Combination of anti-CDH6 antibody-drug conjugate with VEGF inhibitor

Abstract

The present invention provides a pharmaceutical composition and a therapeutic method characterized in that a specific anti-CDH6 antibody-drug conjugate and a VEGF inhibitor are administered in combination. Provided are a pharmaceutical composition and a therapeutic method characterized in that an antibody-drug conjugate, in which a drug linker shown by the formula (in the formula, A represents the binding site with an anti-CDH6 antibody or a functional fragment of the antibody) and the anti-CDH6 antibody or a functional fragment of the antibody are bonded by a thioether bond, is administered in combination with a VEGF inhibitor.

Description

Combination of anti-CDH6 antibody-drug conjugate and VEGF inhibitor

[0001] The present invention relates to a pharmaceutical composition characterized by administering a specific anti-CDH6 antibody-drug conjugate and a VEGF inhibitor in combination, and / or a treatment method characterized by administering a specific anti-CDH6 antibody-drug conjugate and a VEGF inhibitor in combination to an individual.

[0002] Angiogenesis, which contributes to the supply of nutrients and oxygen and the excretion of metabolic waste products, is important for the growth of solid tumors. Vascular endothelial growth factor (VEGF), particularly VEGF-A, has been identified as a key factor for inducing tumor angiogenesis. VEGF activates VEGF signaling in endothelial cells through interaction with VEGF receptors, thereby stimulating endothelial cell proliferation and survival and increasing vascular permeability, thereby supporting the metabolic needs of growing tumors. VEGF inhibitors are known to inhibit angiogenesis by inhibiting the interaction between VEGF and VEGF receptors and exhibit antitumor effects. Examples of such VEGF inhibitors include anti-VEGF antibodies, anti-VEGF receptor antibodies, fusion proteins containing the VEGF receptor extracellular domain, and bispecific antibodies containing an anti-VEGF binding domain (Non-Patent Documents 1 to 4).

[0003] Antibody-drug conjugates (ADCs), which combine a cytotoxic drug with an antibody that binds to an antigen expressed on the surface of cancer cells and can be internalized into the cells, can selectively deliver the drug to cancer cells, thereby allowing the drug to accumulate in the cancer cells and kill the cancer cells. One known antibody-drug conjugate is one that comprises an anti-CDH6 antibody and a derivative of exatecan, a topoisomerase I inhibitor, as components (Patent Document 1).

[0004] However, no test results have been published showing an excellent combined effect when the above-mentioned anti-CDH6 antibody-drug conjugate is used in combination with a VEGF inhibitor, nor any scientific evidence suggesting such test results.

[0005] International Publication No. 2018 / 212136

[0006] Garcia et al., Cancer Treat. Rev. (2020) 86: 102017.Geindreau et al. Int. J. Mol. Sci. (2021) 22(9): 4871.Esfandiari et al., Nat. Rev. Drug Discov. (2022) 21(6): 411-412.Xu et al., Cancer Lett. (2022) 538: 215699.

[0007] The anti-CDH6 antibody-drug conjugate used in the present invention (an anti-CDH6 antibody-drug conjugate comprising an exatecan derivative as a component) has been confirmed to exhibit excellent antitumor effects even when used alone. However, it is desirable to develop a treatment method that can comprehensively suppress cancer cell proliferation and exert even more excellent antitumor effects by using it in combination with other anticancer drugs with different mechanisms of action.

[0008] An objective of the present invention is to provide a pharmaceutical composition characterized by administering a specific anti-CDH6 antibody-drug conjugate and a VEGF inhibitor in combination, and / or a treatment method characterized by administering a specific anti-CDH6 antibody-drug conjugate and a VEGF inhibitor in combination to an individual.

[0009] The present inventors have conducted extensive research to solve the above problems and have found that administering a specific anti-CDH6 antibody-drug conjugate in combination with a VEGF inhibitor exhibits an excellent combined effect (highly safe and significant antitumor effect), thereby completing the present invention.

[0010] That is, the present invention provides the following [1] to

[309] : [1] A pharmaceutical composition comprising an anti-CDH6 antibody-drug conjugate, wherein the anti-CDH6 antibody-drug conjugate and a VEGF inhibitor are administered in combination, and the anti-CDH6 antibody-drug conjugate is represented by the formula

[0011]

[0012] (wherein A represents the binding site to the anti-CDH6 antibody or a functional fragment of the antibody) and the anti-CDH6 antibody or a functional fragment of the antibody via a thioether bond. [2] The pharmaceutical composition according to [1], wherein the anti-CDH6 antibody or the functional fragment of the antibody is an antibody or a functional fragment of the antibody that specifically binds to the amino acid sequence set forth in SEQ ID NO: 1 and has the ability to be internalized into cells.[3] The anti-CDH6 antibody or a functional fragment thereof is a CDRH1, CDRH2, and CDRH3 selected from the group consisting of the following (1) to (5): (1) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 3, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4; (2) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 8, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4; (3) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 9, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 10, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 11; (4) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 15, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 16, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 17; and (5) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 21, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 22, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 23; and The pharmaceutical composition according to [1] or [2], which is an antibody or a functional fragment of the antibody, comprising CDRL1, CDRL2, and CDRL3 selected from the group consisting of the following (6) to (9): (6) CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO:5, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO:6, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO:7, (7) CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO:12, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO:13, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO:14, (8) CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO:18, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO:19, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO:20, and (9) CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO:24, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO:25, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO:26.[4] An anti-CDH6 antibody or a functional fragment thereof, comprising any one of the following (1) to (5): (1) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 3, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4, and a CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 5, a CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 6, and a CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 7; (2) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 8, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4, and a CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 5, a CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 6, and a CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 7; (3) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 9, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 10, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 11, and a CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 12, a CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 13, and a CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 14; (4) The pharmaceutical composition according to any one of [1] to [3], which is an antibody or a functional fragment of the antibody comprising CDRH1, CDRH2, and CDRH3 selected from the group consisting of: (4) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 15, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 16, and CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 17, and CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 18, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 19, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 20, and (5) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 21, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 22, and CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 23, and CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 24, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 25, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 26.[5] The pharmaceutical composition according to any one of [1] to [4], wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody comprising a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 3, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4, and a CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 5, a CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 6, and a CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 7. [6] The pharmaceutical composition according to any one of [1] to [5], wherein the anti-CDH6 antibody or a functional fragment of the antibody is a humanized antibody or a functional fragment of the antibody. [7] An anti-CDH6 antibody or a functional fragment thereof, comprising: a heavy chain variable region selected from the group consisting of the following (1) to (5): (1) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 28; (2) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 31; (3) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 34; (4) an amino acid sequence having at least 95% or more sequence identity to the framework region sequences other than each CDR sequence in the amino acid sequences of (1) to (3); and (5) an amino acid sequence in which one or several amino acids are deleted, substituted, or added in the framework region sequences other than each CDR sequence in the amino acid sequences of (1) to (4); and (6) to (9) below: (6) a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 37; (7) a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 40; (8) an amino acid sequence having at least 95% or more sequence identity to the framework region sequences other than each CDR sequence in the amino acid sequences of (6) to (7); (9) The pharmaceutical composition according to any one of [1] to [6], which is an antibody or a functional fragment of the antibody, comprising: a light chain variable region according to any one selected from the group consisting of: (6) to (8) amino acid sequences in which one or several amino acids are deleted, substituted, or added in the framework region sequences other than each CDR sequence.[8] The pharmaceutical composition of any one of [1] to [7], wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody comprising any of the following heavy chain variable regions and light chain variable regions (1) to (4): (1) a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 28 and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 37, (2) a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 31 and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 37, (3) a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 31 and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 40, or (4) a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 34 and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 37. [9] The pharmaceutical composition of any one of [1] to [8], wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody comprising a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 28 and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 37.

[10] The pharmaceutical composition according to any one of [1] to [9], wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody comprising any of the following (1) to (4): (1) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38, (2) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38, (3) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 41, or (4) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 35 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38.

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

[10] , wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38.

[12] The pharmaceutical composition of any one of [1] to

[11] , wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody, wherein the heavy chain or light chain has undergone one or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue to the N-terminus, amidation of proline residues, pyroglutamic acid oxidation of N-terminal glutamine or N-terminal glutamic acid, and deletion of one or two amino acids at the carboxyl terminus.

[13] The pharmaceutical composition of

[12] , wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody, wherein one or two amino acids are deleted at the carboxyl terminus of the heavy chain.

[14] The pharmaceutical composition according to

[13] , wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody in which one amino acid is deleted at the carboxyl terminus of both of the two heavy chains.

[15] The pharmaceutical composition according to any one of

[12] to

[14] , wherein the deleted amino acid is lysine.

[16] The pharmaceutical composition according to any one of

[12] to

[15] , wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody in which a proline residue at the carboxyl terminus of the heavy chain is further amidated.

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

[16] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 1 to 10.

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

[16] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 2 to 8.

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

[16] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 5 to 8.

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

[16] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7 to 8.

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

[16] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7.5 to 8.

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

[16] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is about 8.

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

[22] , wherein the VEGF inhibitor is an anti-VEGF antibody, an anti-VEGF receptor antibody, a fusion protein comprising a VEGF receptor extracellular domain, or a multispecific antibody comprising an anti-VEGF binding domain.

[24] The pharmaceutical composition according to

[23] , wherein the VEGF inhibitor is an anti-VEGF antibody.

[25] The pharmaceutical composition according to

[24] , wherein the anti-VEGF antibody is bevacizumab.

[26] The pharmaceutical composition according to

[23] , wherein the VEGF inhibitor is an anti-VEGF receptor antibody.

[27] The pharmaceutical composition according to

[26] , wherein the anti-VEGF receptor antibody is ramucirumab.

[28] The pharmaceutical composition according to

[23] , wherein the VEGF inhibitor is a fusion protein comprising a VEGF receptor extracellular domain.

[29] The pharmaceutical composition of

[28] , wherein the fusion protein comprising a VEGF receptor extracellular domain is aflibercept.

[30] The pharmaceutical composition of

[23] , wherein the VEGF inhibitor is a multispecific antibody comprising an anti-VEGF binding domain.

[31] The pharmaceutical composition of

[30] , wherein the multispecific antibody is a bispecific antibody.

[32] The pharmaceutical composition of any one of [1] to

[31] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in different formulations and administered simultaneously (almost simultaneously) or at different times.

[33] The pharmaceutical composition of any one of [1] to

[31] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in the same formulation.

[34] The pharmaceutical composition of any one of [1] to

[33] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in the same formulation.

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

[33] , for the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, ovarian mucinous tumor, thyroid cancer, bile duct cancer, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, neuroblastoma, colorectal cancer, gastric cancer, endometrial cancer, uterine body cancer, and nasopharyngeal cancer.

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

[33] , for treating at least one disease selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, ovarian mucinous tumor, thyroid cancer, bile duct cancer, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, and neuroblastoma.

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

[33] , for treating at least one disease selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, and papillary renal cell carcinoma.

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

[33] , for treating at least one disease selected from the group consisting of ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, and ovarian mucinous tumor.

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

[33] , for treating ovarian cancer.

[40] The pharmaceutical composition according to

[39] , wherein the ovarian cancer is epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

[41] The pharmaceutical composition according to

[39] or

[40] , wherein the ovarian cancer is metastatic.

[42] A pharmaceutical composition comprising an anti-CDH6 antibody-drug conjugate, wherein the anti-CDH6 antibody-drug conjugate and a VEGF inhibitor are administered in combination, and the anti-CDH6 antibody-drug conjugate is represented by the formula:

[0013]

[0014] (wherein the antibody is an anti-CDH6 antibody, the drug linker is bound to the antibody via a thioether bond, and n represents the average number of drug linkers bound per antibody).

[43] The pharmaceutical composition of

[42] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38.

[44] The pharmaceutical composition of

[42] or

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

[45] The pharmaceutical composition of any one of

[42] to

[44] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 1 to 10.

[46] The pharmaceutical composition of any one of

[42] to

[44] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 2 to 8.

[47] The pharmaceutical composition of any one of

[42] to

[44] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 5 to 8.

[48] The pharmaceutical composition of any one of

[42] to

[44] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7 to 8.

[49] The pharmaceutical composition of any one of

[42] to

[44] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7.5 to 8.

[50] The pharmaceutical composition of any one of

[42] to

[44] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is about 8.

[51] The pharmaceutical composition according to any one of

[42] to

[50] , wherein the VEGF inhibitor is an anti-VEGF antibody, an anti-VEGF receptor antibody, or a fusion protein comprising a VEGF receptor extracellular domain or a multispecific antibody comprising an anti-VEGF binding domain.

[52] The pharmaceutical composition according to

[51] , wherein the VEGF inhibitor is an anti-VEGF antibody.

[53] The pharmaceutical composition according to

[52] , wherein the anti-VEGF antibody is bevacizumab.

[54] The pharmaceutical composition according to

[51] , wherein the VEGF inhibitor is an anti-VEGF receptor antibody.

[55] The pharmaceutical composition of

[54] , wherein the anti-VEGF receptor antibody is ramucirumab.

[56] The pharmaceutical composition of

[51] , wherein the VEGF inhibitor is a fusion protein comprising a VEGF receptor extracellular domain.

[57] The pharmaceutical composition of

[56] , wherein the fusion protein comprising a VEGF receptor extracellular domain is aflibercept.

[58] The pharmaceutical composition of

[51] , wherein the VEGF inhibitor is a multispecific antibody comprising an anti-VEGF binding domain.

[59] The pharmaceutical composition of

[58] , wherein the multispecific antibody is a bispecific antibody.

[60] The pharmaceutical composition of any one of

[42] to

[59] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in different formulations and administered simultaneously (almost simultaneously) or at different times.

[61] The pharmaceutical composition of any one of

[42] to

[59] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in the same formulation.

[62] The pharmaceutical composition according to any one of

[42] to

[61] for the treatment of cancer.

[63] The pharmaceutical composition according to any one of

[42] to

[61] for the treatment of at least one cancer selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, ovarian mucinous tumor, thyroid cancer, bile duct cancer, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, neuroblastoma, colorectal cancer, gastric cancer, endometrial cancer, uterine corpus cancer, and nasopharyngeal cancer.

[64] The pharmaceutical composition according to any one of

[42] to

[61] , for the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, ovarian mucinous tumor, thyroid cancer, bile duct cancer, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, and neuroblastoma.

[65] The pharmaceutical composition according to any one of

[42] to

[61] , for treating at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, and papillary renal cell carcinoma.

[66] The pharmaceutical composition according to any one of

[42] to

[61] , for treating at least one selected from the group consisting of ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, and ovarian mucinous tumor.

[67] The pharmaceutical composition according to any one of

[42] to

[61] , for treating ovarian cancer.

[68] The pharmaceutical composition according to

[67] , wherein the ovarian cancer is epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

[69] The pharmaceutical composition according to

[67] or

[68] , wherein the ovarian cancer is metastatic.

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

[69] , wherein the anti-CDH6 antibody-drug conjugate is raludotatug deruxtecan (DS-6000a).

[71] A method of treatment, characterized in that an anti-CDH6 antibody-drug conjugate and a VEGF inhibitor are administered in combination to an individual in need of treatment, wherein the antibody-drug conjugate is represented by the formula:

[0015]

[0016] (wherein A represents the binding site to the anti-CDH6 antibody or a functional fragment of the antibody) and an antibody-drug conjugate in which the anti-CDH6 antibody or a functional fragment of the antibody is bound via a thioether bond.

[72] The method of treatment according to

[71] , wherein the anti-CDH6 antibody or the functional fragment of the antibody is an antibody or a functional fragment of the antibody that specifically binds to the amino acid sequence set forth in SEQ ID NO: 1 and has the ability to be internalized into cells.

[73] An anti-CDH6 antibody or a functional fragment thereof is a CDRH1, CDRH2, and CDRH3 selected from the group consisting of the following (1) to (5): (1) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 3, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4; (2) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 8, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4; (3) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 9, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 10, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 11; (4) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 15, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 16, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 17; and (5) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 21, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 22, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 23; and The method of treatment according to

[71] or

[72] , wherein the antibody comprises CDRL1, CDRL2, and CDRL3 of any one selected from the group consisting of the following (6) to (9): (6) CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO:5, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO:6, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO:7; (7) CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO:12, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO:13, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO:14; (8) CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO:18, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO:19, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO:20; and (9) CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO:24, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO:25, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO:26, or a functional fragment of the antibody.

[74] An anti-CDH6 antibody or a functional fragment thereof, comprising any one of the following (1) to (5): (1) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 3, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4, and a CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 5, a CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 6, and a CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 7; (2) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 8, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4, and a CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 5, a CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 6, and a CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 7; (3) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 9, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 10, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 11, and a CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 12, a CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 13, and a CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 14; (4) A method for treatment according to any one of

[71] to

[73] , wherein the antibody or functional fragment thereof comprises CDRH1, CDRH2, and CDRH3 selected from the group consisting of: (4) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 15, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 16, and CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 17, and CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 18, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 19, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 20; and (5) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 21, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 22, and CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 23, and CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 24, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 25, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 26.

[75] The therapeutic method according to any one of

[71] to

[74] , wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody comprising a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 3, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4, and a CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 5, a CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 6, and a CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 7.

[76] The therapeutic method according to any one of

[71] to

[75] , wherein the anti-CDH6 antibody or a functional fragment of the antibody is a humanized antibody or a functional fragment of the antibody.

[77] An anti-CDH6 antibody or a functional fragment thereof, comprising: a heavy chain variable region selected from the group consisting of the following (1) to (5): (1) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 28; (2) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 31; (3) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 34; (4) an amino acid sequence having at least 95% or more sequence identity to the framework region sequences other than each CDR sequence in the amino acid sequences of (1) to (3); and (5) an amino acid sequence in which one or several amino acids are deleted, substituted, or added in the framework region sequences other than each CDR sequence in the amino acid sequences of (1) to (4); and (6) to (9) below: (6) a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 37; (7) a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 40; (8) an amino acid sequence having at least 95% or more sequence identity to the framework region sequences other than each CDR sequence in the amino acid sequences of (6) to (7); (9) The method of any one of

[71] to

[76] , wherein the antibody or a functional fragment of the antibody comprises a light chain variable region selected from the group consisting of: (10) an amino acid sequence in which one or several amino acids are deleted, substituted, or added in the framework region sequences other than each CDR sequence in the amino acid sequences of (6) to (8).

