Combination of Anti-CDH6 antibody–drug conjugate with other agent

Abstract

[Problem] To provide a novel drug combination treatment for diseases, particularly cancer. [Solution] The present invention provides a combination administration of an anti-CDH6 antibody–drug conjugate with another agent, such as an immune checkpoint inhibitor.

Description

Combination of anti-CDH6 antibody-drug conjugate with other agents

[0001] The present invention relates to pharmaceutical compositions characterized by the use of a specific anti-CDH6 antibody-drug conjugate in combination with another drug such as an immune checkpoint inhibitor, and therapeutic methods characterized by administering a specific anti-CDH6 antibody-drug conjugate in combination with another drug such as an immune checkpoint inhibitor to a subject, etc.

[0002] In cancer treatment, surgical removal of the cancer lesion and the cytocidal effect of anticancer drugs and radiation on cancer cells are expected to lead to a cure or prolong life. However, for many cancers, single-drug anticancer drug treatment is insufficient, and combination use of various drugs is required. Anticancer drugs include chemotherapeutic agents such as paclitaxel, carboplatin, doxorubicin, and docetaxel (Non-Patent Documents 1 and 2), molecularly targeted drugs such as sorafenib, axitinib, sunitinib, pazopanib, everolimus, and olaparib (Non-Patent Document 2), cancer therapeutic antibodies such as bevacizumab and denosumab, and antibody-drug conjugates such as mirvetuximab soravtansine (Patent Document 1) and trastuzumab emtansine (Patent Document 2). The anticancer drug and combination used are determined by the type and stage of cancer and the treatment status.

[0003] Immune checkpoint inhibitors, which have recently become one of the standard treatments for some cancers, are drugs that inhibit the immunosuppressive system and activate anti-tumor immunity (Non-Patent Documents 3 to 5). Examples of immune checkpoint inhibitors include anti-PD-1 antibodies such as nivolumab (Patent Document 3), pembrolizumab (Patent Document 4), spartalizumab (Patent Document 5), cemiplimab (Patent Document 6), and dostarlimab, as well as anti-PD-L1 antibodies such as atezolizumab (Patent Document 7) and durvalumab. b) (Patent Document 8), Avelumab (Patent Document 9), anti-CTLA-4 antibodies Ipilimumab (Patent Document 10) and Tremelimumab (Patent Document 11), anti-TIGIT antibodies Tiragolumab (Patent Document 12) and Vibostolimab (Patent Document 13), and anti-LAG-3 antibody Relatlimab (Patent Document 14), etc. are known.

[0004] Cadherin-6 (CDH6) is a single-pass transmembrane protein consisting of 790 amino acids and classified as a member of the type II cadherin family. It has been reported that CDH6 expression correlates with poor prognosis in human renal cell carcinoma, particularly renal clear cell carcinoma, and that it may be useful as a tumor marker (Non-Patent Documents 6 and 7). High expression of CDH6 has also been reported in human ovarian cancer (Non-Patent Document 8), human cholangiocarcinoma, and human small cell lung cancer, making it a useful target for cancer therapy (Non-Patent Documents 9 and 10).

[0005] STING (Stimulator of Interferon Genes) is a transmembrane adaptor protein localized in the endoplasmic reticulum (Non-Patent Document 11). STING functions as a central molecule in innate immune activation in mammals and serves as the first line of defense against the invasion of pathogens such as bacteria and viruses. It is known that STING activation is triggered by signals generated when multiple cytoplasmic DNA sensors sense exogenous and endogenous DNA (Non-Patent Documents 12-14). Recent studies have shown that STING not only promotes host defense against microorganisms but also antitumor immunity (Non-Patent Document 15). Patent Documents 15-18 describe conjugates in which a STING agonist is used as an immunostimulatory compound and is linked to an antibody via a linker, and include examples of in vivo administration. Patent Document 19 describes an example in which a conjugate in which a STING agonist and an antibody are linked via a linker is combined with trastuzumab or an anti-PD-1 antibody in vivo and administered.

[0006] However, the combined effects of conjugates of a STING agonist having a specific cyclic dinucleotide structure and an antibody (Patent Documents 17 and 18) combined with other drugs are unknown.

[0007] International Publication No. WO 2012 / 135522, International Publication No. WO 2001 / 000244, International Publication No. WO 2006 / 121168, International Publication No. WO 2008 / 156712, International Publication No. WO 2015 / 112900, International Publication No. WO 2015 / 196051, International Publication No. WO 2010 / 077634, International Publication No. WO 2011 / 066389, International Publication No. WO 2013 / 079174 International Publication No. 1 / 014424, International Publication No. 2000 / 037504, International Publication No. 2017 / 053748, International Publication No. 2016 / 028656, International Publication No. 2014 / 008218, International Publication No. 2021 / 202984, International Publication No. 2022 / 097117, International Publication No. 2020 / 050406, International Publication No. 2021 / 177438, International Publication No. 2023 / 172906

[0008] Genes & Diseases 2023, 10, 1367-1401. Exp Mol Med (2022) 54, 1670-1697 Cancers 2016, 8, 106. Nat. Rev. Cancer 2012, 12, 252-264. Cell 2015, 162, 937. Cancer Research, 27 41-2748, July 1, 57, 1997 Cancer, 963-968, 101(5), Sep. 1, 2004 PLoS Medicine, 17 49-1760, 5(12), e232, Dec. 2008 Epigenetics, 7 80-790, 11 (11), 2016 American Journal of Pathology, 207-216, 161, 1, 2002 Nature 2008, 455, 674-678. Mol. Cell 2013, 51, 226-235. Science 2015, 347, aaa2630. J. Virol. 2014, 88, 5328-5341. Immunity 2014, 41, 830-842.

[0009] An objective of the present invention is to provide a novel drug combination therapy for diseases, particularly cancer.

[0010] The present inventors have conducted extensive research to solve the above problems and have found that the combined administration of an anti-CDH6 antibody-drug conjugate of formula (I) below with another drug such as an immune checkpoint inhibitor safely exhibits excellent combined effects (particularly, significant antitumor effects), thereby completing the present invention. Specifically, the present invention provides the following [A1] to [D37].

