Combination of antibody-drug conjugate and kinase inhibitor

Abstract

The present invention relates to the following: a pharmaceutical composition characterized in that an antibody-drug conjugate in which an antibody and a drug linker represented by the formula indicated below (in the formula, A represents the position of bonding with the antibody) are bonded by a thioether bond is combined with a kinase inhibitor (at least one inhibitor selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a P13K inhibitor, an AKT inhibitor, an ERK inhibitor, a MEK inhibitor, a RAF inhibitor, a CDK1 inhibitor, a CDK2 inhibitor, a CHK1 inhibitor, a WEE1 inhibitor, a PLK1 inhibitor, an Aurora kinase inhibitor, a Bcr-Abl inhibitor, an Src inhibitor, an EPH inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, a BTK inhibitor, an FLT3 inhibitor, an ALK inhibitor, a JAK inhibitor, a MET inhibitor, a CSF-1R inhibitor, an NTRK inhibitor, an EGFR inhibitor, and a HER2 inhibitor) and the result is administered; and / or a therapeutic method characterized in that the antibody-drug conjugate and a kinase inhibitor are combined and administered to an individual.

Description

Description Title of invention: COMBINATION OF ANTIBODY-DRUG CONJUGATE AND KINASE INHIRITOR Technical Field

[0001] The present invention relates to a pharmaceutical composition wherein a specific antibody-drug conjugate and a kinase inhibitor are administered in combination, and / or a method of treatment wherein a specific antibody- drug conjugate and a kinase inhibitor are administered in combination to a subject. Background Art

[0002] Abnormal activation of intracellular signaling is associated with proliferation of cancer cells and tumor angiogenesis. Kinase inhibitors are agents that inhibit kinases involved in abnormally activated intracellular signaling to exert an antitumor effect. Examples of such kinase inhibitors include a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an AKT inhibitor, an ERK inhibitor, an MEK inhibitor, an RAF inhibitor, a CDK1l inhibitor, a CDK2 inhibitor, a CHK1l inhibitor, a WEEl inhibitor, an PLKl inhibitor, an Aurora kinase inhibitor, a Bcr-Abl inhibitor, an Src inhibitor, an EPH inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, a BTK inhibitor, an FLT3 inhibitor, an ALK inhibitor, a JAK inhibitor, an MET inhibitor, a CSF-1R inhibitor, and an NTRK inhibitor (Non-Patent References 1 to 11).

[0003] An antibody-drug conjugate (ADC) having a drug with cytotoxicity conjugated to an antibody, whose antigen is expressed on the surface of cancer cells and which also binds to an antigen capable of cellular internalization, and therefore can deliver the drug selectively to cancer cells, is thus expected to cause accumulation of the drug within cancer cells and to kill the cancer cells (Non- Patent References 12 to 16).

[0004] As one such antibody-drug conjugate, an antibody- drug conjugate comprising an antibody and a derivative of exatecan, which is a topoisomerase 1 inhibitor, as its components is known (Patent References 1 to 8, Non-Patent References 17 to 21).

[0005] Patent References 1 to 8 disclose that the antibody- drug conjugate can be administered together with various cancer treating agents.

[0006] However, none of the references describes any test result showing an excellent combined effect when the foregoing antibody-drug conjugate and the kinase inhibitor are used in combination, or any scientific basis for suggesting such a test result. Citation List Patent Literature

[0007] Patent Reference 1: International Publication No. 2014 / 057687 Patent Reference 2: International Publication No. 2014 / 061277 Patent Reference 3: International Publication No. 2015 / 098099 Patent Reference 4: International Publication No. 2015 / 115091 Patent Reference 5: International Publication No. 2015 / 146132 Patent Reference 6: International Publication No. 2015 / 155976 Patent Reference 7: International Publication No. 2015 / 155998 Patent Reference 8: International Publication No. 2018 / 212136 Non-Patent Literature

[0008] Non-Patent Reference 1: Otto T., et al., Nat. Rev. Cancer (2017) 17(2): 93-115. Non-Patent Reference 2: Zhang YJ., et al., Drug Discov. Today (2011) 16(7-8): 325-331. Non-Patent Reference 3: Zaytseva YY., et al., Cancer Lett. (2012) 31%(1): 1-7. Non-Patent Reference 4: Janku F., et al., Nat. Rev. Clin. Oncol. (2018) 15(5): 273-291. Non-Patent Reference 5: Bergholz JS., et al., J. Clin. Oncol. (2018) 36(13): 1339-1342 Non-Patent Reference 6: Zhao Y., et al., Nat. Rev. Clin. Oncol. (2014) 11(7): 385-400. Non-Patent Reference 7: Caunt CJ., et al., Nat. Rev. Cancer (2015) 15(10): 577-592. Non-Patent Reference 8: Ryan MB., et al., Nat. Rev. Clin. Oncol. (2018) 15(11): 709-720. Non-Patent Reference 9: Ferquson FM., et al., Nat. Rev. Drug Discov. (2018) 17(5): 353-377. Non-Patent Reference 10: Konig H., et al., Current Cancer Drug Targets (2015) 15, 803-821. Non-Patent Reference 11: Kheder ES., et al., Clinical Cancer Research (2018) 24(23), 5807-5814. Non-Patent Reference 12: Ducry, L., et al., Bioconjugate Chem. (2010) 21, 5-13. Non-Patent Reference 13: Alley, S. C., et al., Current Opinion in Chemical Biology (2010) 14, 529-537. Non-Patent Reference 14: Damle N. K. Expert Opin. Biol. Ther. (2004) 4, 1445-1452. Non-Patent Reference 15: Senter P. D., et al., Nature Biotechnology (2012) 30, 631-637. Non-Patent Reference 16: Burris HA., et al., J. Clin. Oncol. (2011) 29(4): 398-405. Non-Patent Reference 17: Ogitani Y. et al., Clinical Cancer Research (2016) 22(20), 5097-5108. Non-Patent Reference 18: Ogitani Y. et al., Cancer Science (2016) 107, 1039-1046. Non-Patent Reference 19: Doi T, et al., Lancet Oncol. (2017) 18, 1512-22. Non-Patent Reference 20: Takegawa N, et al., Int. J. Cancer (2017) 141, 1682-1689. Non-Patent Reference 21: Yonesaka K, et al., Int. Oncogene (2018) 141, 1682-1689 (2017). Summary of Invention Technical Problem

[0009] An antibody-drug conjugate used in the present invention (an antibody-drug conjugate including a derivative of exatecan as a component) has been confirmed to exert a superior antitumor effect even as a single agent. However, there has been a need to obtain a method of treatment which can suppress growth of cancer cells in multiple manners and exert a further superior antitumor effect by using the antibody-drug conjugate in combination with another anticancer agent having a different mechanism of action.

[0010] An object of the present invention is to provide a pharmaceutical composition wherein a specific antibody- drug conjugate and a kinase inhibitor are administered in combination, and / or a method of treatment wherein a specific antibody-drug conjugate and a kinase inhibitor are administered in combination to a subject. Solution to Problem

[0011] As a result of diligent studies in order to solve the above problems, the present inventors have found that combined administration of a specific antibody-drug conjugate and a kinase inhibitor exhibits a superior combined effect, and completed the present invention.

[0012] Thus, the present invention provides the following [1] to

[1072] . [1] A pharmaceutical composition wherein an antibody- drug conjugate and a kinase inhibitor are administered in combination, and the antibody-drug conjugate is an antibody-drug conjugate in which a drug-linker represented by the following formula:

[0013] [Formula 1] oO oO I~ o un 9 uw © Ay Reo se~s A A RANK mg ap of H MN H MX H oO H A H A H n H " 0 H 3 AN H oo ANT Me 0 | N Z F N \ fo] Me OH 0 OHO

[0014] wherein A represents a connecting position to an antibody, is conjugated to the antibody via a thioether bond, and the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an AKT inhibitor, an ERK inhibitor, an MEK inhibitor, an RAF inhibitor, a CDK1l inhibitor, a CDK2 inhibitor, a CHK1 inhibitor, a WEEl inhibitor, a PLKl inhibitor, an Aurora kinase inhibitor, a Bcr-Abl inhibitor, an Src inhibitor, an EPH inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, a BTK inhibitor, an FLT3 inhibitor, an ALK inhibitor, a JAK inhibitor, an MET inhibitor, a CSF-1R inhibitor, an NTRK inhibitor, an EGFR inhibitor, and an HER2 inhibitor. [2] The pharmaceutical composition according to [1], wherein the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an RAF inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, an FLT3 inhibitor, an ALK inhibitor, a CSF-1R inhibitor, an EGFR inhibitor, and an HERZ? inhibitor. [3] The pharmaceutical composition according to [2], wherein the kinase inhibitor is a CDK4 / 6 inhibitor. [4] The pharmaceutical composition according to [3], wherein the CDK4 / 6 inhibitor is abemaciclib, palbociclib, ribociclib, trilaciclib, G1T38, PF-06873600, TP-1287, FN- 1501, or KRX-0601, or a pharmacologically acceptable salt thereof. [5] The pharmaceutical composition according to [2], wherein the kinase inhibitor is an mTOR inhibitor. [6] The pharmaceutical composition according to [5], wherein the mTOR inhibitor is everolimus, sirolimus, temsirolimus, TAK-228, CC-223, AzZD8055, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP- BGT226, or PQR309, or a pharmacologically acceptable salt thereof. [7] The pharmaceutical composition according to [2], wherein the kinase inhibitor is a PI3K inhibitor. [8] The pharmaceutical composition according to [7], wherein the PI3K inhibitor is taselisib, alpelisib, TAK- 117, GSK2636771, AZD8186, IPI-549, idelalisib, duvelisib, AMG319, buparlisib, pictilisib, pilaralisib, copanlisib, sonolisib, CH5132799, ZSTK474, GDC-0077, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP- BGT226, PQR309, KRX-0601, or rigosertib, or a pharmacologically acceptable salt thereof. [8] The pharmaceutical composition according to [2], wherein the kinase inhibitor is an RAF inhibitor.

[10] The pharmaceutical composition according to [9], wherein the RAF inhibitor is regorafenib, sorafenib, vemurafenib, dabrafenib, encorafenib, RAF265, GDC-5573, LY3009120, or RO5126766, or a pharmacologically acceptable salt thereof.

[0015]

[11] The pharmaceutical composition according to [2], wherein the kinase inhibitor is a VEGFR inhibitor.

[12] The pharmaceutical composition according to

[11] , wherein the VEGFR inhibitor is regorafenib, sorafenib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, cabozantinib, tivozanib, brivanib, linifanib, lucitanib, ilorasertib, or ENMD-2076, or a pharmacologically acceptable salt thereof.

[13] The pharmaceutical composition according to [2], wherein the kinase inhibitor is a KIT inhibitor.