[78] The method of any one of

[71] to

[77] , wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody comprising any of the following heavy chain variable regions and light chain variable regions (1) to (4): (1) a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 28 and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 37, (2) a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 31 and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 37, (3) a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 31 and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 40, or (4) a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 34 and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 37.

[79] The method of any one of

[71] to

[78] , wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody comprising a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 28 and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 37.

[80] The method of any one of

[71] to

[79] , wherein the anti-CDH6 antibody or a functional fragment of the antibody comprises any of the following (1) to (4): (1) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38, (2) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38, (3) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 41, or (4) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 35 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38.

[81] The method of any one of

[71] to

[80] , wherein the anti-CDH6 antibody or a functional fragment of the antibody comprises a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38, or a functional fragment of the antibody.

[82] The therapeutic method of any one of

[71] to

[81] , wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody, in which the heavy chain or light chain has undergone one or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue to the N-terminus, amidation of proline residues, pyroglutamic acid oxidation of N-terminal glutamine or N-terminal glutamic acid, and deletion of one or two amino acids at the carboxyl terminus.

[83] The therapeutic method of

[82] , wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody in which one or two amino acids are deleted at the carboxyl terminus of the heavy chain.

[84] The therapeutic method according to

[83] , wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody in which one amino acid is deleted at the carboxyl terminus of each of the two heavy chains.

[85] The therapeutic method according to any one of

[82] to

[84] , wherein the deleted amino acid is lysine.

[86] The therapeutic method according to any one of

[82] to

[85] , wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody in which a proline residue at the carboxyl terminus of the heavy chain is further amidated.

[87] The therapeutic method according to any one of

[71] to

[86] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 1 to 10.

[88] The therapeutic method according to any one of

[71] to

[86] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 2 to 8.

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

[71] to

[86] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 5 to 8.

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

[71] to

[86] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7 to 8.

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

[71] to

[86] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7.5 to 8.

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

[71] to

[86] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is about 8.

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

[71] to

[92] , wherein the VEGF inhibitor is an anti-VEGF antibody, an anti-VEGF receptor antibody, a fusion protein comprising a VEGF receptor extracellular domain, or a fusion protein comprising a multispecific antibody comprising an anti-VEGF binding domain.

[94] The method for treatment according to

[93] , wherein the VEGF inhibitor is an anti-VEGF antibody.

[95] The method for treatment according to

[94] , wherein the anti-VEGF antibody is bevacizumab.

[96] The method for treatment according to

[93] , wherein the VEGF inhibitor is an anti-VEGF receptor antibody.

[97] The method for treatment according to

[96] , wherein the anti-VEGF receptor antibody is ramucirumab.

[98] The method for treatment according to

[93] , wherein the VEGF inhibitor is a fusion protein comprising a VEGF receptor extracellular domain.

[99] The therapeutic method according to

[98] , wherein the fusion protein comprising a VEGF receptor extracellular domain is aflibercept.

[100] The therapeutic method according to

[93] , wherein the VEGF inhibitor is a multispecific antibody comprising an anti-VEGF binding domain.

[101] The therapeutic method according to

[100] , wherein the multispecific antibody is a bispecific antibody.

[102] The therapeutic method according to any one of

[71] to

[101] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in different formulations and administered simultaneously (almost simultaneously) or at different times.

[103] The therapeutic method according to any one of

[71] to

[101] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in the same formulation.

[104] The therapeutic method according to any one of

[71] to

[103] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in the same formulation.

[105] The method for treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, ovarian mucinous tumor, thyroid cancer, bile duct cancer, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, neuroblastoma, colorectal cancer, gastric cancer, endometrial cancer, uterine corpus cancer, and nasopharyngeal cancer, according to any one of

[71] to

[103] .

[106] The therapeutic method of any one of

[71] to

[103] , which is for treating at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, ovarian mucinous tumor, thyroid cancer, bile duct cancer, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, and neuroblastoma.

[107] The therapeutic method of any one of

[71] to

[103] , which is for treating at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, and papillary renal cell carcinoma.

[108] The therapeutic method of any one of

[71] to

[103] , which is for treating at least one selected from the group consisting of ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, and ovarian mucinous tumor.

[109] The therapeutic method according to any one of

[71] to

[103] for treating ovarian cancer.

[110] The therapeutic method according to

[109] , wherein the ovarian cancer is epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

[111] The therapeutic method according to

[109] or

[110] , wherein the ovarian cancer is metastatic.

[112] A therapeutic method comprising administering to an individual in need of treatment a combination of an anti-CDH6 antibody-drug conjugate and a VEGF inhibitor, wherein the anti-CDH6 antibody-drug conjugate is represented by the formula:

[0017]

[0018] (wherein the formula is an anti-CDH6 antibody, the drug linker is bound to the antibody via a thioether bond, and n represents the average number of drug linkers bound per antibody).

[113] The therapeutic method according to

[112] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38.

[114] The therapeutic method according to

[112] or

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

[115] The therapeutic method according to any one of

[112] to

[114] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 1 to 10.

[116] The therapeutic method according to any one of

[112] to

[114] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 2 to 8.

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

[112] to

[114] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 5 to 8.

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

[112] to

[114] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7 to 8.

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

[112] to

[114] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7.5 to 8.

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

[112] to

[114] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is about 8.

[121] The method of any one of

[112] to

[120] , wherein the VEGF inhibitor is an anti-VEGF antibody, an anti-VEGF receptor antibody, a fusion protein comprising a VEGF receptor extracellular domain, or a fusion protein comprising a multispecific antibody comprising an anti-VEGF binding domain.

[122] The method of

[121] , wherein the VEGF inhibitor is an anti-VEGF antibody.

[123] The method of

[122] , wherein the anti-VEGF antibody is bevacizumab.

[124] The method of treatment according to

[121] , wherein the VEGF inhibitor is an anti-VEGF receptor antibody.

[125] The method of treatment according to

[124] , wherein the anti-VEGF receptor antibody is ramucirumab.

[126] The method of treatment according to

[121] , wherein the VEGF inhibitor is a fusion protein comprising the VEGF receptor extracellular domain.

[127] The method of treatment according to

[126] , wherein the fusion protein comprising the VEGF receptor extracellular domain is aflibercept.

[128] The method of treatment according to

[121] , wherein the VEGF inhibitor is a multispecific antibody comprising an anti-VEGF binding domain.

[129] The method of treatment according to

[128] , wherein the multispecific antibody is a bispecific antibody.

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

[112] to

[129] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in different formulations and administered simultaneously (almost simultaneously) or at different times.

[131] The therapeutic method according to any one of

[112] to

[129] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in the same formulation.

[132] The therapeutic method according to any one of

[112] to

[131] , for treating cancer.

[133] The therapeutic method according to any one of

[112] to

[131] , for treating at least one cancer selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, ovarian mucinous tumor, thyroid cancer, bile duct cancer, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, neuroblastoma, colorectal cancer, gastric cancer, endometrial cancer, endometrial cancer, and nasopharyngeal cancer.

[134] The method of treatment described in any one of

[112] to

[131] for treating at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, ovarian mucinous tumor, thyroid cancer, bile duct cancer, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, and neuroblastoma.

[135] The therapeutic method according to any one of

[112] to

[131] , for treating at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, and papillary renal cell carcinoma.

[136] The therapeutic method according to any one of

[112] to

[131] , for treating at least one selected from the group consisting of ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, and ovarian mucinous tumor.

[137] The therapeutic method according to any one of

[112] to

[131] , for treating ovarian cancer.

[138] The therapeutic method according to

[137] , wherein the ovarian cancer is epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

[139] The therapeutic method according to

[137] or

[138] , wherein the ovarian cancer is metastatic.

[140] The method of any one of

[71] to

[139] , wherein the anti-CDH6 antibody-drug conjugate is raludotatug deruxtecan (DS-6000a).

[141] A formula for treating a disease by administering in combination with a VEGF inhibitor.

[0019]

[0020] (wherein A represents the binding site to the anti-CDH6 antibody or a functional fragment of the antibody) and an anti-CDH6 antibody or a functional fragment of the antibody via a thioether bond.

[142] The anti-CDH6 antibody-drug conjugate according to

[141] , wherein the anti-CDH6 antibody or the functional fragment of the antibody specifically binds to the amino acid sequence set forth in SEQ ID NO: 1 and is an antibody or a functional fragment of the antibody that has the ability to be internalized and taken up into cells.

[143] An anti-CDH6 antibody or a functional fragment thereof, comprising any one of the following (1) to (5): (1) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 3, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4; (2) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 8, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4; (3) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 9, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 10, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 11; (4) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 15, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 16, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 17; and (5) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 21, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 22, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 23. and the following (6) to (9): (6) CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO:5, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO:6, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO:7, (7) CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO:12, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO:13, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO:14, (8) CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO:18, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO:19, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO:20, and (9) CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO:24, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO:25, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO:26, The anti-CDH6 antibody-drug conjugate according to

[141] or

[142] , which is an antibody or a functional fragment of the antibody comprising CDRL1, CDRL2, and CDRL3 selected from the group consisting of:

[144] An anti-CDH6 antibody or a functional fragment thereof, comprising the following (1) to (5): (1) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 3, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4, and a CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 5, a CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 6, and a CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 7; (2) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 8, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4, and a CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 5, a CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 6, and a CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 7; (3) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 9, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 10, and CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 11, and CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 13, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 14; (4) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 15, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 16, and CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 17, and CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 18, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 19, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 20; and (5) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 21, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 22, and CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 23, and CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 24, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 25, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 26; The anti-CDH6 antibody-drug conjugate according to any one of

[141] to

[143] , which is an antibody or a functional fragment of the antibody comprising CDRH1, CDRH2, and CDRH3, and CDRL1, CDRL2, and CDRL3 selected from the group consisting of:

[145] The anti-CDH6 antibody-drug conjugate according to any one of

[141] to

[144] , wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody comprising a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 3, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4, and a CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 5, a CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 6, and a CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 7.

[146] The anti-CDH6 antibody-drug conjugate according to any one of

[141] to

[145] , wherein the anti-CDH6 antibody or a functional fragment of the antibody is a humanized antibody or a functional fragment of the antibody.

[147] An anti-CDH6 antibody or a functional fragment thereof comprises a heavy chain variable region selected from the group consisting of the following (1) to (5): (1) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 28, (2) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 31, (3) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 34, (4) an amino acid sequence having at least 95% or more sequence identity to the framework region sequences other than each CDR sequence in the amino acid sequences of (1) to (3), and (5) an amino acid sequence in which one or several amino acids are deleted, substituted, or added in the framework region sequences other than each CDR sequence in the amino acid sequences of (1) to (4), and (6) to (9) below: (6) a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 37, (7) a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 40, (8) an amino acid sequence having at least 95% or more sequence identity to the framework region sequences other than each CDR sequence in the amino acid sequences of (6) to (7), and (9) The anti-CDH6 antibody-drug conjugate according to any one of

[141] to

[146] , which is an antibody or a functional fragment of the antibody comprising: a light chain variable region according to any one selected from the group consisting of: (6) to (8) wherein one or several amino acids are deleted, substituted, or added in the framework region sequences other than each CDR sequence.

[148] The anti-CDH6 antibody-drug conjugate according to any one of

[141] to

[147] , wherein the anti-CDH6 antibody or a functional fragment of the antibody comprises any one of the following heavy chain variable regions and light chain variable regions: (1) a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 28 and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 37; (2) a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 31 and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 37; (3) a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 31 and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 40; or (4) a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 34 and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 37.

[149] The anti-CDH6 antibody-drug conjugate according to any one of

[141] to

[148] , wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody comprising a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 28 and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 37.

[150] The anti-CDH6 antibody-drug conjugate according to any one of

[141] to

[149] , wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody comprising any of the following (1) to (4): (1) a heavy chain consisting of the amino acid sequence of SEQ ID NO: 29 and a light chain consisting of the amino acid sequence of SEQ ID NO: 38, (2) a heavy chain consisting of the amino acid sequence of SEQ ID NO: 32 and a light chain consisting of the amino acid sequence of SEQ ID NO: 38, (3) a heavy chain consisting of the amino acid sequence of SEQ ID NO: 32 and a light chain consisting of the amino acid sequence of SEQ ID NO: 41, or (4) a heavy chain consisting of the amino acid sequence of SEQ ID NO: 35 and a light chain consisting of the amino acid sequence of SEQ ID NO: 38.

[151] The anti-CDH6 antibody-drug conjugate according to any one of

[141] to

[150] , wherein the anti-CDH6 antibody or a functional fragment of the antibody comprises a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38, or a functional fragment of the antibody.

[152] The anti-CDH6 antibody-drug conjugate according to any one of

[141] to

[151] , wherein the anti-CDH6 antibody or functional fragment thereof is an antibody or functional fragment thereof, wherein the heavy chain or light chain has undergone one or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue to the N-terminus, amidation of proline residues, pyroglutamic acid oxidation of N-terminal glutamine or N-terminal glutamic acid, and deletion of one or two amino acids at the carboxyl terminus.

[153] The anti-CDH6 antibody-drug conjugate according to

[152] , wherein the anti-CDH6 antibody or functional fragment thereof is an antibody or functional fragment thereof, wherein one or two amino acids are deleted at the carboxyl terminus of the heavy chain.

[154] The anti-CDH6 antibody-drug conjugate according to

[153] , wherein the anti-CDH6 antibody or functional fragment thereof is an antibody or functional fragment thereof in which one amino acid is deleted at the carboxyl termini of both of the two heavy chains.

[155] The anti-CDH6 antibody-drug conjugate according to any one of

[152] to

[154] , wherein the deleted amino acid is lysine.

[156] The anti-CDH6 antibody-drug conjugate according to any one of

[152] to

[155] , wherein the anti-CDH6 antibody or functional fragment thereof is an antibody or functional fragment thereof in which a proline residue at the carboxyl terminus of the heavy chain is further amidated.

[157] The anti-CDH6 antibody-drug conjugate according to any one of

[141] to

[156] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 1 to 10.

[158] The anti-CDH6 antibody-drug conjugate according to any one of

[141] to

[156] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 2 to 8.

[159] The anti-CDH6 antibody-drug conjugate according to any one of

[141] to

[156] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 5 to 8.

[160] The anti-CDH6 antibody-drug conjugate according to any one of

[141] to

[156] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7 to 8.

[161] The anti-CDH6 antibody-drug conjugate according to any one of

[141] to

[156] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7.5 to 8.

[162] The anti-CDH6 antibody-drug conjugate according to any one of

[141] to

[156] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is about 8.

[163] The anti-CDH6 antibody-drug conjugate according to any one of

[141] to

[162] , wherein the VEGF inhibitor is an anti-VEGF antibody, an anti-VEGF receptor antibody, a fusion protein comprising a VEGF receptor extracellular domain, or a fusion protein comprising a multispecific antibody comprising an anti-VEGF binding domain.

[164] The anti-CDH6 antibody-drug conjugate according to

[163] , wherein the VEGF inhibitor is an anti-VEGF antibody.

[165] The anti-CDH6 antibody-drug conjugate according to

[164] , wherein the anti-VEGF antibody is bevacizumab.

[166] The anti-CDH6 antibody-drug conjugate according to

[163] , wherein the VEGF inhibitor is an anti-VEGF receptor antibody.

[167] The anti-CDH6 antibody-drug conjugate according to

[166] , wherein the anti-VEGF receptor antibody is ramucirumab.

[168] The anti-CDH6 antibody-drug conjugate according to

[163] , wherein the VEGF inhibitor is a fusion protein comprising the extracellular domain of a VEGF receptor.

[169] The anti-CDH6 antibody-drug conjugate according to

[168] , wherein the fusion protein comprising the extracellular domain of a VEGF receptor is aflibercept.

[170] The anti-CDH6 antibody-drug conjugate according to

[163] , wherein the VEGF inhibitor is a multispecific antibody comprising an anti-VEGF binding domain.

[171] The anti-CDH6 antibody-drug conjugate according to

[170] , wherein the multispecific antibody is a bispecific antibody.

[172] The anti-CDH6 antibody-drug conjugate according to any one of

[141] to

[171] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in different formulations and are administered simultaneously (almost simultaneously) or at different times.

[173] The anti-CDH6 antibody-drug conjugate according to any one of

[141] to

[171] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in the same formulation.

[174] The anti-CDH6 antibody-drug conjugate according to any one of

[141] to

[173] , for the treatment of cancer.

[175] The anti-CDH6 antibody-drug conjugate of any one of

[141] to

[173] for the treatment of at least one cancer selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, ovarian mucinous tumor, thyroid cancer, bile duct cancer, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, neuroblastoma, colorectal cancer, gastric cancer, endometrial cancer, uterine corpus cancer, and nasopharyngeal cancer.

[176] The anti-CDH6 antibody-drug conjugate of any one of

[141] to

[173] for the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, ovarian mucinous tumor, thyroid cancer, cholangiocarcinoma, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, and neuroblastoma.

[177] The anti-CDH6 antibody-drug conjugate of any one of

[141] to

[173] for the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, and papillary renal cell carcinoma.

[178] The anti-CDH6 antibody-drug conjugate of any one of

[141] to

[173] for the treatment of at least one selected from the group consisting of ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, and ovarian mucinous tumor.

[179] The anti-CDH6 antibody-drug conjugate of any one of

[141] to

[173] for use in treating ovarian cancer.

[180] The anti-CDH6 antibody-drug conjugate of

[179] , wherein the ovarian cancer is epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

[181] The anti-CDH6 antibody-drug conjugate of

[179] or

[180] , wherein the ovarian cancer is metastatic.

[182] A formula for treating a disease by administration in combination with a VEGF inhibitor.

[0021]

[0022] (wherein the formula is an anti-CDH6 antibody, the drug linker is bound to the antibody via a thioether bond, and n represents the average number of drug linkers bound per antibody).

[183] ​​The anti-CDH6 antibody-drug conjugate according to

[182] , wherein the anti-CDH6 antibody comprises a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38.

[184] The anti-CDH6 antibody-drug conjugate according to

[182] or

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

[185] The anti-CDH6 antibody-drug conjugate according to any one of

[182] to

[184] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 1 to 10.

[186] The anti-CDH6 antibody-drug conjugate according to any one of

[182] to

[184] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 2 to 8.

[187] The anti-CDH6 antibody-drug conjugate according to any one of

[182] to

[184] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 5 to 8.

[188] The anti-CDH6 antibody-drug conjugate according to any one of

[182] to

[184] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7 to 8.

