjugate according to any one of

[39] to

[48] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO:11 or SEQ ID NO:13 and a light chain consisting of the amino acid sequence shown in SEQ ID NO:12.

[0063]

[54] An anti-MUC1 antibody-drug conjugate according to any one of

[39] to

[48] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO:11 and a light chain consisting of the amino acid sequence shown in SEQ ID NO:12.

[0064]

[55] The anti-MUC1 antibody-drug conjugate according to

[53] or

[54] , wherein the lysine residue at the carboxyl terminus of the anti-MUC1 antibody heavy chain is deleted.

[0065]

[56] The anti-MUC1 antibody-drug conjugate according to any one of

[39] to

[55] , wherein the average number of drug-linker units conjugated to each antibody molecule in the anti-MUC1 antibody-drug conjugate is in the range of 7 to 8.

[0066]

[57] An anti-MUC1 antibody-drug conjugate according to any one of

[39] to

[55] , wherein the average number of drug-linker units conjugated to each antibody molecule in the anti-MUC1 antibody-drug conjugate is in the range of 7.5 to 8.

[0067]

[58] Use of anti-MUC1 antibody-drug conjugates in the preparation of medicaments for the treatment of cancers with low sensitivity to existing anticancer agents.

[0068]

[59] According to the uses described in

[58] , the anticancer agent is an alkylating agent, a platinum-containing drug, an antifolate agent, a pyridine metabolism inhibitor, a purine metabolism inhibitor, a ribonucleotide reductase inhibitor, a nucleotide analog, a topoisomerase inhibitor, a microtubule polymerization inhibitor, a microtubule depolymerization inhibitor, an antitumor antibiotic, an antihormonal agent, an EGFR inhibitor, a BTK inhibitor, a BCR-ABL inhibitor, an ALK inhibitor, a HER2 inhibitor, an angiogenesis inhibitor, a PARP inhibitor, an mTOR inhibitor, a membrane differentiation antigen-targeting drug, or an antibody-drug conjugate.

[0069]

[60] According to the use described in

[58] , the anticancer agent is an antibody-drug conjugate.

[0070]

[61] According to the use described in

[60] , the antibody-drug conjugate is an anti-TROP2 antibody-drug conjugate, an anti-stem protein-4 antibody-drug conjugate or an anti-HER2 antibody-drug conjugate.

[0071]

[62] According to the use described in

[60] , the antibody-drug conjugate is veentumumab, gosatuzumab, dedabrotuzumab, trastuzumab emtansine or detrastuzumab.

[0072]

[63] The use according to any one of

[58] to

[62] , wherein the cancer expresses TA-MUC1.

[0073]

[64] According to the use described in

[63] , the cancer is selected from ovarian cancer, breast cancer, pancreatic cancer, lung cancer, colon cancer, gastric cancer, liver cancer, kidney cancer, blood cancer, endometrial cancer, thyroid cancer, leukemia, seminoma, melanoma, carcinoma, teratoma, lymphoma, sarcoma, mesothelioma, neuroblastoma, glioma, rectal cancer, adrenal cancer, skin cancer, brain cancer, cervical cancer, intestinal cancer, bowel cancer, head and neck cancer, digestive tract cancer, lymph node cancer, esophageal cancer, colorectal cancer, ear, nose and throat (ENT) cancer, prostate cancer, bladder cancer, uterine cancer, biliary tract cancer and their metastases.

[0074]

[65] According to the use described in

[63] , the cancer is breast cancer, lung cancer or bladder cancer.

[0075]

[66] The use according to any one of

[58] to

[65] , wherein the anti-MUC1 antibody is an anti-TA-MUC1 antibody.

[0076]

[67] In any one of

[58] to

[66] , the anti-MUC1 antibody-drug conjugate is an anti-MUC1 antibody-drug conjugate wherein the drug-linker represented by the following formula is conjugated to the anti-MUC1 antibody via a thioether bond: [Chem.4] Where A represents the binding site with the anti-MUC1 antibody.

[0077]

[68] The use according to any one of

[58] to

[67] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain and a light chain, the heavy chain comprising CDRH1 consisting of the amino acid sequence shown in SEQ ID NO:1, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO:2 or SEQ ID NO:7, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO:3, and the light chain comprising CDRL1 consisting of the amino acid sequence shown in SEQ ID NO:4, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO:5, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO:6.

[0078]

[69] The use according to any one of

[58] to

[67] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain and a light chain, the heavy chain comprising CDRH1 consisting of the amino acid sequence shown in SEQ ID NO:1, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO:2 and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO:3, and the light chain comprising CDRL1 consisting of the amino acid sequence shown in SEQ ID NO:4, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO:5 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO:6.

[0079]

[70] The use according to any one of

[58] to

[67] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain and a light chain, the heavy chain comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO:8 or SEQ ID NO:10, and the light chain comprising a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO:9.

[0080]

[71] The use according to any one of

[58] to

[67] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain and a light chain, the heavy chain comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO:8, and the light chain comprising a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO:9.

[0081]

[72] The use according to any one of

[58] to

[67] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO:11 or SEQ ID NO:13 and a light chain consisting of the amino acid sequence shown in SEQ ID NO:12.

[0082]

[73] The use according to any one of

[58] to

[67] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO:11 and a light chain consisting of the amino acid sequence shown in SEQ ID NO:12.

[0083]

[74] According to the use described in

[72] or

[73] , the lysine residue at the carboxyl terminus of the anti-MUC1 antibody heavy chain is deleted.

[0084]

[75] For use according to any one of

[58] to

[74] , wherein the average number of drug-connector units conjugated to each antibody molecule in the anti-MUC1 antibody-drug conjugate is in the range of 7 to 8.

[0085]

[76] For use according to any one of

[58] to

[74] , wherein the average number of drug-connector units conjugated to each antibody molecule in the anti-MUC1 antibody-drug conjugate is in the range of 7.5 to 8.

[0086] Advantages of the present invention The present invention can provide therapeutic agents and methods for cancers with low sensitivity to existing anticancer agents, including the administration of anti-MUC1 antibody-drug conjugates. Attached Figure Description

[0087] [ Figure 1 ] Figure 1 Figure showing the antitumor effects of TA-MUC1-DXd ADC, control IgG-DXd ADC, stalk protein-4-MMAE ADC and TROP2-SN38 ADC on a bladder cancer PDX model (NIBIO-K071).

[0088] [ Figure 2 ] Figure 2 Figure showing the antitumor effects of TA-MUC1-DXd ADC, control IgG-DXd ADC, and TROP2-SN38 ADC on a model with transplanted breast cancer cell line HCC70.

[0089] [ Figure 3 ] Figure 3 A diagram showing the heavy chain amino acid sequence (SEQ ID NO: 11) of PM-N54Q.

[0090] [ Figure 4 ] Figure 4 A diagram showing the light chain amino acid sequences (SEQ ID NO: 12) of PM-N54Q and PankoMab-GEX(R).

[0091] [ Figure 5 ] Figure 5 A diagram showing the heavy chain amino acid sequence (SEQ ID NO: 13) of PankoMab-GEX(R).

[0092] [ Figure 6 ] Figure 6 Figure showing the antitumor effects of TA-MUC1-DXd ADC and TROP2-DXd ADC on the lung cancer PDX model (NIBIO-NS1).

[0093] [ Figure 7 ] Figure 7Figure showing the antitumor effects of TA-MUC1-DXd ADC, control IgG-DXd ADC, and HER2-DXd ADC on a model with transplanted breast cancer cell line HCC70. Detailed Implementation

[0094] Preferred embodiments for carrying out the invention are described below. The following embodiments are given merely as examples of typical embodiments of the invention and are not intended to limit the scope of the invention.

[0095] As used in this article, the term "low sensitivity" to anticancer agents is not particularly limited and means that cell growth is not eliminated by the anticancer agent, and also includes "lack of sensitivity." Clinically, a situation where cancer cells neither disappear nor shrink after anticancer agent treatment, thus failing to achieve either complete remission (CR) or partial remission (PR), can be defined as having "low sensitivity." A situation where cancer cells, even if initially sensitive to the anticancer agent, acquire resistance through continuous administration can also be defined as having "low sensitivity." On the other hand, a cancer cell line that does not cause cell growth inhibition or only causes weak cell growth inhibition under conditions of anticancer agent addition can be defined as having "low sensitivity."

[0096] Furthermore, cells exhibiting a growth inhibition rate of less than 12.5%, 25%, or 50% at a drug concentration of 100 nM can be defined as having "low sensitivity." In this invention, "cancer" specifically includes ovarian cancer, breast cancer, pancreatic cancer, lung cancer, colon cancer, gastric cancer, liver cancer, kidney cancer, hematologic malignancies, endometrial cancer, thyroid cancer, leukemia, seminoma, melanoma, carcinoma, teratoma, lymphoma, sarcoma, mesothelioma, neuroblastoma, glioma, rectal cancer, adrenal cancer, skin cancer, brain cancer, cervical cancer, intestinal cancer, bowel cancer, head and neck cancer, digestive tract cancer, lymph node cancer, esophageal cancer, colorectal cancer, ear, nose, and throat (ENT) cancer, prostate cancer, bladder cancer, uterine cancer, biliary tract cancer, and their metastases. The term cancer according to this invention includes cancer metastases.