[14] The pharmaceutical composition according to

[13] , wherein the KIT inhibitor is regorafenib, sorafenib, imatinib, ilorasertib, sunitinib, pazopanib, lenvatinib, or dasatinib, or a pharmacologically acceptable salt thereof.

[15] The pharmaceutical composition according to [2], wherein the kinase inhibitor is an RET inhibitor.

[16] The pharmaceutical composition according to

[15] , wherein the RET inhibitor is regorafenib, sorafenib, vandetanib, lenvatinib, or sunitinib, or a pharmacologically acceptable salt thereof.

[17] The pharmaceutical composition according to [2], wherein the kinase inhibitor is a PDGFR inhibitor.

[18] The pharmaceutical composition according to

[17] , wherein the PDGFR inhibitor is regorafenib, sorafenib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, ilorasertib, imatinib, nilotinib, or dasatinib, or a pharmacologically acceptable salt thereof.

[19] The pharmaceutical composition according to [2], wherein the kinase inhibitor is an FGFR inhibitor.

[20] The pharmaceutical composition according to

[19] , wherein the FGFR inhibitor is regorafenib, sorafenib, lenvatinib, nintedanib, axitinib, or pazopanib, or a pharmacologically acceptable salt thereof.

[0016]

[21] The pharmaceutical composition according to [2], wherein the kinase inhibitor is an FLT3 inhibitor.

[22] The pharmaceutical composition according to

[21] , wherein the FLT3 inhibitor is gilteritinib, quizartinib, midostaurin, sorafenib, ilorasertib, ENMD-2076, or sunitinib, or a pharmacologically acceptable salt thereof.

[23] The pharmaceutical composition according to [2], wherein the kinase inhibitor is an ALK inhibitor.

[24] The pharmaceutical composition according to

[23] , wherein the ALK inhibitor is brigatinib, crizotinib, ceritinib, alectinib, or lorlatinib, or a pharmacologically acceptable salt thereof.

[25] The pharmaceutical composition according to [2], wherein the kinase inhibitor is a CSF-1R inhibitor.

[26] The pharmaceutical composition according to

[25] , wherein the CSF-1R inhibitor is pexidartinib, BLZ-945, JNJ-40346527, JNJ-28312141, ilorasertib, imatinib, sunitinib, or axitinib, or a pharmacologically acceptable salt thereof.

[27] The pharmaceutical composition according to [2], wherein the kinase inhibitor is an EGFR inhibitor.

[28] The pharmaceutical composition according to

[27] , wherein the EGFR inhibitor is gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

[29] The pharmaceutical composition according to [2], wherein the kinase inhibitor is an HER2 inhibitor.

[30] The pharmaceutical composition according to

[29] , wherein the HER2 inhibitor is tucatinib, neratinib, mubritinib, lapatinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

[0017]

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

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

[32] The pharmaceutical composition according to

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

[33] The pharmaceutical composition according to

[32] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 consisting of an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 consisting of an amino acid sequence consisting of amino acid residues 397 to 109 of SEQ ID NO: 1, and a light chain comprising CDRL1 consisting of an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 consisting of an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2.

[34] The pharmaceutical composition according to

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

[35] The pharmaceutical composition according to

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

[36] The pharmaceutical composition according to

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

[37] The pharmaceutical composition according to any one of

[32] to

[36] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[38] The pharmaceutical composition according to

[31] , wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody. [3%] The pharmaceutical composition according to

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

[40] The pharmaceutical composition according to

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

[0018]

[41] The pharmaceutical composition according to any one of

[38] to

[40] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[42] The pharmaceutical composition according to

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

[43] The pharmaceutical composition according to

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

[44] The pharmaceutical composition according to

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

[45] The pharmaceutical composition according to any one of

[42] to

[44] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[46] The pharmaceutical composition according to

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

[47] The pharmaceutical composition according to

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

[48] The pharmaceutical composition according to

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

[49] The pharmaceutical composition according to any one of

[46] to

[48] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[50] The pharmaceutical composition according to

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

[0019]

[51] The pharmaceutical composition according to

[50] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 10.

[52] The pharmaceutical composition according to

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

[53] The pharmaceutical composition according to any one of

[50] to

[52] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

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

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

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

[54] , wherein the pharmaceutical composition is for use in treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, endometrial cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.

[56] The pharmaceutical composition according to

[55] , wherein the pharmaceutical composition is for use in treating breast cancer.

[57] The pharmaceutical composition according to

[55] , wherein the pharmaceutical composition is for use in treating colorectal cancer.

[58] The pharmaceutical composition according to

[55] , wherein the pharmaceutical composition is for use in treating gastric cancer.

[59] The pharmaceutical composition according to

[55] , wherein the pharmaceutical composition is for use in treating lung cancer.

[60] The pharmaceutical composition according to

[55] , wherein the pharmaceutical composition is for use in treating pancreatic cancer.

[61] The pharmaceutical composition according to

[55] , wherein the pharmaceutical composition is for use in treating kidney cancer.

[62] The pharmaceutical composition according to

[55] , wherein the pharmaceutical composition is for use in treating ovarian cancer.

[63] A pharmaceutical composition wherein an antibody- drug conjugate and a kinase inhibitor are administered n combination, and the antibody-drug conjugate is an antibody-drug conjugate represented by the following formula:

[0020] [Formula 2] < Antibody — < ¢ 1.81 1 TY Mesa IAA IH mop © oO [oe HG Hg OH 0 H NH Me. o | N F N C Me “Too _ Nn

[0021] wherein a drug-linker is conjugated to an antibody via a thioether bond, and n is the average number of units of the drug-linker conjugated per antibody molecule, and the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an AKT inhibitor, an ERK inhibitor, an MEK inhibitor, an RAF inhibitor, a CDK1l inhibitor, a CDK2 inhibitor, a CHKl inhibitor, a WEEl inhibitor, a PLKl inhibitor, an Aurora kinase inhibitor, a Bcr-Abl inhibitor, an Src inhibitor, an EPH inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, a BTK inhibitor, an FLT3 inhibitor, an ALK inhibitor, a JAK inhibitor, an MET inhibitor, a CSF-1R inhibitor, an NTRK inhibitor, an EGFR inhibitor, and an HER2 inhibitor.

[64] The pharmaceutical composition according to

[63] , wherein the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an RAF inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, an FLT3 inhibitor, an ALK inhibitor, a CSF-1R inhibitor, an EGFR inhibitor, and an HER? inhibitor.

[65] The pharmaceutical composition according to

[64] , wherein the kinase inhibitor is a CDK4 / 6 inhibitor.

[0022]

[66] The pharmaceutical composition according to

[65] , wherein the CDK4 / 6 inhibitor is abemaciclib, palbociclib, ribociclib, trilaciclib, G1T38, PF-06873600, TP-1287, FN- 1501, or KRX-0601, or a pharmacologically acceptable salt thereof.

[67] The pharmaceutical composition according to

[64] , wherein the kinase inhibitor is an mTOR inhibitor.

[68] The pharmaceutical composition according to

[67] , wherein the mTOR inhibitor is everolimus, sirolimus, temsirolimus, TAK-228, CC-223, AzZD8055, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP- BGT226, or PQR30%9, or a pharmacologically acceptable salt thereof.

[69] The pharmaceutical composition according to

[64] , wherein the kinase inhibitor is a PI3K inhibitor.

[70] The pharmaceutical composition according to

[69] , wherein the PI3K inhibitor is taselisib, alpelisib, TAK- 117, GSK2636771, AzZD8186, IPI-549, idelalisib, duvelisib, AMG319, buparlisib, pictilisib, pilaralisib, copanlisib, sonolisib, CH5132799, ZSTK474, GDC-0077, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP- BGT226, PQR309, KRX-0601, or rigosertib, or a pharmacologically acceptable salt thereof.

[71] The pharmaceutical composition according to

[64] , wherein the kinase inhibitor is an RAF inhibitor.

[72] The pharmaceutical composition according to

[71] , wherein the RAF inhibitor is regorafenib, sorafenib, vemurafenib, dabrafenib, encorafenib, RAF265, GDC-5573, LY3009120, or RO5126766, or a pharmacologically acceptable salt thereof.

[73] The pharmaceutical composition according to

[64] , wherein the kinase inhibitor is a VEGFR inhibitor.

[74] The pharmaceutical composition according to

[73] , wherein the VEGFR inhibitor is regorafenib, sorafenib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, cabozantinib, tivozanib, brivanib, linifanib, lucitanib, ilorasertib, or ENMD-2076, or a pharmacologically acceptable salt thereof.

[75] The pharmaceutical composition according to

[64] , wherein the kinase inhibitor is a KIT inhibitor.

[0023]

[76] The pharmaceutical composition according to

[75] , wherein the KIT inhibitor is regorafenib, sorafenib, imatinib, ilorasertib, sunitinib, pazopanib, lenvatinib, or dasatinib, or a pharmacologically acceptable salt thereof.

[77] The pharmaceutical composition according to

[64] , wherein the kinase inhibitor is an RET inhibitor.

[78] The pharmaceutical composition according to

[77] , wherein the RET inhibitor is regorafenib, sorafenib, vandetanib, lenvatinib, or sunitinib, or a pharmacologically acceptable salt thereof.

[79] The pharmaceutical composition according to

[64] , wherein the kinase inhibitor is a PDGFR inhibitor.

[80] The pharmaceutical composition according to

[79] , wherein the PDGFR inhibitor is regorafenib, sorafenib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, ilorasertib, imatinib, nilotinib, or dasatinib, or a pharmacologically acceptable salt thereof.

[81] The pharmaceutical composition according to

[64] , wherein the kinase inhibitor is an FGFR inhibitor.

[82] The pharmaceutical composition according to

[81] , wherein the FGFR inhibitor is regorafenib, sorafenib, lenvatinib, nintedanib, axitinib, or pazopanib, or a pharmacologically acceptable salt thereof.

[83] The pharmaceutical composition according to

[64] , wherein the kinase inhibitor is an FLT3 inhibitor.

[84] The pharmaceutical composition according to

[83] , wherein the FLT3 inhibitor is gilteritinib, quizartinib, midostaurin, sorafenib, ilorasertib, ENMD-2076, or sunitinib, or a pharmacologically acceptable salt thereof.

[85] The pharmaceutical composition according to

[64] , wherein the kinase inhibitor is an ALK inhibitor.

[0024]

[86] The pharmaceutical composition according to

[85] , wherein the ALK inhibitor is brigatinib, crizotinib, ceritinib, alectinib, or lorlatinib, or a pharmacologically acceptable salt thereof.

[87] The pharmaceutical composition according to

[64] , wherein the kinase inhibitor is a CSF-1R inhibitor.

[88] The pharmaceutical composition according to

[87] , wherein the CSF-1R inhibitor is pexidartinib, BLZ-945, JNJ-40346527, JNJ-28312141, ilorasertib, imatinib, sunitinib, or axitinib, or a pharmacologically acceptable salt thereof.