[189] The anti-CDH6 antibody-drug conjugate according to any one of

[182] to

[184] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7.5 to 8.

[190] The anti-CDH6 antibody-drug conjugate according to any one of

[182] to

[184] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is about 8.

[191] The anti-CDH6 antibody-drug conjugate according to any one of

[182] to

[190] , wherein the VEGF inhibitor is an anti-VEGF antibody, an anti-VEGF receptor antibody, a fusion protein comprising a VEGF receptor extracellular domain, or a multispecific antibody comprising an anti-VEGF binding domain.

[192] The anti-CDH6 antibody-drug conjugate according to

[191] , wherein the VEGF inhibitor is an anti-VEGF antibody.

[193] The anti-CDH6 antibody-drug conjugate according to

[192] , wherein the anti-VEGF antibody is bevacizumab.

[194] The anti-CDH6 antibody-drug conjugate according to

[191] , wherein the VEGF inhibitor is an anti-VEGF receptor antibody.

[195] The anti-CDH6 antibody-drug conjugate according to

[194] , wherein the anti-VEGF receptor antibody is ramucirumab.

[196] The anti-CDH6 antibody-drug conjugate according to

[191] , wherein the VEGF inhibitor is a fusion protein comprising a VEGF receptor extracellular domain.

[197] The anti-CDH6 antibody-drug conjugate according to

[196] , wherein the fusion protein comprising a VEGF receptor extracellular domain is aflibercept.

[198] The anti-CDH6 antibody-drug conjugate according to

[191] , wherein the VEGF inhibitor is a multispecific antibody comprising an anti-VEGF-binding domain.

[199] The anti-CDH6 antibody-drug conjugate according to

[198] , wherein the multispecific antibody is a bispecific antibody.

[200] The anti-CDH6 antibody-drug conjugate according to any one of

[182] to

[199] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in different formulations and are administered simultaneously (almost simultaneously) or at different times.

[201] The anti-CDH6 antibody-drug conjugate according to any one of

[182] to

[199] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in the same formulation.

[202] The anti-CDH6 antibody-drug conjugate according to any one of

[182] to

[201] , for the treatment of cancer.

[203] The anti-CDH6 antibody-drug conjugate of any one of

[182] to

[201] , for the treatment of at least one cancer selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, ovarian mucinous tumor, thyroid cancer, bile duct cancer, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, neuroblastoma, colorectal cancer, gastric cancer, endometrial cancer, uterine corpus cancer, and nasopharyngeal cancer.

[204] The anti-CDH6 antibody-drug conjugate of any one of

[182] to

[201] for the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, ovarian mucinous tumor, thyroid cancer, cholangiocarcinoma, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, and neuroblastoma.

[205] The anti-CDH6 antibody-drug conjugate of any one of

[182] to

[201] for the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, and papillary renal cell carcinoma.

[206] The anti-CDH6 antibody-drug conjugate of any one of

[182] to

[201] for the treatment of at least one selected from the group consisting of ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, and ovarian mucinous tumor.

[207] The anti-CDH6 antibody-drug conjugate of any one of

[182] to

[201] for the treatment of ovarian cancer.

[208] The anti-CDH6 antibody-drug conjugate of

[207] , wherein the ovarian cancer is epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

[209] The anti-CDH6 antibody-drug conjugate of

[207] or

[208] , wherein the ovarian cancer is metastatic.

[210] The anti-CDH6 antibody-drug conjugate according to any one of

[141] to

[209] , wherein the anti-CDH6 antibody-drug conjugate is raludotatug deruxtecan (DS-6000a).

[211] A formula for the preparation of a medicament for treating a disease by administering in combination with a VEGF inhibitor.

[0023]

[0024] (wherein A represents the binding site with the anti-CDH6 antibody or a functional fragment of the antibody) and the anti-CDH6 antibody or a functional fragment of the antibody via a thioether bond.

[212] The use according to

[211] , wherein the anti-CDH6 antibody or the functional fragment of the antibody is an antibody or a functional fragment of the antibody that specifically binds to the amino acid sequence set forth in SEQ ID NO: 1 and has the ability to be internalized into cells.

[213] An anti-CDH6 antibody or a functional fragment thereof, comprising any one of the following (1) to (5): (1) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 3, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4; (2) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 8, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4; (3) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 9, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 10, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 11; (4) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 15, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 16, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 17; and (5) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 21, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 22, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 23. and the antibody or a functional fragment of the antibody, comprising CDRL1, CDRL2, and CDRL3 selected from the group consisting of: CDRH1, CDRH2, and CDRH3 of any one selected from the group consisting of (6) to (9) below: (6) CDRL1 consisting of the amino acid sequence of SEQ ID NO:5, CDRL2 consisting of the amino acid sequence of SEQ ID NO:6, and CDRL3 consisting of the amino acid sequence of SEQ ID NO:7; (7) CDRL1 consisting of the amino acid sequence of SEQ ID NO:12, CDRL2 consisting of the amino acid sequence of SEQ ID NO:13, and CDRL3 consisting of the amino acid sequence of SEQ ID NO:14; (8) CDRL1 consisting of the amino acid sequence of SEQ ID NO:18, CDRL2 consisting of the amino acid sequence of SEQ ID NO:19, and CDRL3 consisting of the amino acid sequence of SEQ ID NO:20; and (9) CDRL1 consisting of the amino acid sequence of SEQ ID NO:24, CDRL2 consisting of the amino acid sequence of SEQ ID NO:25, and CDRL3 consisting of the amino acid sequence of SEQ ID NO:26.

[214] An anti-CDH6 antibody or a functional fragment thereof, comprising any one of the following (1) to (5): (1) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 3, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4, and a CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 5, a CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 6, and a CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 7; (2) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 8, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4, and a CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 5, a CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 6, and a CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 7; (3) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 9, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 10, and CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 11, and CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 13, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 14; (4) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 15, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 16, and CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 17, and CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 18, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 19, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 20; and (5) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 21, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 22, and CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 23, and CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 24, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 25, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 26; The use according to any one of

[211] to

[213] , wherein the antibody or functional fragment thereof comprises CDRH1, CDRH2 and CDRH3, and CDRL1, CDRL2 and CDRL3 selected from the group consisting of:

[215] The use according to any one of

[211] to

[214] , wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody comprising a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 3, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4, and a CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 5, a CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 6, and a CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 7.

[216] The use according to any one of

[211] to

[215] , wherein the anti-CDH6 antibody or a functional fragment of the antibody is a humanized antibody or a functional fragment of the antibody.

[217] An anti-CDH6 antibody or a functional fragment thereof comprises a heavy chain variable region selected from the group consisting of the following (1) to (5): (1) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 28, (2) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 31, (3) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 34, (4) an amino acid sequence having at least 95% or more sequence identity to the framework region sequences other than each CDR sequence in the amino acid sequences of (1) to (3), and (5) an amino acid sequence in which one or several amino acids are deleted, substituted, or added in the framework region sequences other than each CDR sequence in the amino acid sequences of (1) to (4), and (6) to (9) below: (6) a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 37, (7) a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 40, (8) an amino acid sequence having at least 95% or more sequence identity to the framework region sequences other than each CDR sequence in the amino acid sequences of (6) to (7), and (9) The use according to any one of

[211] to

[216] , wherein the antibody or a functional fragment thereof comprises a light chain variable region according to any one selected from the group consisting of: (10) an amino acid sequence in which one or several amino acids are deleted, substituted, or added in the framework region sequences other than each CDR sequence in the amino acid sequences of (6) to (8).

[218] The use according to any one of

[211] to

[217] , wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody comprising any of the following heavy chain variable regions and light chain variable regions (1) to (4): (1) a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 28 and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 37, (2) a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 31 and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 37, (3) a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 31 and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 40, or (4) a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 34 and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 37.

[219] The use according to any one of

[211] to

[218] , wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody comprising a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 28 and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 37.

[220] The use according to any one of

[211] to

[219] , wherein the anti-CDH6 antibody or a functional fragment of the antibody comprises any of the following (1) to (4): (1) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38, (2) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38, (3) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 41, or (4) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 35 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38.

[221] The use according to any one of

[211] to

[220] , wherein the anti-CDH6 antibody or a functional fragment of the antibody comprises a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38, or a functional fragment of the antibody.

[222] The use according to any one of

[211] to

[221] , wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody, in which the heavy chain or light chain has undergone one or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue to the N-terminus, amidation of proline residues, pyroglutamic acid oxidation of N-terminal glutamine or N-terminal glutamic acid, and deletion of one or two amino acids at the carboxyl terminus.

[223] The use according to

[222] , wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody in which one or two amino acids are deleted at the carboxyl terminus of the heavy chain.

[224] The use according to

[223] , wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody in which one amino acid is deleted at the carboxyl terminus of both of the two heavy chains.

[225] The use according to any one of

[222] to

[224] , wherein the deleted amino acid is lysine.

[226] The use according to any one of

[222] to

[225] , wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody in which a proline residue at the carboxyl terminus of the heavy chain is further amidated.

[227] The use according to any one of

[211] to

[226] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 1 to 10.

[228] The use according to any one of

[211] to

[226] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 2 to 8.

[229] The use according to any one of

[211] to

[226] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 5 to 8.

[230] The use according to any one of

[211] to

[226] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7 to 8.

[231] The use according to any one of

[211] to

[226] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7.5 to 8.

[232] The use according to any one of

[211] to

[226] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is about 8.

[233] The use according to any one of

[211] to

[232] , wherein the VEGF inhibitor is an anti-VEGF antibody, an anti-VEGF receptor antibody, a fusion protein comprising a VEGF receptor extracellular domain, or a multispecific antibody comprising an anti-VEGF binding domain.

[234] The use according to

[233] , wherein the VEGF inhibitor is an anti-VEGF antibody.

[235] The use according to

[234] , wherein the anti-VEGF antibody is bevacizumab.

[236] The use according to

[233] , wherein the VEGF inhibitor is an anti-VEGF receptor antibody.

[237] The use according to

[236] , wherein the anti-VEGF receptor antibody is ramucirumab.

[238] The use according to

[233] , wherein the VEGF inhibitor is a fusion protein comprising a VEGF receptor extracellular domain.

[239] The use according to

[238] , wherein the fusion protein comprising a VEGF receptor extracellular domain is aflibercept.

[240] The use according to

[233] , wherein the VEGF inhibitor is a multispecific antibody comprising an anti-VEGF binding domain.

[241] The use according to

[240] , wherein the multispecific antibody is a bispecific antibody.

[242] The use according to any one of

[211] to

[241] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in different formulations and administered simultaneously (almost simultaneously) or at different times.

[243] The use according to any one of

[211] to

[241] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in the same formulation.

[244] The use according to any one of

[211] to

[243] , for the treatment of cancer.

[245] The use of any one of

[211] to

[243] for the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, ovarian mucinous tumor, thyroid cancer, bile duct cancer, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, neuroblastoma, colorectal cancer, gastric cancer, endometrial cancer, uterine corpus cancer, and nasopharyngeal cancer.

[246] The use of any one of

[211] to

[243] for the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, ovarian mucinous tumor, thyroid cancer, cholangiocarcinoma, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, and neuroblastoma.

[247] The use of any one of

[211] to

[243] for the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, and papillary renal cell carcinoma.

[248] The use of any one of

[211] to

[243] for the treatment of at least one selected from the group consisting of ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, and ovarian mucinous tumor.

[249] The use according to any one of

[211] to

[243] for the treatment of ovarian cancer.

[250] The use according to

[249] , wherein the ovarian cancer is epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

[251] The use according to

[249] or

[250] , wherein the ovarian cancer is metastatic.

[252] A formula for the manufacture of a medicament for treating a disease by administering in combination with a VEGF inhibitor.

[0025]

[0026] (wherein the formula is an anti-CDH6 antibody, the drug linker is bound to the antibody via a thioether bond, and n represents the average number of drug linkers bound per antibody).

[253] The use according to

[252] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38.

[254] The use according to

[252] or

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

[255] The use according to any one of

[252] to

[254] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 1 to 10.

[256] The use according to any one of

[252] to

[254] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 2 to 8.

[257] The use according to any one of

[252] to

[254] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 5 to 8.

[258] The use according to any one of

[252] to

[254] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7 to 8.

[259] The use according to any one of

[252] to

[254] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7.5 to 8.

[260] The use according to any one of

[252] to

[254] , wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is about 8.

[261] The use according to any one of

[252] to

[260] , wherein the VEGF inhibitor is an anti-VEGF antibody, an anti-VEGF receptor antibody, a fusion protein comprising a VEGF receptor extracellular domain, or a multispecific antibody comprising an anti-VEGF binding domain.

[262] The use according to

[261] , wherein the VEGF inhibitor is an anti-VEGF antibody.

[263] The use according to

[262] , wherein the anti-VEGF antibody is bevacizumab.

[264] The use according to

[261] , wherein the VEGF inhibitor is an anti-VEGF receptor antibody.

[265] The use according to

[264] , wherein the anti-VEGF receptor antibody is ramucirumab.

[266] The use according to

[261] , wherein the VEGF inhibitor is a fusion protein comprising a VEGF receptor extracellular domain.

[267] The use according to

[266] , wherein the fusion protein comprising a VEGF receptor extracellular domain is aflibercept.

[268] The use according to

[261] , wherein the VEGF inhibitor is a multispecific antibody comprising an anti-VEGF binding domain.

[269] The use according to

[268] , wherein the multispecific antibody is a bispecific antibody.

[270] The use according to any one of

[252] to

[269] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in different formulations and administered simultaneously (almost simultaneously) or at different times.

[271] The use according to any one of

[252] to

[269] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in the same formulation.

[272] The use according to any one of

[252] to

[271] , for the treatment of cancer.

[273] The use according to any one of

[252] to

[271] , for the treatment of at least one cancer selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, ovarian mucinous tumor, thyroid cancer, bile duct cancer, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, neuroblastoma, colorectal cancer, gastric cancer, endometrial cancer, endometrial cancer, and nasopharyngeal cancer.

[274] The use of any one of

[252] to

[271] for the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, ovarian mucinous tumor, thyroid cancer, bile duct cancer, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, and neuroblastoma.

[275] The use of any one of

[252] to

[271] for the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, and papillary renal cell carcinoma.

[276] The use of any one of

[252] to

[271] for the treatment of at least one selected from the group consisting of ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, and ovarian mucinous tumor.

[277] The use of any one of

[252] to

[271] for the treatment of ovarian cancer.

[278] The use of

[277] , wherein the ovarian cancer is epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

[279] The use of

[277] or

[278] , wherein the ovarian cancer is metastatic.

[280] The use according to any one of

[211] to

[279] , wherein the anti-CDH6 antibody-drug conjugate is raludotatug deruxtecan (DS-6000a).

[281] A pharmaceutical product containing an anti-CDH6 antibody-drug conjugate and a VEGF inhibitor for combined administration, wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are as defined in any one of [1] to

[31] ,

[42] to

[59] , and

[70] .

[282] The pharmaceutical product according to

[281] , for treating a disease defined in any one of

[34] to

[41] and

[62] to

[69] .

[283] The pharmaceutical product according to

[281] or

[282] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in separate formulations and are administered simultaneously (almost simultaneously) or at different times.

[284] The pharmaceutical product according to

[281] or

[282] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in the same formulation.

[285] A combination pharmaceutical containing an anti-CDH6 antibody-drug conjugate and a VEGF inhibitor, wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are as defined in any one of [1] to

[31] ,

[42] to

[59] , and

[70] .

[286] The combination pharmaceutical according to

[285] , for the treatment of a disease defined in any one of

[34] to

[41] and

[62] to

[69] .

[287] The pharmaceutical combination according to

[285] or

[286] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in different formulations and administered simultaneously (almost simultaneously) or at different times.

[288] The pharmaceutical combination according to

[285] or

[286] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in the same formulation.

[289] A pharmaceutical combination comprising an anti-CDH6 antibody-drug conjugate and a VEGF inhibitor, wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are as defined in any one of [1] to

[31] ,

[42] to

[59] , and

[70] .

[290] The pharmaceutical combination according to

[289] , for the treatment of a disease defined in any one of

[34] to

[41] , and

[62] to

[69] .

[291] The pharmaceutical combination according to

[289] or

[290] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in different formulations and administered simultaneously (almost simultaneously) or at different times.

[292] The pharmaceutical combination according to

[289] or

[290] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in the same formulation.

[293] Use of an anti-CDH6 antibody-drug conjugate in combination with a VEGF inhibitor for the treatment of a disease, wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are as defined in any one of [1] to

[31] ,

[42] to

[59] , and

[70] .

[294] The use according to

[293] , wherein the disease is as defined in any one of

[34] to

[41] , and

[62] to

[69] .

[295] The use according to

[293] or

[294] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in different formulations and are administered simultaneously (almost simultaneously) or at different times.

[296] The use according to

[293] or

[294] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in the same formulation.

[297] A pharmaceutical comprising an anti-CDH6 antibody-drug conjugate and a VEGF inhibitor, wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are administered in combination, and the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are as defined in any one of [1] to

[31] ,

[42] to

[59] , and

[70] .

[298] The pharmaceutical according to

[297] , for treating a disease defined in any one of

[34] to

[41] and

[62] to

[69] .

[299] The pharmaceutical according to

[297] or

[298] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in different formulations and administered simultaneously (almost simultaneously) or at different times.

[300] The pharmaceutical according to

[297] or

[298] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in the same formulation.

[301] A pharmaceutical composition comprising (i) an anti-CDH6 antibody-drug conjugate and (ii) a VEGF inhibitor, wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are administered in combination, and the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are as defined in any one of [1] to

[31] ,

[42] to

[59] , and

[70] .

[302] The pharmaceutical composition according to

[301] , for treating a disease defined in any one of

[34] to

[41] and

[62] to

[69] .

[303] The pharmaceutical composition according to

[301] or

[302] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in separate formulations and administered simultaneously (almost simultaneously) or at different times.

[304] The pharmaceutical composition according to

[301] or

[302] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in the same formulation.

[305] A kit comprising (i) a first composition comprising an anti-CDH6 antibody-drug conjugate and (ii) a second composition comprising a VEGF inhibitor, wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are administered in combination, and the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are as defined in any one of [1] to

[31] ,

[42] to

[59] , and

[70] .

[306] The kit according to

[305] , for treating a disease defined in any one of

[34] to

[41] and

[62] to

[69] .