[0097] As used herein, the term "tumor" refers to a group of cells or tissues formed by misregulated cell growth. Tumors may exhibit a partial or complete lack of structural and functional coordination with normal tissues and typically form distinctive masses of tissue, which can be benign or malignant. The terms "tumor" and "cancer" are used interchangeably.

[0098] As used in this article, the term "metastasis" refers to the spread of cancer cells from the primary tumor site to distant sites within the body. Metastasis occurs through a very complex process and typically involves cancer cells dissociating from the primary tumor, entering the bloodstream and circulation, and settling and proliferating in normal tissues at a distance from the body. When tumor cells metastasize, the new tumor is called a secondary tumor or metastatic tumor, and the cells are often similar to those in the primary tumor. This means, for example, when breast cancer metastasizes to the lungs, the secondary tumor is composed of abnormal breast cells rather than abnormal lung cells. In this case, the tumor in the lung is called metastatic breast cancer, not lung cancer.

[0099] As used herein, the term "existing anticancer agent" refers to clinically used anticancer agents other than the anti-MUC1 antibody-drug conjugate used in this invention, and preferably refers to anticancer agents used in standard treatment. There are no particular limitations on "existing anticancer agents," as long as the above requirements are met. Examples include alkylating agents, platinum-based drugs, antimetabolicagents (e.g., antifolate agents, pyridine metabolism inhibitors, purine metabolism inhibitors, ribonucleotide reductase inhibitors, and nucleotide analogs), topoisomerase inhibitors, microtubule polymerization inhibitors, microtubule depolymerization inhibitors, antitumor antibiotics, antihormonal agents, and molecularly targeted drugs (e.g., EGFR inhibitors, BTK inhibitors, BCR-ABL inhibitors, ALK inhibitors, HER2 inhibitors, angiogenesis inhibitors, PARP inhibitors, mTOR inhibitors, membrane differentiation antigen-targeting drugs, and antibody-drug conjugates).

[0100] Examples of alkylating agents include dacarbazine, nimustine, temozolomide, formazan, cyclophosphamide, and ifosfamide.

[0101] Examples of platinum-containing drugs include cisplatin, carboplatin, and oxaliplatin.

[0102] Examples of antifolic acid agents include pemetrexed, leucovorin, and methotrexate.

[0103] Examples of pyridine metabolism inhibitors include TS-1(R), 5-fluorouracil, UFT, carmoflu, deoxyfluorouridine, and capecitabine.

[0104] Examples of purine metabolism inhibitors include 6-mercaptopurine and azathiopurine.

[0105] Examples of ribonucleotide reductase inhibitors include hydroxyurea.

[0106] Examples of nucleotide analogues include gemcitabine.

[0107] Examples of topoisomerase inhibitors include irinotecan and etoposide.

[0108] Examples of microtubule polymerization inhibitors include vinblastine, vincristine, vinblastine, and eribulin.

[0109] Examples of microtubule depolymerization inhibitors include docetaxel and paclitaxel.

[0110] Examples of antitumor antibiotics include doxorubicin, bleomycin, mitomycin C, and epirubicin.

[0111] Examples of anti-hormonal agents include tamoxifen, fulvestrant, sinemet, leuprorelin, anastrozole, letrozole, and exemestane.

[0112] Examples of EGFR inhibitors include osimertinib, afatinib, gefitinib, erlotinib, cetuximab, and panitumumab.

[0113] Examples of BTK inhibitors include ibrutinib, acalabrutinib, and tirabrutinib.

[0114] Examples of BCR-ABL inhibitors include imatinib, dasatinib, and nilotinib.

[0115] Examples of ALK inhibitors include crizotinib.

[0116] Examples of HER2 inhibitors include trastuzumab, pertuzumab, and lapatinib.

[0117] Examples of angiogenesis inhibitors include regorafenib, axitinib, sorafenib, sunitinib, pazopanib, ramucirumab, and bevacizumab.

[0118] Examples of PARP inhibitors include olaparib, rucaparib, niraparib, talazoparib, and veliparib.

[0119] Examples of mTOR inhibitors include temsirolimus and everolimus.

[0120] Examples of drugs targeting membrane differentiation antigens include ibritumomab tiuxetan, ofatumumab, rituximab, brentuximab vedotin, gemtuzumab ozogamicin, and mogamulizumab.

[0121] Examples of antibody-drug conjugates include anti-HER2 antibody-drug conjugates such as trastuzumab emtansine and detrastuzumab, anti-stem protein-4 antibody-drug conjugates such as veentumumab, and anti-TROP2 antibody-drug conjugates such as gosatuzumab and dedabrotuzumab.

[0122] Examples of cell lines corresponding to cancers with low sensitivity to existing anticancer agents may include NIBIO-K071, HCC70, and NIBIO-NS1. For example, cell lines corresponding to cancers with low sensitivity to existing anticancer agents can be selected by using any cancer cell line and confirming the presence or absence of positive findings using the methods described in Examples 2 and 3.

[0123] The antitumor effect of a drug for cancers with low sensitivity to existing anticancer agents can be confirmed, for example, by in vitro cell growth inhibition activity against the cell line or by in vivo tumor growth inhibition rate in a model in which the cell line has been transplanted into nude mice.

[0124] As used herein, the term "patient" means human, non-human primate or other animal, particularly mammals such as cattle, horses, pigs, sheep, goats, dogs, cats, or rodents such as mice and rats. In a particularly preferred embodiment, the patient is a human.

[0125] As used herein, the term "MUC1" refers to the protein MUC1, also known as mucin-1, polymorphic epithelial mucin (PEM), or cancer antigen 15-3, particularly human MUC1 (retrieval No. P15941). MUC1, a member of the mucin family, encodes a membrane-bound glycosylated phosphoprotein. MUC1 has a core protein mass of 120 to 225 kDa, and this mass increases to 250 to 500 kDa with glycosylation. MUC1 protrudes 200 to 500 nm above the cell surface. The protein is anchored to the apical surface of many epithelial cells via a transmembrane domain. The extracellular domain contains a 20-amino acid variable-number tandem repeat (VNTR) domain, with the number of repeats ranging from 25 to 120 in different individuals. This repeat is rich in serine, threonine, and proline residues, which allow for high levels of O-glycosylation. In some embodiments, the term "MUC1" refers to tumor-associated MUC1 ("TA-MUC1"). TA-MUC1 is a type of MUC1 found on cancer cells. This MUC1 differs from those found on non-cancer cells because TA-MUC1 exhibits much higher expression levels, is localized, and possesses a unique glycosylation pattern. Specifically, TA-MUC1 is present on the entire surface of cancer cells without polarity, whereas MUC1 on non-cancer cells strictly exhibits apical expression and therefore does not allow systemically administered antibodies to approach it. Furthermore, TA-MUC1 possesses anomalous O-glycosylation, exposing novel peptide epitopes in the MUC1 protein backbone, as well as novel hydrocarbon tumor antigens such as N-acetylgalactosamine (Tn), sialic acid α2-6N-acetylgalactosamine (sTn), galactose β1-3N-acetylgalactosamine (TF), or galactose β1-3(sialic acid α2-6)N-acetylgalactosamine (sTF).

[0126] As used herein, the term "antibody" refers to a protein containing at least two heavy chains and two light chains linked by disulfide bonds. Antibodies can be, for example, humanized antibodies, human antibodies, or chimeric antibodies. Antibodies include multivalent antibodies and multispecific antibodies, i.e., antibody constructs having more than two binding sites, each binding to the same epitope, and antibody constructs having one or more binding sites binding to a first epitope, one or more binding sites binding to a second epitope, and even optionally further binding sites binding to further epitopes.

[0127] As used herein, the term "anti-MUC1 antibody" refers to an antibody that specifically binds to MUC1 and has the activity of being internalized in MUC1-expressing cells by binding to MUC1; in other words, the activity of migrating to MUC1-expressing cells after binding to MUC1.

[0128] As used herein, the term "specific binding" preferably means that the antibody binds more strongly to a specific target (e.g., an epitope) than to other targets. Examples of criteria used to determine whether binding is specific may include a dissociation constant (referred to as "K" in this specification). d When the antibody reacts with the first target at a lower dissociation constant (K) than with the second target... d When bound, the antibody binds more strongly to the first target than to the second target. Preferably, the dissociation constant for the antibody-specific binding to the target is 1 / 100, 1 / 200, 1 / 500, or 1 / 1000 of the dissociation constant for the antibody-non-specific binding target. The term "specific binding" further specifically refers to the binding affinity between binding partners, and its affinity constant K. a For at least 10 6 M -1 Preferably at least 10 7 M -1 And more preferably at least 10 8 M -1 Antibodies specific to a particular antigen refer to those capable of specifically targeting an antigen with at least 10... 6 M -1 Preferably at least 10 7 M -1 And more preferably at least 10 8 M -1 K a Antibodies with an affinity for the antigen bind to it. As used herein, the term "anti-MUC1 antibody" refers to an antibody capable of specifically binding to MUC1 and preferably having an affinity of at least 10. 6 M -1 Preferably at least 10 7 M -1 And more preferably at least 10 8 M -1 K a Antibodies that bind to MUC1 with affinity.