[89] The pharmaceutical composition according to

[64] , wherein the kinase inhibitor is an EGFR inhibitor.

[90] The pharmaceutical composition according to

[89] , wherein the EGFR inhibitor is gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

[0025]

[91] The pharmaceutical composition according to

[64] , wherein the kinase inhibitor is an HER2 inhibitor.

[92] The pharmaceutical composition according to

[91] , wherein the HER2 inhibitor is tucatinib, neratinib, mubritinib, lapatinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

[93] The pharmaceutical composition according to any one of

[63] to

[92] , wherein the antibody in the antibody- drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, or an anti-CDH6é antibody.

[94] The pharmaceutical composition according to

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

[95] The pharmaceutical composition according to

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

[96] The pharmaceutical composition according to

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

[97] The pharmaceutical composition according to

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

[98] The pharmaceutical composition according to

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

[99] The pharmaceutical composition according to any one of

[94] to

[98] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[100] The pharmaceutical composition according to

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

[0026]

[101] The pharmaceutical composition according to

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

[102] The pharmaceutical composition according to

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

[103] The pharmaceutical composition according to any one of

[100] to

[102] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[104] The pharmaceutical composition according to

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

[105] The pharmaceutical composition according to

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

[106] The pharmaceutical composition according to

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

[107] The pharmaceutical composition according to any one of

[104] to

[106] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[108] The pharmaceutical composition according to

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

[108] The pharmaceutical composition according to

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

[110] The pharmaceutical composition according to

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

[0027]

[111] The pharmaceutical composition according to any one of

[108] to

[110] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[112] The pharmaceutical composition according to

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

[113] The pharmaceutical composition according to

[112] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 10.

[114] The pharmaceutical composition according to

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

[115] The pharmaceutical composition according to any one of

[112] to

[114] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[116] The pharmaceutical composition according to any one of

[63] to

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

[0028]

[117] The pharmaceutical composition according to any one of

[63] to

[116] , wherein the pharmaceutical composition is for use in treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, endometrial cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.

[118] The pharmaceutical composition according to

[117] , wherein the pharmaceutical composition is for use in treating breast cancer. [11%] The pharmaceutical composition according to

[117] , wherein the pharmaceutical composition is for use in treating colorectal cancer.

[120] The pharmaceutical composition according to

[117] , wherein the pharmaceutical composition is for use in treating gastric cancer.

[121] The pharmaceutical composition according to

[117] , wherein the pharmaceutical composition is for use in treating lung cancer.

[122] The pharmaceutical composition according to

[117] , wherein the pharmaceutical composition is for use in treating pancreatic cancer.

[123] The pharmaceutical composition according to

[117] , wherein the pharmaceutical composition is for use in treating kidney cancer.

[124] The pharmaceutical composition according to

[117] , wherein the pharmaceutical composition is for use in treating ovarian cancer.

[125] A method of treatment, comprising administering an antibody-drug conjugate and a kinase inhibitor in combination to a subject in need of treatment, wherein the antibody-drug conjugate is an antibody-drug conjugate in which a drug-linker represented by the following formula:

[0029] [Formula 3] oO O IE 0 Hw © 4 © H I H H 1 H H A=. |} 1 Hoo Hoo “Ys AA IAA IA onp© 0 H 3 LL H NH AH oo AN Me 0 | N F N / Oo Me OH 0 “OHO 10030] wherein A represents a connecting position to an antibody, is conjugated to the antibody via a thioether bond, and the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an AKT inhibitor, an ERK inhibitor, an MEK inhibitor, an RAF inhibitor, a CDK1 inhibitor, a CDK2 inhibitor, a CHK1 inhibitor, a WEEl inhibitor, a PLK1l inhibitor, an Aurora kinase inhibitor, a Bcr-Abl inhibitor, an Src inhibitor, an EPH inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, a BTK inhibitor, an FLT3 inhibitor, an ALK inhibitor, a JAK inhibitor, an MET inhibitor, a CSF-1R inhibitor, an NTRK inhibitor, an EGFR inhibitor, and an HER2 inhibitor.

[126] The method of treatment according to

[125] , wherein the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an RAF inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, an FLT3 inhibitor, an ALK inhibitor, a CSF-1R inhibitor, an EGFR inhibitor, and an HER2 inhibitor.

[127] The method of treatment according to

[126] , wherein the kinase inhibitor is a CDK4 / 6 inhibitor.

[128] The method of treatment according to

[127] , wherein the CDK4 / 6 inhibitor is abemaciclib, palbociclib, ribociclib, trilaciclib, G1T38, PF-06873600, TP-1287, FN- 1501, or KRX-0601, or a pharmacologically acceptable salt thereof. [12%] The method of treatment according to

[126] , wherein the kinase inhibitor is an mTOR inhibitor.

[130] The method of treatment according to

[129] , wherein the mTOR inhibitor is everolimus, sirolimus, temsirolimus, TAK-228, CC-223, AzZD8055, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP- BGT226, or PQR30%9, or a pharmacologically acceptable salt thereof.

[0031]

[131] The method of treatment according to

[126] , wherein the kinase inhibitor is a PI3K inhibitor.

[132] The method of treatment according to

[131] , wherein the PI3K inhibitor is taselisib, alpelisib, TAK- 117, GSK2636771, AzZD8186, IPI-549, idelalisib, duvelisib, AMG319, buparlisib, pictilisib, pilaralisib, copanlisib, sonolisib, CH5132799, ZSTK474, GDC-0077, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP- BGT226, PQR309, KRX-0601, or rigosertib, or a pharmacologically acceptable salt thereof.

[133] The method of treatment according to

[126] , wherein the kinase inhibitor is an RAF inhibitor.

[134] The method of treatment according to

[133] , wherein the RAF inhibitor is regorafenib, sorafenib, vemurafenib, dabrafenib, encorafenib, RAF265, GDC-5573, LY3009120, or RO5126766, or a pharmacologically acceptable salt thereof.

[135] The method of treatment according to

[126] , wherein the kinase inhibitor is a VEGFR inhibitor.

[136] The method of treatment according to

[135] , wherein the VEGFR inhibitor is regorafenib, sorafenib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, cabozantinib, tivozanib, brivanib, linifanib, lucitanib, ilorasertib, or ENMD-2076, or a pharmacologically acceptable salt thereof.

[137] The method of treatment according to

[126] , wherein the kinase inhibitor is a KIT inhibitor.

[138] The method of treatment according to

[137] , wherein the KIT inhibitor is regorafenib, sorafenib, imatinib, ilorasertib, sunitinib, pazopanib, lenvatinib, or dasatinib, or a pharmacologically acceptable salt thereof.

[133] The method of treatment according to

[126] , wherein the kinase inhibitor is an RET inhibitor.

[140] The method of treatment according to

[139] , wherein the RET inhibitor is regorafenib, sorafenib, vandetanib, lenvatinib, or sunitinib, or a pharmacologically acceptable salt thereof.

[0032]

[141] The method of treatment according to

[126] , wherein the kinase inhibitor is a PDGFR inhibitor.

[142] The method of treatment according to

[141] , wherein the PDGFR inhibitor is regorafenib, sorafenib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, ilorasertib, imatinib, nilotinib, or dasatinib, or a pharmacologically acceptable salt thereof.

[143] The method of treatment according to

[126] , wherein the kinase inhibitor is a FGFR inhibitor.

[144] The method of treatment according to

[143] , wherein the FGFR inhibitor is regorafenib, sorafenib, lenvatinib, nintedanib, axitinib, or pazopanib, or a pharmacologically acceptable salt thereof.

[145] The method of treatment according to

[126] , wherein the kinase inhibitor is a FLT3 inhibitor.

[146] The method of treatment according to

[145] , wherein the FLT3 inhibitor is gilteritinib, quizartinib, midostaurin, sorafenib, ilorasertib, ENMD-2076, or sunitinib, or a pharmacologically acceptable salt thereof.

[147] The method of treatment according to

[126] , wherein the kinase inhibitor is an ALK inhibitor.

[148] The method of treatment according to

[147] , wherein the ALK inhibitor is brigatinib, crizotinib, ceritinib, alectinib, or lorlatinib, or a pharmacologically acceptable salt thereof.

[143] The method of treatment according to

[126] , wherein the kinase inhibitor is a CSF-1R inhibitor.

[150] The method of treatment according to

[149] , wherein the CSF-1R inhibitor is pexidartinib, BLZ-945, JNJ-40346527, JINJ-28312141, ilorasertib, imatinib, sunitinib, or axitinib, or a pharmacologically acceptable salt thereof.

[0033]

[151] The method of treatment according to

[126] , wherein the kinase inhibitor is an EGFR inhibitor.

[152] The method of treatment according to

[151] , wherein the EGFR inhibitor is gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

[153] The method of treatment according to

[126] , wherein the kinase inhibitor is an HER2 inhibitor.

[154] The method of treatment according to

[153] , wherein the HER2 inhibitor is tucatinib, neratinib, mubritinib, lapatinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

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

[125] to

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

[156] The method of treatment according to

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

[157] The method of treatment according to

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

[158] The method of treatment according to

[156] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 120 of SEQ ID NO: . and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 107 of SEQ ID NO: 2. [15%] The method of treatment according to

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

[160] The method of treatment according to

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

[0034]

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

[156] to

[160] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[162] The method of treatment according to

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

[163] The method of treatment according to

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

[164] The method of treatment according to

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

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

[162] to

[164] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[166] The method of treatment according to

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

[167] The method of treatment according to

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

[168] The method of treatment according to

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

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

[166] to

[168] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[170] The method of treatment according to

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

[0035]

[171] The method of treatment according to

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

[172] The method of treatment according to

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

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

[170] to

[172] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[174] The method of treatment according to

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

[175] The method of treatment according to

[174] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 10.

[176] The method of treatment according to

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

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

[174] to

[176] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

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

[125] to

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

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

[125] to

[178] , wherein the method of treatment is for treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, endometrial cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.

[180] The method of treatment according to

[179] , wherein the method of treatment is for treating breast cancer.

[0036]

[181] The method of treatment according to

[179] , wherein the method of treatment is for treating colorectal cancer.

[182] The method of treatment according to

[179] , wherein the method of treatment is for treating gastric cancer.

[183] The method of treatment according to

[179] , wherein the method of treatment is for treating lung cancer.

[184] The method of treatment according to

[179] , wherein the method of treatment is for treating pancreatic cancer.

[185] The method of treatment according to

[179] , wherein the method of treatment is for treating kidney cancer.

[186] The method of treatment according to

[179] , wherein the method of treatment is for treating ovarian cancer.