[307] The kit according to

[305] or

[306] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in separate formulations and are administered simultaneously (almost simultaneously) or at different times.

[308] The kit according to

[305] or

[306] , wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained (as active ingredients) in the same formulation.

[309] A method for treating cancer, characterized in that the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are administered in combination to an individual in need of treatment, wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are as defined in any one of [1] to

[31] ,

[42] to

[59] , and

[70] .

[0027] The present invention can provide a pharmaceutical composition characterized by administering a specific anti-CDH6 antibody-drug conjugate and a VEGF inhibitor in combination, and / or a treatment method characterized by administering a specific anti-CDH6 antibody-drug conjugate and a VEGF inhibitor in combination to an individual.

[0028]

[0023] Figure 1 shows the amino acid sequence of human CDH6 EC3 (SEQ ID NO: 1). Figure 2 shows the amino acid sequence of CDRH1 of the anti-CDH6 antibody heavy chain (SEQ ID NO: 2). Figure 3 shows the amino acid sequence of CDRH2 of the anti-CDH6 antibody heavy chain (SEQ ID NO: 3). Figure 4 shows the amino acid sequence of CDRH3 of the anti-CDH6 antibody heavy chain (SEQ ID NO: 4). Figure 5 shows the amino acid sequence of CDRL1 of the anti-CDH6 antibody light chain (SEQ ID NO: 5). Figure 6 shows the amino acid sequence of CDRL2 of the anti-CDH6 antibody light chain (SEQ ID NO: 6). Figure 7 shows the amino acid sequence of CDRL3 of the anti-CDH6 antibody light chain (SEQ ID NO: 7). Figure 8 shows the amino acid sequence of the anti-CDH6 antibody heavy chain (SEQ ID NO: 27). Figure 9 shows the amino acid sequence of the anti-CDH6 antibody heavy chain variable region (SEQ ID NO: 28). Figure 10 shows the amino acid sequence of the anti-CDH6 antibody mature heavy chain (SEQ ID NO: 29). Figure 11 shows the amino acid sequence of the anti-CDH6 antibody light chain (SEQ ID NO: 36).

[0033] Figure 1 shows the amino acid sequence of the light chain variable region of an anti-CDH6 antibody (SEQ ID NO: 37). Figure 2 shows the amino acid sequence of the mature light chain of an anti-CDH6 antibody (SEQ ID NO: 38). Figure 3 shows the tumor growth inhibitory effect of a group administered a single agent of anti-CDH6 antibody-drug conjugate (1) or bevacizumab, and a group administered a combination of anti-CDH6 antibody-drug conjugate (1) and bevacizumab (Combination) in mice subcutaneously implanted with OV-90 cells. FIG. 1 shows the rate of change in mean tumor volume on Day 21, with the mean tumor volume on Day 0 used as the baseline, for mice subcutaneously implanted with OV-90 cells, in groups administered a single agent of anti-CDH6 antibody-drug conjugate (1) or bevacizumab, and in a group administered a combination of anti-CDH6 antibody-drug conjugate (1) and bevacizumab (Combination).

[0029] Preferred embodiments for carrying out the present invention will be described below. Note that the embodiments described below are examples of typical embodiments of the present invention, and the scope of the present invention should not be construed as being narrow.

[0030] 1. Definition Cadherins are glycoproteins present on the cell membrane surface that function as intercellular adhesion molecules and signaling molecules responsible for cell-cell interactions by binding together their N-terminal extracellular domains in a calcium ion-dependent manner. Within the cadherin superfamily, molecules classified as classic cadherins are single-pass transmembrane proteins consisting of five extracellular domains (EC domains), one transmembrane region, and an intracellular domain. CDH6 (Cadherin-6) is a single-pass transmembrane protein consisting of 790 amino acids and classified into the type II cadherin family, with the N-terminus extracellular and the C-terminus intracellular. The human CDH6 gene was first cloned in 1995 (Shimoyama Y, et al., Cancer Research, 2206-2211, 55, May 15, 1995) and can be referenced by accession numbers such as NM_004932 and NP_004923 (NCBI). The amino acid sequence set forth in SEQ ID NO: 1 is the amino acid sequence of extracellular domain 3 of human CDH6 (herein also referred to as EC domain 3 or EC3).

[0031] As used herein, the terms "cancer" and "tumor" are used interchangeably. As used herein, the term "gene" includes not only DNA but also its mRNA, cDNA, and cRNA. As used herein, "CDH6" may be used interchangeably with CDH6 protein. As used herein, "anti-CDH6 antibody" refers to an antibody that specifically binds to CDH6 (Cadherin-6). Preferably, an anti-CDH6 antibody is an antibody that has the activity of being internalized into CDH6-expressing cells by binding to CDH6. As used herein, the term "functional fragment of an antibody" is also referred to as an "antigen-binding fragment of an antibody," and refers to a partial fragment of an antibody that has antigen-binding activity, including Fab, F(ab')2, Fv, scFv, diabody, linear antibody, and multispecific antibody formed from antibody fragments. Also included within the antigen-binding fragment of an antibody is Fab', a monovalent fragment of the variable region of an antibody obtained by treating F(ab')2 under reducing conditions. However, the term is not limited to these molecules as long as it has the ability to bind to an antigen. Furthermore, these antigen-binding fragments include not only those obtained by treating the full-length antibody protein molecule with an appropriate enzyme, but also proteins produced in appropriate host cells using genetically engineered antibody genes.

[0032] As used herein, "CDR" refers to a complementarity-determining region (CDR). It is known that the heavy and light chains of an antibody molecule each contain three CDRs. CDRs, also known as hypervariable regions, are located within the variable regions of the heavy and light chains of an antibody and are particularly highly variable in their primary structure. They are separated into three regions in the primary structure of the heavy and light chain polypeptide chains. As used herein, the CDRs of an antibody are represented as CDRH1, CDRH2, and CDRH3 from the amino-terminus of the heavy chain amino acid sequence, and CDRL1, CDRL2, and CDRL3 from the amino-terminus of the light chain amino acid sequence. These regions are adjacent to each other in the three-dimensional structure and determine the specificity for the antigen to which they bind. As used herein, the term "about" refers to a value that varies by plus or minus 10%, 8%, 6%, 5%, 4%, 3%, 2%, or 1% from the reference value. Preferably, "about" refers to a range of plus or minus 10%, 5%, or 1% from the reference value. As used herein, "resistance" refers to the property of being unresponsive to treatment with an anticancer drug, and can also be expressed as "resistant," "refractory," "unresponsive," or "refractory." Furthermore, since unresponsiveness prevents tumor growth, it can also be expressed as "intolerance." Furthermore, in the present invention, "resistance" includes cases where a patient's cancer is hyposensitive to treatment with an anticancer drug, where cancer cells do not disappear or shrink, where a complete response (CR) or partial response (PR) is not achieved, and / or where the cancer progresses early (e.g., within 6 months or less in the case of ovarian cancer).

[0033] As used herein, "chemotherapy" refers to treatment using one or more chemotherapeutic agents used to treat cancer. As used herein, "chemotherapeutic agent" refers to an agent for chemotherapy used to treat cancer. Chemotherapeutic agents include alkylating agents (e.g., mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, hexamethylmelamine, thiotepa, busulfan, carmustine, lomustine, semustine, streptozocin, dacarbazine), antimetabolites (e.g., gemcitabine, methotrexate, fluorouracil, doxifluridine, capecitabine, floxuridine, cytarabine, mercaptopurine, thioguanine, pentostatin), vinca alkaloids (e.g., vinblastine, vincristine), epipodophyllotoxins (e.g., etoposide, teniposide, thiazolinone ... anti-inflammatory drugs (e.g., cyclosporin, cyclosporin), cyclosporin ( ...

[0034] As used herein, "platinum-based chemotherapy" refers to cancer treatment using one or more platinum-based drugs, with or without one or more chemotherapeutic agents other than platinum-based drugs. As used herein, "platinum-based drug" refers to a platinum compound used to treat cancer. Platinum-based drugs include, but are not limited to, cisplatin, carboplatin, and oxaliplatin. As used herein, "cancer recurrence" refers to the return of cancer in the same location as the primary tumor or elsewhere in the body after a period in which the cancer could not be detected. "Cancer recurrence" is defined based on the following references: NCI Dictionaries, "recurrence", NCI Dictionary of Cancer Terms [online]. National Cancer Institute [retrieved on 2023-12-27]. Retrieved from<cancer.gov / publications / dictionaries / cancer-terms / def / recurrence> As used herein, the term "chemotherapeutic regimen" refers to a treatment plan for chemotherapy that defines the drug, dosage, frequency, etc. For example, a "chemotherapeutic regimen including a platinum-based drug" refers to a chemotherapy regimen that includes administering a platinum-based drug, and a "chemotherapeutic regimen including a platinum-based drug and a taxane" refers to a chemotherapy regimen that includes administering a platinum-based drug and a taxane.

[0035] 2. Anti-CDH6 Antibody-Drug Conjugate The anti-CDH6 antibody-drug conjugate used in the present invention is represented by the formula

[0036]

[0037] (wherein A represents the binding site to the anti-CDH6 antibody or a functional fragment of the antibody), and the anti-CDH6 antibody or a functional fragment of the antibody are linked via a thioether bond.

[0038] In the present invention, a partial structure of an antibody-drug conjugate consisting of a linker and a drug is referred to as a “drug linker.” This drug linker is bound to a thiol group (in other words, a sulfur atom of a cysteine ​​residue) generated at an interchain disulfide bond site of the antibody (two sites between heavy chains and two sites between heavy chains and light chains).

[0039] The drug linker of the present invention is based on the topoisomerase I inhibitor exatecan (IUPAC name: (1S,9S)-1-amino-9-ethyl-5-fluoro-1,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione, (chemical name: (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione)). Exatecan has the formula

[0040]

[0041] It is a camptothecin derivative having an antitumor effect, represented by the formula:

[0042] The anti-CDH6 antibody-drug conjugate used in the present invention can also be represented by the following formula:

[0043]

[0044] Here, the antibody is an anti-CDH6 antibody or a functional fragment of the antibody (preferably an anti-CDH6 antibody), and the drug linker is bound to the antibody via a thioether bond (each drug linker represented by the structure shown in parentheses in the formula is bound to the antibody via a thioether bond). Furthermore, n is synonymous with the so-called average drug binding number (DAR; Drug-to-Antibody Ratio) and indicates the average number of drug linkers bound per antibody.

[0045] In some embodiments, the anti-CDH6 antibody-drug conjugate is raludotatug deruxtecan (also referred to as R-DXd or DS-6000a).

[0046] The anti-CDH6 antibody-drug conjugate used in the present invention is translocated into cancer cells, and then the linker moiety is cleaved, resulting in the formation of a conjugate of the formula

[0047]

[0048] (hereinafter referred to as compound (A)).

[0049] The above compound is believed to be the basis of the antitumor activity of the anti-CDH6 antibody-drug conjugate used in the present invention, and has been confirmed to have topoisomerase I inhibitory activity (Ogitani Y. et al., Clinical Cancer Research, 2016, Oct 15;22(20):5097-5108, Epub 2016 Mar 29).

[0050] Topoisomerase I is an enzyme involved in DNA synthesis, which changes the higher-order structure of DNA by breaking and recombining single strands of DNA. Therefore, drugs with topoisomerase I inhibitory activity can inhibit DNA synthesis, thereby stopping cell division at the S phase (DNA synthesis phase) of the cell cycle and inducing cell death by apoptosis, thereby suppressing the proliferation of cancer cells.

[0051] The antibody-drug conjugate used in the present invention is also known to have a bystander antitumor effect (Suzuki H, et al., Molecular Cancer Therapeutics, (2024) 23 (3): 257-271).

[0052] This bystander antitumor effect is exerted when the antibody-drug conjugate used in the present invention is internalized into target-expressing cancer cells, and the compound is then released to exert an antitumor effect on nearby cancer cells that do not express the target.

[0053] This bystander antitumor effect is also exhibited as an excellent antitumor effect when the antibody-drug conjugate according to the present invention is used in combination with a VEGF inhibitor.

[0054] Other examples of anti-CDH6 antibody-drug conjugates are not particularly limited as long as they are anti-CDH6 antibodies to which anti-tumor compounds are bound via linker structure moieties, and examples thereof include CUSP06, BSI-709, and those described in WO 2023 / 102875 and WO 2023 / 104188.

[0055] 3. Antibody in Anti-CDH6 Antibody-Drug Conjugate The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention may be derived from any species, but is preferably an anti-CDH6 antibody derived from human, rat, mouse, or rabbit. When the anti-CDH6 antibody is derived from a species other than human, it is preferably chimerized or humanized using well-known techniques. The anti-CDH6 antibody of the present invention may be a polyclonal antibody or a monoclonal antibody, but is preferably a monoclonal antibody.

[0056] The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention preferably has the property of being able to target cancer cells, and preferably has the ability to recognize cancer cells, the ability to bind to cancer cells, the ability to be taken up and internalized within cancer cells, and / or cytocidal activity against cancer cells.

[0057] The binding of antibodies to cancer cells can be confirmed using flow cytometry. Antibody uptake into cancer cells can be confirmed using (1) an assay in which a secondary antibody (fluorescently labeled) that binds to a therapeutic antibody is used to visualize the antibody taken up into the cells using a fluorescence microscope (Cell Death and Differentiation (2008) 15, 751-761), (2) an assay in which a secondary antibody (fluorescently labeled) that binds to a therapeutic antibody is used to measure the amount of fluorescence taken up into the cells (Molecular Biology of the Cell Vol. 15, 5268-5282, December 2004), or (3) a Mab-ZAP assay in which an immunotoxin that binds to a therapeutic antibody is released upon intracellular uptake, thereby inhibiting cell proliferation (BioTechniques 28:162-165, January 2000). A recombinant conjugate protein consisting of the catalytic domain of diphtheria toxin and protein G can also be used as the immunotoxin.

[0058] The antitumor activity of an antibody can be confirmed in vitro by measuring its inhibitory activity against cell proliferation. For example, a cancer cell line overexpressing the antibody's target protein can be cultured, and the antibody can be added to the culture system at various concentrations to measure its inhibitory activity against focus formation, colony formation, and spheroid growth. In vivo, the antitumor activity can be confirmed, for example, by administering the antibody to nude mice transplanted with a cancer cell line overexpressing the target protein and measuring changes in the cancer cells.

[0059] Although it is preferable that the antibody itself has an antitumor effect, since the antibody-drug conjugate is bound to a compound that exerts an antitumor effect, the antibody itself does not necessarily have an antitumor effect. For the purpose of specifically and selectively exerting the cytotoxicity of the antitumor compound on cancer cells, it is important and preferable that the antibody has the property of being internalized and transported into cancer cells.

[0060] The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention can be obtained by known means. For example, it can be obtained by immunizing an animal with a polypeptide that serves as an antigen, and collecting and purifying the antibody produced in the body, using methods commonly used in this field. The origin of the antigen is not limited to humans; animals can also be immunized with antigens derived from animals other than humans, such as mice and rats. In this case, antibodies that are applicable to human diseases can be selected by testing the cross-reactivity of the obtained antibody that binds to the heterologous antigen with human antigens.

[0061] Alternatively, a monoclonal antibody can be obtained by fusing antibody-producing cells that produce an antibody against an antigen with myeloma cells to establish a hybridoma according to known methods (e.g., Kohler and Milstein, Nature (1975) 256, pp. 495-497; Kennet, R. ed., Monoclonal Antibodies, pp. 365-367, Plenum Press, NY (1980)).

[0062] Antigens can be obtained by genetically engineering a gene encoding an antigen protein in a host cell to produce it. Specifically, a vector capable of expressing the antigen gene is prepared, introduced into a host cell to express the gene, and the expressed antigen is purified. Antibodies can also be obtained by immunizing an animal with the above-mentioned genetically engineered antigen-expressing cells or a cell line expressing the antigen.

[0063] The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is preferably a genetically engineered antibody that has been artificially modified for the purpose of reducing heterologous antigenicity to humans, such as a chimeric antibody or a humanized antibody, or is preferably an antibody having only the genetic sequence of a human-derived antibody, i.e., a human antibody. These antibodies can be produced using known methods.

[0064] Chimeric antibodies include antibodies in which the variable and constant regions are of different species, such as chimeric antibodies in which the variable regions of a mouse- or rat-derived antibody are joined to the constant regions of a human-derived antibody (Proc. Natl. Acad. Sci. USA, 81, 6851-6855, (1984)).

[0065] Examples of humanized antibodies include antibodies in which only the complementarity determining region (CDR) of a heterologous antibody has been incorporated into a human-derived antibody (Nature (1986) 321, pp. 522-525), antibodies in which not only the CDR sequence of a heterologous antibody but also some framework amino acid residues of the heterologous antibody have been grafted onto a human antibody by CDR grafting (WO 90 / 07861), and antibodies humanized using a gene conversion mutagenesis strategy (U.S. Pat. No. 5,821,337).

[0066] Examples of human antibodies include antibodies produced using human antibody-producing mice carrying human chromosomal fragments containing human antibody heavy and light chain genes (see, for example, Tomizuka, K. et al., Nature Genetics (1997) 16, pp. 133-143; Kuroiwa, Y. et al., Nucl. Acids Res. (1998) 26, pp. 3447-3448; Yoshida, H. et al., Animal Cell Technology: Basic and Applied Aspects vol. 10, pp. 69-73 (Kitagawa, Y., Matsuda, T. and Iijima, S. eds.), Kluwer Academic Publishers, 1999; Tomizuka, K. et al., Proc. Natl. Acad. Sci. USA (2000) 97, pp. 722-727). Alternatively, antibodies obtained by phage display selected from a human antibody library can also be used (see, for example, Wormstone, I. M. et al., Investigative Ophthalmology & Visual Science. (2002) 43 (7), pp. 2301-2308; Carmen, S. et al., Briefings in Functional Genomics and Proteomics (2002), 1 (2), pp. 189-203; Siriwardena, D. et al., Ophthalmology (2002) 109 (3), pp. 427-431).