[0129] The anti-MUC1 antibody used in this invention specifically binds to epitopes on MUC1. Epitopes are located in the extracellular tandem repeat sequence of MUC1. The anti-MUC1 antibody used in this invention binds to MUC1 in a glycosylation-dependent manner. Specifically, the anti-MUC1 antibody binds more strongly to MUC1 when the threonine residue in the tandem repeat sequence is glycosylated with N-acetylgalactosamine (Tn), sialic acid α2-6 N-acetylgalactosamine (sTn), galactose β1-3 N-acetylgalactosamine (TF), or galactose β1-3 (sialic acid α2-6) N-acetylgalactosamine (sTF), preferably with Tn or TF. Preferably, the hydrocarbon moiety is bound to the threonine residue via an α-O-glycosidic bond. The epitope in the tandem repeat sequence domain of MUC1 specifically comprises the amino acid sequence PDTR (SEQ ID NO:16) or PESR (SEQ ID NO:17). The binding to the epitope preferably depends on the glycosylation described above, and in particular, the binding increases when the hydrocarbon moiety is attached to a threonine residue of the sequence PDTR or PESR.

[0130] The epitopes of the anti-MUC1 antibodies used in this invention are preferably tumor-associated MUC1 epitopes (TA-MUC1). TA-MUC1 epitopes refer to MUC1 epitopes that are present on tumor cells but not on normal cells, and / or allow circulating antibodies in the host to access them only when present on tumor cells, but not when present on normal cells. More preferably, the epitopes of the anti-MUC1 antibodies used in this invention are at least one PDTR sequence comprising a MUC1 tandem repeat sequence, and are glycosylated at a threonine residue of the PDTR sequence using N-acetylgalactosamine (Tn) or galactoseβ1-3N-acetylgalactosamine (TF) preferably via an α-O-glycosidic bond.

[0131] The anti-MUC1 antibody used in this invention can be obtained through procedures known in the art. For example, the antibody of this invention can be obtained using methods commonly practiced in the art, which include immunizing animals with antigenic MUC1 or any polypeptide selected from the amino acid sequence of MUC1 or a human-derived cancer cell line, and collecting and purifying the antibody produced in vivo. The source of the antigen is not limited to humans, and antigens derived from non-human animals such as mice, rats, etc., can also be used to immunize animals.

[0132] On the other hand, according to methods known in the art, antibody-producing cells that generate antibodies against antigens are fused with myeloma cells (e.g., Kohler and Milstein, Nature (1975) 256, pp. 495-497; and Kennet, R. ed., Monoclonal Antibodies, pp. 365-367, Plenum Press, NY (1980)) to establish a hybridoma from which monoclonal antibodies can then be obtained.

[0133] Antigens can be obtained by genetically engineering host cells to produce genes encoding antigenic proteins. Specifically, a vector that allows antigen gene expression is prepared and transferred into host cells, thereby enabling gene expression. The expressed antigen can then be purified. Antibodies can also be obtained by immunizing animals with the aforementioned genetically engineered antigen-expressing cells or cell lines expressing the antigen.

[0134] The anti-MUC1 antibodies used in this invention are preferably recombinant antibodies obtained through artificial modification to reduce heteroantigenicity to humans, such as chimeric antibodies or humanized antibodies, or more preferably antibodies having only the gene sequence of antibodies derived from humans, i.e., human antibodies. These antibodies can be produced using known methods.

[0135] Examples of chimeric antibodies may include antibodies in which the variable region and constant region are derived from different species, such as chimeric antibodies in which the variable region of a mouse or rat-derived antibody is linked to the constant region of a human-derived antibody (Proc. Natl. Acad. Sci. USA, 81, 6851-6855, (1984)).

[0136] Examples of humanized antibodies may include antibodies obtained by integrating only the complementarity-determining region (CDR) of a heterologous antibody into a human-derived antibody (Nature (1986) 321, pp. 522-525); antibodies obtained by grafting some amino acid residues of a heterologous antibody framework and the CDR sequence of the heterologous antibody into a human antibody via a CDR-grafting method (WO90 / 07861); and antibodies humanized using a gene conversion mutagenesis strategy (US Patent No. 5821337).

[0137] Examples of human antibodies may include antibodies produced by human antibody-producing mice using human chromosome segments containing human antibody heavy and light chain genes (see Tomizuka, K. et al., Nature Genetics (1997) 16, pp. 133-143; Kuroiwa, Y. et al., Nucl. Acids Res. (1998) 26, pp. 3447-3448; Yoshida, H. et al., Animal Cell Technology: Basic and Applied Aspects, Vol. 10, pp. 69-73 (edited by Kitagawa, Y., Matsuda, T. and Iijima, S.), Kluwer Academic Publishers, 1999; Tomizuka, K. et al., Proc. Natl. Acad. Sci. USA (2000) 97, pp. 722-727, etc.). On the other hand, examples of human antibodies may include antibodies obtained by phage display, which are selected from human antibody libraries (see Wormstone, IM et al., Investigative Ophthalmology & Visual Science. (2002) 43(7), pp. 2301-2308; Carmen, S. et al., Briefings in Functional Genomics and Proteomics (2002), 1(2), pp. 189-203; Siriwardena, D. et al., Ophthalmology (2002) 109(3), pp. 427-431, etc.).

[0138] The anti-MUC1 antibodies used in this invention also include antibodies derived from chimeric antibodies, humanized antibodies, or human antibodies by replacing 1 to 3 amino acid residues in CDRs with other amino acid residues, provided that the antibody has the ability to specifically bind to the anti-MUC1 epitope. These antibodies can be produced using known methods.

[0139] This invention also includes modified variants of the anti-MUC1 antibody used in this invention. Modified variants refer to variants obtained by subjecting the antibody according to this invention to chemical or biological modifications. Examples of chemically modified variants include variants comprising the linking of a chemical moiety to an amino acid backbone, variants comprising the linking of a chemical moiety to an N-linked or O-linked carbohydrate chain, etc. Examples of biologically modified variants include variants obtained through post-translational modifications (e.g., N- or O-linked glycosylation, N-terminal 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 through expression in prokaryotic host cells. Furthermore, within the meaning of modified variants, antibodies labeled to enable detection or separation of the anti-MUC1 antibody or antigen used in this invention are also included, for example, enzyme-labeled antibodies, fluorescently labeled antibodies, and affinity-labeled antibodies. These modified variants of the anti-MUC1 antibody used in this invention are used to improve antibody stability and blood retention, reduce its antigenicity, detect or separate the antibody or antigen, etc.

[0140] It is known that the lysine residue at the C-terminus of the heavy chain of antibodies produced in cultured mammalian cells is deleted (Journal of Chromatography A, 705:129-134 (1995)), and it is also known that two amino acid residues (glycine and lysine) at the C-terminus of the heavy chain of antibodies produced in cultured mammalian cells are deleted, and a new proline residue at the C-terminus is amidated (Analytical Biochemistry, 360:75-83 (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 cytotoxicity, etc.) of the antibody. Therefore, the anti-MUC1 antibody used in this invention also includes antibodies subjected to such modifications and functional fragments of said antibodies, and also includes deletion variants in which one or two amino acids are missing from the C-terminus of the heavy chain, variants obtained by amidation of the deletion variants (e.g., heavy chains in which the proline residue at the C-terminus has been amidated), etc. The two heavy chains constituting the anti-MUC1 antibody used in this invention can be one type selected from the full-length heavy chain and the above-described deletion variants, or a combination of both. The proportion of each deletion variant may be affected by the type of mammalian cells cultured to produce the anti-MUC1 antibody used in this invention and the culture conditions; however, examples of anti-MUC1 antibodies used in this invention may preferably include antibodies in which one amino acid residue at the carboxyl terminus is deleted in both heavy chains.

[0141] Examples of isotypes of the anti-MUC1 antibody used in this invention may include, for example, humanized or human IgG (IgG1, IgG2, IgG3, IgG4), with IgG1 or IgG4 being preferred, and IgG1 being more preferred. Alternatively, variants thereof may be used as anti-MUC1 antibodies according to this invention.

[0142] Examples of anti-MUC1 antibodies used in this invention may include PankoMab-GEX(R) (International Publication No. WO2011 / 012309), PM-N54Q (International Publication No. WO 2019 / 219889), and variants, active fragments, and modified variants thereof, and may preferably include PM-N54Q. These anti-MUC1 antibodies can be produced by the methods described in the literature. The amino acid sequences of the heavy and light chains of PankoMab-GEX(R) are shown in SEQ ID NO: 13 (…). Figure 5 ) and SEQ ID NO: 12 ( Figure 4 The amino acid sequences of the heavy and light chains of PM-N54Q are shown in SEQ ID NO:11. Figure 3 ) and SEQ ID NO:12 ( Figure 4 )middle.

[0143] As used herein, the term "antibody-drug conjugate" refers to a conjugate of a cytotoxic drug conjugated to an antibody via a linker. Examples of antibody-drug conjugates may include those described in U.S. Patent Nos. 7,097,840, 7,999,083, WO 2010 / 093395, WO 2014 / 057687, WO 2015 / 115091, WO 2017 / 083582, and WO 2019 / 219891, with preference given to those described in WO 2019 / 219891. These antibody-drug conjugates can be produced by methods described in the literature.