[187] A method of treatment, comprising administering an antibody-drug conjugate and a kinase inhibitor in combination to a subject in need of treatment, wherein the antibody-drug conjugate is an antibody-drug conjugate represented by the following formula:

[0037] [Formula 4] < Antibody — < rx tL ik — N N. N a o DB ey H § N ~~ o Ay orp! Me 0 N. F N o Me, OHO “Towo _ Nn

[0038] wherein a drug-linker is conjugated to an antibody via a thioether bond, and n is the average number of units of the drug-linker conjugated per antibody molecule, and the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an AKT inhibitor, an ERK inhibitor, an MEK inhibitor, an RAF inhibitor, a CDK1 inhibitor, a CDK2 inhibitor, a CHK1l inhibitor, a WEE1l inhibitor, a PLK1l inhibitor, an Aurora kinase inhibitor, a Bcr-Abl inhibitor, an Src inhibitor, an EPH inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, a BTK inhibitor, an FLT3 inhibitor, an ALK inhibitor, a JAK inhibitor, an MET inhibitor, a CSF-1R inhibitor, an NTRK inhibitor, an EGFR inhibitor, and an HER2 inhibitor.

[188] The method of treatment according to

[187] , wherein the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an RAF inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, an FLT3 inhibitor, an ALK inhibitor, a CSF-1R inhibitor, an EGFR inhibitor, and an HER? inhibitor.

[183] The method of treatment according to

[188] , wherein the kinase inhibitor is a CDK4 / 6 inhibitor.

[190] The method of treatment according to

[189] , wherein the CDK4 / 6 inhibitor is abemaciclib, palbociclib, ribociclib, trilaciclib, G1T38, PF-06873600, TP-1287, FN- 1501, or KRX-0601, or a pharmacologically acceptable salt thereof.

[0039]

[191] The method of treatment according to

[188] , wherein the kinase inhibitor is an mTOR inhibitor.

[192] The method of treatment according to

[191] , wherein the mTOR inhibitor is everolimus, sirolimus, temsirolimus, TAK-228, CC-223, AZD8055, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP- BGT226, or PQR309, or a pharmacologically acceptable salt thereof.

[193] The method of treatment according to

[188] , wherein the kinase inhibitor is a PI3K inhibitor.

[194] The method of treatment according to

[193] , wherein the PI3K inhibitor is taselisib, alpelisib, TAK- 117, GSK2636771, AzZD8186, IPI-549, idelalisib, duvelisib, AMG319, buparlisib, pictilisib, pilaralisib, copanlisib, sonolisib, CH5132799, ZSTK474, GDC-0077, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP- BGT226, PQR309, KRX-0601, or rigosertib, or a pharmacologically acceptable salt thereof.

[195] The method of treatment according to

[188] , wherein the kinase inhibitor is an RAF inhibitor.

[196] The method of treatment according to

[195] , wherein the RAF inhibitor is regorafenib, sorafenib, vemurafenib, dabrafenib, encorafenib, RAF265, GDC-5573, LY3009120, or RO5126766, or a pharmacologically acceptable salt thereof.

[197] The method of treatment according to

[188] , wherein the kinase inhibitor is a VEGFR inhibitor.

[198] The method of treatment according to

[197] , wherein the VEGFR inhibitor is regorafenib, sorafenib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, cabozantinib, tivozanib, brivanib, linifanib, lucitanib, ilorasertib, or ENMD-2076, or a pharmacologically acceptable salt thereof.

[199] The method of treatment according to

[188] , wherein the kinase inhibitor is a KIT inhibitor.

[200] The method of treatment according to

[199] , wherein the KIT inhibitor is regorafenib, sorafenib, imatinib, ilorasertib, sunitinib, pazopanib, lenvatinib, or dasatinib, or a pharmacologically acceptable salt thereof.

[0040]

[201] The method of treatment according to

[188] , wherein the kinase inhibitor is an RET inhibitor.

[202] The method of treatment according to

[201] , wherein the RET inhibitor is regorafenib, sorafenib, vandetanib, lenvatinib, or sunitinib, or a pharmacologically acceptable salt thereof.

[203] The method of treatment according to

[188] , wherein the kinase inhibitor is a PDGFR inhibitor.

[204] The method of treatment according to

[203] , wherein the PDGFR inhibitor is regorafenib, sorafenib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, ilorasertib, imatinib, nilotinib, or dasatinib, or a pharmacologically acceptable salt thereof.

[205] The method of treatment according to

[188] , wherein the kinase inhibitor is a FGFR inhibitor.

[206] The method of treatment according to

[205] , wherein the FGFR inhibitor is regorafenib, sorafenib, lenvatinib, nintedanib, axitinib, or pazopanib, or a pharmacologically acceptable salt thereof.

[207] The method of treatment according to

[188] , wherein the kinase inhibitor is an FLT3 inhibitor.

[208] The method of treatment according to

[207] , wherein the FLT3 inhibitor is gilteritinib, quizartinib, midostaurin, sorafenib, ilorasertib, ENMD-2076, or sunitinib, or a pharmacologically acceptable salt thereof.

[208] The method of treatment according to

[188] , wherein the kinase inhibitor is an ALK inhibitor.

[210] The method of treatment according to

[209] , wherein the ALK inhibitor is brigatinib, crizotinib, ceritinib, alectinib, or lorlatinib, or a pharmacologically acceptable salt thereof.

[0041]

[211] The method of treatment according to

[188] , wherein the kinase inhibitor is a CSF-1R inhibitor.

[212] The method of treatment according to

[211] , wherein the CSF-1R inhibitor is pexidartinib, BLZ-945, JNJ-40346527, JNJ-28312141, ilorasertib, imatinib, sunitinib, or axitinib, or a pharmacologically acceptable salt thereof.

[213] The method of treatment according to

[188] , wherein the kinase inhibitor is an EGFR inhibitor.

[214] The method of treatment according to

[213] , wherein the EGFR inhibitor is gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

[215] The method of treatment according to

[188] , wherein the kinase inhibitor is an HER2 inhibitor.

[216] The method of treatment according to

[215] , wherein the HER2 inhibitor is tucatinib, neratinib, mubritinib, lapatinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

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

[187] to

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

[218] The method of treatment according to

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

[213] The method of treatment according to

[218] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 consisting of an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 consisting of an amino acid sequence consisting of amino acid residues 397 to 109 of SEQ ID NO: 1, and a light chain comprising CDRL1 consisting of an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 consisting of an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2.

[220] The method of treatment according to

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

[0042]

[221] The method of treatment according to

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

[222] The method of treatment according to

[218] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: . and a light chain consisting of an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 3.

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

[218] to

[222] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[224] The method of treatment according to

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

[225] The method of treatment according to

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

[226] The method of treatment according to

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

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

[224] to

[226] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[228] The method of treatment according to

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

[223] The method of treatment according to

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

[230] The method of treatment according to

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

[0043]

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

[228] to

[230] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[232] The method of treatment according to

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

[233] The method of treatment according to

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

[234] The method of treatment according to

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

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

[232] to

[234] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[236] The method of treatment according to

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

[237] The method of treatment according to

[236] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 10.

[238] The method of treatment according to

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

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

[236] to

[238] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

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

[187] to

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

[0044]

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

[187] to

[240] , wherein the method of treatment is for treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, endometrial cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.

[242] The method of treatment according to

[241] , wherein the method of treatment is for treating breast cancer.

[243] The method of treatment according to

[241] , wherein the method of treatment is for treating colorectal cancer.

[244] The method of treatment according to

[241] , wherein the method of treatment is for treating gastric cancer.

[245] The method of treatment according to

[241] , wherein the method of treatment is for treating lung cancer.

[246] The method of treatment according to

[241] , wherein the method of treatment is for treating pancreatic cancer.

[247] The method of treatment according to

[241] , wherein the method of treatment is for treating kidney cancer.

[248] The method of treatment according to

[241] , wherein the method of treatment is for treating ovarian cancer.

[2439] An antibody-drug conjugate for use in treating a disease through being administered in combination with a kinase inhibitor, wherein a drug-linker represented by the following formula:

[0045] [Formula 5]

[0046] wherein A represents a connecting position to an antibody, is conjugated to the antibody via a thioether bond in the antibody-drug conjugate, and the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an AKT inhibitor, an ERK inhibitor, an MEK inhibitor, an RAF inhibitor, a CDK1 inhibitor, a CDK2 inhibitor, a CHK1 inhibitor, a WEEl inhibitor, a PLKl inhibitor, an Aurora kinase inhibitor, a Bcr-Abl inhibitor, an Src inhibitor, an EPH inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, a BTK inhibitor, an FLT3 inhibitor, an ALK inhibitor, a JAK inhibitor, an MET inhibitor, a CSF-1R inhibitor, an NTRK inhibitor, an EGFR inhibitor, and an HER2 inhibitor.

[250] The antibody-drug conjugate according to

[249] , wherein the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an RAF inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, an FLT3 inhibitor, an ALK inhibitor, a CSF-1R inhibitor, an EGFR inhibitor, and an HERZ? inhibitor.

[0047]

[251] The antibody-drug conjugate according to

[250] , wherein the kinase inhibitor is a CDK4 / 6 inhibitor.

[252] The antibody-drug conjugate according to

[251] , wherein the CDK4 / 6 inhibitor is abemaciclib, palbociclib, ribociclib, trilaciclib, G1T38, PF-06873600, TP-1287, FN- 1501, or KRX-0601, or a pharmacologically acceptable salt thereof.

[253] The antibody-drug conjugate according to

[250] , wherein the kinase inhibitor is an mTOR inhibitor.

[254] The antibody-drug conjugate according to

[253] , wherein the mTOR inhibitor is everolimus, sirolimus, temsirolimus, TAK-228, CC-223, AzZD8055, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP- BGT226, or PQR30%9, or a pharmacologically acceptable salt thereof.

[255] The antibody-drug conjugate according to

[250] , wherein the kinase inhibitor is a PI3K inhibitor.

[256] The antibody-drug conjugate according to

[255] , wherein the PI3K inhibitor is taselisib, alpelisib, TAK- 117, GSK2636771, AzZD8186, IPI-549, idelalisib, duvelisib, AMG319, buparlisib, pictilisib, pilaralisib, copanlisib, sonolisib, CH5132799, ZSTK474, GDC-0077, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP- BGT226, PQR309, KRX-0601, or rigosertib, or a pharmacologically acceptable salt thereof.

[257] The antibody-drug conjugate according to

[250] , wherein the kinase inhibitor is an RAF inhibitor.

[258] The antibody-drug conjugate according to

[257] , wherein the RAF inhibitor is regorafenib, sorafenib, vemurafenib, dabrafenib, encorafenib, RAF265, GDC-5573, LY3009120, or RO5126766, or a pharmacologically acceptable salt thereof.

[259] The antibody-drug conjugate according to

[250] , wherein the kinase inhibitor is a VEGFR inhibitor.

[260] The antibody-drug conjugate according to

[259] , wherein the VEGFR inhibitor is regorafenib, sorafenib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, cabozantinib, tivozanib, brivanib, linifanib, lucitanib, ilorasertib, or ENMD-2076, or a pharmacologically acceptable salt thereof.