[0011] [A1] a) a pharmaceutical composition comprising an anti-CDH6 antibody-drug conjugate, wherein a) the anti-CDH6 antibody-drug conjugate and b) one or more selected from an immune checkpoint inhibitor, a chemotherapeutic agent, and a molecular targeted drug are used in combination, and the anti-CDH6 antibody-drug conjugate is represented by the following formula (I): (In the formula, m ２ represents an integer of 1 or 2, L represents a linker connecting the N297 sugar chain and D, -Lb-La-Lp-Lc-* (wherein the asterisk indicates binding to drug D, and Lb is: (In the structural formula of Lb shown above, the asterisk indicates bonding to La, and the wavy line indicates bonding to the N297 sugar chain), where La is -C(=O)-CH ２ CH ２ Lp represents -GGFG- or -GGPI-, Lc represents -NH-CH ２ Ab is an anti-CDH6 antibody or an antigen-binding fragment thereof comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 4, and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 5, and a light chain comprising CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of the amino acid sequence represented by DAN, and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 7, wherein the N297 sugar chain is N297-(Fuc)MSG1 having the structure represented by the following formula: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of the 1-3 chain side of the branched chain of β-Man in the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1- or 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５ represents an integer of 2 to 5), or N297-(Fuc)SG: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２-NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５ represents an integer of 2 to 5), and D represents (wherein the asterisk indicates binding to L, and W represents -NH-). [A1'] The pharmaceutical composition according to [A1], wherein Ab is an anti-CDH6 antibody comprising an Fc region (wild-type or mutant-type) of the antibody, or an antigen-binding fragment of the antibody. [A2] The pharmaceutical composition according to [A1], wherein D is (wherein the asterisk indicates binding to L). [A3] The pharmaceutical composition according to [A1], wherein the anti-CDH6 antibody-drug conjugate is represented by the following formula: (Wherein Ab, N297 sugar chain and m ２ is as defined above). [A4] The pharmaceutical composition according to [A1] or [A2], wherein the anti-CDH6 antibody-drug conjugate is represented by the following formula: In the formula, m ２ is 2, the Ab comprises a heavy chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 8, and a light chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 9, and the N297 sugar chain is N297-(Fuc)SG having a structure shown in the following formula: (wherein the wavy line indicates binding to Asn297 of Ab, L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２-NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, the asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring, and n ５[A5] The pharmaceutical composition according to any one of [A1] to [A4], wherein Ab comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 8 and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 9. [A6] The pharmaceutical composition according to any one of [A1] to [A5], wherein Ab comprises a heavy chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 1, and a light chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 2. [A7] The pharmaceutical composition according to any one of [A1] to [A6], wherein Ab comprises a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2. [A8] The pharmaceutical composition of any one of [A1] to [A5], wherein the Ab is comprised in an antibody or an antigen-binding fragment of the antibody contained in the anti-CDH6 antibody-drug conjugate of any one of [A1] to [A7], and comprises: (i) a heavy chain consisting of an amino acid sequence in which one or two amino acids are deleted from the carboxyl terminus of the amino acid sequence of the heavy chain; and (ii) a light chain. [A9] The pharmaceutical composition of any one of [A1] to [A8], wherein a) an anti-CDH6 antibody-drug conjugate and b) an immune checkpoint inhibitor are used in combination, and the immune checkpoint inhibitor is an antibody selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-TIGIT antibody, and an anti-LAG-3 antibody, an antigen-binding fragment thereof, or a compound comprising any of them. [A10] The pharmaceutical composition according to [A9], wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, spartalizumab, cemiplimab, or dostarlimab. [A11] The pharmaceutical composition according to [A9], wherein the anti-PD-L1 antibody is atezolizumab, duvalumab, or avelumab. [A12] The pharmaceutical composition according to [A9], wherein the anti-CTLA-4 antibody is ipilimumab or tremelimumab. [A13] The pharmaceutical composition according to [A9], wherein the anti-TIGIT antibody is tiragolumab or vibostolimab.[A14] The pharmaceutical composition according to [A9], wherein the anti-LAG-3 antibody is leratolimab. [A15] The pharmaceutical composition according to any one of [A1] to [A8], wherein a) an anti-CDH6 antibody-drug conjugate and b) a chemotherapeutic agent are used in combination, and the chemotherapeutic agent is an antimetabolite, a tubulin inhibitor, an alkylating agent, a platinum compound, a topoisomerase inhibitor, or an anticancer antibiotic. [A16] The pharmaceutical composition according to [A15], wherein the antimetabolite is gemcitabine or a pharmaceutically acceptable salt thereof. [A17] The pharmaceutical composition according to [A15], wherein the antimetabolite is fluorouracil or a pharmaceutically acceptable salt thereof. [A18] The pharmaceutical composition according to [A15], wherein the tubulin inhibitor is docetaxel or a pharmaceutically acceptable salt thereof. [A19] The pharmaceutical composition according to [A15], wherein the tubulin inhibitor is paclitaxel or a pharmaceutically acceptable salt thereof. [A20] The pharmaceutical composition according to [A15], wherein the platinum preparation is carboplatin or a pharmaceutically acceptable salt thereof. [A21] The pharmaceutical composition according to [A15], wherein the platinum preparation is oxaliplatin or a pharmaceutically acceptable salt thereof. [A22] The pharmaceutical composition according to [A15], wherein the platinum preparation is cisplatin or a pharmaceutically acceptable salt thereof. [A23] The pharmaceutical composition according to [A15], wherein the topoisomerase inhibitor is topotecan or a pharmaceutically acceptable salt thereof. [A24] The pharmaceutical composition according to [A15], wherein the topoisomerase inhibitor is irinotecan or a pharmaceutically acceptable salt thereof. [A25] The pharmaceutical composition according to [A15], wherein the anticancer antibiotic is doxorubicin or liposomal doxorubicin, or a pharmaceutically acceptable salt thereof. [A26] The pharmaceutical composition according to any one of [A1] to [A8], wherein a) an anti-CDH6 antibody-drug conjugate and b) a molecularly targeted drug are used in combination, and the molecularly targeted drug is a multikinase inhibitor, a HIF-2α inhibitor, a VEGF inhibitor, or a PARP inhibitor. [A27] The pharmaceutical composition according to [A26], wherein the multikinase inhibitor is axitinib, cabozantinib, lenvatinib, sunitinib, or a pharmaceutically acceptable salt thereof.[A28] The pharmaceutical composition according to [A26], wherein the HIF-2α inhibitor is velzutifan or a pharmaceutically acceptable salt thereof. [A29] The pharmaceutical composition according to [A26], wherein the VEGF inhibitor is bevacizumab, ramucirumab, or aflibercept beta. [A30] The pharmaceutical composition according to [A26], wherein the PARP inhibitor is olaparib, niraparib, rucaparib, or a pharmaceutically acceptable salt thereof. [A31] The pharmaceutical composition according to any one of [A1] to [A8], wherein a) an anti-CDH6 antibody-drug conjugate and b) a molecular targeted drug are used in combination, and the molecular targeted drug is an anti-folate receptor α antibody-drug conjugate. [A32] The pharmaceutical composition according to [A31], wherein the anti-folate receptor α antibody-drug conjugate is mirvetuximab soravtansine-gynx, farletuzumab ecteribulin, or rubertamabutazebibrin. [A33] The pharmaceutical composition according to any one of [A1] to [A32], wherein a) the anti-CDH6 antibody-drug conjugate; and b) an immune checkpoint inhibitor, a chemotherapeutic agent, or a molecularly targeted drug are contained as active ingredients in separate formulations and administered simultaneously or at different times (asynchronously or separately). [A34] The pharmaceutical composition according to any one of [A1] to [A33], for the treatment of cancer. [A35] The pharmaceutical composition according to [A34], wherein the cancer is at least one selected from the group consisting of lung cancer (non-small cell lung cancer, small cell lung cancer, etc.), renal cancer, urothelial cancer, ovarian cancer (surface epithelial tumor, stromal tumor, germ cell tumor, etc.), pancreatic cancer, endometrial cancer, cervical cancer, thyroid cancer, mesothelioma, gallbladder cancer, bile duct cancer, sarcoma, Wilms' tumor, and neuroblastoma. [A36] The pharmaceutical composition according to [A35], wherein the cancer is renal cancer. [A37] The pharmaceutical composition according to [A35], wherein the cancer is ovarian cancer. [A38] The pharmaceutical composition according to [A35], wherein the cancer is mesothelioma. [A39] The pharmaceutical composition according to [A35], wherein the cancer is pancreatic cancer.[B1] An anti-CDH6 antibody-drug conjugate for use in combination with one or more selected from an immune checkpoint inhibitor, a chemotherapeutic agent, and a molecular targeted drug for the treatment of cancer, wherein the anti-CDH6 antibody-drug conjugate is represented by the following formula (I): (In the formula, m ２ represents an integer of 1 or 2, L represents a linker connecting the N297 sugar chain and D, -Lb-La-Lp-Lc-* (wherein the asterisk indicates binding to drug D, and Lb is: (In the structural formula of Lb shown above, the asterisk indicates bonding to La, and the wavy line indicates bonding to the N297 sugar chain), where La is -C(=O)-CH ２ CH ２ Lp represents -GGFG- or -GGPI-, Lc represents -NH-CH ２ Ab is an anti-CDH6 antibody or an antigen-binding fragment thereof comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 4, and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 5, and a light chain comprising CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of the amino acid sequence represented by DAN, and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 7, wherein the N297 sugar chain is N297-(Fuc)MSG1 having the structure represented by the following formula: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of the 1-3 chain side of the branched chain of β-Man in the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1- or 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５ represents an integer of 2 to 5), or N297-(Fuc)SG: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５ represents an integer of 2 to 5), and D represents (wherein the asterisk indicates binding to L, and W represents -NH-). [B1'] The anti-CDH6 antibody-drug conjugate according to [B1], wherein Ab is an anti-CDH6 antibody comprising an Fc region (wild-type or mutant-type) of the antibody, or an antigen-binding fragment of the antibody. [B2] D is (wherein the asterisk indicates binding to L). [B3] The anti-CDH6 antibody-drug conjugate according to [B1], represented by the following formula: or (wherein Ab, N297 glycan and m ２ [B4] The anti-CDH6 antibody-drug conjugate according to [B1] or [B2], wherein the anti-CDH6 antibody-drug conjugate is represented by the following formula: In the formula, m ２ is 2, the Ab comprises a heavy chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 8, and a light chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 9, and the N297 sugar chain is N297-(Fuc)SG having a structure shown in the following formula: (wherein the wavy line indicates binding to Asn297 of Ab, L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, the asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring, and n ５represents an integer of 3). [B5] The anti-CDH6 antibody-drug conjugate of any one of [B1] to [B4], wherein the Ab comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 8 and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 9. [B6] The anti-CDH6 antibody-drug conjugate of any one of [B1] to [B5], wherein the Ab comprises a heavy chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 1, and a light chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 2. [B7] The anti-CDH6 antibody-drug conjugate according to any one of [B1] to [B6], wherein the Ab comprises a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2. [B8] The anti-CDH6 antibody-drug conjugate according to any one of [B1] to [B7], wherein the Ab is comprised in the antibody or antigen-binding fragment of said antibody comprised in the anti-CDH6 antibody-drug conjugate according to any one of [B1] to [B7], and comprises: (i) a heavy chain consisting of an amino acid sequence in which one or two amino acids are deleted from the carboxyl terminus of the amino acid sequence of the heavy chain; and (ii) a light chain. [B9] An anti-CDH6 antibody-drug conjugate according to any one of [B1] to [B8], for use in combination with an immune checkpoint inhibitor for the treatment of cancer, wherein the immune checkpoint inhibitor is an antibody selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-TIGIT antibody, and an anti-LAG-3 antibody, an antigen-binding fragment thereof, or a compound containing any of them. [B10] The anti-CDH6 antibody-drug conjugate according to [B9], wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, spartalizumab, cemiplimab, or dostarlimab. [B11] The anti-CDH6 antibody-drug conjugate according to [B9], wherein the anti-PD-L1 antibody is atezolizumab, duvalumab, or avelumab.[B12] The anti-CDH6 antibody-drug conjugate according to [B9], wherein the anti-CTLA-4 antibody is ipilimumab or tremelimumab. [B13] The anti-CDH6 antibody-drug conjugate according to [B9], wherein the anti-TIGIT antibody is tiragolumab or vibostolimab. [B14] The anti-CDH6 antibody-drug conjugate according to [B9], wherein the anti-LAG-3 antibody is leratolimab. [B15] The anti-CDH6 antibody-drug conjugate according to any one of [B1] to [B8], for use in combination with a chemotherapeutic agent for the treatment of cancer, wherein the chemotherapeutic agent is an antimetabolite, a tubulin inhibitor, an alkylating agent, a platinum compound, a topoisomerase inhibitor, or an anticancer antibiotic. [B16] The anti-CDH6 antibody-drug conjugate according to [B15], wherein the antimetabolite is gemcitabine or a pharmaceutically acceptable salt thereof. [B17] The anti-CDH6 antibody-drug conjugate according to [B15], wherein the antimetabolite is fluorouracil or a pharmaceutically acceptable salt thereof. [B18] The anti-CDH6 antibody-drug conjugate according to [B15], wherein the tubulin inhibitor is docetaxel or a pharmaceutically acceptable salt thereof. [B19] The anti-CDH6 antibody-drug conjugate according to [B15], wherein the tubulin inhibitor is paclitaxel or a pharmaceutically acceptable salt thereof. [B20] The anti-CDH6 antibody-drug conjugate according to [B15], wherein the platinum agent is carboplatin or a pharmaceutically acceptable salt thereof. [B21] The anti-CDH6 antibody-drug conjugate according to [B15], wherein the platinum agent is oxaliplatin or a pharmaceutically acceptable salt thereof. [B22] The anti-CDH6 antibody-drug conjugate according to [B15], wherein the platinum agent is cisplatin or a pharmaceutically acceptable salt thereof. [B23] The anti-CDH6 antibody-drug conjugate according to [B15], wherein the topoisomerase inhibitor is topotecan or a pharmaceutically acceptable salt thereof. [B24] The anti-CDH6 antibody-drug conjugate according to [B15], wherein the topoisomerase inhibitor is irinotecan or a pharmaceutically acceptable salt thereof.[B25] The anti-CDH6 antibody-drug conjugate according to [B15], wherein the anticancer antibiotic is doxorubicin or liposomal doxorubicin, or a pharmaceutically acceptable salt thereof. [B26] The anti-CDH6 antibody-drug conjugate according to any one of [B1] to [B8], for use in combination with a molecularly targeted drug for the treatment of cancer, wherein the molecularly targeted drug is a multikinase inhibitor, a HIF-2α inhibitor, a VEGF inhibitor, or a PARP inhibitor. [B27] The anti-CDH6 antibody-drug conjugate according to [B26], wherein the multikinase inhibitor is axitinib, cabozantinib, lenvatinib, or sunitinib, or a pharmaceutically acceptable salt thereof. [B28] The anti-CDH6 antibody-drug conjugate according to [B26], wherein the HIF-2α inhibitor is belzutifan or a pharmaceutically acceptable salt thereof. [B29] The anti-CDH6 antibody-drug conjugate according to [B26], wherein the VEGF inhibitor is bevacizumab, ramucirumab, or aflibercept beta. [B30] The anti-CDH6 antibody-drug conjugate according to [B26], wherein the PARP inhibitor is olaparib, niraparib, rucaparib, or a pharmaceutically acceptable salt thereof. [B31] The anti-CDH6 antibody-drug conjugate according to any one of [B1] to [B8], for use in combination with a molecularly targeted drug for the treatment of cancer, wherein the molecularly targeted drug is an anti-folate receptor α antibody-drug conjugate. [B32] The anti-CDH6 antibody-drug conjugate according to [B31], wherein the anti-folate receptor α antibody-drug conjugate is mirvetuximab soravtansine-gynx, farletuzumab ecteribulin, or rubertamabutazebibrin. [B33] The anti-CDH6 antibody-drug conjugate according to any one of [B1] to [B32], wherein the anti-CDH6 antibody-drug conjugate; and the immune checkpoint inhibitor, chemotherapeutic agent, or molecular targeted drug are contained as active ingredients in separate formulations, and are administered simultaneously (simultaneously) or at different times (asynchronously or separately).[B34] The anti-CDH6 antibody-drug conjugate according to any one of [B1] to [B33], wherein the cancer is at least one selected from the group consisting of lung cancer (non-small cell lung cancer, small cell lung cancer, etc.), renal cancer, urothelial cancer, ovarian cancer (surface epithelial tumor, stromal tumor, germ cell tumor, etc.), pancreatic cancer, endometrial cancer, cervical cancer, thyroid cancer, mesothelioma, gallbladder cancer, bile duct cancer, sarcoma, Wilms' tumor, and neuroblastoma. [B35] The anti-CDH6 antibody-drug conjugate according to [B34], wherein the cancer is renal cancer. [B36] The anti-CDH6 antibody-drug conjugate according to [B34], wherein the cancer is ovarian cancer. [B37] The anti-CDH6 antibody-drug conjugate according to [B34], wherein the cancer is mesothelioma. [B38] The anti-CDH6 antibody-drug conjugate according to [B34], wherein the cancer is pancreatic cancer. [C1] Use of an anti-CDH6 antibody-drug conjugate in combination with one or more selected from an immune checkpoint inhibitor, a chemotherapeutic agent, and a molecular targeted drug in the manufacture of a medicament for treating cancer, wherein the anti-CDH6 antibody-drug conjugate is represented by the following formula (I): (In the formula, m ２ represents an integer of 1 or 2, L represents a linker connecting the N297 sugar chain and D, -Lb-La-Lp-Lc-* (wherein the asterisk indicates binding to drug D, and Lb is: (In the structural formula of Lb shown above, the asterisk indicates bonding to La, and the wavy line indicates bonding to the N297 sugar chain), where La is -C(=O)-CH ２ CH ２ Lp represents -GGFG- or -GGPI-, Lc represents -NH-CH ２Ab is an anti-CDH6 antibody or an antigen-binding fragment thereof comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 4, and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 5, and a light chain comprising CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of the amino acid sequence represented by DAN, and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 7, wherein the N297 sugar chain is N297-(Fuc)MSG1 having the structure represented by the following formula: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of the 1-3 chain side of the branched chain of β-Man in the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1- or 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５ represents an integer of 2 to 5), or N297-(Fuc)SG: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５ represents an integer of 2 to 5), and D represents (wherein the asterisk indicates binding to L, and W represents -NH-). [C1'] The use according to [C1], wherein Ab is an anti-CDH6 antibody comprising an Fc region (wild-type or mutant-type) of the antibody, or an antigen-binding fragment of the antibody. [C2] D is (wherein the asterisk indicates binding to L). [C3] The use according to [C1], wherein the anti-CDH6 antibody-drug conjugate is represented by the following formula: (Wherein Ab, N297 sugar chain and m ２ [C4] The use according to [C1] or [C2], wherein the anti-CDH6 antibody-drug conjugate is represented by the following formula: In the formula, m ２ is 2, the Ab comprises a heavy chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 8, and a light chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 9, and the N297 sugar chain is N297-(Fuc)SG having a structure shown in the following formula: (wherein the wavy line indicates binding to Asn297 of Ab, L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, the asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring, and n ５[C5] The use according to any one of [C1] to [C4], wherein the Ab comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 8 and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 9. [C6] The use according to any one of [C1] to [C5], wherein the Ab comprises a heavy chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 1, and a light chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 2. [C7] The use according to any one of [C1] to [C6], wherein the Ab comprises a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2. [C8] The use according to any one of [C1] to [C5], wherein the Ab is comprised in the antibody or antigen-binding fragment of the antibody contained in the anti-CDH6 antibody-drug conjugate according to any one of [C1] to [C7], and comprises: (i) a heavy chain consisting of an amino acid sequence in which one or two amino acids are deleted from the carboxyl terminus of the amino acid sequence of the heavy chain; and (ii) a light chain. [C9] The use according to any one of [C1] to [C8], wherein the use is an anti-CDH6 antibody-drug conjugate in combination with an immune checkpoint inhibitor in the manufacture of a medicament for treating cancer, wherein the immune checkpoint inhibitor is an antibody selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-TIGIT antibody, and an anti-LAG-3 antibody, an antigen-binding fragment thereof, or a compound comprising any of them. [C10] The use according to [C9], wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, spartalizumab, cemiplimab, or dostarlimab. [C11] The use according to [C9], wherein the anti-PD-L1 antibody is atezolizumab, duvalumab, or avelumab. [C12] The use according to [C9], wherein the anti-CTLA-4 antibody is ipilimumab or tremelimumab. [C13] The use according to [C9], wherein the anti-TIGIT antibody is tiragolumab or vibostolimab. [C14] The use according to [C9], wherein the anti-LAG-3 antibody is leratolimab.[C15] The use according to any one of [C1] to [C8], wherein the chemotherapeutic agent is an antimetabolite, a tubulin inhibitor, an alkylating agent, a platinum compound, a topoisomerase inhibitor, or an anticancer antibiotic, in the manufacture of a medicament for the treatment of cancer. [C16] The use according to [C15], wherein the antimetabolite is gemcitabine or a pharmaceutically acceptable salt thereof. [C17] The use according to [C15], wherein the antimetabolite is fluorouracil or a pharmaceutically acceptable salt thereof. [C18] The use according to [C15], wherein the tubulin inhibitor is docetaxel or a pharmaceutically acceptable salt thereof. [C19] The use according to [C15], wherein the tubulin inhibitor is paclitaxel or a pharmaceutically acceptable salt thereof. [C20] The use according to [C15], wherein the platinum compound is carboplatin or a pharmaceutically acceptable salt thereof. [C21] The use according to [C15], wherein the platinum agent is oxaliplatin or a pharmaceutically acceptable salt thereof. [C22] The use according to [C15], wherein the platinum agent is cisplatin or a pharmaceutically acceptable salt thereof. [C23] The use according to [C15], wherein the topoisomerase inhibitor is topotecan or a pharmaceutically acceptable salt thereof. [C24] The use according to [C15], wherein the topoisomerase inhibitor is irinotecan or a pharmaceutically acceptable salt thereof. [C25] The anti-CDH6 antibody-drug conjugate according to [C15], wherein the anticancer antibiotic is doxorubicin or liposomal doxorubicin, or a pharmaceutically acceptable salt thereof. [C26] The use according to any one of [C1] to [C8], wherein the molecular targeted drug is a multikinase inhibitor, a HIF-2α inhibitor, a VEGF inhibitor, or a PARP inhibitor, in the manufacture of a medicament for treating cancer. [C27] The use according to [C26], wherein the multikinase inhibitor is axitinib, cabozantinib, lenvatinib, sunitinib, or a pharmaceutically acceptable salt thereof.[C28] The use according to [C26], wherein the HIF-2α inhibitor is velzutifan or a pharmaceutically acceptable salt thereof. [C29] The use according to [C26], wherein the VEGF inhibitor is bevacizumab, ramucirumab, or aflibercept beta. [C30] The anti-CDH6 antibody-drug conjugate according to [C26], wherein the PARP inhibitor is olaparib, niraparib, rucaparib, or a pharmaceutically acceptable salt thereof. [C31] The use according to any one of [C1] to [C8], wherein the anti-CDH6 antibody-drug conjugate is used in combination with a molecularly targeted drug in the manufacture of a medicament for the treatment of cancer, wherein the molecularly targeted drug is an anti-folate receptor α antibody-drug conjugate. [C32] The anti-CDH6 antibody-drug conjugate according to [C31], wherein the anti-folate receptor α antibody-drug conjugate is mirvetuximab soravtansine-gynx, farletuzumab ecteribulin, or rubertamabutazebibrin. [C33] The use according to any one of [C1] to [C32], wherein the anti-CDH6 antibody-drug conjugate; and the immune checkpoint inhibitor, chemotherapeutic agent, or molecularly targeted drug are contained as active ingredients in different formulations and administered simultaneously or at different times (asynchronously or separately). [C34] The use according to any one of [C1] to [C33], wherein the cancer is at least one selected from the group consisting of lung cancer (non-small cell lung cancer, small cell lung cancer, etc.), renal cancer, urothelial cancer, ovarian cancer (surface epithelial tumor, stromal tumor, germ cell tumor, etc.), pancreatic cancer, endometrial cancer, cervical cancer, thyroid cancer, mesothelioma, gallbladder cancer, bile duct cancer, sarcoma, Wilms' tumor, and neuroblastoma. [C35] The use according to [C34], wherein the cancer is renal cancer. [C36] The use according to [C34], wherein the cancer is ovarian cancer. [C37] The use according to [C34], wherein the cancer is mesothelioma. [C38] The use according to [C34], wherein the cancer is pancreatic cancer.[D1] A method for treating a disease, comprising administering to a subject in need of disease treatment a combination of: a) an anti-CDH6 antibody-drug conjugate; and b) one or more selected from an immune checkpoint inhibitor, a chemotherapeutic agent, and a molecular targeted drug, wherein the anti-CDH6 antibody-drug conjugate is represented by the following formula (I): (In the formula, m ２ represents an integer of 1 or 2, L represents a linker connecting the N297 sugar chain and D, -Lb-La-Lp-Lc-* (wherein the asterisk indicates binding to drug D, and Lb is: (In the structural formula of Lb shown above, the asterisk indicates bonding to La, and the wavy line indicates bonding to the N297 sugar chain), where La is -C(=O)-CH ２ CH ２ Lp represents -GGFG- or -GGPI-, Lc represents -NH-CH ２ Ab is an anti-CDH6 antibody or an antigen-binding fragment thereof comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 4, and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 5, and a light chain comprising CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of the amino acid sequence represented by DAN, and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 7, wherein the N297 sugar chain is N297-(Fuc)MSG1 having the structure represented by the following formula: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of the 1-3 chain side of the branched chain of β-Man in the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1- or 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５represents an integer of 2 to 5), or N297-(Fuc)SG: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５ represents an integer of 2 to 5), and D represents (wherein the asterisk indicates binding to L, and W represents -NH-). [D1'] The method according to [D1], wherein Ab is an anti-CDH6 antibody comprising an Fc region (wild-type or mutant-type) of the antibody, or an antigen-binding fragment of the antibody. [D2] The method according to [D1], wherein D is (wherein the asterisk indicates binding to L). [D3] The method according to [D1], wherein the anti-CDH6 antibody-drug conjugate is represented by the following formula: (wherein Ab, N297 sugar chain and m ２ [D4] The method according to [D1] or [D2], wherein the anti-CDH6 antibody-drug conjugate is represented by the following formula: In the formula, m ２ is 2, the Ab comprises a heavy chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 8, and a light chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 9, and the N297 sugar chain is N297-(Fuc)SG having a structure shown in the following formula: (wherein the wavy line indicates binding to Asn297 of Ab, L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, the asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring, and n ５[D5] The method of any one of [D1] to [D4], wherein the Ab comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 8 and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 9. [D6] The method of any one of [D1] to [D5], wherein the Ab comprises a heavy chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 1, and a light chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 2. [D7] The method of any one of [D1] to [D6], wherein the Ab comprises a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2. [D8] The method of any one of [D1] to [D5], wherein the Ab is comprised in the antibody or antigen-binding fragment of the antibody contained in the anti-CDH6 antibody-drug conjugate of any one of [D1] to [D7], and comprises: (i) a heavy chain consisting of an amino acid sequence in which one or two amino acids are deleted from the carboxyl terminus of the amino acid sequence of the heavy chain; and (ii) a light chain. [D9] The method of any one of [D1] to [D8], wherein the method comprises administering in combination to a subject in need of disease treatment a) an anti-CDH6 antibody-drug conjugate; and b) an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is an antibody selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-TIGIT antibody, and an anti-LAG-3 antibody, an antigen-binding fragment thereof, or a compound comprising any of them. [D10] The method of [D9], wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, spartalizumab, cemiplimab, or dostallimab. [D11] The method of [D9], wherein the anti-PD-L1 antibody is atezolizumab, duvalumab, or avelumab. [D12] The method of [D9], wherein the anti-CTLA-4 antibody is ipilimumab or tremelimumab. [D13] The method of [D9], wherein the anti-TIGIT antibody is tiragolumab or vibostolimab.[D14] The method of [D9], wherein the anti-LAG-3 antibody is leratolimab. [D15] The method of any one of [D1] to [D8], wherein the anti-CDH6 antibody-drug conjugate and b) a chemotherapeutic agent are administered in combination to a subject in need of disease treatment, wherein the chemotherapeutic agent is an antimetabolite, a tubulin inhibitor, an alkylating agent, a platinum compound, a topoisomerase inhibitor, or an anticancer antibiotic. [D16] The method of [D15], wherein the antimetabolite is gemcitabine or a pharmaceutically acceptable salt thereof. [D17] The method of [D15], wherein the antimetabolite is fluorouracil or a pharmaceutically acceptable salt thereof. [D18] The method of [D15], wherein the tubulin inhibitor is docetaxel or a pharmaceutically acceptable salt thereof. [D19] The method of [D15], wherein the tubulin inhibitor is paclitaxel or a pharmaceutically acceptable salt thereof. [D20] The method according to [D15], wherein the platinum preparation is carboplatin or a pharmaceutically acceptable salt thereof. [D21] The method according to [D15], wherein the platinum preparation is oxaliplatin or a pharmaceutically acceptable salt thereof. [D22] The method according to [D15], wherein the platinum preparation is cisplatin or a pharmaceutically acceptable salt thereof. [D23] The method according to [D15], wherein the topoisomerase inhibitor is topotecan or a pharmaceutically acceptable salt thereof. [D24] The method according to [D15], wherein the topoisomerase inhibitor is irinotecan or a pharmaceutically acceptable salt thereof. [D25] The method according to [D15], wherein the anticancer antibiotic is doxorubicin or liposomal doxorubicin, or a pharmaceutically acceptable salt thereof. [D26] A method for treating a disease, comprising administering a) an anti-CDH6 antibody-drug conjugate; and b) a molecular targeted drug in combination to a subject in need of disease treatment, wherein the molecular targeted drug is a multikinase inhibitor, a HIF-2α inhibitor, a VEGF inhibitor, or a PARP inhibitor.[D27] The method according to [D26], wherein the multikinase inhibitor is axitinib, cabozantinib, lenvatinib, or sunitinib, or a pharmaceutically acceptable salt thereof. [D28] The method according to [D26], wherein the HIF-2α inhibitor is velzutifan or a pharmaceutically acceptable salt thereof. [D29] The method according to [D26], wherein the VEGF inhibitor is bevacizumab, ramucirumab, or aflibercept beta. [D30] The method according to [D26], wherein the PARP inhibitor is olaparib, niraparib, rucaparib, or a pharmaceutically acceptable salt thereof. [D31] The method according to any one of [D1] to [D8], wherein the method comprises administering in combination to a subject in need of disease treatment a) an anti-CDH6 antibody-drug conjugate; and b) a molecular targeted drug, wherein the molecular targeted drug is an anti-folate receptor α antibody-drug conjugate. [D32] The method according to [D31], wherein the anti-folate receptor α antibody-drug conjugate is mirvetuximab soravtansine-gynx, farletuzumab ecteribulin, or rubertamabutazebibrin. [D33] The method according to any one of [D1] to [D32], wherein a) the anti-CDH6 antibody-drug conjugate; and b) an immune checkpoint inhibitor, a chemotherapeutic agent, or a molecularly targeted drug are contained as active ingredients in separate formulations and administered simultaneously or at different times (asynchronously or separately). [D34] The method according to any one of [D1] to [D33], wherein the disease is cancer. [D35] The method according to [D34], wherein the cancer is at least one selected from the group consisting of lung cancer (non-small cell lung cancer, small cell lung cancer, etc.), renal cancer, urothelial cancer, ovarian cancer (surface epithelial tumor, stromal tumor, germ cell tumor, etc.), pancreatic cancer, endometrial cancer, cervical cancer, thyroid cancer, mesothelioma, gallbladder cancer, bile duct cancer, sarcoma, Wilms' tumor, and neuroblastoma. [D36] The method according to [D35], wherein the cancer is renal cancer. [D37] The method according to [D35], wherein the cancer is ovarian cancer. [D38] The method according to [D35], wherein the cancer is mesothelioma. [D39] The method according to [D35], wherein the cancer is pancreatic cancer.