[0144] There are no particular limitations on cytotoxic drugs, as long as the drug has antitumor effects and has substituents or partial structures that can be linked to the linker. Examples include camptothecin, galactam, doxorubicin, daunorubicin, mitomycin C, bleomycin, cyclocytidine, vinblastine, methotrexate, cisplatin, oliguria oleracea, metronidazole, paclitaxel, and pyrrolobenzodiazepines. And its derivatives, and may preferably include camptothecin derivatives, more preferably desazatecan derivatives.

[0145] As used herein, the term “drug-connector” refers to the drug and connector portions of an antibody-drug conjugate; in other words, the partial structure of an antibody-drug conjugate excluding the antibody.

[0146] As used herein, the term "anti-MUC1 antibody-drug conjugate" refers to an antibody-drug conjugate having an anti-MUC1 antibody as the antibody-drug conjugate. Examples of anti-MUC1 antibody-drug conjugates may include those described in International Publication No. WO 2019 / 219891, International Publication No. WO 2017 / 083582, and International Publication No. WO 2021 / 247798. These anti-MUC1 antibody-drug conjugates can be produced by the methods described in the literature.

[0147] The anti-MUC1 antibody-drug conjugate more preferably used in this invention is an anti-MUC1 antibody-drug conjugate, wherein the drug-linker represented by the following formula is conjugated to the anti-MUC1 antibody via a thioether bond: [Chem.5] Where A represents the linking site with the anti-MUC1 antibody. The drug-linker is linked to the thiol group (in other words, the sulfur atom of the cysteine ​​residue) formed at the interchain disulfide bond sites (two sites between the heavy chains and two sites between the heavy and light chains) of the antibody.

[0148] The anti-MUC1 antibody-drug conjugate more preferably used in this invention can be represented by the following formula: [Chem.6] In the formula, AB represents the anti-MUC1 antibody, and the drug-linker is conjugated to the antibody via a thioether bond. The meaning of y is the same as that of the so-called drug-to-antibody ratio (DAR), and represents the average number of drug-linker units conjugated to each antibody molecule.

[0149] The anti-MUC1 antibody portion of the anti-MUC1 antibody-drug conjugate used in this invention is an antibody comprising a heavy chain and a light chain. The heavy chain comprises a complementarity-determining region (CDR) CDRH1 having the amino acid sequence of SEQ ID NO:1, CDRH2 having the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:7, and CDRH3 having the amino acid sequence of SEQ ID NO:3. The light chain comprises a complementarity-determining region (CDR) CDRL1 having the amino acid sequence of SEQ ID NO:4, CDRL2 having the amino acid sequence of SEQ ID NO:5, and CDRL3 having the amino acid sequence of SEQ ID NO:6. Preferably, the antibody comprising a heavy chain and a light chain comprises CDRH1 consisting of the amino acid sequence shown in SEQ ID NO:1, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO:2, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO:3. The light chain comprises CDRL1 consisting of the amino acid sequence shown in SEQ ID NO:4, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO:5, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO:6. CDRL3, composed of the amino acid sequence shown in SEQ ID NO:6, more preferably comprises an antibody with a heavy chain and a light chain, wherein the heavy chain includes a heavy chain variable region composed of the amino acid sequence shown in SEQ ID NO:8 or SEQ ID NO:10, and the light chain includes a light chain variable region composed of the amino acid sequence shown in SEQ ID NO:9. More preferably, an antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO:8, and the light chain comprises a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO:9; more preferably, an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO:11 or SEQ ID NO:13 and a light chain consisting of the amino acid sequence shown in SEQ ID NO:12, or an antibody wherein the lysine residue at the carboxyl terminus of the antibody heavy chain is deleted; and more preferably, an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO:11 and a light chain consisting of the amino acid sequence shown in SEQ ID NO:12, or an antibody wherein the lysine residue at the carboxyl terminus of the antibody heavy chain is deleted.

[0150] The drug-linker intermediate for producing the above-mentioned anti-MUC1 antibody-drug conjugate is represented by the following formula: [Chem.7] The aforementioned drug-connector intermediate can be represented by the chemical name N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrolo-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]pyran[3',4':6,7] indene[1,2-b]quinolin-1-yl]amino}-2-oxoethoxy)methyl]glycamide, and can be produced with reference to the descriptions in International Publication No. WO2014 / 057687 and International Publication No. WO 2015 / 155998, etc.

[0151] The anti-MUC1 antibody-drug conjugates preferred in this invention can be produced by reacting the above-mentioned drug-connector intermediate with an anti-MUC1 antibody having a thiol group (alternatively referred to as a mercapto group).

[0152] Thiol-containing anti-MUC1 antibodies can be obtained by methods well known in the art (Hermanson, GT, Bioconjugate Techniques, pp. 56-136, 456-493, Academic Press (1996)). For example, anti-MUC1 antibodies with partially or completely reduced intrachain disulfide bonds can be obtained by reacting each interchain disulfide bond in the antibody with a reducing agent such as tris(2-carboxyethyl)phosphine hydrochloride (TCEP) in a buffer solution containing a chelating agent such as ethylenediaminetetraacetic acid (EDTA).

[0153] Furthermore, by using 2 to 20 molar equivalents of a drug-linker intermediate for each anti-MUC1 antibody with a thiol group, anti-MUC1 antibody-drug conjugates in which each antibody molecule is conjugated to 2 to 8 drug molecules can be generated.

[0154] The average number of drug molecules conjugated to each antibody molecule of the generated anti-MUC1 antibody-drug conjugate can be determined, for example, by a calculation method based on the measurement of ultraviolet absorbance of the anti-MUC1 antibody-drug conjugate and its conjugated precursor at two wavelengths of 280 nm and 370 nm (UV method), or by a calculation method based on quantification by HPLC measurement of fragments obtained by treating the antibody-drug conjugate with a reducing agent (HPLC method).

[0155] The conjugation between anti-MUC1 antibodies and drug-linker intermediates, as well as the calculation of the average number of drug molecules conjugated to each antibody molecule in the anti-MUC1 antibody-drug conjugate, can be performed with reference to the description in international publication No. WO 2015 / 155998, etc.

[0156] In the anti-MUC1 antibody-drug conjugates used in this invention, the average number of drug-linker units conjugated to each antibody molecule 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. In other embodiments, the average number of drug or drug-linker units conjugated to each antibody molecule in the anti-MUC1 antibody-drug conjugates used in this invention is preferably an integer in the range of 2 to 8, more preferably 2, 4, 6 or 8, and even more preferably 8.

[0157] The therapeutic agents and methods of the present invention include the administration of anti-MUC1 antibody-drug conjugates and can be used to treat cancers with low sensitivity to existing anticancer agents.

[0158] The "existing anticancer agents" in "cancers with low sensitivity to existing anticancer agents" are preferably anti-TROP2 antibody-drug conjugates, anti-stem protein-4 antibody-drug conjugates, or anti-HER2 antibody-drug conjugates, more preferably veentumumab, gosatutuzumab, dedabrotuzumab, trastuzumab emtansine, or detrastuzumab, and even more preferably dedabrotuzumab or gosatutuzumab.

[0159] "Cancers with low sensitivity to existing anticancer agents" preferably express MUC1, more preferably TA-MUC1, and even more preferably highly express TA-MUC1. MUC1 expression can be confirmed at the gene product (protein) level of MUC1, for example using immunohistochemistry (IHC), flow cytometry, Western blotting, etc., or at the transcriptional level by in situ hybridization (ISH) or quantitative PCR (q-PCR). High expression of MUC1 can be determined using methods well-known to those skilled in the art.

[0160] Examples of cancers expressing MUC1 may include ovarian cancer, breast cancer, pancreatic cancer, lung cancer, colon cancer, stomach cancer, liver cancer, kidney cancer, hematologic malignancies, endometrial cancer, thyroid cancer, leukemia, seminoma, melanoma, carcinoma, teratoma, lymphoma, sarcoma, mesothelioma, neuroblastoma, glioma, rectal cancer, adrenal cancer, skin cancer, brain cancer, cervical cancer, intestinal cancer, bowel cancer, head and neck cancer, digestive tract cancer, lymph node cancer, esophageal cancer, colorectal cancer, ear, nose and throat (ENT) cancer, prostate cancer, bladder cancer, uterine cancer, biliary tract cancer and their metastases. Preferred cancers are breast cancer, lung cancer, or bladder cancer.

[0161] The therapeutic agents and methods of the present invention are preferably intended for use in patients with a history of treatment with existing anticancer agents. The therapeutic agents and methods of the present invention exhibit excellent antitumor activity against cancers with low sensitivity to existing anticancer agents. Therefore, the therapeutic agents and methods of the present invention exert significant antitumor effects when applied to a group of cancer patients with low sensitivity to existing anticancer agents (patients with a history of treatment with existing anticancer agents). The term "existing anticancer agent" is defined as described above and is preferably an anti-TROP2 antibody-drug conjugate, an anti-stem protein-4 antibody-drug conjugate, or an anti-HER2 antibody-drug conjugate, more preferably veentumumab, goxatuzumab, daboteruumab, trastuzumab emtansine, or daboteruumab, and even more preferably daboteruumab or goxatuzumab.