[0067] The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is preferably an antibody that specifically binds to the amino acid sequence set forth in SEQ ID NO: 1 and has the ability to be internalized into cells. Examples of such anti-CDH6 antibodies include the antibodies described in WO 2018 / 212136 (H01L02, H02L02, H02L03, H04L02, etc.). An antibody that "specifically binds to the amino acid sequence set forth in SEQ ID NO: 1" means that the antibody binds more strongly to the EC3 domain of CDH6 than to other extracellular domains of CDH6. The internalization activity (internalization ability) of an antibody can be evaluated using, for example, a reagent conjugated with a toxin (saporin) that inhibits protein synthesis (e.g., the anti-rat IgG reagent Rat-ZAP (ADVANCED TARGETING SYSTEMS), the anti-human IgG reagent Hum-ZAP (ADVANCED TARGETING SYSTEMS), etc.) (see WO 2018 / 212136).

[0068] The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is preferably an antibody that exhibits a viability (expressed as a relative rate, with the cell viability in the absence of antibody being set at 100%) of 80% or less of CDH6-expressing cells administered with the antibody and a saporin-labeled anti-rat IgG antibody or a saporin-labeled anti-human IgG antibody, more preferably an antibody that exhibits a viability of 70% or less, and even more preferably an antibody that exhibits a viability of 60% or less.The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is preferably one of the following (1) to (5): (1) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 3, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4; (2) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 8, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4; (3) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 9, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 10, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 11; a heavy chain comprising a CDRH1, a CDRH2, and a CDRH3 selected from the group consisting of: (4) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 15, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 16, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 17; and (5) a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 21, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 22, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 23; and The antibody comprises a light chain comprising CDRL1, CDRL2, and CDRL3 selected from the group consisting of the following (6) to (9): (6) CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO:5, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO:6, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO:7; (7) CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO:12, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO:13, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO:14; (8) CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO:18, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO:19, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO:20; and (9) CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO:24, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO:25, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO:26.

[0069] The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is more preferably an antibody comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 3, and CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4, and a light chain comprising CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 5, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 6, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 7.

[0070] The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is more preferably an antibody comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 8, and CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4, and a light chain comprising CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 5, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 6, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 7.

[0071] The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is more preferably an antibody comprising a heavy chain comprising a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 9, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 10, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 11, and a light chain comprising a CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 12, a CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 13, and a CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 14.

[0072] The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is more preferably an antibody comprising a heavy chain comprising a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 15, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 16, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 17, and a light chain comprising a CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 18, a CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 19, and a CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 20. The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is more preferably an antibody comprising a heavy chain comprising a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 21, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 22, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 23, and a light chain comprising a CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 24, a CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 25, and a CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 26.

[0073] The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is even more preferably any one of the following (1) to (3) selected from the group consisting of: (1) the amino acid sequence of SEQ ID NO: 28, 31, or 34; (2) an amino acid sequence having at least 95% or more identity to the amino acid sequence of (1) above (preferably, an amino acid sequence having at least 95% or more sequence identity to the sequence of the framework region other than each CDR sequence); and (3) an amino acid sequence in which one or several amino acids are deleted, substituted, or added in the amino acid sequence of (1) above. Examples of antibodies include antibodies comprising a heavy chain containing a chain variable region, and a light chain containing a light chain variable region described in any combination of (4) to (6) below, selected from the group consisting of (4) the amino acid sequence of SEQ ID NO: 37 or 40, (5) an amino acid sequence having at least 95% or more identity to the amino acid sequence of (4) above (preferably an amino acid sequence having at least 95% or more sequence identity to the sequence of the framework region other than each CDR sequence), and (6) an amino acid sequence in which one or several amino acids have been deleted, substituted, or added in the amino acid sequence of (4) above.

[0074] The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is even more preferably an antibody comprising a heavy chain comprising the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 28, a heavy chain comprising the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 31, or a heavy chain comprising the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 34, and a light chain comprising the light chain variable region amino acid sequence set forth in SEQ ID NO: 37 or a light chain having the light chain variable region amino acid sequence set forth in SEQ ID NO: 40. The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is even more preferably an antibody comprising a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 28 and a light chain comprising a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 37. The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is even more preferably an antibody comprising a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 31 and a light chain comprising a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 37.

[0075] The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is even more preferably an antibody comprising a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 34 and a light chain comprising a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 37. The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is even more preferably an antibody comprising a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 31 and a light chain comprising a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 40. The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is even more preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38, or an antibody in which a lysine residue is deleted at the carboxyl terminus of the heavy chain of the antibody. The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is even more preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain.

[0076] The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is even more preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 35 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38, or an antibody in which a lysine residue at the carboxyl terminus of the heavy chain is deleted. The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is even more preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 41, or an antibody in which a lysine residue at the carboxyl terminus of the heavy chain is deleted. By combining sequences that show high identity with the above heavy chain amino acid sequences and light chain amino acid sequences, it is possible to select antibodies having biological activity equivalent to each of the above antibodies. Such identity is generally 80% or more, preferably 85% or more, more preferably 90% or more, even more preferably 95% or more, and most preferably 99% or more. Identity between two amino acid sequences can be determined by aligning the sequences using the default parameters of ClustalW version 2 (Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H, Valentin F, Wallace IM, Wilm A, Lopez R, Thompson JD, Gibson TJ and Higgins DG (2007), "Clustal W and Clustal X version 2.0", Bioinformatics. 23(21):2947-2948).

[0077] The antibody in the anti-CDH6 antibody-drug conjugate used in the present invention also includes modified antibodies. The modified antibody refers to an antibody obtained by chemically or biologically modifying the antibody of the present invention. Chemical modifications include those having a chemical moiety attached to the amino acid backbone or a chemical moiety attached to an N- or O-linked carbohydrate chain. Biological modifications include those having post-translational modifications (e.g., addition of an N- or O-linked sugar chain, N- or C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, etc.), and those having a methionine residue added to the N-terminus by expression in a prokaryotic host cell. Also included within the meaning of such modified antibodies are those labeled to enable detection or isolation of the antibody or antigen of the present invention, such as enzyme-labeled, fluorescent-labeled, or affinity-labeled antibodies. Such modified antibodies of the present invention are useful for improving antibody stability and blood retention, reducing antigenicity, and detecting or isolating antibodies or antigens, etc.

[0078] Furthermore, antibody-dependent cellular cytotoxicity can be enhanced by modulating the sugar chain modification (glycosylation, defucosylation, etc.) attached to the antibody of the present invention. Techniques for modulating antibody sugar chain modification are known, including, but not limited to, those described in International Publication Nos. 99 / 54342, 00 / 61739, 02 / 31140, 2007 / 133855, and 2013 / 120066. Antibodies of the present invention also include antibodies with modified sugar chain modifications.

[0079] It is known that antibodies produced in cultured mammalian cells have deletions of lysine residues at the carboxyl terminus of their heavy chains (Journal of Chromatography A, 705: 129-134 (1995)). It is also known that two amino acid residues, glycine and lysine, are deleted from the carboxyl terminus of the heavy chain, and a proline residue at the carboxyl terminus is newly amidated (Analytical Biochemistry, 360: 75-83 (2007)). However, these deletions and modifications of the heavy chain sequence do not affect the antigen-binding ability or effector functions (e.g., complement activation and antibody-dependent cellular cytotoxicity) of the antibody. Therefore, the antibodies of the present invention also include antibodies and functional fragments of such antibodies that have undergone such modifications, including deletions in which one or two amino acids are deleted from the carboxyl terminus of the heavy chain, and amidated deletions (e.g., heavy chains in which the proline residue at the carboxyl terminus is amidated). However, as long as the antigen-binding ability and effector function are maintained, the carboxyl-terminal deletions of the heavy chains of the antibody of the present invention are not limited to the above types. The two heavy chains constituting the antibody of the present invention may be any one type of heavy chain selected from the group consisting of full-length and the above-mentioned deletions, or a combination of any two types. The quantitative ratio of each deletion may be affected by the type of cultured mammalian cells producing the antibody of the present invention and the culture conditions, but preferred antibodies of the present invention include those in which one amino acid residue is deleted at the carboxyl terminus of each of the two heavy chains. Preferred examples of the amino acid deleted at the carboxyl terminus of the heavy chain of the antibody of the present invention include lysine residues.

[0080] Examples of the isotype of the antibody of the present invention include IgG (IgG1, IgG2, IgG3, IgG4), and preferably IgG1, IgG2, or IgG4. In the full-length amino acid sequence of the hH01 heavy chain shown in SEQ ID NO: 27, the amino acid sequence consisting of amino acid residues 1 to 19 is a signal sequence, the amino acid sequence consisting of amino acid residues 20 to 141 is a variable region, and the amino acid sequence consisting of amino acid residues 142 to 471 is a constant region. In the full-length amino acid sequence of the hH02 heavy chain shown in SEQ ID NO: 30, the amino acid sequence consisting of amino acid residues 1 to 19 is a signal sequence, the amino acid sequence consisting of amino acid residues 20 to 141 is a variable region, and the amino acid sequence consisting of amino acid residues 142 to 471 is a constant region. In the full-length amino acid sequence of the hH04 heavy chain shown in SEQ ID NO: 33, the amino acid sequence consisting of amino acid residues at positions 1 to 19 is a signal sequence, the amino acid sequence consisting of amino acid residues at positions 20 to 141 is a variable region, and the amino acid sequence consisting of amino acid residues at positions 142 to 471 is a constant region. In the full-length amino acid sequence of the hL02 light chain shown in SEQ ID NO: 36, the amino acid sequence consisting of amino acid residues at positions 1 to 20 is a signal sequence, the amino acid sequence consisting of amino acid residues at positions 21 to 128 is a variable region, and the amino acid sequence consisting of amino acid residues at positions 129 to 233 is a constant region. In the full-length amino acid sequence of the hL03 light chain shown in SEQ ID NO: 39, the amino acid sequence consisting of amino acid residues at positions 1 to 20 is a signal sequence, the amino acid sequence consisting of amino acid residues at positions 21 to 128 is a variable region, and the amino acid sequence consisting of amino acid residues at positions 129 to 233 is a constant region.

[0081] In some embodiments, the antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is raludotatug.

[0082] 4. Production of Anti-CDH6 Antibody-Drug Conjugate The drug linker intermediate used in the production of the anti-CDH6 antibody-drug conjugate of the present invention is represented by the following formula:

[0083]

[0084] The drug linker intermediate shown above is N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]glycylglycyl-L-phenylalanyl-N-[(2-{[(1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4': 6,7] indolizino[1,2-b]quinolin-1-yl]amino}-2-oxoethoxy)methyl] glycinamide, and can be produced with reference to the descriptions in WO 2014 / 057687, WO 2015 / 098099, WO 2015 / 115091, WO 2015 / 155998, and WO 2019 / 044947.

[0085] The anti-CDH6 antibody-drug conjugate used in the present invention can be produced by reacting the aforementioned drug linker intermediate with an anti-CDH6 antibody having a thiol group (also referred to as a sulfhydryl group).

[0086] An anti-CDH6 antibody having a sulfhydryl group can be obtained by methods well known to those skilled in the art (Hermanson, G. T., Bioconjugate Techniques, pp. 56-136, pp. 456-493, Academic Press (1996)). For example, an anti-CDH6 antibody having a sulfhydryl group in which the intra-chain disulfides of the antibody have been partially or completely reduced can be obtained by reacting the anti-CDH6 antibody with a reducing agent such as tris(2-carboxyethyl)phosphine hydrochloride (TCEP) in an amount of 0.3 to 3 molar equivalents per intra-chain disulfide of the antibody in a buffer containing a chelating agent such as ethylenediaminetetraacetic acid (EDTA).

[0087] Furthermore, 2 to 20 molar equivalents of a drug linker intermediate can be used per anti-CDH6 antibody having a sulfhydryl group to produce an anti-CDH6 antibody-drug conjugate in which 2 to 8 drugs are bound per anti-CDH6 antibody.

[0088] The average number of drugs bound per antibody molecule in the produced anti-CDH6 antibody-drug conjugate can be calculated, for example, by a method in which the UV absorbance of the antibody-drug conjugate and its conjugation precursor is measured at two wavelengths, 280 nm and 370 nm (UV method), or by a method in which the antibody-drug conjugate is treated with a reducing agent, and each of the resulting fragments is quantified by HPLC measurement and then calculated (HPLC method).

[0089] Conjugation of an antibody and a drug linker intermediate, and calculation of the average number of drugs bound per antibody molecule in an antibody-drug conjugate can be carried out with reference to the descriptions in WO 2014 / 057687, WO 2015 / 098099, WO 2015 / 115091, WO 2015 / 155998, WO 2018 / 135501, WO 2018 / 212136, and the like.

[0090] In certain embodiments, the average number of drug linkers bound per antibody molecule in the anti-CDH6 antibody-drug conjugate used in the present invention is preferably 1 to 10, more preferably 2 to 8, even more preferably 5 to 8, even more preferably 7 to 8, even more preferably 7.5 to 8, and even more preferably about 8.

[0091] In another embodiment, the number of drugs or bound drug linkers per antibody molecule in the anti-CDH6 antibody-drug conjugate used in the present invention is preferably an integer within the range of 2 to 8, more preferably 2, 4, 6 or 8, and even more preferably 8. Anti-CDH6 antibody-drug conjugates can be produced with reference to the descriptions in WO 2018 / 212136 and the like.

[0092] 5. VEGF Inhibitors In the present invention, the term "VEGF inhibitor" refers to a drug that inhibits the interaction between VEGF and a VEGF receptor.

[0093] The VEGF inhibitor of the present invention is not particularly limited as long as it is a drug having the above-mentioned properties, and may be an antibody, a functional fragment of an antibody, a fusion protein, an immunoadhesin, a nucleic acid, an oligonucleotide, an aptamer, a polypeptide, or a low-molecular-weight compound. The VEGF inhibitor of the present invention is preferably an anti-VEGF antibody, an anti-VEGF receptor antibody, a fusion protein comprising a VEGF receptor extracellular domain, or a multispecific antibody comprising an anti-VEGF-binding domain. In the present invention, the term "anti-VEGF antibody" refers to an antibody that specifically binds to VEGF or a functional fragment of the antibody. In the present invention, the term "anti-VEGF receptor antibody" refers to an antibody that specifically binds to a VEGF receptor or a functional fragment of the antibody. In the present invention, the term "fusion protein comprising a VEGF receptor extracellular domain" refers to a fusion protein having a VEGF-binding domain derived from the VEGF receptor extracellular domain (including mutants of the VEGF-binding domain). In the present invention, a "multispecific antibody comprising an anti-VEGF-binding domain" refers to an antibody or a functional fragment of such an antibody that has binding specificities for at least two different sites, and at least one of the binding specificities is for VEGF.

[0094] In the present invention, a "bispecific antibody comprising an anti-VEGF-binding domain" refers to an antibody or a functional fragment of the antibody having binding specificities for two different sites, at least one of which is for VEGF. The VEGF inhibitor of the present invention is more preferably an anti-VEGF antibody. The anti-VEGF antibody of the present invention is preferably bevacizumab or sevacizumab, more preferably bevacizumab. The VEGF inhibitor of the present invention is more preferably an anti-VEGF receptor antibody. The anti-VEGF receptor antibody of the present invention is preferably ramucirumab. The VEGF inhibitor of the present invention is more preferably a fusion protein comprising a VEGF receptor extracellular domain. The fusion protein comprising a VEGF receptor extracellular domain of the present invention is preferably aflibercept. The VEGF inhibitor of the present invention is more preferably a multispecific antibody comprising an anti-VEGF binding domain, and even more preferably a bispecific antibody comprising an anti-VEGF binding domain. Bispecific antibodies comprising an anti-VEGF-binding domain according to the present invention are preferably ivonescimab (Non-Patent Document 3), CTX-009 (also referred to as ABL-001, Non-Patent Document 4), BI836880 (Clin. Exp. Metastasis (2020) 37(6): 637-648.), Navicixizumab (Non-Patent Document 3), Vanucizumab (Non-Patent Document 4), or PM8002 (Journal of Clinical Oncology 41, no. 16_suppl (June 01, 2023) 2536-2536.).

[0095] The pharmaceutical composition of the present invention can be administered as a pharmaceutical composition containing pharmaceutically acceptable carriers, diluents, solubilizers, emulsifiers, preservatives, adjuvants, etc. Pharmaceutically acceptable carriers can be selected from a wide range of options depending on the type of target disease and the dosage form of the drug. Examples of pharmaceutically acceptable carriers include sterile liquids. Examples of liquids include water and oils (petroleum, animal, plant, or synthetic). Oils include peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is more typical when the pharmaceutical composition is administered intravenously. Saline solutions, as well as aqueous dextrose and glycerol solutions, can also be used as the liquid, particularly for injectable solutions. Suitable pharmaceutical excipients can be selected from those known in the art. Examples of suitable pharmaceutically acceptable carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. The formulations correspond to the mode of administration.

[0096] The method of administration of the antitumor agent of the present invention can be selected appropriately, and examples thereof include injection, local injection, intraperitoneal injection, selective intravenous injection, intravenous injection, subcutaneous injection, and organ perfusion injection. Administration can be by infusion or bolus injection, for example. Injection solutions can be formulated using carriers such as salt solutions, glucose solutions, mixtures of salt solutions and glucose solutions, and various buffer solutions. Alternatively, the agent can be formulated in powder form and mixed with the liquid carrier at the time of use to prepare an injection solution. In certain preferred embodiments, the antibody-drug conjugates and VEGF inhibitors used in the present invention are administered by injection. Parenteral administration is a preferred route of administration.

[0097] Other administration methods can also be appropriately selected based on the development of the formulation. For example, oral administration can be performed in the form of oral liquids, powders, pills, capsules, and tablets. Oral liquids, such as suspensions and syrups, can be prepared using water, sugars such as sucrose, sorbitol, and fructose, glycols such as polyethylene glycol, oils such as sesame oil and soybean oil, preservatives such as alkyl parahydroxybenzoate, and flavors such as strawberry flavor and peppermint. Powders, pills, capsules, and tablets can be formulated using excipients such as lactose, glucose, sucrose, and mannitol, disintegrants such as starch and sodium alginate, lubricants such as magnesium stearate and talc, binders such as polyvinyl alcohol, hydroxypropyl cellulose, and gelatin, surfactants such as fatty acid esters, and plasticizers such as glycerin. Tablets and capsules are preferred unit dosage forms due to their ease of administration. When preparing tablets and capsules, solid pharmaceutical carriers are used.

[0098] 6. Pharmaceuticals Pharmaceutical compositions and methods of treatment characterized by administering the anti-CDH6 antibody-drug conjugate of the present invention in combination with a VEGF inhibitor are described below. The present invention includes pharmaceutical compositions comprising an anti-CDH6 antibody-drug conjugate used in combination with a VEGF inhibitor or administered in combination with a VEGF inhibitor.