[0012] The present invention provides a novel, safe drug combination therapy that exhibits significant antitumor effects against diseases, particularly cancer.

[0013] Figure 1 shows the amino acid sequence of the heavy chain of anti-CDH6 antibody 1 (SEQ ID NO: 1). Figure 2 shows the amino acid sequence of the light chain of anti-CDH6 antibody 1 (SEQ ID NO: 2). Figure 3 shows the amino acid sequences of CDRH1 (SEQ ID NO: 3), CDRH2 (SEQ ID NO: 4), CDRH3 (SEQ ID NO: 5), CDRL1 (SEQ ID NO: 6), CDRL2, and CDRL3 (SEQ ID NO: 7) of anti-CDH6 antibody 1. Figure 4 shows the amino acid sequence of the heavy chain variable region of anti-CDH6 antibody 1 (SEQ ID NO: 8) and the amino acid sequence of the light chain variable region of anti-CDH6 antibody 1 (SEQ ID NO: 9). Figure 1 shows the antitumor combination effect of intravenous administration of anti-CDH6 antibody-drug conjugate 1 and an anti-PD-1 surrogate antibody in mice subcutaneously implanted with CT26.WT-hCDH6 cells, a mouse colon cancer cell line created by introducing the human CDH6 gene into CT26.WT. In the figure, the black square line indicates the average tumor volume of the vehicle group, the black circle line indicates the anti-CDH6 antibody-drug conjugate 1 group, the white diamond line indicates the anti-PD-1 surrogate antibody group, and the white triangle line indicates the combined use group of anti-CDH6 antibody-drug conjugate 1 and anti-PD-1 surrogate antibody. The vertical axis indicates tumor volume (mm ３), the horizontal axis indicates the number of days after tumor implantation. Mouse colon cancer cell line CT26. CT26. WT, in which the human CDH6 gene was introduced. WT-hCDH6 cells were subcutaneously implanted. Mouse survival curves are shown for mice upon intravenous administration of anti-CDH6 antibody-drug conjugate 1 and anti-PD-1 surrogate antibody. The black line in the figure indicates the vehicle group, the double black line indicates the anti-CDH6 antibody-drug conjugate 1 group, the dotted black line indicates the anti-PD-1 surrogate antibody group, and the dashed black line indicates the group treated with a combination of anti-CDH6 antibody-drug conjugate 1 and anti-PD-1 surrogate antibody. The vertical axis indicates survival rate (%), and the horizontal axis indicates the number of days after tumor implantation. Mouse colon cancer cell line CT26. CT26. WT, in which the human CDH6 gene was introduced. This figure shows the antitumor combined effect of intravenous administration of anti-CDH6 antibody-drug conjugate 1 and anti-CTLA-4 surrogate antibody in mice subcutaneously implanted with WT-hCDH6 cells. In the figure, the black square line represents the vehicle group, the black circle line represents the anti-CDH6 antibody-drug conjugate 1 group, the white diamond line represents the anti-CTLA-4 surrogate antibody group, and the white triangle line represents the mean tumor volume in the group treated with anti-CDH6 antibody-drug conjugate 1 in combination with anti-CTLA-4 surrogate antibody. The vertical axis represents tumor volume (mm ３), the horizontal axis indicates the number of days after tumor implantation. Mouse colon cancer cell line CT26. CT26. WT, in which the human CDH6 gene was introduced. WT-hCDH6 cells were subcutaneously implanted. Mouse survival curves are shown for mice upon intravenous administration of anti-CDH6 antibody-drug conjugate 1 and anti-CTLA-4 surrogate antibody. The black line in the figure indicates the vehicle group, the double black line indicates the anti-CDH6 antibody-drug conjugate 1 group, the dotted black line indicates the anti-CTLA-4 surrogate antibody group, and the dashed black line indicates the group administered with anti-CDH6 antibody-drug conjugate 1 and anti-CTLA-4 surrogate antibody in combination. The vertical axis indicates the survival rate (%), and the horizontal axis indicates the number of days after tumor implantation. Mouse colon cancer cell line CT26. CT26. WT, in which the human CDH6 gene was introduced. This figure shows the antitumor combined effect of intravenous administration of anti-CDH6 antibody-drug conjugate 1 and anti-PD-L1 surrogate antibody in mice subcutaneously implanted with WT-hCDH6 cells. In the figure, the black square line indicates the vehicle group, the black circle line indicates the anti-CDH6 antibody-drug conjugate 1 group, the white diamond line indicates the anti-PD-L1 surrogate antibody group, and the white triangle line indicates the combined use group of anti-CDH6 antibody-drug conjugate 1 and anti-PD-L1 surrogate antibody. The vertical axis indicates tumor volume (mm ３), the horizontal axis indicates the number of days after tumor implantation. Mouse colon cancer cell line CT26. CT26. WT, in which the human CDH6 gene was introduced. WT-hCDH6 cells were subcutaneously implanted. Mouse survival curves are shown for mice upon intravenous administration of anti-CDH6 antibody-drug conjugate 1 and anti-PD-L1 surrogate antibody. The black line in the figure indicates the vehicle group, the double black line indicates the anti-CDH6 antibody-drug conjugate 1 group, the dotted black line indicates the anti-PD-L1 surrogate antibody group, and the dashed black line indicates the group treated with a combination of anti-CDH6 antibody-drug conjugate 1 and anti-PD-L1 surrogate antibody. The vertical axis indicates survival rate (%), and the horizontal axis indicates the number of days after tumor implantation. Mouse colon cancer cell line CT26. CT26. WT, in which the human CDH6 gene was introduced. This figure shows the antitumor combined effect of intravenous administration of anti-CDH6 antibody-drug conjugate 1 and oral administration of axitinib in mice subcutaneously implanted with WT-hCDH6 cells. In the figure, the black square line indicates the vehicle group, the black circle line indicates the anti-CDH6 antibody-drug conjugate 1 group, the white diamond line indicates the axitinib group, and the white triangle line indicates the group administered the combined use of anti-CDH6 antibody-drug conjugate 1 and axitinib. The vertical axis indicates tumor volume (mm ３ The horizontal axis represents the number of days after tumor implantation. This figure shows the antitumor combination effect of intravenous administration of anti-CDH6 antibody-drug conjugate 1 and oral administration of cabozantinib in mice subcutaneously implanted with CT26.WT-hCDH6 cells, a mouse colon cancer cell line CT26.WT introduced with the human CDH6 gene. In the figure, the black square line represents the vehicle group, the black circle line represents the anti-CDH6 antibody-drug conjugate 1 group, the white diamond line represents the cabozantinib group, and the white triangle line represents the group treated with the combination of anti-CDH6 antibody-drug conjugate 1 and cabozantinib. The vertical axis represents tumor volume (mm ３ The horizontal axis represents the number of days after tumor implantation. This figure shows the antitumor combination effect of intravenous administration of anti-CDH6 antibody-drug conjugate 1 and oral administration of lenvatinib in mice subcutaneously implanted with CT26.WT-hCDH6 cells, a mouse colon cancer cell line CT26.WT introduced with the human CDH6 gene. In the figure, the black square line represents the mean tumor volume of the vehicle group, the black circle line represents the anti-CDH6 antibody-drug conjugate 1 group, the white diamond line represents the lenvatinib group, and the white triangle line represents the group administered in combination with anti-CDH6 antibody-drug conjugate 1 and lenvatinib. The vertical axis represents tumor volume (mm３ ), and the horizontal axis indicates the number of days after tumor implantation. This figure shows the antitumor combined effect of intravenous administration of anti-CDH6 antibody-drug conjugate 1 and oral administration of belzutifan in mice subcutaneously implanted with the human renal cancer cell line A-498. In the figure, the black square line indicates the vehicle group, the black circle line indicates the anti-CDH6 antibody-drug conjugate 1 group, the white diamond line indicates the belzutifan group, and the white triangle line indicates the mean tumor volume of the group using the combined use of anti-CDH6 antibody-drug conjugate 1 and belzutifan. The vertical axis indicates tumor volume (mm ３ The horizontal axis represents the number of days after tumor implantation. This figure shows the antitumor effect of intravenous administration of anti-CDH6 antibody-drug conjugate 1 and gemcitabine in mice subcutaneously implanted with CT26.WT-hCDH6 cells, a mouse colon cancer cell line CT26.WT introduced with the human CDH6 gene. The black square line represents the vehicle group, the black circle line represents the anti-CDH6 antibody-drug conjugate 1 group, the white diamond line represents the gemcitabine group, and the white triangle line represents the group treated with the combination of anti-CDH6 antibody-drug conjugate 1 and gemcitabine. The vertical axis represents tumor volume (mm ３ The horizontal axis indicates the days after tumor implantation. This figure shows the antitumor effect of intravenous administration of anti-CDH6 antibody-drug conjugate 1 and carboplatin in mice subcutaneously implanted with CT26.WT-hCDH6 cells, a mouse colon cancer cell line CT26.WT introduced with the human CDH6 gene. The black square line indicates the vehicle group, the black circle line indicates the anti-CDH6 antibody-drug conjugate 1 group, the white diamond line indicates the carboplatin group, and the white triangle line indicates the group treated with the combination of anti-CDH6 antibody-drug conjugate 1 and carboplatin. The vertical axis indicates tumor volume (mm ３ ), the horizontal axis indicates the days after tumor implantation. Figure 1 shows the antitumor effect of intravenous administration of anti-CDH6 antibody-drug conjugate 1 and anti-VEGF surrogate antibody in mice subcutaneously implanted with CT26.WT-hCDH6 cells, a mouse colon cancer cell line CT26.WT introduced with the human CDH6 gene. The black square line indicates the vehicle group, the black circle line indicates the anti-CDH6 antibody-drug conjugate 1 group, the white diamond line indicates the anti-VEGF surrogate antibody group, and the white triangle line indicates the group treated with the combination of anti-CDH6 antibody-drug conjugate 1 and anti-VEGF surrogate antibody. The vertical axis indicates tumor volume (mm ３ ), the horizontal axis indicates days after tumor implantation.

[0014] Preferred embodiments for carrying out the present invention will be described below. Note that the embodiment described below shows one example of a typical embodiment of the present invention, and the scope of the present invention should not be construed as being narrow.

[0015] 1. Anti-CDH6 Antibody-Drug Conjugate The anti-CDH6 antibody-drug conjugate used in the present invention has the following formula (I): It is expressed as:

[0016] Ab represents an anti-CDH6 antibody or an antigen-binding fragment of the antibody, N297 sugar chain represents an N-linked sugar chain bound to the side chain of Asn at position 297 of the IgG heavy chain contained in Ab, L represents a linker connecting the N297 sugar chain and D, D represents a drug that is a cyclic dinucleotide derivative, and m ２ represents an integer of 1 or 2.

[0017] 1-1. Anti-CDH6 Antibody The anti-CDH6 antibody in the antibody-drug conjugate used in the present invention may be derived from any species, but is preferably an antibody derived from human, rat, mouse, or rabbit. When the antibody is derived from a species other than human, it is preferably chimerized or humanized using well-known techniques. The anti-CDH6 antibody in the antibody-drug conjugate used in the present invention may be a polyclonal or monoclonal antibody, but is preferably a monoclonal antibody.

[0018] It is known that the heavy and light chains of an antibody molecule each contain three complementarity determining regions (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. In this specification, 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 close to each other in the three-dimensional structure and determine the specificity for the antigen to which they bind. In the present invention, the positions and lengths of CDRs were determined according to the IMGT definition (Developmental and Comparative Immunology 27 (2003) 55-77).

[0019] It is known that there are multiple allotypes of antibody constant regions. For example, for IgG1 heavy chains, allotypes include G1m17, G1m3, G1m1, and G1m2. The antibody constant region used in the present invention is not particularly limited, but it is preferable to use G1m17 or G1m3.

[0020] In the present invention, an "antigen-binding fragment of an anti-CDH6 antibody" refers to an antibody fragment that has antigen-binding activity and has a well-conserved N-linked glycan (referred to as "Asn297 glycan" or "N297 glycan" in the present specification and claims) at the 297th asparagine residue in the Fc region of the IgG heavy chain (hereinafter referred to as "Asn297 or N297"). However, the antigen-binding fragment is not limited to these molecules as long as it has antigen-binding ability. 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.

[0021] The "anti-CDH6 antibody" in the antibody-drug conjugate used in the present invention is an antibody that specifically binds to CDH6 (cadherin-6), and preferably has the activity of being internalized into CDH6-expressing cells by binding to CDH6.

[0022] Examples of anti-CDH6 antibodies include antibodies (antibody X), NOV0712, and LTV977 having a light chain consisting of the amino acid sequence set forth in positions 21 to 233 of SEQ ID NO: 61 described in WO 2018 / 212136 and a heavy chain consisting of the amino acid sequence set forth in positions 20 to 471 of SEQ ID NO: 69, and preferably antibody X.

[0023] Substitution of some amino acid residues in the constant region can adjust effector function (see WO88 / 07089, WO94 / 28027, WO94 / 29351). An example of an IgG1 mutant is the IgG1 LALA mutation (IgG1-L234A, L235A). L234A and L235A represent substitutions of leucine with alanine at positions 234 and 235, as defined by the EU index (Proceedings of the National Academy of Sciences of the United States of America, Vol. 63, No. 1 (May 15, 1969), pp. 78-85).

[0024] Examples of anti-CDH6 antibodies include antibodies whose heavy chain constant region is that of human IgG1, in which the leucine at position 234, the leucine at position 235, and the aspartic acid at position 265, as shown in the EU index, are substituted with alanine, alanine, and glycine, respectively. More preferred examples of anti-CDH6 antibodies include antibodies which contain a heavy chain constant region of human IgG1 having the above amino acid substitutions, and which include a heavy chain comprising a CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 3, a CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 4, and a CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 5, and an anti-CDH6 antibody consisting of an amino acid sequence represented by SEQ ID NO: 6. Examples of such antibodies include an antibody comprising a light chain comprising a CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 1, a CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 2, and a CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 7; more preferably an antibody comprising a heavy chain constant region of human IgG1 having the amino acid substitution, and comprising a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 8 and a light chain comprising a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 9; and even more preferably an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2.

[0025] Furthermore, it is known that when antibodies are produced in cultured mammalian cells, the lysine residue at the carboxyl terminus of the heavy chain is deleted (Journal of Chromatography A, 705:129-134 (1995)), and that two amino acid residues, glycine and lysine, are deleted from the carboxyl terminus of the heavy chain, and a proline residue newly positioned at the carboxyl terminus is amidated (Analytical Biochemistry, 360:75-83 (2007)). Thus, the antibodies of the present invention also include deletion antibodies in which one or two amino acids are deleted from the carboxy terminus of the heavy chain, as well as amidated versions of such deletion antibodies (for example, antibodies in which the proline residue at the carboxyl terminus of the heavy chain is amidated).

[0026] In the present invention, examples of the heavy and light chains contained in an anti-CDH6 antibody, i.e., an antibody that binds to CDH6, or an antigen-binding fragment of the antibody include the following (i) to (vi): (i) (i-H) a heavy chain comprising a CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 3, a CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 4, and a CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 5, and (i-L) a light chain comprising a CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 6, a CDRL2 consisting of the amino acid sequence represented by DAN, and a CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 7; (ii) a combination of the heavy and light chains described in (i), wherein (ii-H) a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence represented by SEQ ID NO: 8, and (ii-L) a light chain comprising a light chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence represented by SEQ ID NO: 9; (iii) A combination of heavy and light chains according to (i) or (ii), wherein (iii-H) a heavy chain comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 8, and (iii-L) a light chain comprises a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 9; (iv) A combination of heavy and light chains according to (i), (ii), or (iii), wherein (iv-H) a heavy chain comprises an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 1, and (iv-L) a light chain comprises an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 2; (v) A combination of a heavy chain and a light chain according to (i), (ii), (iii) or (iv), wherein the heavy chain comprises a heavy chain constant region of human IgG1 in which leucine at position 234, leucine at position 235, and aspartic acid at position 265, as defined by the EU index, are substituted with alanine, alanine, and glycine, respectively, and the light chain;(vi) A combination of a heavy chain and a light chain according to (i), (ii), (iii), (iv), or (v), wherein (v-H) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1, and (v-L) a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2; (vii) a heavy chain consisting of an amino acid sequence in which one or two amino acids are deleted from the carboxyl terminus of the amino acid sequence of the heavy chain (heavy chain a) set forth in any one of (i-H) to (v-H), and a light chain (light chain a) combined with heavy chain a in (i) to (v); Examples include, but are not limited to, preferred examples are (i) to (vii), and more preferred examples are (vi) and (vii). The anti-CDH6 antibody or antigen-binding fragment thereof of the present invention preferably comprises an antibody Fc region (wild-type or mutant), more preferably an IgG-derived Fc region (wild-type or mutant), and even more preferably an IgG-derived Fc region (wild-type or mutant). The mutant Fc region may be either naturally occurring or artificially created, and preferably includes one in which the leucine at position 234, the leucine at position 235, and the aspartic acid at position 265, as indicated by the EU index, are substituted with alanine, alanine, and glycine, respectively.

[0027] In the above (ii) or (iv), the numerical values ​​"80%, " "90%" or "95%" are not limited to these and may be, for example, any of 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, and may preferably be any of the numerical values ​​of 90% or more, and more preferably be any of the numerical values ​​of 95% or more.

[0028] 1-2. Antibody N297 Glycan Chain IgG has a well-conserved N-linked glycan (hereinafter referred to as "Asn297 glycan" or "N297 glycan") at the 297th asparagine residue (hereinafter referred to as "Asn297" or "N297") in the Fc region of its heavy chain, and is known to contribute to the activity, kinetics, etc. of antibody molecules (Eon-Duval, A. et al., Biotechnol. Prog. 2012, 28, 608-622; Sanglier-Cianferani, S., Anal. Chem. 2013, 85, 715-736).

[0029] The amino acid sequence in the constant region of IgG is well conserved, and in a report by Edelman et al. (Proc. Natl. Acad. Sci. U.S.A., 63, 78-85, (1969)), each amino acid is identified by an EU number (EU INDEX). For example, Asn297, to which an N-linked sugar chain is added in the Fc region, corresponds to position 297 in the EU numbering. Even if the actual amino acid position changes due to molecular fragmentation or region deletion, the amino acid can be uniquely identified by displaying it by EU numbering.

[0030] The N297 sugar chain used in the antibody-drug conjugate of the present invention is N297-(Fuc)SG or N297-(Fuc)MSG1, preferably N297-(Fuc)SG.

[0031] N297-(Fuc)SG is represented by the following structural formula or sequence formula:

[0032]

[0033]

[0034] In the above formula, the wavy line indicates binding to Asn297 of the antibody, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２-NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, and the asterisk indicates that it is bonded to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring of Lb in the linker L, in particular, ５ is an integer of 2 to 5, preferably 3.