[0048]

[261] The antibody-drug conjugate according to

[250] , wherein the kinase inhibitor is a KIT inhibitor.

[262] The antibody-drug conjugate according to

[261] , wherein the KIT inhibitor is regorafenib, sorafenib, imatinib, ilorasertib, sunitinib, pazopanib, lenvatinib, or dasatinib, or a pharmacologically acceptable salt thereof.

[263] The antibody-drug conjugate according to

[250] , wherein the kinase inhibitor is an RET inhibitor.

[264] The antibody-drug conjugate according to

[263] , wherein the RET inhibitor is regorafenib, sorafenib, vandetanib, lenvatinib, or sunitinib, or a pharmacologically acceptable salt thereof.

[265] The antibody-drug conjugate according to

[250] , wherein the kinase inhibitor is a PDGFR inhibitor.

[266] The antibody-drug conjugate according to

[265] , wherein the PDGFR inhibitor is regorafenib, sorafenib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, ilorasertib, imatinib, nilotinib, or dasatinib, or a pharmacologically acceptable salt thereof.

[267] The antibody-drug conjugate according to

[250] , wherein the kinase inhibitor is an FGFR inhibitor.

[268] The antibody-drug conjugate according to

[267] , wherein the FGFR inhibitor is regorafenib, sorafenib, lenvatinib, nintedanib, axitinib, or pazopanib, or a pharmacologically acceptable salt thereof.

[263] The antibody-drug conjugate according to

[250] , wherein the kinase inhibitor is an FLT3 inhibitor.

[270] The antibody-drug conjugate according to

[269] , wherein the FLT3 inhibitor is gilteritinib, quizartinib, midostaurin, sorafenib, ilorasertib, ENMD-2076, or sunitinib, or a pharmacologically acceptable salt thereof.

[0049]

[271] The antibody-drug conjugate according to

[250] , wherein the kinase inhibitor is an ALK inhibitor.

[272] The antibody-drug conjugate according to

[271] , wherein the ALK inhibitor is brigatinib, crizotinib, ceritinib, alectinib, or lorlatinib, or a pharmacologically acceptable salt thereof.

[273] The antibody-drug conjugate according to

[250] , wherein the kinase inhibitor is a CSF-1R inhibitor.

[274] The antibody-drug conjugate according to

[273] , wherein the CSF-1R inhibitor is pexidartinib, BLZ-945, JNJ-40346527, JNJ-28312141, ilorasertib, imatinib, sunitinib, or axitinib, or a pharmacologically acceptable salt thereof.

[275] The antibody-drug conjugate according to

[250] , wherein the kinase inhibitor is an EGFR inhibitor.

[276] The antibody-drug conjugate according to

[275] , wherein the EGFR inhibitor is gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

[277] The antibody-drug conjugate according to

[250] , wherein the kinase inhibitor is an HER2 inhibitor.

[278] The antibody-drug conjugate according to

[277] , wherein the HER2 inhibitor is tucatinib, neratinib, mubritinib, lapatinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

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

[249] to

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

[280] The antibody-drug conjugate according to [27%], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[0050]

[281] The antibody-drug conjugate according to

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

[282] The antibody-drug conjugate according to

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

[283] The antibody-drug conjugate according to

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

[284] The antibody-drug conjugate according to

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

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

[280] to

[284] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[286] The antibody-drug conjugate according to

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

[287] The antibody-drug conjugate according to

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

[288] The antibody-drug conjugate according to

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

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

[286] to

[288] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[290] The antibody-drug conjugate according to

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

[0051]

[291] The antibody-drug conjugate according to

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

[292] The antibody-drug conjugate according to

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

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

[290] to

[292] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[294] The antibody-drug conjugate according to

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

[295] The antibody-drug conjugate according to

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

[296] The antibody-drug conjugate according to

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

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

[294] to

[296] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[298] The antibody-drug conjugate according to

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

[2939] The antibody-drug conjugate according to

[298] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 10.

[300] The antibody-drug conjugate according to [299%], wherein the anti-CDH6 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0052]

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

[298] to

[300] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

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

[249] to

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

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

[249] to

[302] , wherein the antibody-drug conjugate is for use in treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, endometrial cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.

[304] The antibody-drug conjugate according to

[303] , wherein the antibody-drug conjugate is for use in treating breast cancer.

[305] The antibody-drug conjugate according to

[303] , wherein the antibody-drug conjugate is for use in treating colorectal cancer.

[306] The antibody-drug conjugate according to

[303] , wherein the antibody-drug conjugate is for use in treating gastric cancer.

[307] The antibody-drug conjugate according to

[303] , wherein the antibody-drug conjugate is for use in treating lung cancer.

[308] The antibody-drug conjugate according to

[303] , wherein the antibody-drug conjugate is for use in treating pancreatic cancer.

[303] The antibody-drug conjugate according to

[303] , wherein the antibody-drug conjugate is for use in treating kidney cancer.

[310] The antibody-drug conjugate according to

[303] , wherein the antibody-drug conjugate is for use in treating ovarian cancer.

[311] An antibody-drug conjugate for use in treating a disease through being administered in combination with a kinase inhibitor, wherein the antibody-drug conjugate is an antibody-drug conjugate represented by the following formula:

[0053] [Formula 6] < P i R i Cid ~~, o Antibody — < fT iA, Wop o H 0 Hn oH wo H 0 H o H 0 w NH Me o N. P N 0 Me Toko _ nN

[0054] wherein a drug-linker is conjugated to an antibody via a thioether bond, and n is the average number of units of the drug-linker conjugated per antibody molecule, and the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an AKT inhibitor, an ERK inhibitor, an MEK inhibitor, an RAF inhibitor, a CDK1l inhibitor, a CDK2 inhibitor, a CHK1 inhibitor, a WEEl inhibitor, a PLKl inhibitor, an Aurora kinase inhibitor, a Bcr-Abl inhibitor, an Src inhibitor, an EPH inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, a BTK inhibitor, an FLT3 inhibitor, an ALK inhibitor, a JAK inhibitor, an MET inhibitor, a CSF-1R inhibitor, an NTRK inhibitor, an EGFR inhibitor, and an HER2 inhibitor.

[312] The antibody-drug conjugate according to

[311] , wherein the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an RAF inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, an FLT3 inhibitor, an ALK inhibitor, a CSF-1R inhibitor, an EGFR inhibitor, and an HER? inhibitor.

[313] The antibody-drug conjugate according to

[312] , wherein the kinase inhibitor is a CDK4 / 6 inhibitor.

[314] The antibody-drug conjugate according to

[313] , wherein the CDK4 / 6 inhibitor is abemaciclib, palbociclib, ribociclib, trilaciclib, G1T38, PF-06873600, TP-1287, FN- 1501, or KRX-0601, or a pharmacologically acceptable salt thereof.

[315] The antibody-drug conjugate according to

[312] , wherein the kinase inhibitor is an mTOR inhibitor.

[0055]

[316] The antibody-drug conjugate according to

[315] , wherein the mTOR inhibitor is everolimus, sirolimus, temsirolimus, TAK-228, CC-223, AZD8055, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP- BGT226, or PQR309, or a pharmacologically acceptable salt thereof.

[317] The antibody-drug conjugate according to

[312] , wherein the kinase inhibitor is a PI3K inhibitor.

[318] The antibody-drug conjugate according to

[317] , wherein the PI3K inhibitor is taselisib, alpelisib, TAK- 117, GSK2636771, AZD8186, IPI-549, idelalisib, duvelisib, AMG319, buparlisib, pictilisib, pilaralisib, copanlisib, sonolisib, CH5132799, ZSTK474, GDC-0077, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP- BGT226, PQR309, KRX-0601, or rigosertib, or a pharmacologically acceptable salt thereof. [31%] The antibody-drug conjugate according to

[312] , wherein the kinase inhibitor is an RAF inhibitor.

[320] The antibody-drug conjugate according to

[319] , wherein the RAF inhibitor is regorafenib, sorafenib, vemurafenib, dabrafenib, encorafenib, RAF265, GDC-5573, LY3009120, or RO5126766, or a pharmacologically acceptable salt thereof.

[0056]

[321] The antibody-drug conjugate according to

[312] , wherein the kinase inhibitor is a VEGFR inhibitor.

[322] The antibody-drug conjugate according to

[321] , wherein the VEGFR inhibitor is regorafenib, sorafenib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, cabozantinib, tivozanib, brivanib, linifanib, lucitanib, ilorasertib, or ENMD-2076, or a pharmacologically acceptable salt thereof.

[323] The antibody-drug conjugate according to

[312] , wherein the kinase inhibitor is a KIT inhibitor.

[324] The antibody-drug conjugate according to

[323] , wherein the KIT inhibitor is regorafenib, sorafenib, imatinib, ilorasertib, sunitinib, pazopanib, lenvatinib, or dasatinib, or a pharmacologically acceptable salt thereof.

[325] The antibody-drug conjugate according to

[312] , wherein the kinase inhibitor is an RET inhibitor.

[326] The antibody-drug conjugate according to

[325] , wherein the RET inhibitor is regorafenib, sorafenib, vandetanib, lenvatinib, or sunitinib, or a pharmacologically acceptable salt thereof.

[327] The antibody-drug conjugate according to

[312] , wherein the kinase inhibitor is a PDGFR inhibitor.

[328] The antibody-drug conjugate according to

[327] , wherein the PDGFR inhibitor is regorafenib, sorafenib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, ilorasertib, imatinib, nilotinib, or dasatinib, or a pharmacologically acceptable salt thereof. [32%] The antibody-drug conjugate according to

[312] , wherein the kinase inhibitor is an FGFR inhibitor.

[330] The antibody-drug conjugate according to

[329] , wherein the FGFR inhibitor is regorafenib, sorafenib, lenvatinib, nintedanib, axitinib, or pazopanib, or a pharmacologically acceptable salt thereof.

[0057]

[331] The antibody-drug conjugate according to

[312] , wherein the kinase inhibitor is an FLT3 inhibitor.

[332] The antibody-drug conjugate according to

[331] , wherein the FLT3 inhibitor is gilteritinib, quizartinib, midostaurin, sorafenib, ilorasertib, ENMD-2076, or sunitinib, or a pharmacologically acceptable salt thereof.

[333] The antibody-drug conjugate according to

[312] , wherein the kinase inhibitor is an ALK inhibitor.

[334] The antibody-drug conjugate according to

[333] , wherein the ALK inhibitor is brigatinib, crizotinib, ceritinib, alectinib, or lorlatinib, or a pharmacologically acceptable salt thereof.

[335] The antibody-drug conjugate according to

[312] , wherein the kinase inhibitor is a CSF-1R inhibitor.

[336] The antibody-drug conjugate according to

[335] , wherein the CSF-1R inhibitor is pexidartinib, BLZ-945, JNJ-40346527, JNJ-28312141, ilorasertib, imatinib, sunitinib, or axitinib, or a pharmacologically acceptable salt thereof.