[0162] The therapeutic agents and methods of the present invention may include one or more additional drugs (e.g., a second drug) besides the anti-MUC1 antibody-drug conjugate used in the present invention. Specifically, the anti-MUC1 antibody-drug conjugate used in the therapeutic agents and methods of the present invention may be administered in combination with other drugs. The anticancer effect may therefore be enhanced. Other drugs for this purpose may be administered simultaneously, separately, or continuously with the anti-MUC1 antibody-drug conjugate used in the present invention, or these agents may be administered in an alternating manner. The other drugs or second drugs are preferably anticancer agents. Such anticancer agents are not limited, as long as the drugs have antitumor activity. Anticancer agents include, for example, paclitaxel, docetaxel, SBT-1214, cyclophosphamide, imatinib, pazopanib, capecitabine, cytarabine, vincristine, gemcitabine, daunorubicin, doxorubicin, epirubicin, idarubicin, pentorubicin, mitoxantrone, aminoglutethimide, testosterone, anastrozole, letrozole, exemestane, vorazole, formestain, fastrozole, 4-hydroxyandrostenedione, androst-1,4,6-trien-3,17-dione (ATD), 4-androsten-3,6,17-trione (6-oxo), irinotecan, topotecan, camptothecin, lamellarin D, etoposide, teniposide, mitoxantrone, acridine, elliptic roserine, and aurintricarboxylic acid. Acid), HU-331, cisplatin, carboplatin, oxaliplatin, olaparib, rucaparib, niraparib, imiquimod, resiquimod, methotrexate, pemetrexed, raltitrexed, pralatrexate, fluorouracil, gemcitabine, fluorouridine, 5-fluorouracil, tegafuridine, cetuximab, tomuzotuximab, panitumumab, zalutumumab, nimotuzumab, matuzu The preferred active ingredients are paclitaxel, docetaxel, cisplatin, carboplatin, gemcitabine, or cetuximab.

[0163] The therapeutic agents and methods of the present invention can be selected and used as agents in drug therapy, a primary method for treating cancer, and can result in delaying the development of cancer cells, inhibiting their growth, and further killing cancer cells. These effects can allow cancer patients to get rid of cancer-induced symptoms or achieve improvements in their quality of life (QOL), and achieve therapeutic effects by sustaining the life of cancer patients. Even if the therapeutic agents and methods of the present invention do not kill cancer cells, they can still achieve a higher quality of life for cancer patients while achieving longer survival by inhibiting or controlling the growth of cancer cells.

[0164] In this drug therapy, the therapeutic agents and methods of the present invention can be used as standalone agents, and also as agents to be combined with additional therapies in adjuvant therapy, and can be used in combination with surgery, radiotherapy, hormone therapy, etc. Furthermore, the therapeutic agents and methods of the present invention can also be used as agents in drug therapy within adjuvant cancer therapy.

[0165] In addition to the therapeutic uses described above, preventative effects of the therapeutic agents and methods of the present invention can also be anticipated, for example, such as inhibiting the growth of small metastatic cancer cells and further killing them. For example, the effect of inhibiting and killing cancer cells in body fluids during metastasis, or the effect of inhibiting and killing small cancer cells immediately after implantation into any tissue, can be anticipated. Therefore, in particular, the inhibitory or preventative effect of cancer metastasis can be anticipated after surgical removal of cancer.

[0166] The therapeutic agents and methods of the present invention can be applied to patients as systemic therapy, as well as applied locally to cancerous tissue to exert therapeutic effects.

[0167] The therapeutic agents and methods of the present invention are preferably used in mammals, and more preferably in humans.

[0168] The therapeutic agents of the present invention can be administered as pharmaceutical compositions containing at least one pharmaceutically suitable ingredient. The substances that can be used in the pharmaceutical compositions of the present invention can be appropriately selected and applied from pharmaceutical additives and the like commonly used in the art, depending on the dosage, concentration, etc. The pharmaceutical compositions generally contain, for example, at least one pharmaceutical carrier (e.g., a sterile liquid). In this context, the liquid includes, for example, water and oil (oil of petroleum, animal, plant, or synthetic origin). The oil can be, for example, peanut oil, soybean oil, mineral oil, or sesame oil. Water is a more general carrier when the pharmaceutical composition is administered intravenously. Aqueous solutions of saline, glucose, and glycerol can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers can be appropriately selected from those known in the art. The pharmaceutical composition may also contain trace amounts of a moisturizing agent, emulsifier, or pH buffer, if desired. Examples of suitable pharmaceutical carriers are disclosed in EWMartin's "Remington's Pharmaceutical Sciences". The formulation corresponds to the method of administration.

[0169] Various delivery systems are known and can be used to administer the pharmaceutical compositions of the present invention. Examples of routes of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, and subcutaneous routes. Administration can be performed, for example, by injection or bolus injection. In a particularly preferred embodiment, the antibody-drug conjugate is administered by injection. Parenteral administration is a preferred route of administration.

[0170] In representative embodiments, the pharmaceutical composition is prescribed as a composition suitable for intravenous administration to humans, following standard procedures. Compositions for intravenous administration are generally solutions in sterile and isotonic buffered aqueous solutions. If necessary, the drug may also contain a solvent and a local anesthetic to reduce pain at the injection site (e.g., lidocaine). Typically, the above components are provided individually or together as a mixture in unit dosage forms, as freeze-dried powders or anhydrous concentrates contained in containers obtained by sealing, for example, ampoules or sachets indicating the amount of active agent. When the pharmaceutical composition is to be administered by injection, it can be administered using, for example, vials containing sterile pharmaceutical-grade water or saline. When the drug is to be administered by injection, ampoules of sterile water or saline for injection can be provided, allowing the above components to be mixed together before administration.

[0171] The dosage of the anti-MUC1 antibody-drug conjugate used in this invention is preferably in the range of 0.1 mg / kg to 50 mg / kg, more preferably in the range of 1 mg / kg to 25 mg / kg, and even more preferably in the range of 3 mg / kg to 10 mg / kg.

[0172] The preferred dosing intervals for the anti-MUC1 antibody-drug conjugate used in this invention are once a week (q1w), once every two weeks (q2w), once every three weeks (q3w), or once every four weeks (q4w), and more preferably once every three weeks (q3w).

[0173] The anti-MUC1 antibody-drug conjugate used in this invention is preferably administered once every week to every four weeks at a dose of 0.1 mg / kg to 50 mg / kg, more preferably once every two to three weeks at a dose of 1 mg / kg to 25 mg / kg, and even more preferably once every three weeks at a dose of 3 mg / kg to 10 mg / kg.

[0174] Example The invention will be described in detail below with reference to specific embodiments. However, the invention is not limited to these embodiments. These embodiments are not to be interpreted in any limiting sense.

[0175] Example 1: Preparation of anti-MUC1 antibody-drug conjugate An anti-TA-MUC1 antibody-drug conjugate was prepared according to the method described in Example 1 of International Publication No. WO 2019 / 219891, wherein the drug-linker represented by the following formula is conjugated to the anti-TA-MUC1 antibody via a thioether bond: [Chem.8] Where A represents the binding site with the antibody, using an amino acid sequence shown in SEQ ID NO:11 ( Figure 3 The heavy chain consists of a heavy chain and the amino acid sequence shown in SEQ ID NO:12. Figure 4 The anti-TA-MUC1 antibody (PM-N54Q) is composed of a light chain (in this invention, the conjugate is referred to as TA-MUC1-DXd ADC). The average number of drug molecules conjugated to each antibody in TA-MUC1-DXd ADC is in the range of 7 to 8.

[0176] Reference Example 1: Preparation of Goxatozumab Goxatozumab (TROP2-SN38ADC) was prepared using an hRS7 antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO:14 and a light chain consisting of the amino acid sequence shown in SEQ ID NO:15, with reference to the method described in Example 12 of U.S. Patent No. 7999083.

[0177] Reference Example 2: Preparation of dedabrotuzumab Dedabrotuzumab (TROP2-DXd ADC) was prepared according to the methods described in WO 2015 / 098099 and WO 2017 / 002776, wherein the drug-linker represented by the following formula is conjugated to the anti-TROP2 antibody via a thioether bond: [Chem.9] Wherein A represents the linking position with the antibody, and an anti-TROP2 antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO:26 and a light chain consisting of the amino acid sequence shown in SEQ ID NO:27 is used.

[0178] Reference Example 3: Preparation of trastuzumab Detrastuzumab (HER2-DXd ADC) was prepared according to the method described in WO 2015 / 115091, wherein the drug-linker represented by the following formula is conjugated to the anti-HER2 antibody via a thioether bond: [Chem.10] Wherein A represents the linking position with the antibody, using an anti-HER2 antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO:36 and a light chain consisting of the amino acid sequence shown in SEQ ID NO:37.