[0035] N297-(Fuc)MSG1 is represented by the following structural formula or sequence formula:

[0036]

[0037]

[0038] In the above formula, the wavy line indicates binding to Asn297 of the antibody, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, which indicates that the amino group at the right end of L (PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of the 1-3 chain side of the branched chain of β-Man in the N297 sugar chain; an asterisk indicates that the linker L, particularly the linker L, is bonded to the nitrogen atom at the 1- or 3-position on the 1,2,3-triazole ring of Lb; ５ is an integer of 2 to 5, preferably 3.

[0039] When the N297 sugar chain of the antibody in the antibody-drug conjugate of the present invention is N297-(Fuc)SG, the antibody-drug conjugate is a molecule to which four linkers L and four drugs D are bound (the above m ２ = 2).

[0040] When the N297 sugar chain of the antibody in the antibody-drug conjugate of the present invention is N297-(Fuc)MSG1, the antibody-drug conjugate is a molecule in which two linkers L and two drugs D are bound (the above m ２ = 1).

[0041] When the N297 sugar chain of the antibody in the antibody-drug conjugate of the present invention is N297-(Fuc)SG or N297-(Fuc)MSG1, a highly homogeneous ADC can be obtained.

[0042] 1-3. Drug The drug of the anti-CDH6 antibody-drug conjugate used in the present invention (D in formula (I) above, also referred to as drug D) is (wherein the asterisk indicates bonding to L, and W represents —NH—).

[0043] Preferably, and more preferably, (where the asterisk indicates binding to L).

[0044] 1-4. Linker The linker connecting the N297 sugar chain and drug D is represented by -Lb-La-Lp-Lc-*, where the asterisk indicates binding to drug D, Lp is -GGGFG- or -GGPI-, preferably -GGGFG-, and La is -C(=O)-CH ２ CH ２ Lb represents —C(═O)—; (In the structural formula of Lb shown above, the asterisk indicates bonding to La, and the wavy line indicates bonding to the N297 sugar chain), and Lc represents -NH-CH ２ Indicates -.

[0045] In the present invention, a drug linker refers to a compound in which a drug D in an antibody-drug conjugate is bound to a linker moiety, and a drug linker of the following formula x1, x2, y1, or y2 is preferably used, and a drug linker of formula x1 or x2 is more preferably used. (In the above formulae x1, x2, y1 and y2, the wavy lines indicate binding to the N297 sugar chain).

[0046] 2. Production of anti-CDH6 antibody-drug conjugates 2-1. Production of antibodies The anti-CDH6 antibodies described in 1-1 can be obtained by known means (e.g., WO 2018 / 212136, etc.).

[0047] Recently, a method has been reported in which heterogeneous antibody sugar chains are remodeled (modified) by enzymatic reaction to uniformly introduce sugar chains bearing functional groups (ACS Chem. Biol. 2012, 7, 110-122, ACS Med. Chem. Lett. 2016, 7, 1005-1008). Attempts have also been made to use this sugar chain remodeling technique to site-specifically introduce drugs and synthesize homogeneous ADCs (Bioconjugate Chem. 2015, 26, 2233-2242, Angew. Chem. Int. Ed. 2016, 55, 2361-2367, US2016361436).

[0048] The antibody having an N297 sugar chain used in the present invention can be produced by applying sugar chain remodeling technology to the antibody described in 1-1., for example, in accordance with the methods described in WO2018 / 003983, WO2020 / 050406, WO2021 / 177438, WO2022 / 050300, WO2023 / 167238, PLOS ONE 2018, 13, e0193534, etc.

[0049] 2-2. Production of Drugs and Linkers The drugs and linkers used in the present invention can be produced with reference to the descriptions in WO 2020 / 050406, WO 2021 / 177438, WO 2022 / 163846, and the like.

[0050] 2-3. Production of Drug Linker Intermediate (Conjugation Precursor) The drug linker intermediate (conjugation precursor) used in the production of the anti-CDH6 antibody-drug conjugate used in the present invention is represented by the following formula:

[0051] More preferably, a drug linker intermediate (conjugation precursor) represented by the following formula is used:

[0052] The above drug linker intermediate (conjugation precursor) can be produced with reference to the descriptions in WO 2020 / 050406, WO 2021 / 177438, WO 2022 / 163846, etc.

[0053] 2-4. Production of Anti-CDH6 Antibody-Drug Conjugates The anti-CDH6 antibody-drug conjugates used in the present invention can be produced by linking the aforementioned drug linker intermediate (conjugation precursor) with an antibody having an N297 sugar chain via a cycloaddition reaction. Examples of cycloaddition reactions include the Diels-Alder reaction and the 1,3-dipolar cycloaddition reaction, preferably the 1,3-dipolar cycloaddition reaction. Examples of 1,3-dipolar cycloaddition reactions include the cycloaddition reaction of an azide with a terminal alkyne and the SPAAC (strain-promoted azide-alkyne cycloaddition: J. Am. Chem. Soc. 2004, 126, 15046-15047) reaction, preferably the SPAAC reaction.

[0054] The above anti-CDH6 antibody-drug conjugate can be produced with reference to the descriptions in WO 2020 / 050406, WO 2021 / 177438, WO 2022 / 163846, and the like.

[0055] 3. Immune Checkpoint Inhibitors In the present invention, the term "immune checkpoint inhibitor" refers to a drug that inhibits the immunosuppressive system and activates tumor immunity. The immune checkpoint inhibitor used in the present invention is not particularly limited, but preferred examples include anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA-4 antibodies, anti-TIGIT antibodies, and anti-LAG-3 antibodies, and more preferred examples include anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-CTLA-4 antibodies.

[0056] In the present invention, the term "anti-PD-1 antibody" refers to an antibody that specifically binds to PD-1 (programmed cell death-1; CD279; PDCD1), and preferably refers to an antibody that has the effect of reducing, inhibiting, and / or interfering with signal transduction resulting from the interaction between PD-1 and its binding partners, PD-L1 and PD-L2. The anti-PD-1 antibody used in the present invention is not particularly limited as long as its clinical efficacy and safety have been confirmed. Preferred examples include nivolumab (WO 2006 / 121168, etc.), pembrolizumab (WO 2008 / 156712, etc.), dostarlimab, spartalizumab (WO 2015 / 112900, etc.), and cemiplimab (WO 2015 / 196051, etc.). Furthermore, for the purpose of confirming the combined effect of the antibody-drug conjugate used in the present invention in preclinical studies, commercially available anti-PD-1 antibodies for research use (e.g., clone RMP1-14, Anti-mPD-1 mIgG1e3), etc. These anti-PD-1 antibodies are commonly used as surrogate antibodies that inhibit PD-1 signaling in mice.

[0057] In the present invention, the term "anti-PD-L1 antibody" refers to an antibody that specifically binds to PD-L1 (Programmed cell death ligand 1; CD274; B7-H1), and preferably refers to an antibody that has the effect of reducing, inhibiting, and / or interfering with signal transduction resulting from the interaction between PD-L1 and its binding partners, PD-1 and B7.1 (CD80). The anti-PD-L1 antibody used in the present invention is not particularly limited as long as its clinical efficacy and safety have been confirmed, but preferred examples include atezolizumab (WO 2010 / 077634, etc.), durvalumab (WO 2011 / 066389, etc.), and avelumab (WO 2013 / 079174, etc.). Furthermore, for the purpose of confirming the combined effect of the antibody-drug conjugate used in the present invention in preclinical studies, commercially available anti-PD-L1 antibodies for research use (e.g., clone 10F.9G2) can also be used. These anti-PD-L1 antibodies are commonly used as surrogate antibodies that inhibit PD-L1 signaling in mice.

[0058] In the present invention, the term "anti-CTLA-4 antibody" refers to an antibody that specifically binds to CTLA-4 (cytotoxic T-lymphocyte-associated protein 4; CD152), and preferably refers to an antibody that has the effect of reducing, inhibiting, and / or interfering with signal transduction resulting from the interaction between CTLA-4 and its binding partners, B7.1 (CD80) and B7.2 (CD86). The anti-CTLA-4 antibody used in the present invention is not particularly limited as long as its clinical efficacy and safety have been confirmed, but preferred examples include ipilimumab (WO 2001 / 014424, etc.) and tremelimumab (WO 2000 / 037504, etc.). Furthermore, for the purpose of confirming the combined effect of the anti-CDH6 antibody-drug conjugate used in the present invention in preclinical studies, commercially available anti-CTLA-4 antibodies for research use (e.g., clones 9D9 and 9H10) can also be used. These anti-CTLA-4 antibodies are commonly used as surrogate antibodies that inhibit CTLA-4 signaling in mice.

[0059] In the present invention, the term "anti-TIGIT antibody" refers to an antibody that specifically binds to TIGIT (T cell immunoreceptor with Ig and ITIM domains), and preferably refers to an antibody that has the effect of reducing, inhibiting, and / or interfering with signal transduction resulting from the interaction between TIGIT and its binding partner, CD155 or the like. The anti-TIGIT antibody used in the present invention is not particularly limited as long as its clinical efficacy and safety have been confirmed, but preferred examples include tiragolumab (WO 2017 / 053748) and vibostolimab (WO 2016 / 028656). Furthermore, for the purpose of confirming the combined effect of the anti-CDH6 antibody-drug conjugate used in the present invention in preclinical studies, commercially available anti-TIGIT antibodies for research use (e.g., clone 1G9) and the like can also be used.

[0060] In the present invention, the term "anti-LAG-3 antibody" refers to an antibody that specifically binds to LAG-3 (lymphocyte-activation gene 3), and preferably refers to an antibody that has the effect of reducing, inhibiting, and / or interfering with signal transduction resulting from the interaction between LAG-3 and its binding partner, major histocompatibility complex (MHC) class II. The anti-LAG-3 antibody used in the present invention is not particularly limited as long as its clinical efficacy and safety have been confirmed, and a preferred example is relatlimab. In addition, for the purpose of confirming the combined effect of the anti-CDH6 antibody-drug conjugate used in the present invention in preclinical studies, commercially available research anti-LAG-3 antibodies (e.g., clone C9B7W) and the like can also be used.

[0061] In the present invention, the immune checkpoint inhibitor used in combination with the anti-CDH6 antibody-drug conjugate may be an antigen-binding fragment of any of the above antibodies, or a compound containing the antibody or the antigen-binding fragment. Here, the antigen-binding fragment refers to a fragment of an antibody that has antigen-binding activity, and includes Fab, F(ab')2, Fv, scFv, diabody, linear antibody, and multispecific antibody formed from antibody fragments. However, the antigen-binding fragment is not limited to these molecules as long as it has antigen-binding ability.

[0062] 4. Chemotherapeutic Agents In the present invention, the term "chemotherapeutic agent" refers to a chemically synthesized drug among compounds having anticancer or antitumor activity. The chemotherapeutic agent used in the present invention is not particularly limited, but suitable examples include topoisomerase inhibitors, tubulin inhibitors, antimetabolites, platinum compounds, DNA demethylating agents, anticancer antibiotics, and alkylating agents, and may also be pharmaceutically acceptable salts of these drugs.

[0063] Examples of topoisomerase inhibitors include irinotecan, topotecan, etoposide, etc., and preferably irinotecan or topotecan.

[0064] Examples of tubulin inhibitors include paclitaxel, docetaxel, vincristine, vinblastine, vindesine, eribulin, vinorelbine, albumin-suspended paclitaxel (Nab-paclitaxel), and the like, and preferred examples include paclitaxel or docetaxel.

[0065] Examples of the antimetabolite include fluorouracil (also called 5-FU), mercaptopurine, decitabine, gemcitabine (also called GEM), azacitidine (also called 5-Aza), methotrexate, tegafur, UFT, S-1, carmofur, doxifluridine, capecitabine, etc., and preferred examples include gemcitabine or fluorouracil.

[0066] Examples of platinum preparations include oxaliplatin, carboplatin, cisplatin, nedaplatin, etc., and preferred examples include carboplatin, oxaliplatin, or cisplatin.

[0067] Examples of DNA demethylating agents include azacytidine and decitabine.

[0068] Examples of anticancer antibiotics include doxorubicin, bleomycin, and liposomal doxorubicin, and preferably doxorubicin or liposomal doxorubicin.

[0069] Examples of the alkylating agent include ifosfamide, cyclophosphamide, dacarbazine, etc., and preferably cyclophosphamide.

[0070] However, the chemotherapeutic agents used in combination with the anti-CDH6 antibody-drug conjugates of the present invention are not limited to these.

[0071] 5. Molecularly Targeted Drugs In the present invention, the term "molecularly targeted drug" refers to a drug designed to attack genes or proteins present in or around cancer cells, particularly those involved in cancer cell proliferation, with the primary targets being cell surface antigens, signaling molecules, ligands, and the like. The molecularly targeted drug used in the present invention is not particularly limited, but preferred examples include angiogenesis inhibitors, kinase inhibitors, HIF-2α inhibitors, PARP inhibitors, and mTOR inhibitors. More preferred examples of angiogenesis inhibitors include VEGF inhibitors, and more preferred examples of kinase inhibitors include multikinase inhibitors and HIF-2α inhibitors, and pharmaceutically acceptable salts of these drugs may also be used. Preferred examples of VEGF inhibitors include bevacizumab, ramucirumab, aflibercept beta, and the like. Preferred examples of PARP inhibitors include olaparib, niraparib, rucaparib, talazoparib, and the like, with preferred examples being olaparib and niraparib. Preferred examples of mTOR inhibitors include everolimus, temsirolimus, sirolimus, etc. Preferred examples of multikinase inhibitors include axitinib, cabozantinib, lenvatinib, sorafenib, sunitinib, pazopanib, regorafenib, etc., and more preferred examples are axitinib, cabozantinib, and lenvatinib. Preferred examples of HIF-2α inhibitors include velzutifan, etc.

[0072] In a further embodiment of the present invention, the molecularly targeted drug is an anti-folate receptor α antibody-drug conjugate. Suitable examples of the anti-folate receptor α antibody-drug conjugate include mirvetuximab soravtansine-gynx, farletuzumab ecteribulin, and rubertamabutazebibrin.

[0073] 6. Pharmaceutical compositions, treatment methods, etc.

[0074] Hereinafter, the pharmaceutical composition used in the combination therapy of the anti-CDH6 antibody-drug conjugate according to the present invention with an immune checkpoint inhibitor, a chemotherapeutic agent, or a molecular targeted drug, and the combination therapy (treatment method) will be described.

[0075] In the present invention, "used in combination" means that a recipient takes in multiple drugs into their body over a certain period of time. Furthermore, multiple drugs do not need to be present in the body at the same time; they only need to be taken into the body over a certain period of time (e.g., one month, preferably one week, more preferably several days, and even more preferably one day), and the other active ingredient may have disappeared from the body by the time one of them is administered. In the present invention, the anti-CDH6 antibody-drug conjugate and the immune checkpoint inhibitor, chemotherapeutic agent, or molecularly targeted drug may each be contained as active ingredients in separate formulations. In such cases, the timing and number of administrations are not particularly limited. For example, they may be administered simultaneously (simultaneously) or at different times (asynchronously or separately), preferably simultaneously. When administered at different times, they may be administered consecutively or discontinuously. When administered at different times, the administration interval and order can be changed as appropriate. Furthermore, in the present invention, the anti-CDH6 antibody-drug conjugate and the immune checkpoint inhibitor, chemotherapeutic agent, or molecular targeted drug may be contained as active ingredients in a single formulation.

[0076] The present invention also encompasses embodiments in which an anti-CDH6 antibody-drug conjugate is used in combination with two or more drugs selected from immune checkpoint inhibitors, chemotherapeutic agents, and molecularly targeted drugs. In this case, the two or more drugs may be selected from drugs belonging to the same category (e.g., two drugs belonging to immune checkpoint inhibitors) or from drugs belonging to different categories (e.g., a drug belonging to immune checkpoint inhibitors and a drug belonging to chemotherapeutic agents). For example, in one embodiment of the present invention, a pharmaceutical composition comprising an anti-CDH6 antibody-drug conjugate can be used in combination with two or more drugs selected from immune checkpoint inhibitors, chemotherapeutic agents, and molecularly targeted drugs. Furthermore, a pharmaceutical composition comprising an immune checkpoint inhibitor, chemotherapeutic agent, or molecularly targeted drug can be used in combination with the anti-CDH6 antibody-drug conjugate and one or more other drugs selected from immune checkpoint inhibitors, chemotherapeutic agents, and molecularly targeted drugs. In another aspect of the present invention, a pharmaceutical composition comprising an anti-CDH6 antibody-drug conjugate further comprises two or more drugs selected from an immune checkpoint inhibitor, a chemotherapeutic agent, and a molecularly targeted drug; and in yet another aspect of the present invention, a pharmaceutical composition comprising an anti-CDH6 antibody-drug conjugate and an immune checkpoint inhibitor, a chemotherapeutic agent, or a molecularly targeted drug may be used in combination with one or more additional drugs selected from an immune checkpoint inhibitor, a chemotherapeutic agent, and a molecularly targeted drug.

[0077] The pharmaceutical composition and treatment method of the present invention can be used to treat cancer, and preferably can be used to treat at least one cancer selected from the group consisting of lung cancer (non-small cell lung cancer, small cell lung cancer, etc.), renal cancer, urothelial cancer, ovarian cancer (surface epithelial tumor, stromal tumor, germ cell tumor, etc.), pancreatic cancer, endometrial cancer, cervical cancer, thyroid cancer, mesothelioma, gallbladder cancer, bile duct cancer, sarcoma, Wilms' tumor, and neuroblastoma. Renal cancer includes renal cell carcinoma.

[0078] In another embodiment, the pharmaceutical compositions and treatment methods of the present invention can be used to treat renal cancer.

[0079] In another embodiment, the pharmaceutical compositions and treatment methods of the present invention can be used to treat ovarian cancer.

[0080] In another aspect, the pharmaceutical compositions and methods of treatment of the present invention can be used to treat mesothelioma.

[0081] In another embodiment, the pharmaceutical compositions and treatment methods of the present invention can be used to treat pancreatic cancer.

[0082] In one aspect, the present invention relates to a pharmaceutical composition comprising an anti-CDH6 antibody-drug conjugate and an immune checkpoint inhibitor, a chemotherapeutic agent, or a molecularly targeted drug.

[0083] In one aspect, the present invention relates to an anti-CDH6 antibody-drug conjugate for use in combination with an immune checkpoint inhibitor, a chemotherapeutic agent, or a molecularly targeted drug for the treatment of cancer.

[0084] In one aspect, the present invention relates to an immune checkpoint inhibitor, a chemotherapeutic agent, or a molecularly targeted drug for use in combination with an anti-CDH6 antibody-drug conjugate for the treatment of cancer.