[0099] The pharmaceutical composition and treatment method of the present invention may be characterized in that the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained as active ingredients in separate formulations and administered simultaneously (a person skilled in the art will naturally understand that "simultaneously" may or may not mean "almost simultaneously") or at different times, or may be characterized in that the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained as active ingredients in a single formulation and administered.

[0100] Furthermore, the pharmaceutical composition and treatment method of the present invention may be administered by combining two or more of the VEGF inhibitors used in the present invention.

[0101] The pharmaceutical composition and treatment method of the present invention can be used for the treatment of cancer, and preferably can be used for the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, ovarian mucinous tumor, thyroid cancer, bile duct cancer, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, neuroblastoma, colorectal cancer, gastric cancer, endometrial cancer, uterine cancer, and nasopharyngeal cancer, and more preferably can be used for the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, ovarian mucinous tumor, thyroid cancer, bile duct cancer, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, neuroblastoma, colorectal cancer, gastric cancer, endometrial cancer, uterine cancer, and nasopharyngeal cancer, and The present invention can be used to treat at least one cancer selected from the group consisting of renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian carcinoma, ovarian mucinous tumor, thyroid cancer, bile duct cancer, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, and neuroblastoma, and more preferably can be used to treat at least one cancer selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian carcinoma, and ovarian mucinous tumor.

[0102] The pharmaceutical composition and treatment method of the present invention can be even more preferably used to treat at least one cancer selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, and papillary renal cell carcinoma. The pharmaceutical composition and treatment method of the present invention can be even more preferably used to treat at least one cancer selected from the group consisting of ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, and ovarian mucinous tumor, even more preferably used to treat ovarian cancer, and even more preferably used to treat epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. The cancer targeted by the pharmaceutical composition and treatment method of the present invention is preferably metastatic cancer. The pharmaceutical composition and treatment method of the present invention can be used to treat cancer with HRD (also called homologous recombination deficiency, homologous recombination repair deficiency, homologous recombination repair deficiency, etc.), and can be preferably used to treat ovarian cancer with HRD. HRD cancer refers to cancer that exhibits an impaired ability to repair DNA double-strand breaks through homologous recombination. HRD ovarian cancer refers to ovarian cancer that exhibits an impaired ability to repair DNA double-strand breaks through homologous recombination.

[0103] The pharmaceutical composition and treatment method of the present invention can be used to treat HRP (homologous recombination proficiency, also known as HRD-negative, homologous recombination proficient, etc.) cancer, and preferably can be used to treat HRP ovarian cancer. HRP cancer refers to cancer that retains the ability to properly carry out DNA repair (also known as homologous recombination DNA repair, homologous recombination repair) through homologous recombination. HRP ovarian cancer refers to ovarian cancer that retains the ability to properly carry out DNA repair through homologous recombination (also called homologous recombination DNA repair, HRR).

[0104] The pharmaceutical compositions and treatment methods of the present invention can be used to treat cancers resistant to platinum-based chemotherapy. The pharmaceutical compositions and treatment methods of the present invention can be used to treat cancers resistant to chemotherapy comprising a platinum-based drug and a taxane. The pharmaceutical compositions and treatment methods of the present invention can be used to treat cancers that show recurrence before administration of the pharmaceutical compositions of the present invention or treatment. The cancer recurrence may occur within 6 months (or about 6 months) of completing a chemotherapy regimen comprising a platinum-based drug. The cancer recurrence may occur less than 6 months (or about 6 months) of completing a chemotherapy regimen comprising a platinum-based drug. The cancer recurrence may occur within 6 months (or about 6 months) of completing a chemotherapy regimen comprising a platinum-based drug and a taxane. The cancer recurrence may occur less than 6 months (or about 6 months) of completing a chemotherapy regimen comprising a platinum-based drug and a taxane. The cancer recurrence may occur more than 6 months (or about 6 months) of completing a chemotherapy regimen comprising a platinum-based drug. The cancer recurrence may occur more than 6 months (or about 6 months) after completion of a chemotherapy regimen including a platinum-based agent. The cancer recurrence may occur more than 6 months (or about 6 months) after completion of a chemotherapy regimen including a platinum-based agent and a taxane. The cancer recurrence may occur more than 6 months (or about 6 months) after completion of a chemotherapy regimen including a platinum-based agent and a taxane.

[0105] The anti-CDH6 antibody-drug conjugates used in the present invention can be suitably used when CDH6 expression has been confirmed in cancer. The presence or absence of the CDH6 tumor marker can be confirmed, for example, by collecting tumor tissue from a cancer patient, examining the formalin-fixed, paraffin-embedded (FFPE) specimen at the gene product (protein) level using immunohistochemistry (IHC), a flow cytometer, Western blot analysis, or the like, or by examining the gene transcription level using in situ hybridization (ISH), quantitative PCR (q-PCR), microarray analysis, or the like. Alternatively, cell-free circulating tumor DNA (ctDNA) in the blood of a cancer patient can be collected and confirmed by testing using a method such as next-generation sequencing (NGS).

[0106] The pharmaceutical composition and treatment method of the present invention can be preferably used in mammals, and more preferably in humans.

[0107] The antitumor effect of the pharmaceutical composition and treatment method of the present invention can be confirmed, for example, by preparing a model in which cancer cells are transplanted into a test animal and measuring the reduction in tumor volume and the life-prolonging effect of administering the pharmaceutical composition and treatment method of the present invention. The combined effect of the antibody-drug conjugate and VGF inhibitor used in the present invention can then be confirmed by comparing the antitumor effect with that of the antibody-drug conjugate and the VEGF inhibitor used in the present invention when administered alone.

[0108] The antitumor effects of the pharmaceutical composition and treatment method of the present invention can be confirmed in clinical trials by the Response Evaluation Criteria in Solid Tumors (RECIST) evaluation method, the WHO evaluation method, the Macdonald evaluation method, weight measurement, and other methods, and the results can be evaluated for complete response (CR), partial response (PR), progressive disease (PD), objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and other important parameters. The survival rate can be determined by an index such as OS (Optical Survival Rate).

[0109] By the above-mentioned method, it is possible to confirm the superiority of the antitumor effect of the pharmaceutical composition and treatment method of the present invention over existing pharmaceutical compositions and treatment methods for cancer treatment.

[0110] The pharmaceutical composition and treatment method of the present invention can slow the growth of cancer cells, suppress their proliferation, and even destroy them. These actions can relieve cancer patients from cancer-related symptoms and improve their quality of life, thereby achieving therapeutic effects while preserving the lives of cancer patients. Even if cancer cells are not destroyed, the inhibition and control of cancer cell proliferation can enable cancer patients to achieve a higher quality of life and longer survival.

[0111] The pharmaceutical composition of the present invention can be applied to patients as a systemic therapy, and can also be applied locally to cancer tissue to achieve therapeutic effects.

[0112] The pharmaceutical compositions of the present invention can be administered containing one or more pharmaceutically compatible ingredients. The pharmaceutically compatible ingredients can be appropriately selected from formulation additives and other ingredients commonly used in this field depending on the dose and administration concentration of the antibody-drug conjugate and VEGF inhibitor used in the present invention. For example, the antibody-drug conjugate used in the present invention can be administered as a pharmaceutical composition containing a buffer such as a histidine buffer, an excipient such as sucrose or trehalose, and a surfactant such as polysorbate 80 or 20. The pharmaceutical composition containing the anti-CDH6 antibody-drug conjugate used in the present invention can be preferably used as an injection, more preferably as an aqueous injection or a lyophilized injection, and even more preferably as a lyophilized injection.

[0113] When the pharmaceutical composition containing the anti-CDH6 antibody-drug conjugate used in the present invention is an aqueous injection, it can be preferably administered intravenously by infusion after being diluted with an appropriate diluent. Examples of the diluent include glucose solution and physiological saline, preferably glucose solution, and more preferably 5% glucose solution.

[0114] When the pharmaceutical composition containing the anti-CDH6 antibody-drug conjugate used in the present invention is in the form of a lyophilized injection, it is preferably dissolved in water for injection, diluted with an appropriate diluent at a required amount, and then administered by intravenous infusion. Examples of the diluent include glucose solution and physiological saline, preferably glucose solution, and more preferably 5% glucose solution.

[0115] Examples of introduction routes that can be used to administer the pharmaceutical composition of the present invention include intravenous, intradermal, subcutaneous, intramuscular, and intraperitoneal routes, and preferably the intravenous route. The anti-CDH6 antibody-drug conjugate used in the present invention can be administered to a human at intervals of once every 1 to 180 days, preferably once every 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks, more preferably once every 3 or 4 weeks, and even more preferably once every 3 weeks. Furthermore, the anti-CDH6 antibody-drug conjugate used in the present invention can be administered at a single dose of about 0.001 to 100 mg / kg, preferably about 0.1 to about 15 mg / kg, more preferably about 0.5 to about 12 mg / kg, even more preferably about 1.0 to about 10 mg / kg, even more preferably about 1.6 to about 9.6 mg / kg, and even more preferably about 4.8 to about 8.0 mg / kg.Furthermore, the anti-CDH6 antibody-drug conjugate used in the present invention may be administered in the amount of about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, or about 2.7 per dose. , about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1 , about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8.0, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, about 8.6, about 8.7, about 8.8, about 8.9, about 9.0, about 9.1, about 9.2, about 9.3, about 9.4, about 9.5 , about 9.6, about 9.7, about 9.8, about 9.9, about 10.0, about 10.1, about 10.2, about 10.3, about 10.4, about 10.5, about 10.6, about 10.7, about 10.8, about 10.9, about 11.0, about 11.1, about 11.2, about 11.3, about 11.4, about 11.5, about 11.6, about 11.7, about 11.8, about 11.9, about 12.0 mg / kg or more.

[0116] Furthermore, the anti-CDH6 antibody-drug conjugate used in the present invention can be preferably administered at a single dose of about 1.6 mg / kg, about 3.2 mg / kg, about 4.8 mg / kg, about 5.4 mg / kg, about 5.6 mg / kg, about 6.4 mg / kg, about 8.0 mg / kg, or about 9.6 mg / kg, more preferably about 3.2 mg / kg, about 4.8 mg / kg, about 5.4 mg / kg, about 5.6 mg / kg, about 6.4 mg / kg, about 8.0 mg / kg, or about 9.6 mg / kg, and even more preferably about 4.8 mg / kg, about 5.4 mg / kg, about 5.6 mg / kg, about 6.4 mg / kg, or about 8.0 mg / kg. Furthermore, the anti-CDH6 antibody-drug conjugate used in the present invention can be administered at a single dose of 0.001 to 100 mg / kg, preferably 0.1 to 15 mg / kg, more preferably 0.5 to 12 mg / kg, even more preferably 1.0 to 10 mg / kg, even more preferably 1.6 to 9.6 mg / kg, and even more preferably 4.8 to 8.0 mg / kg.

[0117] The anti-CDH6 antibody-drug conjugate used in the present invention may be administered in the following amounts per dose: 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, It can be administered at 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0 mg / kg or more.

[0118] Furthermore, the anti-CDH6 antibody-drug conjugate used in the present invention can be preferably administered at a single dose of 1.6 mg / kg, 3.2 mg / kg, 4.8 mg / kg, 5.4 mg / kg, 5.6 mg / kg, 6.4 mg / kg, 8.0 mg / kg, or 9.6 mg / kg, more preferably at 3.2 mg / kg, 4.8 mg / kg, 5.4 mg / kg, 5.6 mg / kg, 6.4 mg / kg, or 8.0 mg / kg, and even more preferably at 4.8 mg / kg, 5.4 mg / kg, 5.6 mg / kg, 6.4 mg / kg, or 8.0 mg / kg. Furthermore, the anti-CDH6 antibody-drug conjugate used in the present invention can be administered at a single dose of about 5 to about 3000 mg, preferably about 10 to about 2000 mg, more preferably about 100 to about 1500 mg, and even more preferably about 200 to about 1000 mg.

[0119] Furthermore, the anti-CDH6 antibody-drug conjugate used in the present invention is preferably administered in a single dose of about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about 490 mg, about 505 mg, about 510 mg, about 515 mg, about 520 mg, about 525 mg, about 530 mg, about 535 mg, about 540 mg, about 545 mg, about 550 mg, about 555 mg, about 560 mg, mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 39 0mg, about 395mg, about 400mg, about 405mg, about 410mg, about 415mg, about 420mg, about 425mg, about 430mg, about 4 35mg, about 440mg, about 445mg, about 450mg, about 455mg, about 460mg, about 465mg, about 470mg, about 475mg, about 480mg, about 485mg, about 490mg, about 495mg, about 500mg, about 505mg, about 510mg, about 515mg, about 520mg, Approximately 525mg, approximately 530mg, approximately 535mg, approximately 540mg, approximately 545mg, approximately 550mg, approximately 555mg, approximately 560mg, approximately 565mg , about 570mg, about 575mg, about 580mg, about 585mg, about 590mg, about 595mg, about 600mg, about 605mg, about 610m g, about 615 mg, about 620 mg, about 625 mg, about 630 mg, about 635 mg, about 640 mg, about 645 mg, about 650 mg, about 655 mg, about 660 mg, about 665 mg, about 670 mg, about 675 mg, about 680 mg, about 685 mg, about 690 mg, about 695 mg, about 70 0mg, about 705mg, about 710mg, about 715mg, about 720mg, about 725mg, about 730mg, about 735mg, about 740mg, about 7 45mg, about 750mg, about 755mg, about 760mg, about 765mg, about 770mg, about 775mg, about 780mg, about 785mg, about 790mg, about 795mg, about 800mg, about 805mg, about 810mg, about 815mg, about 820mg, about 825mg, about 830mg, about 835 mg, about 840 mg, about 845 mg, about 850 mg, about 855 mg, about 860 mg, about 865 mg, about 870 mg, about 875 mg,It can be administered in a dosage of about 880 mg, about 885 mg, about 890 mg, about 895 mg, about 900 mg, about 905 mg, about 910 mg, about 915 mg, about 920 mg, about 925 mg, about 930 mg, about 935 mg, about 940 mg, about 945 mg, about 950 mg, about 955 mg, about 960 mg, about 965 mg, about 970 mg, about 975 mg, about 980 mg, about 985 mg, about 990 mg, about 995 mg or about 1000 mg.

[0120] Furthermore, the anti-CDH6 antibody-drug conjugate used in the present invention is preferably administered in a single dose of 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 380 mg, 385 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 82 mg, 375mg, 380mg, 385mg, 390mg, 395mg, 400mg, 405mg, 410mg, 415mg, 420mg , 425mg, 430mg, 435mg, 440mg, 445mg, 450mg, 455mg, 460mg, 465mg, 470mg, 4 75mg, 480mg, 485mg, 490mg, 495mg, 500mg, 505mg, 510mg, 515mg, 520mg, 525 mg, 530mg, 535mg, 540mg, 545mg, 550mg, 555mg, 560mg, 565mg, 570mg, 575mg, 580mg, 585mg, 590mg, 595mg, 600mg, 605mg, 610mg, 615mg, 620mg, 625mg, 63 0mg, 635mg, 640mg, 645mg, 650mg, 655mg, 660mg, 665mg, 670mg, 675mg, 680m g, 685mg, 690mg, 695mg, 700mg, 705mg, 710mg, 715mg, 720mg, 725mg, 730mg, 735mg, 740mg, 745mg, 750mg, 755mg, 760mg, 765mg, 770mg, 775mg, 780mg, 785 mg, 790mg, 795mg, 800mg, 805mg, 810mg, 815mg, 820mg, 825mg, 830mg, 835mg , 840mg, 845mg, 850mg, 855mg, 860mg, 865mg, 870mg, 875mg, 880mg, 885mg, 8 90mg, 895mg, 900mg, 905mg, 910mg, 915mg, 920mg, 925mg, 930mg, 935mg, 940 mg, 945mg, 950mg, 955mg, 960mg, 965mg, 970mg, 975mg, 980mg, 985mg, 990mg,It can be administered in doses of 995 mg or 1000 mg.

[0121] Furthermore, the administration regimen of the anti-CDH6 antibody-drug conjugate used in the present invention is, for example, 0.1 mg / kg (every 3 weeks, hereinafter referred to as "q3w"), 0.2 mg / kg (q3w), 0.3 mg / kg (q3w), 0.4 mg / kg (q3w), 0.5 mg / kg (q3w), 0.6 mg / kg (q3w), 0.7 mg / kg (q3w), 0.8 mg / kg (q3w), 0.9 mg / kg (q3w), 1.0 mg / kg (q3w), 1.1 mg / kg (q3w), 1.2 mg / kg (q3w), 1.3 mg / kg (q3w), 1.4 mg / kg (q3w), w), 1.5 mg / kg (q3w), 1.6 mg / kg (q3w), 1.7 mg / kg (q3w), 1.8 mg / kg (q3w), 1.9 mg / kg (q3w), 2.0 mg / kg (q3w), 2.1 mg / kg (q3w), 2.2 mg / kg (q3w), 2.3 mg / kg ( q3w), 2.4mg / kg (q3w), 2.5mg / kg (q3w), 2.6mg / kg (q3w), 2.7mg / kg (q3w), 2 .8mg / kg (q3w), 2.9mg / kg (q3w), 3.0mg / kg (q3w), 3.1mg / kg (q3w), 3.2mg / k g (q3w), 3.3mg / kg (q3w), 3.4mg / kg (q3w), 3.5mg / kg (q3w), 3.6mg / kg (q3w) , 3.7 mg / kg (q3w), 3.8 mg / kg (q3w), 3.9 mg / kg (q3w), 4.0 mg / kg (q3w), 4.1 mg / kg (q3w), 4.2mg / kg (q3w), 4.3mg / kg (q3w), 4.4mg / kg (q3w), 4.5mg / kg (q3w) w), 4.6 mg / kg (q3w), 4.7 mg / kg (q3w), 4.8 mg / kg (q3w), 4.9 mg / kg (q3w), 5.0 mg / kg (q3w), 5.1 mg / kg (q3w), 5.2 mg / kg (q3w), 5.3 mg / kg (q3w), 5.4 mg / kg ( q3w), 5.5mg / kg (q3w), 5.6mg / kg (q3w), 5.7mg / kg (q3w), 5.8mg / kg (q3w), 5 .9mg / kg (q3w), 6.0mg / kg (q3w), 6.1mg / kg (q3w), 6.2mg / kg (q3w), 6.3mg / k g (q3w), 6.4mg / kg (q3w), 6.5mg / kg (q3w), 6.6mg / kg (q3w), 6.7mg / kg (q3w),6.8 mg / kg (q3w), 6.9 mg / kg (q3w), 7.0 mg / kg (q3w), 7.1 mg / kg (q3w), 7.2 mg / kg (q3w), 7.3 mg / kg (q3w), 7.4 mg / kg (q3w) ), 7.5 mg / kg (q3w), 7.6 mg / kg (q3w), 7.7 mg / kg (q3w), 7.8 mg / kg (q3w), 7.9 mg / kg (q3w), 8.0 mg / kg (q3w), 8.1 mg / kg (q 3w), 8.2mg / kg (q3w), 8.3mg / kg (q3w), 8.4mg / kg (q3w), 8.5mg / kg (q3w), 8.6mg / kg (q3w), 8.7mg / kg (q3w), 8.8mg / kg (q3w), 8.9mg / kg (q3w), 9.0mg / kg (q3w), 9.1mg / kg (q3w), 9.2mg / kg (q3w), 9.3mg / kg (q3w), 9.4mg / kg (q3w), 9.5mg / k g (q3w), 9.6 mg / kg (q3w), 9.7 mg / kg (q3w), 9.8 mg / kg (q3w), 9.9 mg / kg (q3w), 10.0 mg / kg (q3w), 10.1 mg / kg (q3w), 10. 2mg / kg (q3w), 10.3mg / kg (q3w), 10.4mg / kg (q3w), 10.5mg / kg (q3w), 10.6mg / kg (q3w), 10.7mg / kg (q3w), 10.8mg / kg ( The dose may be 10.9 mg / kg (q3w), 11.0 mg / kg (q3w), 11.1 mg / kg (q3w), 11.2 mg / kg (q3w), 11.3 mg / kg (q3w), 11.4 mg / kg (q3w), 11.5 mg / kg (q3w), 11.6 mg / kg (q3w), 11.7 mg / kg (q3w), 11.8 mg / kg (q3w), 11.9 mg / kg (q3w), or 12.0 mg / kg (q3w).