[337] The antibody-drug conjugate according to

[312] , wherein the kinase inhibitor is an EGFR inhibitor.

[338] The antibody-drug conjugate according to

[337] , wherein the EGFR inhibitor is gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

[333] The antibody-drug conjugate according to

[312] , wherein the kinase inhibitor is an HER2 inhibitor.

[340] The antibody-drug conjugate according to

[339] , wherein the HER2 inhibitor is tucatinib, neratinib, mubritinib, lapatinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

[0058]

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

[311] to

[340] , wherein the antibody in the antibody- drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, or an anti-CDH6é antibody.

[342] The antibody-drug conjugate according to

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

[343] The antibody-drug conjugate according to

[342] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 consisting of an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 consisting of an amino acid sequence consisting of amino acid residues 397 to 109 of SEQ ID NO: 1, and a light chain comprising CDRL1 consisting of an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 consisting of an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2.

[344] The antibody-drug conjugate according to

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

[345] The antibody-drug conjugate according to

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

[0059]

[346] The antibody-drug conjugate according to

[342] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: . and a light chain consisting of an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 3.

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

[342] to

[346] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[348] The antibody-drug conjugate according to

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

[349] The antibody-drug conjugate according to

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

[350] The antibody-drug conjugate according to

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

[0060]

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

[348] to

[350] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[352] The antibody-drug conjugate according to

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

[353] The antibody-drug conjugate according to

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

[354] The antibody-drug conjugate according to

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

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

[352] to

[354] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[356] The antibody-drug conjugate according to

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

[357] The antibody-drug conjugate according to

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

[358] The antibody-drug conjugate according to

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

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

[356] to

[358] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[360] The antibody-drug conjugate according to

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

[0061]

[361] The antibody-drug conjugate according to

[360] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 10.

[362] The antibody-drug conjugate according to

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

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

[360] to

[362] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

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

[311] to

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

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

[311] to

[364] , wherein the antibody-drug conjugate is for use in treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, endometrial cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.

[366] The antibody-drug conjugate according to

[365] , wherein the antibody-drug conjugate is for use in treating breast cancer.

[367] The antibody-drug conjugate according to

[365] , wherein the antibody-drug conjugate is for use in treating colorectal cancer.

[368] The antibody-drug conjugate according to

[365] , wherein the antibody-drug conjugate is for use in treating gastric cancer.

[363] The antibody-drug conjugate according to

[365] , wherein the antibody-drug conjugate is for use in treating lung cancer.

[370] The antibody-drug conjugate according to

[365] , wherein the antibody-drug conjugate is for use in treating pancreatic cancer.

[371] The antibody-drug conjugate according to

[365] , wherein the antibody-drug conjugate is for use in treating kidney cancer.

[372] The antibody-drug conjugate according to

[365] , wherein the antibody-drug conjugate is for use in treating ovarian cancer.

[373] Use of an antibody-drug conjugate for the manufacture of a medicament for treating a disease through being administered in combination with a kinase inhibitor, wherein a drug-linker represented by the following formula:

[0062] wherein A represents a connecting position to an antibody, is conjugated to the antibody via a thicether bond in the antibody-drug conjugate, and the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an AKT inhibitor, an ERK inhibitor, an MEK inhibitor, an RAF inhibitor, a CDK1l inhibitor, a CDK2 inhibitor, a CHK1 inhibitor, a WEEl inhibitor, a PLK1l inhibitor, an Aurora kinase inhibitor, a Bcr-Abl inhibitor, an Src inhibitor, an EPH inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, a BTK inhibitor, an FLT3 inhibitor, an ALK inhibitor, a JAK inhibitor, an MET inhibitor, a CSF-1R inhibitor, an NTRK inhibitor, an EGFR inhibitor, and an HER2 inhibitor.

[374] The use according to

[373] , wherein the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an RAF inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, an FLT3 inhibitor, an ALK inhibitor, a CSF-1R inhibitor, an EGFR inhibitor, and an HER2 inhibitor.

[375] The use according to

[374] , wherein the kinase inhibitor is a CDK4 / 6 inhibitor.

[0064]

[376] The use according to

[375] , wherein the CDK4 / 6 inhibitor is abemaciclib, palbociclib, ribociclib, trilaciclib, G1T38, PF-06873600, TP-1287, FN-1501, or KRX-0601, or a pharmacologically acceptable salt thereof.

[377] The use according to

[374] , wherein the kinase inhibitor is an mTOR inhibitor.

[378] The use according to

[377] , wherein the mTOR inhibitor is everolimus, sirolimus, temsirolimus, TAK-228, CC-223, AzZD8055, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP-BGT226, or PQR309, or a pharmacologically acceptable salt thereof.

[379] The use according to

[374] , wherein the kinase inhibitor is a PI3K inhibitor.

[380] The use according to

[379] , wherein the PI3K inhibitor is taselisib, alpelisib, TAK-117, GSK2636771, AZD8186, IPI-549, idelalisib, duvelisib, AMG319, buparlisib, pictilisib, pilaralisib, copanlisib, sonolisib, CH5132799, ZSTK474, GDC-0077, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP- BGT226, PQR309, KRX-0601, or rigosertib, or a pharmacologically acceptable salt thereof.

[381] The use according to

[374] , wherein the kinase inhibitor is an RAF inhibitor.

[382] The use according to

[381] , wherein the RAF inhibitor is regorafenib, sorafenib, vemurafenib, dabrafenib, encorafenib, RAF265, GDC-5573, LY3009120, or RO5126766, or a pharmacologically acceptable salt thereof.

[383] The use according to

[374] , wherein the kinase inhibitor is a VEGFR inhibitor.

[384] The use according to

[383] , wherein the VEGFR inhibitor is regorafenib, sorafenib, vandetanib, axitinib, pazopanib, lenvatinib, nintedanib, cabozantinib, tivozanib, brivanib, linifanib, lucitanib, ilorasertib, or ENMD-2076, or a pharmacologically acceptable salt thereof.

[385] The use according to

[374] , wherein the kinase inhibitor is a KIT inhibitor.

[0065]

[386] The use according to

[385] , wherein the KIT inhibitor is regorafenib, sorafenib, imatinib, ilorasertib, sunitinib, pazopanib, lenvatinib, or dasatinib, or a pharmacologically acceptable salt thereof.

[387] The use according to

[374] , wherein the kinase inhibitor is an RET inhibitor.

[388] The use according to

[387] , wherein the RET inhibitor is regorafenib, sorafenib, vandetanib, lenvatinib, or sunitinib, or a pharmacologically acceptable salt thereof.

[3839] The use according to

[374] , wherein the kinase inhibitor is a PDGFR inhibitor.

[390] The use according to [38%], wherein the PDGFR inhibitor is regorafenib, sorafenib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, ilorasertib, imatinib, nilotinib, or dasatinib, or a pharmacologically acceptable salt thereof.

[391] The use according to

[374] , wherein the kinase inhibitor is an FGFR inhibitor.

[392] The use according to

[391] , wherein the FGFR inhibitor is regorafenib, sorafenib, lenvatinib, nintedanib, axitinib, or pazopanib, or a pharmacologically acceptable salt thereof.

[393] The use according to

[374] , wherein the kinase inhibitor is an FLT3 inhibitor.

[394] The use according to

[393] , wherein the FLT3 inhibitor is gilteritinib, quizartinib, midostaurin, sorafenib, ilorasertib, ENMD-2076, or sunitinib, or a pharmacologically acceptable salt thereof.

[395] The use according to

[374] , wherein the kinase inhibitor is an ALK inhibitor.

[0066]

[396] The use according to

[395] , wherein the ALK inhibitor is brigatinib, crizotinib, ceritinib, alectinib, or lorlatinib, or a pharmacologically acceptable salt thereof.

[397] The use according to

[374] , wherein the kinase inhibitor is a CSF-1R inhibitor.

[398] The use according to

[397] , wherein the CSF-1R inhibitor is pexidartinib, BLZ-945, JNJ-40346527, JNJ- 28312141, ilorasertib, imatinib, sunitinib, or axitinib, or a pharmacologically acceptable salt thereof.

[399] The use according to

[374] , wherein the kinase inhibitor is an EGFR inhibitor.

[400] The use according to

[399] , wherein the EGFR inhibitor is gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

[0067]

[401] The use according to

[374] , wherein the kinase inhibitor is an HER2 inhibitor.

[402] The use according to

[401] , wherein the HER2 inhibitor is tucatinib, neratinib, mubritinib, lapatinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

[403] The use according to any one of

[373] to

[402] , wherein the antibody in the use is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti- B7-H3 antibody, or an anti-CDH6é antibody.

[404] The use according to

[403] , wherein the antibody in the use is an anti-HER2 antibody.

[405] The use according to

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

[406] The use according to

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

[407] The use according to

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

[408] The use according to

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

[409] The use according to any one of

[404] to

[408] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the use is in the range of from 7 to 8.

[410] The use according to

[403] , wherein the antibody in the use is an anti-HER3 antibody.

[0068]

[411] The use according to

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

[412] The use according to

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

[413] The use according to any one of

[410] to

[412] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the use is in the range of from 7 to 8.

[414] The use according to

[403] , wherein the antibody in the use is an anti-TROP2 antibody.

[415] The use according to

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

[416] The use according to

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

[417] The use according to any one of

[414] to

[416] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the use is in the range of from 3.5 to 4.5.

[418] The use according to

[403] , wherein the antibody in the use is an anti-B7-H3 antibody.

[419] The use according to

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

[420] The use according to

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

[0069]

[421] The use according to any one of

[418] to

[420] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the use is in the range of from 3.5 to 4.5.

[422] The use according to

[403] , wherein the antibody in the use is an anti-CDH6 antibody.

[423] The use according to

[422] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 10.

[424] The use according to

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

[425] The use according to any one of

[422] to

[424] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the use is in the range of from 7 to 8.

[426] The use according to any one of

[373] to

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

[427] The use according to any one of

[373] to

[426] , wherein the use is for treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroespophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, endometrial cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.

[428] The use according to

[427] , wherein the use is for treating breast cancer.

[429] The use according to

[427] , wherein the use is for treating colorectal cancer.

[430] The use according to

[427] , wherein the use is for treating gastric cancer.

[0070]

[431] The use according to

[427] , wherein the use is for treating lung cancer.

[432] The use according to

[427] , wherein the use is for treating pancreatic cancer.

[433] The use according to

[427] , wherein the use is for treating kidney cancer.

[434] The use according to

[427] , wherein the use is for treating ovarian cancer.