[0085] In one aspect, the present invention relates to the use of an anti-CDH6 antibody-drug conjugate in combination with an immune checkpoint inhibitor, a chemotherapeutic agent, or a molecularly targeted drug in the manufacture of a medicament for the treatment of cancer. In another aspect of the present invention, the present invention relates to the use of an immune checkpoint inhibitor, a chemotherapeutic agent, or a molecularly targeted drug in combination with an anti-CDH6 antibody-drug conjugate in the manufacture of a medicament for the treatment of cancer. In another aspect of the present invention, the present invention relates to the use of an anti-CDH6 antibody-drug conjugate and an immune checkpoint inhibitor, a chemotherapeutic agent, or a molecularly targeted drug in the manufacture of a medicament for the combination treatment of cancer; the use of an anti-CDH6 antibody-drug conjugate in the manufacture of a cancer therapeutic agent in combination with an immune checkpoint inhibitor, a chemotherapeutic agent, or a molecularly targeted drug; or the use of an immune checkpoint inhibitor, a chemotherapeutic agent, or a molecularly targeted drug in the manufacture of a cancer therapeutic agent in combination with an anti-CDH6 antibody-drug conjugate.

[0086] In one aspect, the present invention relates to a method for treating a disease, comprising administering an anti-CDH6 antibody-drug conjugate and an immune checkpoint inhibitor, a chemotherapeutic agent, or a molecularly targeted drug in combination to a subject in need of disease treatment.

[0087] In one aspect, the present invention relates to a pharmaceutical composition for the treatment of cancer, comprising an anti-CDH6 antibody-drug conjugate, for use in combination with an immune checkpoint inhibitor, a chemotherapeutic agent, or a molecularly targeted drug. In another aspect, the present invention relates to a pharmaceutical composition for the treatment of cancer, comprising an immune checkpoint inhibitor, a chemotherapeutic agent, or a molecularly targeted drug, for use in combination with an anti-CDH6 antibody-drug conjugate.

[0088] In one aspect, the present invention relates to a cancer therapeutic agent which is used in combination with an immune checkpoint inhibitor, a chemotherapeutic agent, or a molecularly targeted drug, and which contains an anti-CDH6 antibody-drug conjugate as an active ingredient and is intended for patients undergoing treatment with the immune checkpoint inhibitor, a chemotherapeutic agent, or a molecularly targeted drug. In another aspect, the present invention relates to a cancer therapeutic agent which is used in combination with an anti-CDH6 antibody-drug conjugate, and which contains an immune checkpoint inhibitor, a chemotherapeutic agent, or a molecularly targeted drug as an active ingredient and is intended for patients undergoing treatment with the anti-CDH6 antibody-drug conjugate.

[0089] In one aspect, the present invention relates to a cancer therapeutic agent for use in the treatment of cancer, which comprises an anti-CDH6 antibody-drug conjugate as an active ingredient, wherein the treatment comprises the administration of an immune checkpoint inhibitor, a chemotherapeutic agent, or a molecularly targeted drug in addition to the anti-CDH6 antibody-drug conjugate. In another aspect, the present invention relates to a cancer therapeutic agent for use in the treatment of cancer, which comprises an immune checkpoint inhibitor, a chemotherapeutic agent, or a molecularly targeted drug as an active ingredient, wherein the treatment comprises the administration of an anti-CDH6 antibody-drug conjugate in addition to the immune checkpoint inhibitor, the chemotherapeutic agent, or the molecularly targeted drug.

[0090] The pharmaceutical composition and treatment method of the present invention can be suitably used when CDH6 expression is confirmed in cancer.

[0091] CDH6 expression can be confirmed, for example, by detection at the CDH6 gene product (protein) level using immunohistochemistry (IHC), a flow cytometer, western blot, or the like, or by detection at the gene transcription level using in situ hybridization (ISH) or quantitative PCR (q-PCR).

[0092] As used herein, a "subject" or "patient" refers to a human or other animal in need of such treatment, and in one embodiment, a human in need of such treatment.

[0093] The antitumor effects of the pharmaceutical compositions and treatment methods 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 compositions and treatment methods of the present invention. The combined effect of the anti-CDH6 antibody-drug conjugate used in the present invention and the immune checkpoint inhibitor, chemotherapeutic agent, or molecular targeted drug can then be confirmed by comparing the antitumor effects with those of the anti-CDH6 antibody-drug conjugate, immune checkpoint inhibitor, chemotherapeutic agent, or molecular targeted drug used in the present invention when administered alone.

[0094] 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).

[0095] 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.

[0096] The pharmaceutical composition and treatment method of the present invention can suppress the proliferation of cancer cells and even eliminate cancer cells. These actions can relieve cancer patients from cancer-related symptoms and improve their quality of life, thereby achieving a therapeutic effect while preserving the life of the cancer patient. Even if the cancer cells are not eliminated, the suppression and control of cancer cell proliferation can enable cancer patients to achieve a higher quality of life and longer survival.

[0097] The pharmaceutical composition 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, administration concentration, etc. of the anti-CDH6 antibody-drug conjugate, immune checkpoint inhibitor, chemotherapeutic agent, or molecular targeted drug used in the present invention.

[0098] The pharmaceutical compositions and treatment methods of the present invention may further comprise a cancer therapeutic agent other than the anti-CDH6 antibody-drug conjugate, immune checkpoint inhibitor, chemotherapeutic agent, or molecularly targeted drug of the present invention. The pharmaceutical compositions of the present invention can 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 simultaneously with the pharmaceutical composition of the present invention (simultaneously) or at different times (asynchronously or separately). When administered at different times, they may be administered consecutively or discontinuously. When administered at different times, the administration interval and order can be changed as appropriate. Such cancer therapeutic agents are not limited as long as they have anti-tumor activity, but examples include at least one selected from the group consisting of endocrine therapy agents, immunotherapeutic agents such as interferon preparations or BCG, and antibodies other than anti-CDH6 antibodies or antigen-binding fragments of such antibodies. Here, the antigen-binding fragment refers to a fragment of an antibody that has binding activity to an antigen, and includes Fab, F(ab')2, Fv, scFv, diabody, linear antibody, and multispecific antibody formed from antibody fragments, etc. However, it is not limited to these molecules as long as it has the ability to bind to an antigen.

[0099] The pharmaceutical composition and treatment method of the present invention can also be used in combination with radiation therapy and / or cellular immunotherapy. For example, a cancer patient may receive radiation therapy and / or cellular immunotherapy before and / or after, or simultaneously with, treatment with the pharmaceutical composition of the present invention.

[0100] 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.

[0101] In addition to the therapeutic uses described above, the pharmaceutical composition and treatment method of the present invention can also be expected to have a preventive effect, such as suppressing the proliferation and even eliminating microscopic metastatic cancer cells. For example, they can be expected to have an effect of suppressing the proliferation and eliminating cancer cells in body fluids during the metastasis process, as well as an effect of suppressing the proliferation and eliminating microscopic cancer cells immediately after metastasis to any tissue. Therefore, they can be expected to have an inhibitory and preventive effect on cancer metastasis, particularly after surgical removal of cancer.

[0102] The pharmaceutical compositions of the present invention can be administered as pharmaceutical compositions containing one or more pharmaceutically compatible ingredients. The substances used in the pharmaceutical compositions of the present invention can be appropriately selected from formulation additives and other substances commonly used in this field, depending on the dosage and administration concentration. For example, the pharmaceutical composition typically contains one or more pharmaceutical carriers (e.g., a sterile liquid). Liquids include, for example, water and oils (petroleum, animal, plant, or synthetic). Oils may include, for example, peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is a more typical carrier when the pharmaceutical composition is administered intravenously. Saline solutions, as well as aqueous dextrose and glycerol solutions, can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients can be appropriately selected from those known in the art. The pharmaceutical composition may also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired. Examples of suitable pharmaceutical carriers are described in E. W. The formulation corresponds to the mode of administration.

[0103] Various delivery systems are known and can be used to administer the pharmaceutical compositions of the present invention. Routes of introduction can include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, and subcutaneous routes. Administration can be, for example, by infusion or bolus injection. In certain preferred embodiments, administration of the antibody-drug conjugate is by infusion. Parenteral administration is a preferred route of administration.

[0104] When the anti-CDH6 antibody-drug conjugate used in the present invention is administered to a human, the dose and interval of administration are not limited, and for example, about 0.001 to 100 mg / kg can be administered once or multiple times at intervals of once every 1 to 180 days.

[0105] The immune checkpoint inhibitor, chemotherapeutic agent, or molecular targeted drug used in the present invention can be administered at a single dose of 0.1 mg to 3000 mg, and preferably at a single dose of 50 mg to 2000 mg.

[0106] The immune checkpoint inhibitor according to the present invention can be administered to a human at intervals of 1 to 4 times every 1 to 56 days, and preferably at intervals of once every 7 days, once every 14 days, once every 21 days, once every 28 days, or once every 42 days. The chemotherapeutic agent or molecular targeted drug can be administered to a human at intervals of 1 to 3 times per day, or 1 to 4 times per 1 to 56 days, and preferably at intervals of once per day, twice per day, or once every 7 days, once every 14 days, once every 21 days, once every 28 days, or once every 42 days.

[0107] The present invention will be specifically explained by the following examples, but the present invention is not limited to these examples. Furthermore, these examples should not be interpreted as limiting in any sense.

[0108] (Production Example 1) Synthesis of anti-CDH6 antibody-drug conjugate 1

[0109] (Production Example 1-1) Production of anti-CDH6 antibody 1 According to the production method described in WO 2020 / 050406, an anti-CDH6 antibody (referred to as "anti-CDH6 antibody 1" in the present invention) was produced, comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 (FIG. 1) and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2 (FIG. 2).

[0110] (Production Example 1-2) Synthesis of Glycochain Remodeling Antibody 1 Anti-CDH6 antibody 1-[SG-(N ３ ) ２ ] ２ Preparation of [Synthetic scheme] (Step 1) Preparation of (Fucα1,6)GlcNAc-anti-CDH6 antibody 1 A solution of wild-type EndoS in phosphate buffered saline (0.185 mL, 7.52 mg / mL) was added to a solution of anti-CDH6 antibody 1 prepared according to Production Example 1-1 in phosphate buffered saline (20 mL, 13.90 mg / mL, pH 6.0), and the mixture was shaken at 37°C for 4 hours. The progress of the reaction was monitored using an Agilent 2100 Bioanalyzer Electrophoresis System (Agilent Technologies). After completion of the reaction, the mixture was purified by affinity chromatography and hydroxyapatite column chromatography according to the following methods.

[0111] (1) Purification by affinity chromatography Purification apparatus: AKTA avant 25 (GE Healthcare) Column: HiTrap rProtein A FF (5 mL) (GE Healthcare) Flow rate: 5 mL / min (1.25 mL / min during charging) For binding to the column, the reaction solution was added directly to the column, and binding buffer [20 mM phosphate buffer (pH 6.0)] was flowed at 1.25 mL / min for 2 CV, followed by 5 mL / min for 5 CV. For intermediate washing, 15 CV of washing solution [20 mM phosphate buffer (pH 7.0), 0.5 M sodium chloride solution] was flowed. For elution, 6 CV of elution buffer (IgG Elution buffer, Thermo Scientific) was flowed. The eluate was immediately neutralized with 1 M Tris buffer (pH 9.0). The fractions containing the target product were subjected to buffer exchange with 5 mM phosphate buffer, 50 mM 2-morpholinoethanesulfonic acid (MES) solution (pH 6.8) according to the method described in Common Procedure C. The antibody concentration in the resulting buffer was measured according to the method described in Common Procedure B, and a solution of the crudely purified title antibody was obtained.

[0112] (2) Purification by Hydroxyapatite Chromatography Purification apparatus: AKTA Avant 25 Column: Bio-Scale Mini CHT Type I Cartridge (5 mL) (BIO-RAD) Flow rate: 5 mL / min (1.25 mL / min during charging) The solution obtained in (1) above was added to the column, and Solution A [5 mM phosphate buffer, 50 mM MES solution (pH 6.8)] was run at 1.25 mL / min for 2 CV, and then at 5 mL / min for 3 CV. Then, Solution A and Solution B [5 mM phosphate buffer, 50 mM MES solution (pH 6.8), 2 M sodium chloride solution] were used for elution. The elution conditions were Solution A: Solution B = 100:0 to 0:100 (5 CV). Furthermore, 5 CV of a wash solution [500 mM phosphate buffer (pH 6.5)] was applied. The fraction containing the target substance was subjected to buffer exchange with 20 mM phosphate buffer (pH 6.0) according to the method described in Common Procedure C. The antibody concentration in the resulting buffer was measured according to the method described in Common Procedure B, and a 20 mM phosphate buffer solution of the title antibody (16 mL, 15.12 mg / mL, pH 6.0) was obtained.

[0113] (Step 2) Anti-CDH6 antibody 1-[SG-(N ３ ) ２ ] ２ Preparation of [N ３ -PEG(3)] ２ A solution of 40.6 mg of SG(10)Ox and 0.567 mL of EndoS (D233Q / Q303L) in phosphate buffered saline (4.8 mg / mL) was added and the mixture was shaken at 30°C for 4 hours. The progress of the reaction was monitored using an Agilent 2100 Bioanalyzer electrophoresis system. [N ３ -PEG(3)] ２-SG(10)Ox (8.9 mg) was added and the mixture was shaken at 30°C for 2 hours. After completion of the reaction, purification by affinity chromatography and hydroxyapatite chromatography was carried out in the same manner as in step 1 above. The fraction containing the target product was subjected to buffer exchange with phosphate-buffered saline (pH 6.0) according to the method described in common procedure C. The antibody concentration in the resulting buffer was measured according to the method described in common procedure B, and a solution of the title antibody in phosphate-buffered saline (9 mL, 13.23 mg / mL, pH 6.0) was obtained.

[0114] (Production Example 1-3) Synthesis of anti-CDH6 antibody-drug conjugate 1 A solution of sugar chain remodeling antibody 1 in phosphate buffered saline (2.00 mL, 13.23 mg / mL, pH 6.0) was diluted with propylene glycol (1.00 mL). To this solution was added drug linker 17a (bis(N,N-diethylethanaminium) N-[4-(11,12-didehydrodibenzo[b,f]azocin-5(6H)-yl)-4-oxobutanoyl]glycylglycyl-L-phenylalanyl-N-[(2-{9-[(5R,7R,8R,12aR,14R,15R,15aR,16R)-15-fluoro-16-hydroxy-2,10-dioxo-2,10-disulfide-14-(6,7,8,9-tetrahydro-2H-2,3,5,6-tetraazabenzo[cd]azulen-2-yl)octahydro-2H,10H,12H-5,8-methano-2λ ５ , 10λ ５A mixture of a 10 mM dimethyl sulfoxide solution (0.146 mL, 8 equivalents per antibody molecule) of -furo[3,2-l][1,3,6,9,11,2,10]pentaoxadiphosphacyclotetradecin-7-yl]-6-oxo-6,9-dihydro-1H-purin-1-yl}ethoxy)methyl]glycinamide (prepared by the method described in WO 2020 / 050406)) and propylene glycol (0.854 mL) was added, and the reaction was carried out at room temperature for 44 hours using a tube rotator (MTR-103, AS ONE Corporation). The reaction solution was purified according to the method described in Common Procedure D to obtain an ABS solution (12.0 mL) of the desired antibody-drug conjugate. This solution was purified by hydrophobic interaction chromatography. The fractions containing the target substance were buffer exchanged with ABS using a NAP column and then concentrated according to the method described in Common Procedure A to obtain an ABS solution (7.5 mL) of the target antibody-drug conjugate. Analysis was performed according to the methods described in Common Procedures E and G, and the following results were obtained. Antibody concentration: 1.20 mg / mL Antibody yield: 9.02 mg (34%) Average drug binding number: 3.8 [Purification conditions for hydrophobic interaction chromatography] Purification apparatus: AKTA avant 25 Column: HiTrap Butyl HP (5 mL) (GE Healthcare) Flow rate: 5 mL / min (2.5 mL / min during charging) Mobile phase A: 25 mM phosphate buffer (pH 7.0) containing 1.5 M ammonium sulfate Mobile phase B: 25 mM phosphate buffer (pH 7.0) / isopropyl alcohol mixture (3:1) Gradient program (mobile phase B): 0% (2 CV), 40% (3 CV), 50% (3 CV), 60% (3 CV), 100% (5 CV)

[0115] Common Procedure A: Concentration of Aqueous Antibody Solution The antibody or antibody-drug conjugate solution was placed in an Amicon (registered trademark) Ultra centrifugal filter device (50,000 NMWL, Merck Millipore Ltd.), and the antibody or antibody-drug conjugate solution was concentrated by centrifugation (centrifugation at 2000 G to 4000 G for 5 to 20 minutes) using a centrifuge (Allegra X-15R, Beckman Coulter, Inc.).

[0116] Common Procedure B: Measurement of Antibody Concentration Antibody concentrations were measured using a UV measurement device (Nanodrop 1000, Thermo Fisher Scientific, Inc.) according to the method specified by the manufacturer.

[0117] Common Procedure C: Buffer Exchange of Antibody A buffer solution (phosphate buffered saline (pH 6.0), phosphate buffer (pH 6.0), etc.) was added to an aqueous antibody solution, and the solution was concentrated according to the method described in Common Procedure A. After repeating this procedure several times, the antibody concentration was measured according to the method described in Common Procedure B. An appropriate buffer solution (phosphate buffered saline (pH 6.0), phosphate buffer (pH 6.0), etc.) was added to this antibody buffer solution to prepare an antibody buffer solution of the desired concentration (for example, about 10 mg / mL).

[0118] Common Procedure D: Purification of Antibody-Drug Conjugate (Gel Filtration Chromatography) A NAP column (NAP-5, NAP-10, NAP-25 (manufactured by GE Healthcare)) was equilibrated with acetate buffer (10 mM acetate buffer, 5% sorbitol, pH 5.5; referred to herein as ABS) or another appropriate buffer. The antibody-drug conjugate reaction solution was charged onto this NAP column, and a manufacturer-specified amount of buffer was allowed to flow down by gravity, and the antibody fraction was collected. This fraction was again charged onto the NAP column, and a manufacturer-specified amount of buffer was allowed to flow down by gravity, and the antibody fraction was collected. This procedure was repeated two to three times in total to obtain an antibody-drug conjugate from which unbound drug linker, dimethyl sulfoxide, and propylene glycol had been removed. If necessary, the concentration of the antibody-drug conjugate solution was adjusted by common procedures A and C.