[0179] Example 2: Evaluation of the antitumor activity of TA-MUC1-DXdADC in a xenograft model derived from bladder cancer patients. NIBIO-K071 was obtained from the National Institute of Biomedical Innovation as a patient-derived xenograft (PDX) model for bladder cancer. Frozen tumor sections from NIBIO-K071 were thawed and subcutaneously transplanted into 4- to 6-week-old female NSG mice (NOD.Cg-Prkdc). <scid>Il2rg <tm1wjl> / SzJ: purchased from Charles River Laboratories Japan, Inc.). Growing tumors were collected, cut into small pieces, and re-transplanted into female NSG mice or female nude mice (CAnN.Cg-Foxn1nu / CrlCrlj: purchased from Charles River Laboratories Japan, Inc.) using a skeletal needle, followed by enlarged growth. Immunohistochemical staining (IHC) confirmed the presence of TA-MUC1-, stalk protein-4-, and TROP2- in the tumors of the described models. The estimated tumor volume (ETV) was calculated as described below.

[0180] Estimated tumor volume (volume, mm) 3 = Major axis (mm) × Minor axis (mm) 2 / 2 Female nude mice with transplanted NIBIO-K071 were grouped 25 days post-transplantation, at which time their average tumor volume had increased to approximately 200 mm. 3 Then, the TA-MUC1-DXd ADC prepared in Example 1, the control IgG-DXd ADC, the TROP2-SN38 ADC (prepared according to Example 1), or veentumumab (stem protein-4-MMAE ADC, prepared at 10 mg / mL from a lyophilized product purchased from Gilead Sciences, Inc. using Otsuka distilled water (manufactured by Otsuka Pharmaceutical Factory, Inc.)) was diluted with ABS buffer (10 mM acetate buffer, pH 5.5, 5% sorbitol) and administered intravenously to the tail at a volume of 10 mL / kg body weight per mouse (day 0). The TA-MUC1-DXd ADC with a DAR of 7.8 was used. The dosing schedule was set as follows: QW×3 doses (days 0, 7, and 14) of stalk protein-4-MMAEADC (3 mg / kg); Q3W×2 doses (days 0 and 21) of TA-MUC1-DXd ADC and control IgG-DXd ADC (3 or 10 mg / kg); and QW×2 doses (days 0 and 7) of TROP2-SN38 ADC (10 mg / kg). ABS buffer was administered to the mediator administration groups. Six mice were used in each group in all categories. Body weight and tumor size were measured twice weekly after initial administration, and estimated tumor volume was calculated. The antigen-dependent efficacy of TA-MUC1-DXd ADC was analyzed using a t-test. The efficacy of the drugs in each group was compared using the Dunnett multiple comparisons parameter.

[0181] Figure 1 The changes in tumor volume estimated in the above antitumor assays are shown. On day 21, TA-MUC1-DXd ADC at 3 mg / kg and 10 mg / kg showed statistically significant antitumor activity compared with the same dose of control IgG-DXd ADC as a negative control (Table 1) (P < 0.0001 in all cases, t-test). TA-MUC1-DXd ADC in the 3 mg / kg and 10 mg / kg administration groups also showed statistically significant antitumor activity based on stalk protein-4-MMAE ADC and TROP2-SN38 ADC (Table 1) (P < 0.0001 in all cases, parameter Dunnett multiple comparisons).

[0182] [Table 1] These results reveal that, in the NIBIO-K071 model, TA-MUC1-DXdADC exhibits significantly stronger antitumor activity in an antigen-specific manner, compared to stem protein-4-MMAEADC and TROP2-SN38 ADC.

[0183] In the stalk protein-4-MMAE ADC administration group and the TROP2-SN38 ADC administration group, which did not achieve tumor regression in the aforementioned test, TA-MUC1-DXd ADC was administered sequentially at 10 mg / kg on days 21 and 28, followed by evaluation and observation for approximately 3 weeks. Results showed strong regression effects in both groups after administration of TA-MUC1-DXd ADC. No weight loss was observed due to the sequential administration of the reagents.

[0184] The above results reveal that TA-MUC1-DXdADC not only exhibits significantly stronger antitumor effects compared to stem protein-4-MMAEADC and TROP2-SN38ADC, but also shows strong pharmacological efficacy against tumors that were found to have not regressed after their administration.

[0185] Example 3: Antitumor evaluation of TA-MUC1-DXd ADC in a model with transplanted breast cancer cell line HCC70 The human breast cancer cell line HCC70 was purchased from ATCC and reconstituted using RPMI 1640 medium (manufactured by Thermo Fisher Scientific Inc.) containing 10% fetal bovine serum in an incubator set to 37°C and 5% CO2. The cells were then passaged once or twice a week. Cells of this sufficient number were recovered from the flasks using trypsin (manufactured by Thermo Fisher Scientific Inc.) and passaged at 1 × 10⁶ cells / year. 8 Cells / mL were suspended in Otsuka saline. The suspension was subcutaneously transplanted at 100 μL into each 5-week-old female nude mouse (1 × 10⁶ cells / mL). 7 (cells / 100μL / head). Mice were grouped 18 days post-transplantation, at which time their average tumor volume had increased to approximately 165 mm. 3 .

[0186] Then, the TA-MUC1-DXd ADC, control IgG-DXd ADC, or TROP2-SN38 ADC prepared in Example 1 (prepared at 10 mg / mL using Otsuka saline (manufactured by Otsuka Pharmaceutical Factory, Inc.) from a lyophilized product purchased from Seagen Inc.) was diluted with ABS buffer and administered intravenously to the tail at a volume of 10 mL / kg body weight per mouse (day 0). TA-MUC1-DXd ADC with a DAR of 7.9 was used. The dosing schedule was set as Q3W × three doses (days 0, 21, and 42) of TA-MUC1-DXd ADC (10 mg / kg), Q3W × one dose (day 0) of control IgG-DXd ADC (10 mg / kg), and QW × two doses (days 0 and 7) of TROP2-SN38 ADC (10 mg / kg). ABS buffer was administered to the mediator administration groups. Six mice were used in each group in all groups. Following initial administration, body weight and tumor size were measured once or twice weekly, and estimated tumor volume was calculated. Statistical analysis was performed using the Dunnett multiple comparison test to assess the significant differences in drug efficacy among the TA-MUC1-DXdADC-based reagents. IHC staining also confirmed the positivity of TA-MUC1- and TROP2- in the tumors of the described model.

[0187] Figure 2 The changes in estimated tumor volume in the HCC70 model are shown. On day 21, a strong regression effect was confirmed in the TA-MUC1-DXd ADC 10 mg / kg administration group, which showed statistically significant antitumor activity compared with the mediator administration group, the control IgG-DXd ADC administration group, and the TROP2-SN38 ADC administration group (Table 2).

[0188] [Table 2] These results reveal that, in the HCC70 model, TA-MUC1-DXd ADC exhibits significantly stronger antitumor activity in an antigen-specific manner, as compared to TROP2-SN38 ADC.

[0189] In the TROP2-SN38 ADC administration group where no tumor regression was observed in the test, TA-MUC1-DXd ADC was administered sequentially at 10 mg / kg on days 21 and 42, and evaluation and observation continued until day 65. As a result, a strong regression effect was confirmed after administration of TA-MUC1-DXd ADC. No weight loss was observed due to the sequential administration of the reagents.

[0190] The above results reveal that the TA-MUC1-DXd ADC not only exhibits a significantly stronger anti-tumor effect compared to the TROP2-SN38 ADC in the aforementioned model, but also shows strong pharmacological efficacy even against tumors that were found to have not regressed by the latter.

[0191] Example 4: Evaluation of the antitumor activity of TA-MUC1-DXd ADC and TROP2-DXd ADC against NIBIO-NS1, a xenograft model derived from lung cancer patients. NIBIO-NS1 was obtained from the National Institute for Biomedical Innovation as a PDX model for lung cancer. Frozen tumor sections of NIBIO-NS1 were thawed and subcutaneously transplanted into 5-week-old female NSG mice (NOD.Cg-Prkdc) using a trocar. <scid>Il2rg <tm1wjl> / SzJ: purchased from Jackson Laboratory Japan, Inc.). The growing tumors were collected, cut into small pieces, and then re-transplanted into female nude mice (CAnN.Cg-Foxn1nu / CrlCrlj: purchased from Jackson Laboratory Japan, Inc.) using a trocar, which then allowed for further growth.

[0192] Female nude mice with transplanted NIBIO-NS1 were grouped 10 days post-transplantation, at which time their average tumor volume had increased to approximately 157 mm. 3 Then, the TA-MUC1-DXd ADC or TROP2-DXd ADC prepared in Example 1 (refer to the preparation in Example 2) was diluted with ABS buffer and administered intravenously to the tail at a volume of 10 mL / kg body weight per mouse (day 0). Group configurations are shown in Table 3. The mediator administration groups used ABS buffer and employed TA-MUC1-DXd ADC with a DAR of 7.9 and TROP2-DXd ADC with a DAR of 4.0. Six mice were used in each of groups 1 and 2, and 12 mice were used in group 3. Body weight and tumor size were measured once or twice weekly, and estimated tumor volume was calculated. The efficacy of the drugs was compared between reagents using Dunnett multiple comparison analysis. The positivity of TA-MUC1- and TROP2- in the tumors of the model was confirmed by IHC staining.

[0193] Figure 6 The changes in tumor volume estimated in the above antitumor tests are shown. A strong regression effect was confirmed in the TA-MUC1-DXdADC 10 mg / kg administration group, demonstrating statistically significant antitumor activity compared to the mediator administration group and the TROP2-DXd ADC 10 mg / kg administration group (Table 4).