[435] Use of an antibody-drug conjugate for the manufacture of a medicament for treating a disease through being administered in combination with a kinase inhibitor, wherein the antibody-drug conjugate is an antibody-drug conjugate represented by the following formula:

[0071] [Formula 8] Antibody

[0072] ’ wherein a drug-linker is conjugated to an antibody via a thioether bond, and n is the average number of units of the drug-linker conjugated per antibody molecule, and the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an AKT inhibitor, an ERK inhibitor, an MEK inhibitor, an RAF inhibitor, a CDK1l inhibitor, a CDK2 inhibitor, a CHK1 inhibitor, a WEEl inhibitor, a PLKl inhibitor, an Aurora kinase inhibitor, a Bcr-Abl inhibitor, an Src inhibitor, an EPH inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, a BTK inhibitor, an FLT3 inhibitor, an ALK inhibitor, a JAK inhibitor, an MET inhibitor, a CSF-1R inhibitor, an NTRK inhibitor, an EGFR inhibitor, and an HER2 inhibitor.

[436] The use according to

[435] , wherein the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an RAF inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, an FLT3 inhibitor, an ALK inhibitor, a CSF-1R inhibitor, an EGFR inhibitor, and an HER2 inhibitor.

[437] The use according to

[436] , wherein the kinase inhibitor is a CDK4 / 6 inhibitor.

[438] The use according to

[437] , wherein the CDK4 / 6 inhibitor is abemaciclib, palbociclib, ribociclib, trilaciclib, G1T38, PF-06873600, TP-1287, FN-1501, or KRX-0601, or a pharmacologically acceptable salt thereof.

[439] The use according to

[436] , wherein the kinase inhibitor is an mTOR inhibitor.

[440] The use according to [43%], wherein the mTOR inhibitor is everolimus, sirolimus, temsirolimus, TAK-228, CC-223, AZD8055, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP-BGT226, or PQR309, or a pharmacologically acceptable salt thereof.

[0073]

[441] The use according to

[436] , wherein the kinase inhibitor is a PI3K inhibitor.

[442] The use according to

[441] , wherein the PI3K inhibitor is taselisib, alpelisib, TAK-117, GSK2636771, AZD8186, IPI-549, idelalisib, duvelisib, AMG319, buparlisib, pictilisib, pilaralisib, copanlisib, sonolisib, CH5132799, ZSTK474, GDC-0077, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP- BGT226, PQR309, KRX-0601, or rigosertib, or a pharmacologically acceptable salt thereof.

[443] The use according to

[436] , wherein the kinase inhibitor is an RAF inhibitor.

[444] The use according to

[443] , wherein the RAF inhibitor is regorafenib, sorafenib, vemurafenib, dabrafenib, encorafenib, RAF265, GDC-5573, LY3009120, or RO5126766, or a pharmacologically acceptable salt thereof.

[445] The use according to

[436] , wherein the kinase inhibitor is a VEGFR inhibitor.

[446] The use according to

[445] , wherein the VEGFR inhibitor is regorafenib, sorafenib, vandetanib, axitinib, pazopanib, lenvatinib, nintedanib, cabozantinib, tivozanib, brivanib, linifanib, lucitanib, ilorasertib, or ENMD-2076, or a pharmacologically acceptable salt thereof.

[447] The use according to

[436] , wherein the kinase inhibitor is a KIT inhibitor.

[448] The use according to

[447] , wherein the KIT inhibitor is regorafenib, sorafenib, imatinib, ilorasertib, sunitinib, pazopanib, lenvatinib, or dasatinib, or a pharmacologically acceptable salt thereof.

[449] The use according to

[436] , wherein the kinase inhibitor is an RET inhibitor.

[450] The use according to

[449] , wherein the RET inhibitor is regorafenib, sorafenib, vandetanib, lenvatinib, or sunitinib, or a pharmacologically acceptable salt thereof.

[0074]

[451] The use according to

[436] , wherein the kinase inhibitor is a PDGFR inhibitor.

[452] The use according to

[451] , wherein the PDGFR inhibitor is regorafenib, sorafenib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, ilorasertib, imatinib, nilotinib, or dasatinib, or a pharmacologically acceptable salt thereof.

[453] The use according to

[436] , wherein the kinase inhibitor is an FGFR inhibitor.

[454] The use according to

[453] , wherein the FGFR inhibitor is regorafenib, sorafenib, lenvatinib, nintedanib, axitinib, or pazopanib, or a pharmacologically acceptable salt thereof.

[455] The use according to

[436] , wherein the kinase inhibitor is an FLT3 inhibitor.

[456] The use according to

[455] , wherein the FLT3 inhibitor is gilteritinib, quizartinib, midostaurin, sorafenib, ilorasertib, ENMD-2076, or sunitinib, or a pharmacologically acceptable salt thereof.

[457] The use according to

[436] , wherein the kinase inhibitor is an ALK inhibitor.

[458] The use according to

[457] , wherein the ALK inhibitor is brigatinib, crizotinib, ceritinib, alectinib, or lorlatinib, or a pharmacologically acceptable salt thereof.

[459] The use according to

[436] , wherein the kinase inhibitor is a CSF-1R inhibitor.

[460] The use according to

[459] , wherein the CSF-1R inhibitor is pexidartinib, BLZ-945, JNJ-40346527, JNJ- 28312141, ilorasertib, imatinib, sunitinib, or axitinib, or a pharmacologically acceptable salt thereof.

[0075]

[461] The use according to

[436] , wherein the kinase inhibitor is an EGFR inhibitor.

[462] The use according to

[461] , wherein the EGFR inhibitor is gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

[463] The use according to

[436] , wherein the kinase inhibitor is an HER2 inhibitor.

[464] The use according to

[463] , wherein the HER2 inhibitor is tucatinib, neratinib, mubritinib, lapatinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

[465] The use according to any one of

[435] to

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

[466] The use according to

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

[467] The pharmaceutical composition according to

[466] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 consisting of an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 consisting of an amino acid sequence consisting of amino acid residues 397 to 109 of SEQ ID NO: 1, and a light chain comprising CDRL1 consisting of an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 consisting of an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2.

[468] The pharmaceutical composition according to

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

[469] The pharmaceutical composition according to

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

[470] The use according to

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

[0076]

[471] The use according to any one of

[466] to

[470] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[472] The use according to

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

[473] The use according to

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

[474] The use according to

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

[475] The use according to any one of

[472] to

[474] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[476] The use according to

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

[477] The use according to

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

[478] The use according to

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

[479] The use according to any one of

[476] to

[478] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[480] The use according to

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

[0077]

[481] The use according to

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

[482] The use according to

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

[483] The use according to any one of

[480] to

[482] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[484] The use according to

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

[485] The use according to

[484] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 10.

[486] The use according to

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

[487] The use according to any one of

[484] to

[486] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[488] The use according to any one of

[435] to

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

[489] The use according to any one of

[435] to

[488] , wherein the use is for treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, endometrial cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.

[490] The use according to

[489] , wherein the use is for treating breast cancer.

[0078]

[491] The use according to [48%], wherein the use is for treating colorectal cancer.

[492] The use according to

[489] , wherein the use is for treating gastric cancer.

[493] The use according to [48%], wherein the use is for treating lung cancer.

[494] The use according to

[489] , wherein the use is for treating pancreatic cancer.

[495] The use according to [48%], wherein the use is for treating kidney cancer.

[496] The use according to

[489] , wherein the use is for treating ovarian cancer.

[497] A pharmaceutical composition wherein an antibody- drug conjugate and a kinase inhibitor are administered in combination, and the antibody-drug conjugate is an antibody-drug conjugate in which a drug-linker represented by the following formula:

[0079] wherein A represents a connecting position to an antibody, is conjugated to the antibody via a thioether bond, and the kinase inhibitor is at least one selected from the group consisting of abemaciclib, palbociclib, ribociclib, trilaciclib, G1T38, PF-06873600, TP-1287, FN- 1501, KRX-0601, everolimus, sirolimus, temsirolimus, TAK- 228, CC-223, AZD8055, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP-BGT226, PQR309, taselisib, alpelisib, TAK-117, GSK2636771, AZD8186, IPI-549, idelalisib, duvelisib, AMG3193, buparlisib, pictilisib, pilaralisib, copanlisib, sonolisib, CH5132799, ZSTK474, GDC-0077, rigosertib, ipatasertib, uprosertib, MK-2206, BAY1125976, AZD5363, TAS-117, ONC201, BVD-523, CC-90003, GDC-0994, LY3214996, MK-8353, trametinib, binimetinib, selumetinib, refametinib, pimasertib, cobimetinib, E6201, PD-0325901, RO5126766, GDC-0623, regorafenib, sorafenib, vemurafenib, dabrafenib, encorafenib, RAF265, GDC-5573, LY3009120, dinaciclib, milciclib, seliciclib, alvocidib, roniciclib, voruciclib, AT7519, PHA-793887, CYC-065, MK- 8776, LY2606368, LY2603618, CBP501, GDC-0425, CCT245737, AZD1775, volasertib, alisertib, ilorasertib, ENMD-2076, AMG900, imatinib, dasatinib, bosutinib, nilotinib, ponatinib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, cabozantinib, tivozanib, brivanib, linifanib, lucitanib, ibrutinib, acalabrutinib, tirabrutinib, gilteritinib, quizartinib, midostaurin, brigatinib, crizotinib, ceritinib, alectinib, lorlatinib, ruxolitinib, tofacitinib, baricitinib, pacritinib, capmatinib, tepotinib, pexidartinib, BLZ-945, JNJ- 40346527, JNJ-28312141, entrectinib, GR-389988, gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, pyrotinib, poziotinib, tucatinib, and mubritinib, and pharmacologically acceptable salts thereof.

[498] The pharmaceutical composition according to

[497] , wherein the kinase inhibitor is abemaciclib or a pharmacologically acceptable salt thereof.

[499] The pharmaceutical composition according to

[497] , wherein the kinase inhibitor is palbociclib or a pharmacologically acceptable salt thereof.

[500] The pharmaceutical composition according to

[497] , wherein the kinase inhibitor is everolimus or a pharmacologically acceptable salt thereof.

[0081]

[501] The pharmaceutical composition according to

[497] , wherein the kinase inhibitor is taselisib or a pharmacologically acceptable salt thereof.

[502] The pharmaceutical composition according to

[497] , wherein the kinase inhibitor is alpelisib or a pharmacologically acceptable salt thereof.

[503] The pharmaceutical composition according to

[497] , wherein the kinase inhibitor is regorafenib or a pharmacologically acceptable salt thereof.

[504] The pharmaceutical composition according to

[497] , wherein the kinase inhibitor is cabozantinib or a pharmacologically acceptable salt thereof.

[505] The pharmaceutical composition according to

[497] , wherein the kinase inhibitor is sunitinib or a pharmacologically acceptable salt thereof.

[506] The pharmaceutical composition according to

[497] , wherein the kinase inhibitor is nintedanib or a pharmacologically acceptable salt thereof.

[507] The pharmaceutical composition according to

[497] , wherein the kinase inhibitor is brigatinib or a pharmacologically acceptable salt thereof.