[0122] Furthermore, the administration regimen of the anti-CDH6 antibody-drug conjugate used in the present invention is preferably 1.6 mg / kg (q3w), 3.2 mg / kg (q3w), 4.8 mg / kg (q3w), 5.4 mg / kg (q3w), 5.6 mg / kg (q3w), 6.4 mg / kg (q3w), 8.0 mg / kg (q3w), or 9.6 mg / kg (q3w), and more preferably 3. Preferably, the dose is 2 mg / kg (q3w), 4.8 mg / kg (q3w), 5.4 mg / kg (q3w), 5.6 mg / kg (q3w), 6.4 mg / kg (q3w) or 8.0 mg / kg (q3w), and even more preferably, 4.8 mg / kg (q3w), 5.4 mg / kg (q3w), 5.6 mg / kg (q3w), 6.4 mg / kg (q3w) or 8.0 mg / kg (q3w).

[0123] Furthermore, the administration regimen of the anti-CDH6 antibody-drug conjugate used in the present invention is preferably 200 mg (q3w), 205 mg (q3w), 210 mg (q3w), 215 mg (q3w), 220 mg (q3w), 225 mg (q3w), 230 mg (q3w), 235 mg (q3w), 240 mg (q3w), 245 mg (q3w), 250 mg (q3w), 255 mg (q3w), 260 mg (q3w), 265 mg (q3w), 270 mg (q3w), 275 mg (q3w), 280 mg (q3w), 285 mg (q3w), 290 mg (q3w), 300 mg (q3w), 305 ... q3w), 295mg (q3w), 300mg (q3w), 305mg (q3w), 310mg (q3w), 315mg (q3w), 3 20mg (q3w), 325mg (q3w), 330mg (q3w), 335mg (q3w), 340mg (q3w), 345mg (q3w) w), 350mg (q3w), 355mg (q3w), 360mg (q3w), 365mg (q3w), 370mg (q3w), 375m g (q3w), 380mg (q3w), 385mg (q3w), 390mg (q3w), 395mg (q3w), 400mg (q3w), 405mg (q3w), 410mg (q3w), 415mg (q3w), 420mg (q3w), 425mg (q3w), 430mg ( q3w), 435mg (q3w), 440mg (q3w), 445mg (q3w), 450mg (q3w), 455mg (q3w), 46 0mg (q3w), 465mg (q3w), 470mg (q3w), 475mg (q3w), 480mg (q3w), 485mg (q3w) ), 490mg (q3w), 495mg (q3w), 500mg (q3w), 505mg (q3w), 510mg (q3w), 515mg (q3w), 520mg (q3w), 525mg (q3w), 530mg (q3w), 535mg (q3w), 540mg (q3w), 5 45mg (q3w), 550mg (q3w), 555mg (q3w), 560mg (q3w), 565mg (q3w), 570mg (q3w) w), 575mg (q3w), 580mg (q3w), 585mg (q3w), 590mg (q3w), 595mg (q3w), 600m g (q3w), 605mg (q3w), 610mg (q3w), 615mg (q3w), 620mg (q3w), 625mg (q3w),630 mg (q3w), 635 mg (q3w), 640 mg (q3w), 645 mg (q3w), 650 mg (q3w), 655 mg (q3w), 660 mg (q3w), 665 mg (q3w), 670 mg (q3w), 675 mg (q3w), 680 mg (q3w), 685 mg (q3w), 690 mg (q3w), 695 mg (q3w), 700 mg (q3w), 705 mg (q3w), 710 mg (q3w), 715 mg (q3w), 720 mg (q3w), 725 mg (q3w), 730 mg (q3w), 735 mg (q3w), 740 mg (q3w), 745 mg (q3w), 750 mg (q3w), 755 mg (q3w), 760 mg (q3w), 765 mg (q3w), 770 mg (q3w), 775 mg (q3w), 780 mg (q3w), 785 mg (q3w), 790 mg (q3w), 795 mg (q3w), 800 mg (q3w), 805 mg (q3w), 810 mg (q3w), 815 mg (q3w), 820 mg (q3w), 825 mg (q3w), 830 mg (q3w), 835 mg (q3w), 840 mg (q3w), 845 mg (q3w), 850 mg (q3w), 855 mg (q3w), 860 mg (q3w), 865 mg (q3w), 870 mg (q3w), 875 mg (q3w), 880 mg (q3w), 885 mg (q3w), 890 mg (q3w), 895 mg (q3w), 900 mg (q3w), 905 mg (q3w), 910 mg (q3w), 915 mg (q, 3w), 920 mg (q3w), 925 mg (q3w), 930 mg (q3w), 935 mg (q3w), 940 mg (q3w), 945 mg (q3w), 950 mg (q3w), 955 mg (q3w), 960 mg (q3w), 965 mg (q3w), 970 mg (q3w), 975 mg (q3w), 980 mg (q3w), 985 mg (q3w), 990 mg (q3w), 995 mg (q3w) or 1000 mg (q3w).

[0124] When the VEGF inhibitor used in the present invention is bevacizumab, examples of administration methods include, but are not limited to, the following dosage and administration methods. For example, bevacizumab is administered intravenously at a dose of 5 mg / kg (body weight) or 10 mg / kg (body weight). The administration interval is at least two weeks. As an alternative dosage and administration method, bevacizumab is administered intravenously at a dose of 7.5 mg / kg (body weight). The administration interval is at least three weeks. As an alternative dosage and administration method, bevacizumab is administered intravenously at a dose of 15 mg / kg (body weight). The administration interval is at least three weeks. As an alternative dosage and administration method, bevacizumab is administered intravenously at a dose of 10 mg / kg (body weight). The administration interval is at least two weeks. An alternative dosage regimen involves intravenous infusion of bevacizumab at 10 mg / kg (body weight) every two weeks or 15 mg / kg (body weight) every three weeks.An alternative dosage regimen involves intravenous infusion of bevacizumab at 5 mg / kg or 10 mg / kg every two weeks.An alternative dosage regimen involves intravenous infusion of bevacizumab at 15 mg / kg every three weeks.An alternative dosage regimen involves intravenous infusion of bevacizumab at 10 mg / kg every two weeks.

[0125] When the VEGF inhibitor used in the present invention is ramucirumab, examples of administration methods include, but are not limited to, the following dosage and administration methods. For example, ramucirumab is administered by intravenous infusion at 8 mg / kg (body weight) once every two weeks over approximately 60 minutes. The administration time from the second dose onwards can be shortened to 30 minutes. As an alternative dosage and administration method, ramucirumab is administered by intravenous infusion at 10 mg / kg (body weight) once every three weeks over approximately 60 minutes. The administration time from the second dose onwards can be shortened to 30 minutes. As an alternative dosage and administration method, ramucirumab is administered by intravenous infusion at 10 mg / kg (body weight) once every two weeks over approximately 60 minutes. The administration time from the second dose onwards can be shortened to 30 minutes. When the VEGF inhibitor used in the present invention is aflibercept, examples of administration methods include, but are not limited to, the following dosage and administration methods. For example, aflibercept is administered by intravenous infusion over 60 minutes at a dose of 4 mg / kg (body weight) once every two weeks.

[0126] The pharmaceutical composition and treatment method of the present invention may further comprise a cancer therapeutic agent other than the anti-CDH6 antibody-drug conjugate and VEGF inhibitor of the present invention. The pharmaceutical composition and treatment method of the present invention may also be administered in combination with other cancer therapeutic agents, thereby enhancing the anti-tumor effect. The other cancer therapeutic agents used for such purposes may be administered to an individual simultaneously (almost simultaneously), separately, or consecutively with the pharmaceutical composition of the present invention, or may be administered at different administration intervals. Such cancer therapeutic agents are not limited as long as they are drugs having antitumor activity, and examples thereof include irinotecan (CPT-11), cisplatin, carboplatin, oxaliplatin, fluorouracil (5-FU), gemcitabine, capecitabine, doxorubicin, epirubicin, cyclophosphamide, and mitomycin C. C), Tegafur / Gimeracil / Oteracil combination drug, Panitumumab, Regorafenib, Trifluridine / Tipiracil combination drug, Gefitinib, Erlotinib, Afatinib, Methotrexor Examples of the anti-cancer drug include at least one selected from the group consisting of methotrexate, pemetrexed, tamoxifen, toremifene, fulvestrant, leuprorelin, goserelin, letrozole, anastrozole, a progesterone formulation, and lapatinib.

[0127] The pharmaceutical compositions and treatment methods of the present invention can also be used in combination with radiation therapy. For example, a cancer patient may receive radiation therapy before and / or after, or simultaneously (almost simultaneously) with, treatment with the pharmaceutical composition of the present invention.

[0128] The pharmaceutical composition and treatment method of the present invention can also be used as adjuvant chemotherapy in combination with surgery. The pharmaceutical composition of the present invention can be administered before surgery to reduce tumor size (neoadjuvant chemotherapy, or neoadjuvant therapy), or after surgery to prevent tumor recurrence (postoperative adjuvant chemotherapy, or adjuvant therapy). The pharmaceutical composition and treatment method of the present invention can also be used as maintenance therapy. For example, subsequent treatment can be administered after the initial chemotherapy to prevent recurrence.

[0129] The present invention includes a method for treating a disease, characterized in that the anti-CDH6 antibody-drug conjugate of the present application and a VEGF inhibitor are administered in combination to an individual in need of treatment. The present invention includes the anti-CDH6 antibody-drug conjugate of the present application for use in combination with a VEGF inhibitor for the treatment of a disease. The present invention includes the use of the anti-CDH6 antibody-drug conjugate of the present application in combination with a VEGF inhibitor in the manufacture of a medicament for the treatment of a disease. The present invention includes a pharmaceutical product containing the anti-CDH6 antibody-drug conjugate of the present application and a VEGF inhibitor. The present invention includes a pharmaceutical combination containing the anti-CDH6 antibody-drug conjugate of the present application and a VEGF inhibitor. The present invention includes a pharmaceutical combination containing the anti-CDH6 antibody-drug conjugate of the present application and a VEGF inhibitor. The present invention includes the use of the anti-CDH6 antibody-drug conjugate of the present application in combination with a VEGF inhibitor for the treatment of a disease. The present invention includes a medicament containing the anti-CDH6 antibody-drug conjugate of the present application and a VEGF inhibitor.

[0130] The present invention will be specifically described with reference to the following examples, but the present invention is not limited to these examples. Furthermore, these examples should not be construed as limiting in any sense.

[0131] Production Example 1: Production of anti-CDH6 antibody-drug conjugate According to the production method described in WO 2018 / 212136, a humanized anti-CDH6 antibody (an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38) was used to produce a drug conjugate of the formula

[0132]

[0133] An antibody-drug conjugate (hereinafter referred to as "anti-CDH6 antibody-drug conjugate (1)") was produced in which an anti-CDH6 antibody was linked to a drug linker represented by the formula: (wherein A represents the binding site to the antibody) via a thioether bond. The DAR of anti-CDH6 antibody-drug conjugate (1) was 7.9.

[0134] Example 1: Antitumor test (1) Mice: 6-week-old female BALB / c nude mice (Charles River Japan, Inc.) were used in the experiment.

[0135] Measurement and calculation formula: The major and minor axes of the tumor were measured two or three times a week using an electronic digital caliper (CD-15CX, Mitutoyo Corp.), and the tumor volume (mm ３ The calculation formula is as follows: Tumor volume (mm ３ ) = 1 / 2 x major axis (mm) x [minor axis (mm)] ２ Anti-CDH6 antibody-drug conjugate (1) was diluted with ABS buffer (10 mM acetate buffer (pH 5.5), 5% sorbitol) and administered intravenously at a volume of 10 mL / kg. Bevacizumab (Avastin (registered trademark) 100 mg / 4 mL) was diluted with saline and administered intraperitoneally at a volume of 10 mL / kg.

[0136] OV-90 cells, a human ovarian cancer cell line purchased from ATCC (American Type Culture Collection), were suspended in Matrigel basement membrane matrix and cultured at 2.5 × 10 ６The cells were subcutaneously transplanted into the right flank of female nude mice, and 17 days after transplantation, the mice were randomly assigned to groups (Day 0). The anti-CDH6 antibody-drug conjugate (1) was administered at a dose of 3 mg / kg on Day 0. Bevacizumab was administered at a dose of 5 mg / kg on Day 0. Groups for each drug alone and in combination, as well as a control group administered with ABS buffer, were set up.

[0137] The results of the combined use of anti-CDH6 antibody-drug conjugate (1) and bevacizumab are shown in Figure 14. In Figure 14, the horizontal axis represents the number of days after the start of administration, and the vertical axis represents the tumor volume. The tumor growth inhibition rate (TGI) was calculated using the following formula.

[0138] TGI (%) = [1 - (mean tumor volume of drug-treated group / mean tumor volume of control group)] x 100 As of Day 21, the tumor growth inhibition rate (TGI) by single-agent administration of bevacizumab was 35%. The TGI by single-agent administration of anti-CDH6 antibody-drug conjugate (1) was 79%. On the other hand, combined administration of anti-CDH6 antibody-drug conjugate (1) and bevacizumab showed a significantly superior tumor growth inhibitory effect than single-agent administration of anti-CDH6 antibody-drug conjugate (1) and single-agent administration of bevacizumab (P = 0.0045 and P < 0.0001, respectively. Calculated by Dunnett's test using common logarithm-transformed values ​​of tumor volume). Furthermore, the tumor growth inhibition rate was higher (TGI, 92%) than that of each drug administered alone, indicating that the antitumor effect was enhanced by the combined use. The change from baseline (%) in the mean tumor volume on Day 21, with the mean tumor volume on Day 0 as the baseline, was calculated using the following formula and is shown in Figure 15.

[0139]

[0140] In addition, the change from baseline (%) for each group is shown in Table 1. As shown in Figure 15 and Table 1, in the combined administration group, a strong combined effect accompanied by regression was observed, as indicated by the negative value of change from baseline (%).

[0141]

[0142] Furthermore, antitumor activity was evaluated as described by Bissery et al., Cancer Res., 51: 4845-4852 (1991), i.e., when the median tumor volume in the control group was 750 to 1500 mm ３ At this time, T / C (%) was calculated using the following formula, and a T / C of more than 42% was evaluated as "inactive," a T / C of 42% or less was evaluated as "active," and a T / C of less than 10% was evaluated as "highly active."

[0143]

[0144] On Day 10, the median tumor volume in the control group was 885 mm ３ The median tumor volume after single administration of anti-CDH6 antibody-drug conjugate (1) was 231 mm ３ (T / C = 26%), the median tumor volume after bevacizumab monotherapy was 630 mm ３ (T / C = 71%), the median tumor volume in the combined administration of anti-CDH6 antibody-drug conjugate (1) and bevacizumab was 129 mm ３ (T / C = 15%). On Day 14, the median tumor volume in the control group was 1357 mm ３ The median tumor volume after single administration of anti-CDH6 antibody-drug conjugate (1) was 169 mm ３ (T / C = 12%), the median tumor volume after bevacizumab monotherapy was 852 mm ３ (T / C = 63%), the median tumor volume in the combined administration of anti-CDH6 antibody-drug conjugate (1) and bevacizumab was 78 mm ３ (T / C = 6%). From the above, it was found that as of Day 14, the group administered with anti-CDH6 antibody-drug conjugate (1) alone was "active" and the group administered with bevacizumab alone was "inactive," whereas the group administered with anti-CDH6 antibody-drug conjugate (1) in combination with bevacizumab was "highly active" (Table 2).

[0145]

[0146] Furthermore, no significant findings such as weight loss were observed in any of the single-agent or combination administration groups. Therefore, the combination of anti-CDH6 antibody-drug conjugate (1) and bevacizumab increased efficacy without increasing toxicity.

[0147] From the above experimental results, it was found that the antibody-drug conjugate according to the present invention exhibits excellent antitumor effects when administered in combination with a VEGF inhibitor.