[0194] [Table 3] [Table 4] These results reveal that the NIBIO-NS1 model has low sensitivity to TROP2-DXdADC, while the TA-MUC1-DXdADC in the model exhibits significantly stronger antitumor activity compared to TROP2-DXdADC.

[0195] The estimated tumor volume of tumor-bearing mice in the TROP2-DXd ADC administration group, in which no tumor regression was found during the test, was calculated on day 11 (at which time their average tumor volume became approximately 453 mm). 3 The mice were regrouped to include six mice in each group. One group was administered TA-MUC1-DXdADC sequentially at 10 mg / kg, and the mice were evaluated and observed until day 31. The other group was administered TROP2-DXdADC continuously at 10 mg / kg, and the mice were evaluated and observed until day 21.

[0196] As a result, tumors continued to grow in the TROP2-DXd ADC administration group, while a strong tumor regression effect was demonstrated in the TROP2-DXd ADC→TA-MUC1-DXd ADC sequential administration group.

[0197] No weight loss was found due to the sequential administration of the reagents.

[0198] The above results reveal that TA-MUC1-DXd ADC not only exhibits significant anti-tumor effects in the model, which, despite being TROP2-positive, has low sensitivity to TROP2-DXd ADC, but also shows strong drug efficacy even against tumors that were found not to have regressed after administration of TROP2-DXd ADC.

[0199] Example 5: Antitumor evaluation of TA-MUC1-DXdADC, control IgG-DXdADC and HER2-DXdADC in a model with transplanted breast cancer cell line HCC70 The human breast cancer cell line HCC70 was purchased from ATCC and reconstituted using RPMI 1640 medium (manufactured by Thermo Fisher Scientific Inc.) containing 10% fetal bovine serum. The cells were then cultured in an incubator set to 37°C and 5% CO2, and passaged once or twice weekly. Cells that had reached such a sufficient number were recovered from the flasks using trypsin (manufactured by Thermo Fisher Scientific Inc.) and passaged at 1 × 10⁶ cells / year. 8 Cells / mL were suspended in D-PBS (-) (manufactured by FUJIFILM Wako Pure Chemical Corp.). The suspension was subcutaneously transplanted into each 5-week-old female nude mouse (1×10⁶ cells / mL). 7 (cells / 100μL / mouse). Mice were grouped 21 days post-transplantation, at which time the average tumor volume in mice with transplants had increased to approximately 198 mm. 3 .

[0200] Then, the TA-MUC1-DXd ADC, control IgG-DXd ADC, or HER2-DXd ADC (prepared according to Example 3) prepared in Example 1 were diluted with ABS buffer and administered intravenously to the tail at a volume of 10 mL / kg body weight per mouse (day 0). Group configurations are shown in Table 5. The mediator administration groups used ABS buffer and employed TA-MUC1-DXd ADC with a DAR of 7.9 and HER2-DXd ADC with a DAR of 7.8. Six mice were used in each of groups 1, 2, and 3, and 12 mice were used in group 4. Body weight and tumor size were measured once or twice weekly, and estimated tumor volume was calculated. Drug efficacy was compared between reagents using the Dunnett multiple comparison analysis parameter. TA-MUC1- positivity and low HER2 expression in the tumors of the model were confirmed by IHC staining.

[0201] Figure 7 The changes in tumor volume estimated in the HCC70 model are shown. A strong regression effect was confirmed in the TA-MUC1-DXdADC 10 mg / kg administration group, demonstrating statistically significant antitumor activity compared to the mediator administration group and the control IgG-DXd ADC administration group and HER2-DXd ADC administration group given the same dose (Table 6).

[0202] [Table 5] [Table 6] These results reveal that the HCC70 model has low sensitivity to HER2-DXd ADC, while the TA-MUC1-DXd ADC in the model exhibits significantly stronger antitumor activity compared to HER2-DXd ADC.

[0203] The tumor-bearing mice in the HER2-DXd ADC administration group, in which no tumor regression was found during the test, had their estimated tumor volume (at which point their average tumor volume became approximately 443 mm) on day 21. 3 Mice were regrouped to include six mice per group. One group was administered TA-MUC1-DXd ADC sequentially at 10 mg / kg (Q3W×3) and evaluated and observed until day 84. The other group was administered HER2-DXd ADC continuously at 10 mg / kg and evaluated and observed until day 42. Results showed that tumors continued to grow in the HER2-DXd ADC group, while a strong tumor regression effect was observed in the TA-MUC1-DXd ADC group. No weight loss was observed due to the sequential administration of the reagents.

[0204] The above results reveal that TA-MUC1-DXd ADC not only exhibits significant anti-tumor effects in the model, which has low sensitivity to HER2-DXd ADC, but also shows strong drug efficacy even in tumors that were found not to have regressed after administration of HER2-DXd ADC.

[0205] Free text of sequence lists Amino acid sequences of CDRH1 in SEQ ID NO:1-PM-N54Q and PankoMab-GEX(R) The amino acid sequence of CDRH2 of SEQ ID NO:2-PM-N54Q Amino acid sequences of CDRH3 of SEQ ID NO:3-PM-N54Q and PankoMab-GEX(R) Amino acid sequences of CDRL1 in SEQ ID NO:4-PM-N54Q and PankoMab-GEX(R) Amino acid sequences of CDRL2 in SEQ ID NO:5-PM-N54Q and PankoMab-GEX(R) Amino acid sequences of CDRL3 in SEQ ID NO:6-PM-N54Q and PankoMab-GEX(R) Amino acid sequence of CDRH2 of SEQ ID NO:7-PankoMab-GEX(R) The amino acid sequence of the heavy chain variable region of SEQ ID NO:8-PM-N54Q Amino acid sequences of the light chain variable region of SEQ ID NO:9-PM-N54Q and PankoMab-GEX(R) The amino acid sequence of the heavy chain variable region of SEQ ID NO:10-PankoMab-GEX(R) The amino acid sequence of the heavy chain of SEQ ID NO:11-PM-N54Q Amino acid sequences of the light chains of SEQ ID NO:12-PM-N54Q and PankoMab-GEX(R) The amino acid sequence of the heavy chain of SEQ ID NO:13-PankoMab-GEX(R) The amino acid sequence of the heavy chain of the SEQ ID NO:14-hRS7 antibody The amino acid sequence of the light chain of the SEQ ID NO:15-hRS7 antibody SEQ ID NO:16 - Amino acid sequence of the epitope SEQ ID NO:17 - Amino acid sequence of the epitope SEQ ID NO:18 - Amino acid sequence of CDRH1 of anti-TROP2 antibody SEQ ID NO:19 - Amino acid sequence of CDRH2 for anti-TROP2 antibody SEQ ID NO:20 - Amino acid sequence of CDRH3 of anti-TROP2 antibody SEQ ID NO:21 - Amino acid sequence of CDRL1 of anti-TROP2 antibody SEQ ID NO:22 - Amino acid sequence of CDRL2 of anti-TROP2 antibody SEQ ID NO:23 - Amino acid sequence of CDRL3 of anti-TROP2 antibody SEQ ID NO:24 - Amino acid sequence of the heavy chain variable region of anti-TROP2 antibody SEQ ID NO:25 - Amino acid sequence of the light chain variable region of anti-TROP2 antibody SEQ ID NO:26 - Amino acid sequence of the heavy chain of anti-TROP2 antibody SEQ ID NO:27 - Amino acid sequence of the light chain of anti-TROP2 antibody SEQ ID NO:28 - Amino acid sequence of CDRH1 of anti-HER2 antibody SEQ ID NO:29 - Amino acid sequence of CDRH2 for anti-HER2 antibody SEQ ID NO:30 - Amino acid sequence of CDRH3 of anti-HER2 antibody SEQ ID NO:31 - Amino acid sequence of CDRL1 of anti-HER2 antibody SEQ ID NO:32 - Amino acid sequence of CDRL2 of anti-HER2 antibody SEQ ID NO:33 - Amino acid sequence of CDRL3 of anti-HER2 antibody SEQ ID NO:34 - Amino acid sequence of the heavy chain variable region of anti-HER2 antibody SEQ ID NO:35 - Amino acid sequence of the light chain variable region of the anti-HER2 antibody SEQ ID NO:36 - Amino acid sequence of the heavy chain of anti-HER2 antibody SEQ ID NO:37 - Amino acid sequence of the light chain of anti-HER2 antibody < / scid> < / scid>

Claims

1. A therapeutic agent for cancers with low sensitivity to existing anticancer agents, comprising an anti-MUC1 antibody-drug conjugate as the active ingredient.

2. The therapeutic agent according to claim 1, wherein the anticancer agent is an alkylating agent, a platinum-containing drug, an antifolate agent, a pyridine metabolism inhibitor, a purine metabolism inhibitor, a ribonucleotide reductase inhibitor, a nucleotide analog, a topoisomerase inhibitor, a microtubule polymerization inhibitor, a microtubule depolymerization inhibitor, an antitumor antibiotic, an antihormonal agent, an EGFR inhibitor, a BTK inhibitor, a BCR-ABL inhibitor, an ALK inhibitor, a HER2 inhibitor, an angiogenesis inhibitor, a PARP inhibitor, an mTOR inhibitor, a membrane differentiation antigen-targeting drug, or an antibody-drug conjugate.