[0119] Common Procedure E: Measurement of antibody concentration in antibody-drug conjugate and average number of drugs bound per antibody molecule (UV method) The bound drug concentration in an antibody-drug conjugate can be calculated by measuring the absorbance of an aqueous antibody-drug conjugate solution at two wavelengths, 280 nm and 250 nm, using an absorptiometer (UV / VIS Spectrometer Lambda 25, PerkinElmer, Inc.), and then performing the following calculation. Since the total absorbance at a certain wavelength is equal to the sum of the absorbances of all absorbing chemical species present in the system (additivity of absorbance), assuming that there is no change in the molar extinction coefficients of the antibody and drug before and after conjugation of the antibody with the drug, the antibody concentration and drug concentration in the antibody-drug conjugate are expressed by the following relationship: A ２８０ = A Ｄ , ２８０ +A Ａ , ２８０ = ε Ｄ , ２８０ C Ｄ +ε Ａ , ２８０ C Ａ Formula (I) A ２５０ = A Ｄ , ２５０ +A Ａ , ２５０ = ε Ｄ , ２５０ C Ｄ +ε Ａ , ２５０ C Ａ Formula (II) where A ２８０ indicates the absorbance of an aqueous solution of an antibody-drug conjugate at 280 nm, and A ２５０ indicates the absorbance of an aqueous solution of an antibody-drug conjugate at 250 nm, and A Ａ , ２８０ indicates the absorbance of the antibody at 280 nm, and A Ａ , ２５０ indicates the absorbance of the antibody at 250 nm, and A Ｄ , ２８０ denotes the absorbance of the conjugate precursor at 280 nm, and A Ｄ , ２５０ denotes the absorbance of the conjugate precursor at 250 nm, and ε Ａ ,２８０ denotes the molar extinction coefficient of the antibody at 280 nm, and ε Ａ , ２５０ denotes the molar extinction coefficient of the antibody at 250 nm, and ε Ｄ , 280 denotes the molar extinction coefficient of the conjugate precursor at 280 nm, and ε Ｄ , ２５０ denotes the molar extinction coefficient of the conjugate precursor at 250 nm, and C Ａ indicates the antibody concentration in the antibody-drug conjugate, and C Ｄ denotes the drug concentration in the antibody-drug conjugate, where ε Ａ , ２８０ , ε Ａ , ２５０ , ε Ｄ , ２８０ , ε Ｄ , ２５０ A value prepared in advance (calculated estimated value or actual measured value) is used for ε. Ａ , ２８０ can be estimated from the amino acid sequence of the antibody by a known calculation method (Protein Science, 1995, vol. 4, 2411-2423). Ａ , ２５０ is the difference between the measured value obtained from UV measurement of the antibody and ε Ａ , ２８０ In the examples, the molar extinction coefficient of anti-CDH6 antibody 1 was calculated as ε Ａ , ２８０ = 223400 and ε Ａ , ２５０ = 74671 was used. Ｄ , ２８０ and ε Ｄ , ２５０ The A of the antibody-drug conjugate solution was measured using the Beer-Lambert law (absorbance = molar concentration × molar extinction coefficient × cell path length) by dissolving the conjugate precursor to be used at a certain molar concentration. The A of the antibody-drug conjugate solution was measured using the Beer-Lambert law (absorbance = molar concentration × molar extinction coefficient × cell path length). The molar extinction coefficient of the conjugate precursor in the examples was obtained by UV measurement. ２８０ and A ２５０ These values ​​are substituted into the equations (I) and (II) to solve the simultaneous equations, thereby obtaining CＡ and C Ｄ Furthermore, C Ｄ C Ａ By dividing by this, the average number of drugs bound per antibody molecule can be calculated.

[0120] Common Procedure F: Measurement of antibody concentration in antibody-drug conjugates and average number of drugs bound per antibody molecule (reverse-phase high-performance liquid chromatography: RP-HPLC) The antibody concentration in antibody-drug conjugates and average number of drugs bound per antibody molecule can be determined by high-performance liquid chromatography analysis using the following method, in addition to the above-mentioned common procedure E.

[0121] [F-1. Preparation of sample for HPLC analysis (reduction of antibody-drug conjugate)] The antibody-drug conjugate solution (approximately 1 mg / mL, 60 μL) was mixed with an aqueous dithiothreitol (DTT) solution (100 mM, 15 μL). The mixture was incubated at 37°C for 30 minutes to cleave the disulfide bond between the L chain and H chain of the antibody-drug conjugate. This reaction solution was used directly for HPLC analysis.

[0122] [F-2. HPLC analysis] Typical analytical conditions are as follows: HPLC system: Agilent 1290 HPLC system (Agilent Technologies) Detector: UV spectrophotometer (measurement wavelength: 280 nm) Column: Acquity BEH Phenyl (2.1 x 50 mm, 1.7 μm, manufactured by Waters) Column temperature: 75°C Flow rate: 0.8 mL / min Sample injection volume: 10 μL Mobile phase A: 0.1% trifluoroacetic acid (TFA), 15% isopropyl alcohol aqueous solution Mobile phase B: 0.075% TFA, 15% isopropyl alcohol acetonitrile solution Gradient program (mobile phase B): 14%-36% (0 min-15 min), 36%-80% (15-17 min), 80%-14% (17 min-17.1 min), 14%-14% (17.1 min-23 min)

[0123] [F-3. Data Analysis] [F-3-1] In the case of sugar chain conjugation in the SPAAC reaction, the H chains to which drugs are bound (H chains to which one drug is bound: H1, H chains to which two drugs are bound: H2) become more hydrophobic and have longer retention times in proportion to the number of drugs bound, compared to the L chain (L0) and H chain (H0) of an antibody to which no drug is bound. Therefore, they are eluted in the order of L0, H0, H1, and H2 in principle. By comparing the retention times of L0 and H0, the detected peak can be assigned to either L0, H0, H1, or H2. Similarly, in the case of cysteine ​​conjugation, the hydrophobicity of drug-bound L chains (L chains with one drug bound: L1) and drug-bound H chains (H chains with one drug bound: H1, H chains with two drugs bound: H2, H chains with three drugs bound: H3) increases in proportion to the number of drugs bound, and the retention time increases, so they are eluted in the order of L0, L1, H0, H1, H2, and H3 in principle. By comparing the retention times of L0 and H0, the detected peak can be assigned to either L0, L1, H0, H1, H2, or H3.

[0124] [F-3-2] Because the drug linker has UV absorption, in the case of sugar chain conjugation in the SPAAC reaction, the peak area was corrected according to the number of drug linkers bound using the molar extinction coefficients of the H chain and drug linker according to the following formula: In the case of cysteine ​​conjugation in which the drug is also bound to the L chain, the peak area was similarly corrected for the L chain.

[0125]

[0126] Here, the molar extinction coefficients (280 nm) of the L chain and H chain of each antibody were estimated values ​​calculated by the known calculation method described in Common Procedure E. In the case of anti-CDH6 antibody 1, 31712 was used as the molar extinction coefficient of the L chain, and 79988 was used as the molar extinction coefficient of the H chain. For the molar extinction coefficient (280 nm) of the drug linker, in the case of sugar chain conjugation by SPAAC reaction, the actual measured value of the conjugation precursor was used, and in the case of cysteine ​​conjugation, the actual measured value of the compound in which the conjugation precursor was reacted with mercaptoethanol or N-acetylcysteine ​​to convert the maleimide group to succinimide thioether was used.

[0127] [F-3-3] The ratio (%) of each chain peak area to the total corrected peak area was calculated according to the following formula.

[0128]

[0129] [F-3-4] The average number of drugs bound per antibody molecule (DAR) in the antibody-drug conjugate was calculated according to the following formula.

[0130]

[0131] [F-3-5] The antibody concentration in the antibody-drug conjugate was calculated according to the following formula.

[0132]

[0133] Here, the absorbance (280 nm) of the antibody-drug conjugate was determined using the actual measured value of the antibody-drug conjugate aqueous solution. The dilution factor indicates how many times the antibody-drug conjugate aqueous solution was diluted when measuring absorbance, and is usually 4-fold. The molar extinction coefficient (280 nm) of the antibody was an estimated value calculated using the known calculation method described in Common Procedure E. The average number of drugs bound was used as the value obtained in [F-3-4]. For the molar extinction coefficient (280 nm) of the drug linker, the actual measured value of the conjugation precursor was used in the case of sugar chain conjugation by SPAAC reaction, and for cysteine ​​conjugation, the actual measured value of the compound obtained by reacting the conjugation precursor with mercaptoethanol or N-acetylcysteine ​​to convert the maleimide group to succinimide thioether was used.

[0134] Common Procedure G: Measurement of antibody concentration in antibody-drug conjugates and average number of drugs bound per antibody molecule (hydrophobic interaction-high performance liquid chromatography: HI-HPLC) The antibody concentration in antibody-drug conjugates and average number of drugs bound per antibody molecule can be determined by high performance liquid chromatography analysis using the following method, in addition to the above-mentioned common procedures E and F.

[0135] [G-1. Preparation of sample for HPLC analysis] The antibody-drug conjugate solution (approximately 1 mg / mL, 60 μL) was used directly for HPLC analysis.

[0136] [G-2. HPLC Analysis] The following two typical analytical conditions are used. HPLC system: SHIMADZU CBM-20A (Shimadzu Corporation) Detector: UV spectrophotometer (measurement wavelength: 280 nm) Column: TSK-gel Butyl-NPR (4.6 x 100 mm, 2.5 μm, manufactured by TOSOH) Column temperature: constant temperature around 25°C Mobile phase A: 25 mM phosphate buffer (pH = 7.0) containing 1.5 M ammonium sulfate Mobile phase B: 25 mM phosphate buffer (pH = 7.0) / isopropyl alcohol mixture (3:1) Flow rate: 0.8 mL / min Sample injection volume: 15 μL Gradient program (mobile phase B): 10% - 15% (0 min - 5 min), 15% - 65% (5 min - 20 min) or HPLC system: SHIMADZU CBM-20A (Shimadzu Corporation) Detector: UV spectrophotometer (measurement wavelength: 280 nm) Column: PolyPROPYL A (4.6 x 100 mm, 3 μm, 1500 Å, manufactured by PolyLC) Column temperature: constant temperature around 40°C Mobile phase A: 20 mM phosphate buffer (pH = 7.4) containing 1.5 M ammonium sulfate Mobile phase B: 20 ​​mM phosphate buffer (pH = 7.4) Flow rate: 0.8 mL / min Sample injection volume: 15 μL Gradient program (mobile phase B): 40% - 80% (0 min - 20 min)

[0137] [G-3. Data Analysis] [G-3-1] Since hydrophobicity increases in proportion to the number of drugs bound to the antibody and retention time increases, in the case of sugar chain conjugation in the SPAAC reaction, elution generally occurs in the order of DAR=0, DAR=2, and DAR=4. By comparing the retention time with DAR=0, the detected peak can be assigned to either DAR=2 or DAR=4. Depending on the type of antibody and drug linker, peaks with DAR=1 and DAR=3 may also be detected. The DAR of the detected peak may also be estimated by measuring the mass spectrum after fractionating the peak by HI-HPLC.

[0138] [G-3-2] Because the drug linker has UV absorption, the peak area value was corrected according to the number of drug linkers bound using the molar absorption coefficients of the antibody and drug linker according to the following formula.

[0139]

[0140] Here, the molar extinction coefficient (280 nm) of the antibody was an estimated value calculated by the known calculation method described in Common Procedure E. The molar extinction coefficient (280 nm) of the drug linker was the actually measured value of the conjugation precursor.

[0141] [G-3-3] The antibody peak area ratio (%) to the total corrected peak area was calculated according to the following formula.

[0142]

[0143] [G-3-4] The average number of drugs bound per antibody molecule in the antibody-drug conjugate was calculated according to the following formula.

[0144]

[0145] [G-3-5] The antibody concentration in the antibody-drug conjugate was calculated according to the formula described in [F-3-5], and the average number of drugs bound was calculated using the value obtained in [G-3-4].

[0146] The anti-CDH6 antibody-drug conjugate 1 obtained in Production Example 1 has the following structure: In the above formula, m ２The anti-CDH6 antibody-drug conjugate of =2 is "anti-CDH6 antibody-drug conjugate 1."

[0147] (Anti-tumor test) Explanation common to all anti-tumor tests (measurement and calculation formulas are as follows): In all tests, the major and minor diameters of the tumor were measured 2-3 times a week using an electronic digital calibrator (CD-15CX, Mitutoyo Corp.), and the tumor volume (mm ３ The formula was: tumor volume (mm ３ ) = 1 / 2 x major axis (mm) x [minor axis (mm)] ２ When there is no tumor to be measured due to the antitumor effect of the administered drug, the tumor volume is set to 0 mm ３ The individual was designated as a complete response (CR). In the survival analysis by endpoint evaluation, the tumor volume was 3000 mm ３ Individuals with a major axis of 20 mm or more were deemed to have died, or the measurement was terminated from the viewpoint of a humane endpoint.

[0148] (Combination with immune checkpoint inhibitors) Test Example 1: Combination with anti-PD-1 antibody <Test conditions> Test Examples 1 and 2 were conducted simultaneously, and therefore Figures 5, 6, 7, and 8 were created using the same data for the vehicle group and the anti-CDH6 antibody-drug conjugate 1 group. CT26.WT-hCDH6 cells were generated by introducing the human CDH6 gene into the mouse colon cancer cell line CT26.WT (CRL-2638) purchased from American Type Culture Collection. CT26.WT-hCDH6 cells were subcutaneously implanted into the right axilla of BALB / c mice (Day 0), and 8 days later, mice were randomly assigned to groups. Anti-CDH6 antibody-drug conjugate 1 was administered intravenously once on Day 8 at a dose of 0.3 mg / kg. Anti-PD-1 surrogate antibody (Anti-mPD-1 mIgG1e3, InvivoGen) was administered intravenously at a dose of 5 mg / kg three times in total on Day 8, Day 11, and Day 15. The number of mice in each group was 8 for the vehicle group and anti-PD-1 surrogate antibody group, and 25 for the anti-CDH6 antibody-drug conjugate 1 group and the group administered in combination with anti-CDH6 antibody-drug conjugate 1 and anti-PD-1 surrogate antibody. <Tumor volume evaluation> The results are shown in Figure 5. In the figure, the black square line indicates the vehicle group, the black circle line indicates the anti-CDH6 antibody-drug conjugate 1 group, the white diamond line indicates the anti-PD-1 surrogate antibody group, and the white triangle line indicates the average tumor volume for the group administered in combination with anti-CDH6 antibody-drug conjugate 1 and anti-PD-1 surrogate antibody. The vertical axis indicates tumor volume (mm ３), the horizontal axis indicates the number of days after tumor inoculation. Tumor growth progressed in the vehicle group and the anti-PD-1 surrogate antibody group. In contrast, tumor growth was inhibited in the anti-CDH6 antibody-drug conjugate 1 group, and tumor growth was further inhibited in the combination group. <CR rate> As of Day 53, no CR individuals were observed in the vehicle group or the anti-PD-1 surrogate antibody group, 2 out of 25 in the anti-CDH6 antibody-drug conjugate 1 group, and 13 out of 25 in the group using the combination of anti-CDH6 antibody-drug conjugate 1 and anti-PD-1 surrogate antibody. The CR rate was significantly improved by the combination of anti-CDH6 antibody-drug conjugate 1 and anti-PD-1 surrogate antibody. <Survival rate> The results of survival analysis by endpoint evaluation are shown in Figure 6. The vertical axis indicates the survival rate (%), and the horizontal axis indicates the number of days after tumor inoculation. In the figure, the black line represents the vehicle group, the double black line represents the anti-CDH6 antibody-drug conjugate 1 group, the dotted black line represents the anti-PD-1 surrogate antibody group, and the dashed black line represents the combined use group of anti-CDH6 antibody-drug conjugate 1 and anti-PD-1 surrogate antibody. In the vehicle group, individuals were observed to have completed measurements from Day 21, and by Day 24, all individuals had completed measurements, i.e., the survival rate was 0%. In the anti-PD-1 surrogate antibody group, individuals were observed to have completed measurements from Day 21, and by Day 29, all individuals had completed measurements, i.e., the survival rate was 0%. In the anti-CDH6 antibody-drug conjugate 1 group, individuals were observed to have completed measurements from Day 22, but by Day 63, when evaluation was completed, not all individuals had completed measurements and the survival rate was 8%. In contrast, in the group using the anti-CDH6 antibody-drug conjugate 1 in combination with the anti-PD-1 surrogate antibody, tumor growth was significantly suppressed, and measurements were completed in some individuals from Day 24 onwards. By the end of evaluation on Day 63, not all individual measurements had been completed, and the survival rate was 44%. In other words, a significant improvement in survival rate was observed in the combination group.

[0149] Test Example 2: Combination Use with Anti-CTLA-4 Antibody <Test Conditions> CT26.WT-hCDH6 cells, which were prepared by introducing the human CDH6 gene into the mouse colon cancer cell line CT26.WT, were subcutaneously transplanted into the right axilla of BALB / c mice (Day 0), and 8 days later, the mice were randomly assigned to groups. Anti-CDH6 antibody-drug conjugate 1 was administered intravenously once on Day 8 at a dose of 0.3 mg / kg. Anti-CTLA-4 surrogate antibody (clone No. 9D9) was administered intravenously twice on Day 8 and Day 15 at a dose of 10 mg / kg. The number of mice in each group was 8 for the vehicle group and the anti-CTLA-4 surrogate antibody group, and 25 for the anti-CDH6 antibody-drug conjugate 1 group and the group using anti-CDH6 antibody-drug conjugate 1 in combination with anti-CTLA-4 surrogate antibody. <Tumor volume evaluation> The results are shown in Figure 7. In the figure, the black square line indicates the vehicle group, the black circle line indicates the anti-CDH6 antibody-drug conjugate 1 group, the white diamond line indicates the anti-CTLA-4 surrogate antibody group, and the white triangle line indicates the average tumor volume for the group using anti-CDH6 antibody-drug conjugate 1 in combination with anti-CTLA-4 surrogate antibody. The vertical axis represents tumor volume (mm ３), the horizontal axis indicates the number of days after tumor implantation. Tumor growth progressed in the vehicle group. In contrast, tumor growth was suppressed in the anti-CDH6 antibody-drug conjugate 1 group and the anti-CTLA-4 surrogate antibody group, and tumor growth was further suppressed in the group treated with the anti-CDH6 antibody-drug conjugate 1 in combination with the anti-CTLA-4 surrogate antibody. <CR rate> As of Day 53, no CRs were observed in the vehicle group or the anti-CTLA-4 surrogate antibody group, while the number of CRs was 2 out of 25 in the anti-CDH6 antibody-drug conjugate 1 group and 11 out of 25 in the group treated with the anti-CDH6 antibody-drug conjugate 1 in combination with the anti-CTLA-4 surrogate antibody. The CR rate was significantly improved by the combined use of anti-CDH6 antibody-drug conjugate 1 and anti-CTLA-4 surrogate antibody. <Survival rate> The results of survival analysis by endpoint assessment are shown in Figure 8. The vertical axis represents survival rate (%), and the horizontal axis represents the number of days after tumor transplantation. In the figure, the black line represents the vehicle group, the double black line represents the anti-CDH6 antibody-drug conjugate 1 group, the dotted black line represents the anti-CTLA-4 surrogate antibody group, and the dashed black line represents the group treated with a combination of anti-CDH6 antibody-drug conjugate 1 and anti-CTLA-4 surrogate antibody. In the vehicle group and the anti-CTLA-4 surrogate antibody group, measurements were completed in some individuals from Day 21, and by Day 29, measurements had been completed for all individuals, i.e., the survival rate was 0%. In the anti-CDH6 antibody-drug conjugate 1 group, measurements were completed in some individuals from Day 22, but by Day 63, when evaluation was completed, measurements had not been completed for all individuals, and the survival rate was 8%. In contrast, in the group using anti-CDH6 antibody-drug conjugate 1 in combination with an anti-CTLA-4 surrogate antibody, tumor growth was significantly suppressed, and measurements were completed in some individuals from Day 28 onwards, but by the end of evaluation on Day 63, measurements had not been completed for all individuals, and the survival rate was 44%. In other words, a significant improvement in survival rate was observed in the group using anti-CDH6 antibody-drug conjugate 1 in combination with an anti-CTLA-4 surrogate antibody.