[0148] SEQ ID NO: 1: Amino acid sequence of human CDH6 EC3 SEQ ID NO: 2: Amino acid sequence of CDRH1 of chG019 SEQ ID NO: 3: Amino acid sequence of CDRH2 of chG019 SEQ ID NO: 4: Amino acid sequence of CDRH3 of chG019 SEQ ID NO: 5: Amino acid sequence of CDRL1 of chG019 SEQ ID NO: 6: Amino acid sequence of CDRL2 of chG019 SEQ ID NO: 7: Amino acid sequence of CDRL3 of chG019 SEQ ID NO: 8: Amino acid sequence of CDRH2 of rG019 SEQ ID NO: 9: Amino acid sequence of CDRH1 of rG055 SEQ ID NO: 10: Amino acid sequence of CDRH2 of rG055 SEQ ID NO: 11: Amino acid sequence of CDRH3 of rG055 SEQ ID NO: 12: Amino acid sequence of CDRL1 of rG055 SEQ ID NO: 13: Amino acid sequence of CDRL2 of rG055 SEQ ID NO: 14: Amino acid sequence of CDRL3 of rG055 SEQ ID NO: 15: Amino acid sequence of CDRH1 of rG056 SEQ ID NO: 16: Amino acid sequence of CDRH2 of rG056 SEQ ID NO: 17: Amino acid sequence of CDRH3 of rG056 SEQ ID NO: 18: Amino acid sequence of CDRL1 of rG056 SEQ ID NO: 19: Amino acid sequence of CDRL2 of rG056 SEQ ID NO: 20: Amino acid sequence of CDRL3 of rG056 SEQ ID NO: 21: Amino acid sequence of CDRH1 of rG061 SEQ ID NO: 22: Amino acid sequence of CDRH2 of rG061 SEQ ID NO: 23: Amino acid sequence of CDRH3 of rG061 SEQ ID NO: 24: Amino acid sequence of CDRL1 of rG061 SEQ ID NO: 25: Amino acid sequence of CDRL2 of rG061 SEQ ID NO: 26: Amino acid sequence of CDRL3 of rG061 SEQ ID NO: 27: Amino acid sequence of full-length hH01 heavy chain SEQ ID NO: 28: Amino acid sequence of hH01 heavy chain variable region SEQ ID NO: 29: Amino acid sequence of the full-length hH01 heavy chain minus the signal sequence SEQ ID NO: 30: Amino acid sequence of the full-length hH02 heavy chain SEQ ID NO: 31: Amino acid sequence of the hH02 heavy chain variable region SEQ ID NO: 32: Amino acid sequence of the full-length hH02 heavy chain minus the signal sequence SEQ ID NO: 33: Amino acid sequence of the full-length hH04 heavy chain SEQ ID NO: 34: Amino acid sequence of the hH04 heavy chain variable region SEQ ID NO: 35: Amino acid sequence of the full-length hH04 heavy chain minus the signal sequence SEQ ID NO: 36: Amino acid sequence of the full-length hL02 light chain SEQ ID NO: 37: Amino acid sequence of the hL02 light chain variable region SEQ ID NO: 38: Amino acid sequence of the full-length hL02 light chain minus the signal sequenceSEQ ID NO: 39: Amino acid sequence of the full-length hL03 light chain SEQ ID NO: 40: Amino acid sequence of the hL03 light chain variable region SEQ ID NO: 41: Amino acid sequence of the full-length hL03 light chain excluding the signal sequence

Claims

1. A pharmaceutical composition comprising an anti-CDH6 antibody-drug conjugate, wherein the anti-CDH6 antibody-drug conjugate and a VEGF inhibitor are administered in combination, and the anti-CDH6 antibody-drug conjugate has the formula (wherein A represents a binding site with respect to the anti-CDH6 antibody or a functional fragment of the antibody), and an antibody-drug conjugate in which the drug linker represented by the formula:

2. The pharmaceutical composition according to claim 1, wherein the anti-CDH6 antibody or a functional fragment of said antibody is an antibody or a functional fragment of said antibody that specifically binds to the amino acid sequence set forth in SEQ ID NO:1 and has the ability to be internalized into cells.

3. The pharmaceutical composition according to claim 1 or 2, wherein the anti-CDH6 antibody or a functional fragment of said antibody is an antibody or a functional fragment of said antibody comprising a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO:2, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO:3, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO:4, and a CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO:5, a CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO:6, and a CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO:

7.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the anti-CDH6 antibody or a functional fragment of said antibody is an antibody or a functional fragment of said antibody comprising a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO:28 and a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO:

37.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the anti-CDH6 antibody or a functional fragment of said antibody is an antibody or a functional fragment of said antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO:29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO:

38.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody, in which the heavy or light chain has undergone one or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, isomerization of aspartic acid, oxidation of methionine, addition of a methionine residue to the N-terminus, amidation of proline residues, pyroglutamic oxidation of N-terminal glutamine or N-terminal glutamic acid, and deletion of one or two amino acids at the carboxyl terminus.

7. The pharmaceutical composition according to claim 6, wherein the anti-CDH6 antibody or a functional fragment of said antibody is an antibody or a functional fragment of said antibody in which one or two amino acids are deleted at the carboxyl terminus of the heavy chain.

8. The pharmaceutical composition according to claim 7, wherein the anti-CDH6 antibody or a functional fragment of said antibody is an antibody or a functional fragment of said antibody in which one amino acid is deleted at the carboxyl terminus of both of the two heavy chains.

9. A pharmaceutical composition according to any one of claims 6 to 8, wherein the deleted amino acid is lysine.

10. The pharmaceutical composition according to any one of claims 6 to 9, wherein the anti-CDH6 antibody or a functional fragment of said antibody is an antibody or a functional fragment of said antibody in which the proline residue at the carboxyl terminus of the heavy chain is further amidated.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the average number of drug-linker structures bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 1 to 10.

12. The pharmaceutical composition according to any one of claims 1 to 10, wherein the average number of drug-linker structures bound per antibody in the anti-CDH6 antibody-drug conjugate is 7 to 8.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the VEGF inhibitor is an anti-VEGF antibody, an anti-VEGF receptor antibody, a fusion protein containing a VEGF receptor extracellular domain, or a multispecific antibody containing an anti-VEGF binding domain.

14. The pharmaceutical composition according to claim 13, wherein the VEGF inhibitor is an anti-VEGF antibody.

15. The pharmaceutical composition of claim 14, wherein the anti-VEGF antibody is bevacizumab.

16. The pharmaceutical composition of claim 13, wherein the VEGF inhibitor is an anti-VEGF receptor antibody.

17. The pharmaceutical composition according to claim 16, wherein the anti-VEGF receptor antibody is ramucirumab.

18. The pharmaceutical composition of claim 13, wherein the VEGF inhibitor is a fusion protein comprising the extracellular domain of a VEGF receptor.

19. The pharmaceutical composition according to claim 18, wherein the fusion protein comprising the VEGF receptor extracellular domain is aflibercept.

20. The pharmaceutical composition of claim 13, wherein the VEGF inhibitor is a multispecific antibody comprising an anti-VEGF binding domain.

21. The pharmaceutical composition of claim 20, wherein the multispecific antibody is a bispecific antibody.

22. The pharmaceutical composition according to any one of claims 1 to 21, wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained in different formulations and are administered simultaneously or at different times.

23. The pharmaceutical composition according to any one of claims 1 to 21, wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained in the same formulation.

24. A pharmaceutical composition according to any one of claims 1 to 23 for the treatment of cancer.

25. The pharmaceutical composition according to any one of claims 1 to 23 for the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian carcinoma, ovarian mucinous tumor, thyroid cancer, cholangiocarcinoma, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, neuroblastoma, colorectal cancer, gastric cancer, endometrial cancer and nasopharyngeal carcinoma.

26. A pharmaceutical composition according to any one of claims 1 to 23 for the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma and papillary renal cell carcinoma.

27. A pharmaceutical composition according to any one of claims 1 to 23 for the treatment of at least one selected from the group consisting of ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian carcinoma and ovarian mucinous tumor.

28. A pharmaceutical composition according to any one of claims 1 to 23 for the treatment of ovarian cancer.

29. The pharmaceutical composition of claim 28, wherein the ovarian cancer is epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

30. The pharmaceutical composition of claim 28 or 29, wherein the ovarian cancer is metastatic.

31. A pharmaceutical composition comprising an anti-CDH6 antibody-drug conjugate, wherein the anti-CDH6 antibody-drug conjugate and a VEGF inhibitor are administered in combination, and the anti-CDH6 antibody-drug conjugate is represented by the formula (wherein the antibody is an anti-CDH6 antibody, the drug linker is bound to the antibody via a thioether bond, and n represents the average number of drug linkers bound per antibody), 32. The pharmaceutical composition according to claim 31, wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO:29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO:

38.

33. The pharmaceutical composition of claim 31 or 32, wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.

34. The pharmaceutical composition according to any one of claims 31 to 33, wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7 to 8.

35. The pharmaceutical composition of any one of claims 31 to 34, wherein the VEGF inhibitor is an anti-VEGF antibody, an anti-VEGF receptor antibody, a fusion protein containing a VEGF receptor extracellular domain, or a multispecific antibody containing an anti-VEGF binding domain.

36. The pharmaceutical composition of claim 35, wherein the VEGF inhibitor is an anti-VEGF antibody.

37. The pharmaceutical composition of claim 36, wherein the anti-VEGF antibody is bevacizumab.

38. The pharmaceutical composition of claim 35, wherein the VEGF inhibitor is an anti-VEGF receptor antibody.

39. The pharmaceutical composition of claim 38, wherein the anti-VEGF receptor antibody is ramucirumab.

40. The pharmaceutical composition of claim 35, wherein the VEGF inhibitor is a fusion protein comprising a VEGF receptor extracellular domain.

41. The pharmaceutical composition of claim 40, wherein the fusion protein containing the VEGF receptor extracellular domain is aflibercept.

42. The pharmaceutical composition of claim 35, wherein the VEGF inhibitor is a multispecific antibody comprising an anti-VEGF binding domain.

43. The pharmaceutical composition of claim 42, wherein the multispecific antibody is a bispecific antibody.

44. The pharmaceutical composition according to any one of claims 31 to 43, wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained in different formulations and are administered simultaneously or at different times.

45. The pharmaceutical composition according to any one of claims 31 to 43, wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained in the same formulation.

46. ​​A pharmaceutical composition according to any one of claims 31 to 45 for the treatment of cancer.

47. The pharmaceutical composition of any one of claims 31 to 45 for the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian carcinoma, ovarian mucinous tumor, thyroid cancer, cholangiocarcinoma, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, and neuroblastoma.

48. A pharmaceutical composition according to any one of claims 31 to 45 for treating at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma and papillary renal cell carcinoma.

49. A pharmaceutical composition according to any one of claims 31 to 45 for the treatment of at least one selected from the group consisting of ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian carcinoma and ovarian mucinous tumor.

50. A pharmaceutical composition according to any one of claims 31 to 45 for the treatment of ovarian cancer.

51. The pharmaceutical composition of claim 50, wherein the ovarian cancer is epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

52. The pharmaceutical composition of claim 50 or 51, wherein the ovarian cancer is metastatic.

53. The pharmaceutical composition of any one of claims 1 to 52, wherein the anti-CDH6 antibody-drug conjugate is raludotatug deruxtecan (DS-6000a).

54. A method of treatment comprising administering to an individual in need of treatment an anti-CDH6 antibody-drug conjugate in combination with a VEGF inhibitor, the antibody-drug conjugate being represented by the formula: (wherein A represents the binding site with respect to the anti-CDH6 antibody or a functional fragment of the antibody), and an antibody-drug conjugate in which the drug linker represented by the formula:

55. The method of treatment according to claim 54, wherein the anti-CDH6 antibody or a functional fragment of said antibody specifically binds to the amino acid sequence set forth in SEQ ID NO:1 and has the ability to be internalized into cells, or a functional fragment of said antibody.

56. The method of treatment according to claim 54 or 55, wherein the anti-CDH6 antibody or a functional fragment of said antibody is an antibody or a functional fragment of said antibody comprising a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO:2, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO:3, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO:4, and a CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO:5, a CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO:6, and a CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO:

7.

57. A method for treatment according to any one of claims 54 to 56, wherein the anti-CDH6 antibody or a functional fragment of said antibody is an antibody or a functional fragment of said antibody comprising a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO:28 and a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO:

37.

58. A method for treatment according to any one of claims 54 to 57, wherein the anti-CDH6 antibody or a functional fragment of said antibody is an antibody or a functional fragment of said antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO:29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO:

38.

59. The method for treatment according to any one of claims 54 to 58, wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody, in which the heavy or light chain has undergone one or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, isomerization of aspartic acid, oxidation of methionine, addition of a methionine residue to the N-terminus, amidation of proline residues, pyroglutamic oxidation of N-terminal glutamine or N-terminal glutamic acid, and deletion of one or two amino acids at the carboxyl terminus.

60. The method of treatment of claim 59, wherein the anti-CDH6 antibody or a functional fragment of said antibody is an antibody or a functional fragment of said antibody having one or two amino acids deleted at the carboxyl terminus of the heavy chain.

61. The method of claim 60, wherein the anti-CDH6 antibody or a functional fragment of said antibody is an antibody or a functional fragment of said antibody in which one amino acid is deleted at the carboxyl terminus of both of its two heavy chains.

62. A method of treatment according to any one of claims 59 to 61, wherein the missing amino acid is lysine.

63. A therapeutic method according to any one of claims 59 to 62, wherein the anti-CDH6 antibody or a functional fragment of said antibody is an antibody or a functional fragment of said antibody in which the proline residue at the carboxyl terminus of the heavy chain is further amidated.

64. A therapeutic method according to any one of claims 54 to 63, wherein the average number of drug-linker structures bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 1 to 10.

65. A therapeutic method according to any one of claims 54 to 63, wherein the average number of drug-linker structures bound per antibody in the anti-CDH6 antibody-drug conjugate is 7 to 8.

66. A method of treatment according to any one of claims 54 to 65, wherein the VEGF inhibitor is an anti-VEGF antibody, an anti-VEGF receptor antibody, a fusion protein containing a VEGF receptor extracellular domain, or a multispecific antibody containing an anti-VEGF binding domain.

67. The method of treatment according to claim 66, wherein the VEGF inhibitor is an anti-VEGF antibody.

68. The method of treatment of claim 67, wherein the anti-VEGF antibody is bevacizumab.

69. The method of treatment according to claim 66, wherein the VEGF inhibitor is an anti-VEGF receptor antibody.

70. The method of treatment of claim 69, wherein the anti-VEGF receptor antibody is ramucirumab.

71. The method of treatment of claim 66, wherein the VEGF inhibitor is a fusion protein comprising the extracellular domain of a VEGF receptor.

72. The method of treatment according to claim 71, wherein the fusion protein comprising the VEGF receptor extracellular domain is aflibercept.

73. The method of treatment of claim 66, wherein the VEGF inhibitor is a multispecific antibody comprising an anti-VEGF binding domain.

74. The method of treatment of claim 73, wherein the multispecific antibody is a bispecific antibody.

75. A therapeutic method according to any one of claims 54 to 74, characterized in that the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained in different formulations and administered simultaneously or at different times.

76. A therapeutic method according to any one of claims 54 to 74, wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained in the same formulation.

77. A method according to any one of claims 54 to 76 for the treatment of cancer.

78. The method of any one of claims 54 to 76 for treating at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian carcinoma, ovarian mucinous tumor, thyroid cancer, cholangiocarcinoma, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, and neuroblastoma.

79. A method for treating at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, and papillary renal cell carcinoma, according to any one of claims 54 to 76.

80. A method for treating at least one selected from the group consisting of ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian carcinoma, and ovarian mucinous tumors, according to any one of claims 54 to 76.

81. A method of treatment according to any one of claims 54 to 76 for the treatment of ovarian cancer.

82. The method of claim 81, wherein the ovarian cancer is epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

83. The method of treatment of claim 81 or 82, wherein the ovarian cancer is metastatic.

84. A method of treatment comprising administering to an individual in need of treatment an anti-CDH6 antibody-drug conjugate in combination with a VEGF inhibitor, the anti-CDH6 antibody-drug conjugate being represented by the formula: (wherein the antibody is an anti-CDH6 antibody, the drug linker is bound to the antibody via a thioether bond, and n represents the average number of drug linkers bound per antibody).

85. The therapeutic method according to claim 84, wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO:29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO:

38.

86. The therapeutic method of claim 84 or 85, wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.

87. A therapeutic method according to any one of claims 84 to 86, wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7 to 8.

88. A method of treatment according to any one of claims 84 to 87, wherein the VEGF inhibitor is an anti-VEGF antibody, an anti-VEGF receptor antibody, a fusion protein containing a VEGF receptor extracellular domain, or a multispecific antibody containing an anti-VEGF binding domain.

89. The method of treatment of claim 88, wherein the VEGF inhibitor is an anti-VEGF antibody.

90. The method of treatment of claim 89, wherein the anti-VEGF antibody is bevacizumab.

91. The method of treatment of claim 88, wherein the VEGF inhibitor is an anti-VEGF receptor antibody.

92. The method of treatment of claim 91, wherein the anti-VEGF receptor antibody is ramucirumab.

93. The method of treatment of claim 88, wherein the VEGF inhibitor is a fusion protein comprising the extracellular domain of a VEGF receptor.

94. The method of treatment of claim 93, wherein the fusion protein containing the VEGF receptor extracellular domain is aflibercept.

95. The method of treatment of claim 88, wherein the VEGF inhibitor is a multispecific antibody comprising an anti-VEGF binding domain.

96. The method of treatment of claim 95, wherein the multispecific antibody is a bispecific antibody.

97. A therapeutic method according to any one of claims 84 to 96, characterized in that the antibody-drug conjugate and the VEGF inhibitor are contained in different formulations and are administered simultaneously or at different times.

98. A therapeutic method according to any one of claims 84 to 96, wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are contained in the same formulation.

99. A method according to any one of claims 84 to 98 for the treatment of cancer.

100. The method of any one of claims 84 to 98 for treating at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian carcinoma, ovarian mucinous tumor, thyroid cancer, cholangiocarcinoma, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, and neuroblastoma.

101. A method for treating at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, and papillary renal cell carcinoma, according to any one of claims 84 to 98.

102. A method for treating at least one selected from the group consisting of ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian carcinoma, and ovarian mucinous tumors, according to any one of claims 84 to 98.

103. A method of treatment according to any one of claims 84 to 98 for the treatment of ovarian cancer.

104. The method of claim 103, wherein the ovarian cancer is epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

105. The method of treatment of claim 103 or 104, wherein the ovarian cancer is metastatic.

106. The therapeutic method of any one of claims 54 to 105, wherein the anti-CDH6 antibody-drug conjugate is raludotatug deruxtecan (DS-6000a).