3. The therapeutic agent according to claim 1, wherein the anticancer agent is an antibody-drug conjugate.

4. The therapeutic agent according to claim 3, wherein the antibody-drug conjugate is an anti-TROP2 antibody-drug conjugate, an anti-stem protein-4 antibody-drug conjugate, or an anti-HER2 antibody-drug conjugate.

5. The therapeutic agent according to claim 4, wherein the antibody-drug conjugate is veentumumab, gosatuzumab, dedabrotuzumab, trastuzumab emtansine, or detrastuzumab.

6. The therapeutic agent according to any one of claims 1 to 5, wherein the cancer expresses TA-MUC1.

7. The therapeutic agent according to claim 6, wherein the cancer is selected from ovarian cancer, breast cancer, pancreatic cancer, lung cancer, colon cancer, gastric cancer, liver cancer, kidney cancer, hematologic malignancies, endometrial cancer, thyroid cancer, leukemia, seminoma, melanoma, carcinoma, teratoma, lymphoma, sarcoma, mesothelioma, neuroblastoma, glioma, rectal cancer, adrenal cancer, skin cancer, brain cancer, cervical cancer, intestinal cancer, bowel cancer, head and neck cancer, digestive tract cancer, lymph node cancer, esophageal cancer, colorectal cancer, ear, nose and throat (ENT) cancer, prostate cancer, bladder cancer, uterine cancer, biliary tract cancer, and their metastases.

8. The therapeutic agent according to claim 6, wherein the cancer is breast cancer, lung cancer, or bladder cancer.

9. The therapeutic agent according to any one of claims 1 to 8, wherein the anti-MUC1 antibody is an anti-TA-MUC1 antibody.

10. The therapeutic agent according to any one of claims 1 to 9, wherein the anti-MUC1 antibody-drug conjugate is an anti-MUC1 antibody-drug conjugate, wherein the drug-linker represented by the following formula is conjugated to the anti-MUC1 antibody via a thioether bond: [Chem.1] Where A represents the binding site with the anti-MUC1 antibody.

11. The therapeutic agent according to any one of claims 1 to 10, wherein the anti-MUC1 antibody is an antibody comprising a heavy chain and a light chain, the heavy chain comprising CDRH1 consisting of the amino acid sequence shown in SEQ ID NO:1, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO:2 or SEQ ID NO:7, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO:3, and the light chain comprising CDRL1 consisting of the amino acid sequence shown in SEQ ID NO:4, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO:5, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO:

6.

12. The therapeutic agent according to any one of claims 1 to 10, wherein the anti-MUC1 antibody is an antibody comprising a heavy chain and a light chain, the heavy chain comprising CDRH1 consisting of the amino acid sequence shown in SEQ ID NO:1, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO:2, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO:3, and the light chain comprising CDRL1 consisting of the amino acid sequence shown in SEQ ID NO:4, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO:5, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO:

6.

13. The therapeutic agent according to any one of claims 1 to 10, wherein the anti-MUC1 antibody is an antibody comprising a heavy chain and a light chain, the heavy chain comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO:8 or SEQ ID NO:10, and the light chain comprising a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO:

9.

14. The therapeutic agent according to any one of claims 1 to 10, wherein the anti-MUC1 antibody is an antibody comprising a heavy chain and a light chain, the heavy chain comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO:8, and the light chain comprising a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO:

9.

15. The therapeutic agent according to any one of claims 1 to 10, wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO:11 or SEQ ID NO:13 and a light chain consisting of the amino acid sequence shown in SEQ ID NO:

12.

16. The therapeutic agent according to any one of claims 1 to 10, wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO:11 and a light chain consisting of the amino acid sequence shown in SEQ ID NO:

12.

17. The therapeutic agent according to claim 15 or 16, wherein the lysine residue at the carboxyl terminus of the anti-MUC1 antibody heavy chain is deleted.

18. The therapeutic agent according to any one of claims 1 to 17, wherein the average number of drug-connector units conjugated to each antibody molecule in the anti-MUC1 antibody-drug conjugate is in the range of 7 to 8.

19. The therapeutic agent according to any one of claims 1 to 17, wherein the average number of drug-connector units conjugated to each antibody molecule in the anti-MUC1 antibody-drug conjugate is in the range of 7.5 to 8.

20. A method for treating cancers with low sensitivity to existing anticancer agents, comprising administering an anti-MUC1 antibody-drug conjugate.

21. The treatment method according to claim 20, wherein the anticancer agent is an alkylating agent, a platinum-containing drug, an antifolate agent, a pyridine metabolism inhibitor, a purine metabolism inhibitor, a ribonucleotide reductase inhibitor, a nucleotide analog, a topoisomerase inhibitor, a microtubule polymerization inhibitor, a microtubule depolymerization inhibitor, an antitumor antibiotic, an antihormonal agent, an EGFR inhibitor, a BTK inhibitor, a BCR-ABL inhibitor, an ALK inhibitor, a HER2 inhibitor, an angiogenesis inhibitor, a PARP inhibitor, an mTOR inhibitor, a membrane differentiation antigen-targeting drug, or an antibody-drug conjugate.

22. The treatment method according to claim 20, wherein the anticancer agent is an antibody-drug conjugate.

23. The treatment method according to claim 22, wherein the antibody-drug conjugate is an anti-TROP2 antibody-drug conjugate, an anti-stem protein-4 antibody-drug conjugate, or an anti-HER2 antibody-drug conjugate.

24. The treatment method according to claim 22, wherein the antibody-drug conjugate is veentumumab, gosatuzumab, dedabrotuzumab, trastuzumab emtansine, or detrastuzumab.

25. The treatment method according to any one of claims 20 to 24, wherein the cancer expresses TA-MUC1.

26. The treatment method according to claim 25, wherein the cancer is selected from ovarian cancer, breast cancer, pancreatic cancer, lung cancer, colon cancer, gastric cancer, liver cancer, kidney cancer, hematologic malignancies, endometrial cancer, thyroid cancer, leukemia, seminoma, melanoma, carcinoma, teratoma, lymphoma, sarcoma, mesothelioma, neuroblastoma, glioma, rectal cancer, adrenal cancer, skin cancer, brain cancer, cervical cancer, intestinal cancer, bowel cancer, head and neck cancer, digestive tract cancer, lymph node cancer, esophageal cancer, colorectal cancer, ear, nose and throat (ENT) cancer, prostate cancer, bladder cancer, uterine cancer, biliary tract cancer, and their metastases.

27. The treatment method according to claim 25, wherein the cancer is breast cancer, lung cancer, or bladder cancer.

28. The treatment method according to any one of claims 20 to 27, wherein the anti-MUC1 antibody is an anti-TA-MUC1 antibody.

29. The treatment method according to any one of claims 20 to 28, wherein the anti-MUC1 antibody-drug conjugate is an anti-MUC1 antibody-drug conjugate, wherein the drug-linker represented by the following formula is conjugated to the anti-MUC1 antibody via a thioether bond: [Chem.2] Where A represents the binding site with the anti-MUC1 antibody.

30. The treatment method according to any one of claims 20 to 29, wherein the anti-MUC1 antibody is an antibody comprising a heavy chain and a light chain, the heavy chain comprising CDRH1 consisting of the amino acid sequence shown in SEQ ID NO:1, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO:2 or SEQ ID NO:7, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO:3, and the light chain comprising CDRL1 consisting of the amino acid sequence shown in SEQ ID NO:4, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO:5, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO:

6.

31. The treatment method according to any one of claims 20 to 29, wherein the anti-MUC1 antibody is an antibody comprising a heavy chain and a light chain, the heavy chain comprising CDRH1 consisting of the amino acid sequence shown in SEQ ID NO:1, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO:2, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO:3, and the light chain comprising CDRL1 consisting of the amino acid sequence shown in SEQ ID NO:4, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO:5, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO:

6.

32. The treatment method according to any one of claims 20 to 29, wherein the anti-MUC1 antibody is an antibody comprising a heavy chain and a light chain, the heavy chain comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO:8 or SEQ ID NO:10, and the light chain comprising a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO:

9.

33. The treatment method according to any one of claims 20 to 29, wherein the anti-MUC1 antibody is an antibody comprising a heavy chain and a light chain, the heavy chain comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO:8, and the light chain comprising a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO:

9.

34. The treatment method according to any one of claims 20 to 29, wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO:11 or SEQ ID NO:13 and a light chain consisting of the amino acid sequence shown in SEQ ID NO:

12.

35. The treatment method according to any one of claims 20 to 29, wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO:11 and a light chain consisting of the amino acid sequence shown in SEQ ID NO:

12.

36. The treatment method according to claim 34 or 35, wherein the lysine residue at the carboxyl terminus of the anti-MUC1 antibody heavy chain is deleted.

37. The treatment method according to any one of claims 20 to 36, wherein the average number of drug-connector units conjugated to each antibody molecule in the anti-MUC1 antibody-drug conjugate is in the range of 7 to 8.

38. The treatment method according to any one of claims 20 to 36, wherein the average number of drug-connector units conjugated to each antibody molecule in the anti-MUC1 antibody-drug conjugate is in the range of 7.5 to 8.

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