[0150] Test Example 3: Combination with Anti-PD-L1 Antibody <Test Conditions> CT26.WT-hCDH6 cells were subcutaneously transplanted into the right axilla of BALB / c mice (Day 0), and 7 days later, mice were randomly assigned to groups. Anti-CDH6 antibody-drug conjugate 1 was administered once on Day 7 at a dose of 0.3 mg / kg. Anti-PD-L1 surrogate antibody (clone number 10F.9G2) was administered twice on Day 7 and Day 14 at a dose of 10 mg / kg. The number of mice in each group was 8 for the vehicle group, 7 for the anti-PD-L1 surrogate antibody group, 30 for the anti-CDH6 antibody-drug conjugate 1 group, and 17 for the group administered anti-CDH6 antibody-drug conjugate 1 in combination with anti-PD-L1 surrogate antibody. <Tumor Volume Evaluation> The results are shown in Figure 9. In the figure, the black square line indicates the average tumor volume of the vehicle group, the black circle line indicates the anti-CDH6 antibody-drug conjugate 1 group, the white diamond line indicates the anti-PD-L1 surrogate antibody group, and the white triangle line indicates the combined use group of anti-CDH6 antibody-drug conjugate 1 and anti-PD-L1 surrogate antibody. The vertical axis indicates tumor volume (mm ３), the horizontal axis indicates the number of days after tumor implantation. Tumor growth progressed in the vehicle group and the anti-PD-L1 surrogate antibody group. In contrast, tumor growth was suppressed in the anti-CDH6 antibody-drug conjugate 1 group, and tumor growth was further suppressed in the group treated with the combination of anti-CDH6 antibody-drug conjugate 1 and anti-PD-L1 surrogate antibody. <CR rate> As of Day 41, no CRs were observed in the vehicle group or the anti-PD-L1 surrogate antibody group, while the number of CRs was 4 out of 30 in the anti-CDH6 antibody-drug conjugate 1 group and 14 out of 17 in the group treated with the combination of anti-CDH6 antibody-drug conjugate 1 and anti-PD-L1 surrogate antibody. The CR rate was significantly improved by the combination of anti-CDH6 antibody-drug conjugate 1 and anti-PD-L1 surrogate antibody. <Survival rate> The results of survival analysis by endpoint assessment are shown in Figure 10. The vertical axis represents survival rate (%), and the horizontal axis represents the number of days after tumor implantation. In the figure, the black line represents the vehicle group, the double black line represents the anti-CDH6 antibody-drug conjugate 1 group, the dotted black line represents the anti-PD-L1 surrogate antibody group, and the dashed black line represents the group receiving a combination of anti-CDH6 antibody-drug conjugate 1 and anti-PD-L1 surrogate antibody. In the vehicle group, measurements were completed in some individuals from Day 21 onwards, and by Day 26, all individuals had completed measurements, i.e., the survival rate was 0%. In the anti-PD-L1 surrogate antibody group, measurements were completed in some individuals from Day 19 onwards, and by Day 30, all individuals had completed measurements, i.e., the survival rate was 0%. In the anti-CDH6 antibody-drug conjugate 1 group, measurements were completed in some individuals from Day 21 onwards, but at the end of evaluation on Day 41, there were individuals for which measurements were not completed, resulting in a survival rate of 13%. In contrast, in the group using a combination of anti-CDH6 antibody-drug conjugate 1 and an anti-PD-L1 surrogate antibody, tumor growth was significantly suppressed, and measurement termination antibodies were observed from Day 33. At the end of evaluation on Day 41, not all individual measurements were terminated, and the survival rate was 88%. In other words, a significant improvement in survival rate was observed in the combination group.

[0151] (Combination with a multikinase inhibitor) Test Example 4: Combination with axitinib <Test conditions> CT26.WT-hCDH6 cells were subcutaneously transplanted into the right axilla of BALB / c mice (Day 0), and seven days later, mice were randomly assigned to groups. Anti-CDH6 antibody-drug conjugate 1 was administered intravenously once on Day 7 at a dose of 0.1 mg / kg. Axitinib was orally administered twice daily (5 days on, 2 days off: administration on weekdays, with weekends off) from Day 7 to Day 21, for a total of 22 doses. Each group contained six mice. <Tumor volume evaluation> The results are shown in Figure 11. In the figure, the black square line indicates the average tumor volume of the vehicle group, the black circle line indicates the anti-CDH6 antibody-drug conjugate 1 group, the white diamond line indicates the axitinib group, and the white triangle line indicates the combined use group of anti-CDH6 antibody-drug conjugate 1 and axitinib. The vertical axis indicates tumor volume (mm ３ ), the horizontal axis indicates the number of days after tumor implantation. Tumor growth progressed in the vehicle group. In contrast, tumor growth was suppressed in the anti-CDH6 antibody-drug conjugate 1 group and the axitinib group, and tumor growth was further suppressed in the group treated with CDH6 antibody-drug conjugate 1 in combination with axitinib.

[0152] Test Example 5: Combination with Cabozantinib <Test Conditions> Test Examples 5 and 6 were conducted simultaneously, and therefore Figures 12 and 13 were created using the same data for the vehicle group and the anti-CDH6 antibody-drug conjugate 1 group. CT26.WT-hCDH6 cells were subcutaneously implanted into the right axilla of BALB / c mice (Day 0), and seven days later, mice were randomly assigned to groups. Anti-CDH6 antibody-drug conjugate 1 was administered intravenously once on Day 7 at a dose of 0.1 mg / kg. Cabozantinib (cabozantinib malate) was orally administered once daily from Day 7 to Day 22 (5 days on, 2 days off: weekday administration, weekend rest), for a total of 12 doses. Each group contained eight mice. <Tumor Volume Evaluation> The results are shown in Figure 12. In the figure, the black square line represents the average tumor volume of the vehicle group, the black circle line represents the anti-CDH6 antibody-drug conjugate 1 group, the white diamond line represents the cabozantinib (cabozantinib malate) group, and the white triangle line represents the combined use group of anti-CDH6 antibody-drug conjugate 1 and cabozantinib. The vertical axis represents tumor volume (mm ３), the horizontal axis indicates the number of days after tumor implantation. Tumor growth progressed in the vehicle group. In contrast, tumor growth was suppressed in the anti-CDH6 antibody-drug conjugate 1 group and the cabozantinib (cabozantinib malate) group, and tumor growth was further suppressed in the group treated with the anti-CDH6 antibody-drug conjugate 1 in combination with cabozantinib.

[0153] Test Example 6: Combination with Lenvatinib <Test Conditions> CT26.WT-hCDH6 cells were subcutaneously transplanted into the right axilla of BALB / c mice (Day 0), and seven days later, mice were randomly assigned to groups. Anti-CDH6 antibody-drug conjugate 1 was administered intravenously once on Day 7 at a dose of 0.1 mg / kg. Lenvatinib (lenvatinib mesylate) was orally administered once daily (5 days on, 2 days off: administration on weekdays, with weekends off) from Day 7 to Day 22, for a total of 12 doses. Each group contained eight mice. <Tumor Volume Evaluation> The results are shown in Figure 13. In the figure, the black square line represents the mean tumor volume of the vehicle group, the black circle line represents the anti-CDH6 antibody-drug conjugate 1 group, the white diamond line represents the lenvatinib group, and the white triangle line represents the group treated with anti-CDH6 antibody-drug conjugate 1 in combination with lenvatinib. The vertical axis represents tumor volume (mm ３ ), the horizontal axis represents the number of days after tumor inoculation. Tumor growth progressed in the vehicle group. In contrast, tumor growth was suppressed in the anti-CDH6 antibody-drug conjugate 1 group and the lenvatinib (lenvatinib mesylate) group, and tumor growth was further suppressed in the group treated with anti-CDH6 antibody-drug conjugate 1 in combination with lenvatinib.

[0154] (Combination with HIF-2α Inhibitor) Test Example 7: Combination with Belzutifan Human renal cancer cell line A498 (HTB-44) purchased from American Type Culture Collection was subcutaneously transplanted into the right axilla of BALB / c-nu mice (Day 0), and 22 days later, mice were randomly assigned to groups. Anti-CDH6 antibody-drug conjugate 1 was administered intravenously once at a dose of 0.1 mg / kg at the time of group assignment. Belzutifan was orally administered at a dose of 1 mg / kg once daily (5 days on, 2 days off: administration on weekdays, with no administration on weekends) for 3 weeks from the day of group assignment. Each group consisted of 6 mice. The results are shown in Figure 14. In the figure, the black square line indicates the average tumor volume of the vehicle group, the black circle line indicates the anti-CDH6 antibody-drug conjugate 1 group, the white diamond line indicates the belzutifan group, and the white triangle line indicates the combined use group of anti-CDH6 antibody-drug conjugate 1 and belzutifan. The vertical axis indicates tumor volume (mm ３ ), the horizontal axis indicates the number of days after tumor implantation. Tumor growth progressed in the vehicle group. In contrast, tumor growth was suppressed in the anti-CDH6 antibody-drug conjugate 1 group and the velzutifan group, and tumor growth was further suppressed in the group treated with anti-CDH6 antibody-drug conjugate 1 in combination with velzutifan.

[0155] (Combination with Chemotherapeutic Agents) Test Example 8: Combination with Gemcitabine CT26.WT-hCDH6 cells were subcutaneously transplanted into the right axilla of BALB / c mice (Day 0), and seven days later, the mice were randomly divided into groups. Anti-CDH6 antibody-drug conjugate 1 was administered intravenously once on Day 7 at a dose of 0.1 mg / kg. Gemcitabine was administered intravenously twice on Day 7 and Day 14 at a dose of 30 mg / kg. Each group consisted of six mice. The results are shown in Figure 15. In the figure, the black square line represents the vehicle group, the black circle line represents the anti-CDH6 antibody-drug conjugate 1 group, the white diamond line represents the gemcitabine group, and the white triangle line represents the group receiving the combination of anti-CDH6 antibody-drug conjugate 1 and gemcitabine. The vertical axis represents tumor volume (mm ３), the horizontal axis indicates the number of days after tumor implantation. Tumor growth progressed in the vehicle group. In contrast, tumor growth was suppressed in the anti-CDH6 antibody-drug conjugate 1 group and gemcitabine group, and tumor growth was further suppressed in the group treated with anti-CDH6 antibody-drug conjugate 1 in combination with gemcitabine.

[0156] Test Example 9: Combination with Carboplatin CT26.WT-hCDH6 cells were subcutaneously transplanted into the right axilla of BALB / c mice (Day 0), and seven days later, mice were randomly assigned to groups. Anti-CDH6 antibody-drug conjugate 1 was administered intravenously once on Day 7 at a dose of 0.1 mg / kg. Carboplatin was administered intravenously twice on Day 7 and Day 14 at a dose of 40 mg / kg. Each group consisted of six mice. The results are shown in Figure 16. In the figure, the black square line indicates the vehicle group, the black circle line indicates the anti-CDH6 antibody-drug conjugate 1 group, the white diamond line indicates the carboplatin group, and the white triangle line indicates the group receiving the combination of anti-CDH6 antibody-drug conjugate 1 and carboplatin. The vertical axis indicates tumor volume (mm ３ ), the horizontal axis indicates the number of days after tumor implantation. Tumor growth progressed in the vehicle group. In contrast, tumor growth was suppressed in the anti-CDH6 antibody-drug conjugate 1 group and the carboplatin group, and tumor growth was further suppressed in the anti-CDH6 antibody-drug conjugate 1 and carboplatin combination group.

[0157] (Combination of molecular targeted drugs with angiogenesis inhibitors) Test Example 10: Combination with anti-VEGF antibodies CT26. WT-hCDH6 cells were subcutaneously transplanted into the right axilla of BALB / c mice (Day 0), and seven days later, mice were randomly assigned to groups. Anti-CDH6 antibody-drug conjugate 1 was administered intravenously once on Day 7 at a dose of 0.1 mg / kg. Anti-VEGF surrogate antibody (clone number G6-31, humanized Fc, L234A and L235A mutations) was administered intravenously twice on Day 7 and Day 11 at a dose of 5 mg / kg. Each group contained six mice. The results are shown in Figure 17. In the figure, the black square line indicates the average tumor volume of the vehicle group, the black circle line indicates the anti-CDH6 antibody-drug conjugate 1 group, the white diamond line indicates the anti-VEGF surrogate antibody group, and the white triangle line indicates the combined use group of anti-CDH6 antibody-drug conjugate 1 and anti-VEGF surrogate antibody. The vertical axis indicates tumor volume (mm ３ ), the horizontal axis indicates the number of days after tumor implantation. Tumor growth progressed in the vehicle group. In contrast, tumor growth was suppressed in the anti-CDH6 antibody-drug conjugate 1 group and the anti-VEGF surrogate antibody group, and tumor growth was further suppressed in the group treated with anti-CDH6 antibody-drug conjugate 1 in combination with anti-VEGF surrogate antibody.

[0158] In Test Examples 1 to 10, no particularly noticeable findings such as weight loss were observed in any of the single drug and combination drug groups.

[0159] SEQ ID NO: 1: Amino acid sequence of the heavy chain of anti-CDH6 antibody 1 SEQ ID NO: 2: Amino acid sequence of the light chain of anti-CDH6 antibody 1 SEQ ID NO: 3: Amino acid sequence of CDRH1 of anti-CDH6 antibody 1 SEQ ID NO: 4: Amino acid sequence of CDRH2 of anti-CDH6 antibody 1 SEQ ID NO: 5: Amino acid sequence of CDRH3 of anti-CDH6 antibody 1 SEQ ID NO: 6: Amino acid sequence of CDRL1 of anti-CDH6 antibody 1 SEQ ID NO: 7: Amino acid sequence of CDRL3 of anti-CDH6 antibody 1 SEQ ID NO: 8: Amino acid sequence of the heavy chain variable region of anti-CDH6 antibody 1 SEQ ID NO: 9: Amino acid sequence of the light chain variable region of anti-CDH6 antibody 1

Claims

1. a) A pharmaceutical composition comprising an anti-CDH6 antibody-drug conjugate, wherein a) the anti-CDH6 antibody-drug conjugate and b) one or more selected from an immune checkpoint inhibitor, a chemotherapeutic agent, and a molecular targeted drug are used in combination, and the anti-CDH6 antibody-drug conjugate is represented by the following formula (I): (In the formula, m ２ represents an integer of 1 or 2, L represents a linker connecting the N297 sugar chain and D, -Lb-La-Lp-Lc-* (wherein the asterisk indicates binding to drug D, and Lb is: (In the structural formula of Lb shown above, the asterisk indicates bonding to La, and the wavy line indicates bonding to the N297 sugar chain), where La is -C(=O)-CH ２ CH ２ Lp represents -GGFG- or -GGPI-, Lc represents -NH-CH ２ Ab is an anti-CDH6 antibody or an antigen-binding fragment thereof comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 4, and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 5, and a light chain comprising CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of the amino acid sequence represented by DAN, and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 7, wherein the N297 sugar chain is N297-(Fuc)MSG1 having the structure represented by the following formula: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of the 1-3 chain side of the branched chain of β-Man in the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1- or 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５ represents an integer of 2 to 5), or N297-(Fuc)SG: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５ represents an integer of 2 to 5), and D represents (wherein the asterisk indicates bonding to L, and W represents -NH-).

2. D is The pharmaceutical composition according to claim 1, which is represented by the formula: (wherein the asterisk indicates binding to L).

3. The anti-CDH6 antibody-drug conjugate has the following formula: , or (wherein Ab, N297 glycan and m ２ The pharmaceutical composition according to claim 1 or claim 2, wherein:

4. The anti-CDH6 antibody-drug conjugate has the following formula: In the formula, m ２ is 2, the Ab comprises a heavy chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 8, and a light chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 9, and the N297 sugar chain is N297-(Fuc)SG having a structure shown in the following formula: (wherein the wavy line indicates binding to Asn297 of Ab, L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, the asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring, and n ５ The pharmaceutical composition according to any one of claims 1 to 3, wherein R is an integer of 1 to 3.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the Ab comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 8 and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO:

9.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the Ab comprises a heavy chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 1, and a light chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO:

2.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the Ab comprises a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO:

2.

8. The pharmaceutical composition according to any one of claims 1 to 5, wherein the Ab is comprised in the antibody or antigen-binding fragment of the antibody contained in the anti-CDH6 antibody-drug conjugate according to any one of claims 1 to 7, and comprises: (i) a heavy chain consisting of an amino acid sequence in which one or two amino acids are deleted from the carboxyl terminus of the amino acid sequence of the heavy chain; and (ii) a light chain.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein a) an anti-CDH6 antibody-drug conjugate and b) an immune checkpoint inhibitor are used in combination, and the immune checkpoint inhibitor is an antibody selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-TIGIT antibody, and an anti-LAG-3 antibody, an antigen-binding fragment thereof, or a compound comprising any of them.

10. The pharmaceutical composition according to claim 9, wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, spartalizumab, cemiplimab, or dostarlimab.

11. The pharmaceutical composition according to claim 9, wherein the anti-PD-L1 antibody is atezolizumab, duvalumab, or avelumab.

12. The pharmaceutical composition of claim 9, wherein the anti-CTLA-4 antibody is ipilimumab or tremelimumab.

13. The pharmaceutical composition according to claim 9, wherein the anti-TIGIT antibody is tiragolumab or vibostolimab.

14. The pharmaceutical composition of claim 9, wherein the anti-LAG-3 antibody is leratolimab.

15. The pharmaceutical composition according to any one of claims 1 to 8, wherein a) the anti-CDH6 antibody-drug conjugate and b) a chemotherapeutic agent are used in combination, and the chemotherapeutic agent is an antimetabolite, a tubulin inhibitor, an alkylating agent, a platinum compound, a topoisomerase inhibitor, or an anticancer antibiotic.

16. The pharmaceutical composition of claim 15, wherein the antimetabolite is gemcitabine or a pharmaceutically acceptable salt thereof.

17. The pharmaceutical composition of claim 15, wherein the antimetabolite is fluorouracil or a pharmaceutically acceptable salt thereof.

18. The pharmaceutical composition of claim 15, wherein the tubulin inhibitor is docetaxel or a pharmaceutically acceptable salt thereof.

19. The pharmaceutical composition of claim 15, wherein the tubulin inhibitor is paclitaxel or a pharmaceutically acceptable salt thereof.

20. The pharmaceutical composition according to claim 15, wherein the platinum agent is carboplatin or a pharmaceutically acceptable salt thereof.

21. The pharmaceutical composition according to claim 15, wherein the platinum agent is oxaliplatin or a pharmaceutically acceptable salt thereof.

22. The pharmaceutical composition according to claim 15, wherein the platinum agent is cisplatin or a pharmaceutically acceptable salt thereof.

23. The pharmaceutical composition of claim 15, wherein the topoisomerase inhibitor is topotecan or a pharmaceutically acceptable salt thereof.

24. The pharmaceutical composition of claim 15, wherein the topoisomerase inhibitor is irinotecan or a pharmaceutically acceptable salt thereof.

25. The pharmaceutical composition of claim 15, wherein the anticancer antibiotic is doxorubicin or liposomal doxorubicin, or a pharmaceutically acceptable salt thereof.

26. The pharmaceutical composition according to any one of claims 1 to 8, wherein a) an anti-CDH6 antibody-drug conjugate and b) a molecularly targeted drug are used in combination, and the molecularly targeted drug is a multikinase inhibitor, a HIF-2α inhibitor, a VEGF inhibitor, or a PARP inhibitor.

27. The pharmaceutical composition of claim 26, wherein the multikinase inhibitor is axitinib, cabozantinib, lenvatinib, or sunitinib, or a pharmaceutically acceptable salt thereof.

28. The pharmaceutical composition of claim 26, wherein the HIF-2α inhibitor is velzutifan or a pharmaceutically acceptable salt thereof.

29. The pharmaceutical composition of claim 26, wherein the VEGF inhibitor is bevacizumab, ramucirumab, or aflibercept beta.

30. The pharmaceutical composition of claim 26, wherein the PARP inhibitor is olaparib, niraparib, rucaparib, or a pharmaceutically acceptable salt thereof.

31. The pharmaceutical composition according to any one of claims 1 to 8, wherein a) an anti-CDH6 antibody-drug conjugate and b) a molecular targeted drug are used in combination, and the molecular targeted drug is an anti-folate receptor α antibody-drug conjugate.

32. The pharmaceutical composition of claim 31, wherein the anti-folate receptor α antibody-drug conjugate is mirvetuximab soravtansine-gynx, farletuzumab ecteribulin, or rubertamabutazebibrin.

33. The pharmaceutical composition according to any one of claims 1 to 32, wherein a) the anti-CDH6 antibody-drug conjugate; and b) the immune checkpoint inhibitor, chemotherapeutic agent, or molecular targeted drug are contained as active ingredients in separate formulations and administered simultaneously or asynchronously or separately.

34. A pharmaceutical composition according to any one of claims 1 to 33 for the treatment of cancer.

35. The pharmaceutical composition of claim 34, wherein the cancer is at least one selected from the group consisting of lung cancer (non-small cell lung cancer, small cell lung cancer, etc.), renal cancer, urothelial cancer, ovarian cancer (surface epithelial tumor, stromal tumor, germ cell tumor, etc.), pancreatic cancer, endometrial cancer, cervical cancer, thyroid cancer, mesothelioma, gallbladder cancer, bile duct cancer, sarcoma, Wilms' tumor, and neuroblastoma.

36. The pharmaceutical composition of claim 35, wherein the cancer is renal cancer.

37. The pharmaceutical composition of claim 35, wherein the cancer is ovarian cancer.

38. The pharmaceutical composition of claim 35, wherein the cancer is mesothelioma.

39. The pharmaceutical composition of claim 35, wherein the cancer is pancreatic cancer.

40. An anti-CDH6 antibody-drug conjugate for use in combination with one or more selected from an immune checkpoint inhibitor, a chemotherapeutic agent, and a molecular targeted drug for the treatment of cancer, wherein the anti-CDH6 antibody-drug conjugate is represented by the following formula (I): (In the formula, m ２ represents an integer of 1 or 2, L represents a linker connecting the N297 sugar chain and D, -Lb-La-Lp-Lc-* (wherein the asterisk indicates binding to drug D, and Lb is: (In the structural formula of Lb shown above, the asterisk indicates bonding to La, and the wavy line indicates bonding to the N297 sugar chain), where La is -C(=O)-CH ２ CH ２ Lp represents -GGFG- or -GGPI-, Lc represents -NH-CH ２ Ab is an anti-CDH6 antibody or an antigen-binding fragment thereof comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 4, and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 5, and a light chain comprising CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of the amino acid sequence represented by DAN, and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 7, wherein the N297 sugar chain is N297-(Fuc)MSG1 having the structure represented by the following formula: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of the 1-3 chain side of the branched chain of β-Man in the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1- or 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５ represents an integer of 2 to 5), or N297-(Fuc)SG: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５ represents an integer of 2 to 5), and D represents (wherein the asterisk indicates binding to L, and W represents -NH-) 41. D. The anti-CDH6 antibody-drug conjugate of claim 40, represented by the formula: (wherein the asterisk indicates binding to L).

42. The anti-CDH6 antibody-drug conjugate has the following formula: (Wherein Ab, N297 sugar chain and m ２ The anti-CDH6 antibody-drug conjugate of claim 40 or claim 41, wherein:

43. The anti-CDH6 antibody-drug conjugate has the following formula: In the formula, m ２ is 2, the Ab comprises a heavy chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 8, and a light chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 9, and the N297 sugar chain is N297-(Fuc)SG having a structure shown in the following formula: (wherein the wavy line indicates binding to Asn297 of Ab, L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, the asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring, and n ５ The anti-CDH6 antibody-drug conjugate according to any one of claims 40 to 42, wherein R represents an integer of 3.

44. The anti-CDH6 antibody-drug conjugate of any one of claims 40 to 43, wherein the Ab comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 8 and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO:

9.

45. The anti-CDH6 antibody-drug conjugate of any one of claims 40 to 44, wherein the Ab comprises a heavy chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 1, and a light chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO:

2.

46. ​​The anti-CDH6 antibody-drug conjugate of any one of claims 40 to 45, wherein the Ab comprises a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO:

2.

47. The anti-CDH6 antibody-drug conjugate according to any one of claims 40 to 44, wherein the Ab is comprised in an antibody or an antigen-binding fragment of the antibody contained in the anti-CDH6 antibody-drug conjugate according to any one of claims 40 to 46, and comprises: (i) a heavy chain consisting of an amino acid sequence in which one or two amino acids are deleted from the carboxyl terminus of the amino acid sequence of the heavy chain; and (ii) a light chain.

48. An anti-CDH6 antibody-drug conjugate according to any one of claims 40 to 47, for use in combination with an immune checkpoint inhibitor for the treatment of cancer, wherein the immune checkpoint inhibitor is an antibody selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-TIGIT antibody, and an anti-LAG-3 antibody, an antigen-binding fragment thereof, or a compound comprising any of them.

49. The anti-CDH6 antibody-drug conjugate of claim 48, wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, spartalizumab, cemiplimab, or dostarlimab.

50. The anti-CDH6 antibody-drug conjugate of claim 48, wherein the anti-PD-L1 antibody is atezolizumab, duvalumab, or avelumab.

51. The anti-CDH6 antibody-drug conjugate of claim 48, wherein the anti-CTLA-4 antibody is ipilimumab or tremelimumab.

52. The anti-CDH6 antibody-drug conjugate of claim 48, wherein the anti-TIGIT antibody is tiragolumab or vibostolimab.

53. The anti-CDH6 antibody-drug conjugate of claim 48, wherein the anti-LAG-3 antibody is leratolimab.

54. An anti-CDH6 antibody-drug conjugate according to any one of claims 40 to 47, for use in combination with a chemotherapeutic agent for the treatment of cancer, wherein the chemotherapeutic agent is an antimetabolite, a tubulin inhibitor, an alkylating agent, a platinum compound, a topoisomerase inhibitor, or an anticancer antibiotic.

55. The anti-CDH6 antibody-drug conjugate of claim 54, wherein the antimetabolite is gemcitabine or a pharmaceutically acceptable salt thereof.

56. The anti-CDH6 antibody-drug conjugate of claim 54, wherein the antimetabolite is fluorouracil or a pharmaceutically acceptable salt thereof.

57. The anti-CDH6 antibody-drug conjugate of claim 54, wherein the tubulin inhibitor is docetaxel or a pharmaceutically acceptable salt thereof.

58. The anti-CDH6 antibody-drug conjugate of claim 54, wherein the tubulin inhibitor is paclitaxel or a pharmaceutically acceptable salt thereof.

59. The anti-CDH6 antibody-drug conjugate of claim 54, wherein the platinum agent is carboplatin or a pharmaceutically acceptable salt thereof.

60. The anti-CDH6 antibody-drug conjugate of claim 54, wherein the platinum agent is oxaliplatin or a pharmaceutically acceptable salt thereof.

61. The anti-CDH6 antibody-drug conjugate of claim 54, wherein the platinum agent is cisplatin or a pharmaceutically acceptable salt thereof.

62. The anti-CDH6 antibody-drug conjugate of claim 54, wherein the topoisomerase inhibitor is topotecan or a pharmaceutically acceptable salt thereof.

63. The anti-CDH6 antibody-drug conjugate of claim 54, wherein the topoisomerase inhibitor is irinotecan or a pharmaceutically acceptable salt thereof.

64. The anti-CDH6 antibody-drug conjugate of claim 54, wherein the anticancer antibiotic is doxorubicin or liposomal doxorubicin, or a pharmaceutically acceptable salt thereof.

65. An anti-CDH6 antibody-drug conjugate according to any one of claims 40 to 47, for use in combination with a molecularly targeted drug for the treatment of cancer, wherein the molecularly targeted drug is a multikinase inhibitor, a HIF-2α inhibitor, a VEGF inhibitor, or a PARP inhibitor.

66. The anti-CDH6 antibody-drug conjugate of claim 65, wherein the multikinase inhibitor is axitinib, cabozantinib, lenvatinib, or sunitinib, or a pharmaceutically acceptable salt thereof.

67. The anti-CDH6 antibody-drug conjugate of claim 65, wherein the HIF-2α inhibitor is velzutifan or a pharmaceutically acceptable salt thereof.

68. The anti-CDH6 antibody-drug conjugate of claim 65, wherein the VEGF inhibitor is bevacizumab, ramucirumab, or aflibercept beta.

69. The anti-CDH6 antibody-drug conjugate of claim 65, wherein the PARP inhibitor is olaparib, niraparib, rucaparib, or a pharmaceutically acceptable salt thereof.

70. An anti-CDH6 antibody-drug conjugate according to any one of claims 40 to 47, for use in combination with a molecularly targeted drug for the treatment of cancer, wherein the molecularly targeted drug is an anti-folate receptor α antibody-drug conjugate.

71. The anti-CDH6 antibody-drug conjugate of claim 70, wherein the anti-folate receptor α antibody-drug conjugate is mirvetuximab soravtansine-gynx, farletuzumab ecteribulin, or rubertamabutazebibrin.

72. The anti-CDH6 antibody-drug conjugate according to any one of claims 40 to 71, wherein the anti-CDH6 antibody-drug conjugate; and the immune checkpoint inhibitor, chemotherapeutic agent, or molecular targeted drug are contained as active ingredients in separate formulations and administered simultaneously or asynchronously or separately.

73. The anti-CDH6 antibody-drug conjugate of any one of claims 40 to 72, wherein the cancer is at least one selected from the group consisting of lung cancer (non-small cell lung cancer, small cell lung cancer, etc.), renal cancer, urothelial cancer, ovarian cancer (surface epithelial tumor, stromal tumor, germ cell tumor, etc.), pancreatic cancer, endometrial cancer, cervical cancer, thyroid cancer, mesothelioma, gallbladder cancer, bile duct cancer, sarcoma, Wilms' tumor, and neuroblastoma.

74. The anti-CDH6 antibody-drug conjugate of claim 73, wherein the cancer is renal cancer.

75. The anti-CDH6 antibody-drug conjugate of claim 73, wherein the cancer is ovarian cancer.

76. The anti-CDH6 antibody-drug conjugate of claim 73, wherein the cancer is mesothelioma.

77. The anti-CDH6 antibody-drug conjugate of claim 73, wherein the cancer is pancreatic cancer.

78. A method for treating a disease, comprising administering to a subject in need of disease treatment a combination of: a) an anti-CDH6 antibody-drug conjugate; and b) one or more selected from an immune checkpoint inhibitor, a chemotherapeutic agent, and a molecular targeted drug, wherein the anti-CDH6 antibody-drug conjugate is represented by the following formula (I): (In the formula, m ２ represents an integer of 1 or 2, L represents a linker connecting the N297 sugar chain and D, -Lb-La-Lp-Lc-* (wherein the asterisk indicates binding to drug D, and Lb is: (In the structural formula of Lb shown above, the asterisk indicates bonding to La, and the wavy line indicates bonding to the N297 sugar chain), where La is -C(=O)-CH ２ CH ２ Lp represents -GGFG- or -GGPI-, Lc represents -NH-CH ２ Ab is an anti-CDH6 antibody or an antigen-binding fragment thereof comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 4, and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 5, and a light chain comprising CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of the amino acid sequence represented by DAN, and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 7, wherein the N297 sugar chain is N297-(Fuc)MSG1 having the structure represented by the following formula: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of the 1-3 chain side of the branched chain of β-Man in the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1- or 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５ represents an integer of 2 to 5), or N297-(Fuc)SG: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５ represents an integer of 2 to 5), and D represents (wherein the asterisk indicates bonding to L, and W represents -NH-).

79. D.

79. The method of claim 78, wherein the formula is represented by the formula: (wherein the asterisk indicates binding to L).

80. An anti-CDH6 antibody-drug conjugate having the following formula: (Wherein Ab, N297 sugar chain and m ２ 80. The method of claim 78 or claim 79, wherein:

81. An anti-CDH6 antibody-drug conjugate having the following formula: In the formula, m ２ is 2, the Ab comprises a heavy chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 8, and a light chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 9, and the N297 sugar chain is N297-(Fuc)SG having a structure shown in the following formula: (wherein the wavy line indicates binding to Asn297 of Ab, L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, the asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring, and n ５ The method according to any one of claims 78 to 80, wherein represents an integer of 3.

82. The method of any one of claims 78 to 81, wherein the Ab comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO:8 and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO:

9.

83. The method of any one of claims 78 to 82, wherein the Ab comprises a heavy chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence set forth in SEQ ID NO:1, and a light chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence set forth in SEQ ID NO:

2.

84. The method of any one of claims 78 to 83, wherein the Ab comprises a heavy chain consisting of the amino acid sequence shown in SEQ ID NO:1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO:

2.

85. The method of any one of claims 78 to 82, wherein the Ab is comprised in an antibody or an antigen-binding fragment of the antibody contained in the anti-CDH6 antibody-drug conjugate of any one of claims 78 to 84, and comprises: (i) a heavy chain consisting of an amino acid sequence in which one or two amino acids are deleted from the carboxyl terminus of the amino acid sequence of the heavy chain; and (ii) a light chain.

86. A method for treating a disease, comprising administering in combination to a subject in need of disease treatment: a) an anti-CDH6 antibody-drug conjugate; and b) an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is an antibody selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-TIGIT antibody, and an anti-LAG-3 antibody, an antigen-binding fragment thereof, or a compound comprising any of them. The method of any one of claims 78 to 85.

87. The method of claim 86, wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, spartalizumab, cemiplimab, or dostarlimab.

88. The method of claim 86, wherein the anti-PD-L1 antibody is atezolizumab, duvalumab, or avelumab.

89. The method of claim 86, wherein the anti-CTLA-4 antibody is ipilimumab or tremelimumab.

90. The method of claim 86, wherein the anti-TIGIT antibody is tiragolumab or vibostolimab.

91. The method of claim 86, wherein the anti-LAG-3 antibody is leratolimab.

92. A method for treating a disease, comprising administering to a subject in need of disease treatment a) an anti-CDH6 antibody-drug conjugate; and b) a chemotherapeutic agent in combination, wherein the chemotherapeutic agent is an antimetabolite, a tubulin inhibitor, an alkylating agent, a platinum compound, a topoisomerase inhibitor, or an anticancer antibiotic, according to any one of claims 78 to 85.

93. The method of claim 92, wherein the antimetabolite is gemcitabine or a pharmaceutically acceptable salt thereof.

94. The method of claim 92, wherein the antimetabolite is fluorouracil or a pharmaceutically acceptable salt thereof.

95. The method of claim 92, wherein the tubulin inhibitor is docetaxel or a pharmaceutically acceptable salt thereof.

96. The method of claim 92, wherein the tubulin inhibitor is paclitaxel or a pharmaceutically acceptable salt thereof.

97. The method of claim 92, wherein the platinum agent is carboplatin or a pharmaceutically acceptable salt thereof.

98. The method of claim 92, wherein the platinum agent is oxaliplatin or a pharmaceutically acceptable salt thereof.

99. The method of claim 92, wherein the platinum agent is cisplatin or a pharmaceutically acceptable salt thereof.

100. The method of claim 92, wherein the topoisomerase inhibitor is topotecan or a pharmaceutically acceptable salt thereof.

101. The method of claim 92, wherein the topoisomerase inhibitor is irinotecan or a pharmaceutically acceptable salt thereof.

102. The method of claim 92, wherein the anticancer antibiotic is doxorubicin or liposomal doxorubicin, or a pharmaceutically acceptable salt thereof.

103. A method for treating a disease, comprising administering a) an anti-CDH6 antibody-drug conjugate; and b) a molecular targeted drug in combination to a subject in need of disease treatment, wherein the molecular targeted drug is a multikinase inhibitor, a HIF-2α inhibitor, a VEGF inhibitor, or a PARP inhibitor. The method according to any one of claims 78 to 85.

104. The method of claim 103, wherein the multikinase inhibitor is axitinib, cabozantinib, lenvatinib, or sunitinib, or a pharmaceutically acceptable salt thereof.

105. The method of claim 103, wherein the HIF-2α inhibitor is velzutifan or a pharmaceutically acceptable salt thereof.

106. The method of claim 103, wherein the VEGF inhibitor is bevacizumab, ramucirumab, or aflibercept beta.

107. The method of claim 103, wherein the PARP inhibitor is olaparib, niraparib, rucaparib, or a pharmaceutically acceptable salt thereof.

108. A method for treating a disease, comprising administering a) an anti-CDH6 antibody-drug conjugate; and b) a molecular targeted drug in combination to a subject in need of disease treatment, wherein the molecular targeted drug is an anti-folate receptor α antibody-drug conjugate. The method according to any one of claims 78 to 85.

109. The method of claim 108, wherein the anti-folate receptor alpha antibody-drug conjugate is mirvetuximab soravtansine-gynx, farletuzumab ecteribulin, or rubertamabutazebibrin.

110. The method according to any one of claims 78 to 109, wherein a) the anti-CDH6 antibody-drug conjugate; and b) the immune checkpoint inhibitor, chemotherapeutic agent, or molecular targeted drug are contained as active ingredients in separate formulations and administered simultaneously or asynchronously or separately.

111. The method of any one of claims 78 to 110, wherein the disease is cancer.

112. The method of claim 111, wherein the cancer is at least one selected from the group consisting of lung cancer (non-small cell lung cancer, small cell lung cancer, etc.), renal cancer, urothelial cancer, ovarian cancer (surface epithelial tumor, stromal tumor, germ cell tumor, etc.), pancreatic cancer, endometrial cancer, cervical cancer, thyroid cancer, mesothelioma, gallbladder cancer, bile duct cancer, sarcoma, Wilms' tumor, and neuroblastoma.

113. The method of claim 112, wherein the cancer is renal cancer.

114. The method of claim 112, wherein the cancer is ovarian cancer.

115. The method of claim 112, wherein the cancer is mesothelioma.

116. The method of claim 112, wherein the cancer is pancreatic cancer.

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