[508] The pharmaceutical composition according to

[497] , wherein the kinase inhibitor is erlotinib or a pharmacologically acceptable salt thereof.

[503] The pharmaceutical composition according to

[497] , wherein the kinase inhibitor is neratinib or a pharmacologically acceptable salt thereof.

[510] The pharmaceutical composition according to

[497] , wherein the kinase inhibitor is poziotinib or a pharmacologically acceptable salt thereof.

[0082]

[511] The pharmaceutical composition according to

[497] , wherein the kinase inhibitor is tucatinib or a pharmacologically acceptable salt thereof.

[512] The pharmaceutical composition according to

[497] , wherein the kinase inhibitor is mubritinib or a pharmacologically acceptable salt thereof.

[513] The pharmaceutical composition according to any one of

[497] to

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

[514] The pharmaceutical composition according to

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

[515] The pharmaceutical composition according to

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

[516] The pharmaceutical composition according to

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

[517] The pharmaceutical composition according to

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

[518] The pharmaceutical composition according to

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

[519] The pharmaceutical composition according to any one of

[514] to

[518] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[520] The pharmaceutical composition according to

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

[0083]

[521] The pharmaceutical composition according to

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

[522] The pharmaceutical composition according to

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

[523] The pharmaceutical composition according to any one of

[520] to

[522] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[524] The pharmaceutical composition according to

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

[525] The pharmaceutical composition according to

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

[526] The pharmaceutical composition according to

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

[527] The pharmaceutical composition according to any one of

[524] to

[526] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[528] The pharmaceutical composition according to

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

[523] The pharmaceutical composition according to

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

[530] The pharmaceutical composition according to

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

[0084]

[531] The pharmaceutical composition according to any one of

[528] to

[530] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[532] The pharmaceutical composition according to

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

[533] The pharmaceutical composition according to

[532] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 10.

[534] The pharmaceutical composition according to

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

[535] The pharmaceutical composition according to any one of

[532] to

[534] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[536] The pharmaceutical composition according to any one of

[497] to

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

[537] The pharmaceutical composition according to any one of

[497] to

[536] , wherein the pharmaceutical composition is for use in treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, endometrial cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.

[538] The pharmaceutical composition according to

[537] , wherein the pharmaceutical composition is for use in treating breast cancer. [53%] The pharmaceutical composition according to

[537] , wherein the pharmaceutical composition is for use in treating colorectal cancer.

[540] The pharmaceutical composition according to

[537] , wherein the pharmaceutical composition is for use in treating gastric cancer.

[0085]

[541] The pharmaceutical composition according to

[537] , wherein the pharmaceutical composition is for use in treating lung cancer.

[542] The pharmaceutical composition according to

[537] , wherein the pharmaceutical composition is for use in treating pancreatic cancer.

[543] The pharmaceutical composition according to

[537] , wherein the pharmaceutical composition is for use in treating kidney cancer.

[544] The pharmaceutical composition according to

[537] , wherein the pharmaceutical composition is for use in treating ovarian cancer.

[545] A pharmaceutical composition wherein an antibody- drug conjugate and a kinase inhibitor are administered in combination, and the antibody-drug conjugate is an antibody-drug conjugate represented by the following formula:

[0086] [Formula 10] Antibody n

[0087] wherein a drug-linker is conjugated to an antibody via a thioether bond, and n is the average number of units of the drug-linker conjugated per antibody molecule, and the kinase inhibitor is at least one selected from the group consisting of abemaciclib, palbociclib, ribociclib, trilaciclib, G1T38, PF-06873600, TP-1287, FN- 1501, KRX-0601, everolimus, sirolimus, temsirolimus, TAK- 228, CC-223, AZD8055, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP-BGT226, PQR309, taselisib, alpelisib, TAK-117, GSK2636771, AZD8186, IPI-549, idelalisib, duvelisib, AMG319, buparlisib, pictilisib, pilaralisib, copanlisib, sonolisib, CH5132799, ZSTK474, GDC-0077, rigosertib, ipatasertib, uprosertib, MK-2206, BAY1125976, AZD5363, TAS-117, ONC201, BVD-523, CC-90003, GDC-0994, LY3214996, MK-8353, trametinib, binimetinib, selumetinib, refametinib, pimasertib, cobimetinib, E6201, PD-0325901, RO5126766, GDC-0623, regorafenib, sorafenib, vemurafenib, dabrafenib, encorafenib, RAF265, GDC-5573, LY3009120, dinaciclib, milciclib, seliciclib, alvocidib, roniciclib, voruciclib, AT7519, PHA-793887, CYC-065, MK- 8776, LY2606368, LY2603618, CBP501, GDC-0425, CCT245737, AZD1775, volasertib, alisertib, ilorasertib, ENMD-2076, AMG900, imatinib, dasatinib, bosutinib, nilotinib, ponatinib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, cabozantinib, tivozanib, brivanib, linifanib, lucitanib, ibrutinib, acalabrutinib, tirabrutinib, gilteritinib, quizartinib, midostaurin, brigatinib, crizotinib, ceritinib, alectinib, lorlatinib, ruxolitinib, tofacitinib, baricitinib, pacritinib, capmatinib, tepotinib, pexidartinib, BLZ-945, JNJ- 40346527, JNJ-28312141, entrectinib, GR-389988, gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, pyrotinib, poziotinib, tucatinib, and mubritinib, and pharmacologically acceptable salts thereof.

[0088]

[546] The pharmaceutical composition according to

[545] , wherein the kinase inhibitor is abemaciclib or a pharmacologically acceptable salt thereof.

[547] The pharmaceutical composition according to

[545] , wherein the kinase inhibitor is palbociclib or a pharmacologically acceptable salt thereof.

[548] The pharmaceutical composition according to

[545] , wherein the kinase inhibitor is everolimus or a pharmacologically acceptable salt thereof.

[549] The pharmaceutical composition according to

[545] , wherein the kinase inhibitor is taselisib or a pharmacologically acceptable salt thereof.

[550] The pharmaceutical composition according to

[545] , wherein the kinase inhibitor is alpelisib or a pharmacologically acceptable salt thereof.

[551] The pharmaceutical composition according to

[545] , wherein the kinase inhibitor is regorafenib or a pharmacologically acceptable salt thereof.

[552] The pharmaceutical composition according to

[545] , wherein the kinase inhibitor is cabozantinib or a pharmacologically acceptable salt thereof.

[553] The pharmaceutical composition according to

[545] , wherein the kinase inhibitor is sunitinib or a pharmacologically acceptable salt thereof.

[554] The pharmaceutical composition according to

[545] , wherein the kinase inhibitor is nintedanib or a pharmacologically acceptable salt thereof.

[555] The pharmaceutical composition according to

[545] , wherein the kinase inhibitor is brigatinib or a pharmacologically acceptable salt thereof.

[0089]

[556] The pharmaceutical composition according to

[545] , wherein the kinase inhibitor is erlotinib or a pharmacologically acceptable salt thereof.

[557] The pharmaceutical composition according to

[545] , wherein the kinase inhibitor is neratinib or a pharmacologically acceptable salt thereof.

[558] The pharmaceutical composition according to

[545] , wherein the kinase inhibitor is poziotinib or a pharmacologically acceptable salt thereof.

[559] The pharmaceutical composition according to

[545] , wherein the kinase inhibitor is tucatinib or a pharmacologically acceptable salt thereof.

[560] The pharmaceutical composition according to

[545] , wherein the kinase inhibitor is mubritinib or a pharmacologically acceptable salt thereof.

[561] The pharmaceutical composition according to any one of

[545] to

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

[562] The pharmaceutical composition according to

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

[563] The pharmaceutical composition according to

[562] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 consisting of an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 consisting of an amino acid sequence consisting of amino acid residues 397 to 109 of SEQ ID NO: 1, and a light chain comprising CDRL1 consisting of an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 consisting of an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2.

[564] The pharmaceutical composition according to

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

[565] The pharmaceutical composition according to

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

[0090]

[566] The pharmaceutical composition according to

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

[567] The pharmaceutical composition according to any one of

[562] to

[566] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[568] The pharmaceutical composition according to

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

[569] The pharmaceutical composition according to

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

[570] The pharmaceutical composition according to

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

[571] The pharmaceutical composition according to any one of

[568] to

[570] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[572] The pharmaceutical composition according to

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

[573] The pharmaceutical composition according to

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

[574] The pharmaceutical composition according to

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

[575] The pharmaceutical composition according to any one of

[572] to

[574] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[0091]

[576] The pharmaceutical composition according to

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

[577] The pharmaceutical composition according to

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

[578] The pharmaceutical composition according to

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

[579] The pharmaceutical composition according to any one of

[576] to

[578] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[580] The pharmaceutical composition according to

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

[581] The pharmaceutical composition according to

[580] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 10:

[582] The pharmaceutical composition according to

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

[583] The pharmaceutical composition according to any one of

[580] to

[582] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[584] The pharmaceutical composition according to any one of

[545] to

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

[0092]

[585] The pharmaceutical composition according to any one of

[545] to

[584] , wherein the pharmaceutical composition is for use in treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, endometrial cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.

[586] The pharmaceutical composition according to

[585] , wherein the pharmaceutical composition is for use in treating breast cancer.

[587] The pharmaceutical composition according to

[585] , wherein the pharmaceutical composition is for use in treating colorectal cancer.

[588] The pharmaceutical composition according to

[585] , wherein the pharmaceutical composition is for use in treating gastric cancer. [58%] The pharmaceutical composition according to

[585] , wherein the pharmaceutical composition is for use in treating lung cancer.

[590] The pharmaceutical composition according to

[585] , wherein the pharmaceutical composition is for use in treating pancreatic cancer.

[591] The pharmaceutical composition according to

[585] , wherein the pharmaceutical composition is for use in treating kidney cancer.

[592] The pharmaceutical composition according to

[585] , wherein the pharmaceutical composition is for use in treating ovarian cancer.

[593] A method of treatment, comprising administering an antibody-drug conjugate and a kinase inhibitor in combination to a subject in need of treatment, wherein the antibody-drug conjugate is an antibody-drug conjugate in which a drug-linker represented by the following formula:

[0093] [Formula 11] wherein A represents a connecting position to an antibody, is conjugated to the antibody via a thioether bond, and the kinase inhibitor is at least one selected from the group consisting of abemaciclib, palbociclib, ribociclib, trilaciclib, G1T38, PF-06873600, TP-1287, FN- 1501, KRX-0601, everolimus, sirolimus, temsirolimus, TAK- 228, CC-223, AZD8055, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP-BGT226, PQR309, taselisib, alpelisib, TAK-117, GSK2636771, AZD8186, IPI-549, idelalisib, duvelisib, AMG3193, buparlisib, pictilisib, pilaralisib, copanlisib, sonolisib, CH5132799, ZSTK474, GDC-0077, rigosertib, ipatasertib, uprosertib, MK-2206, BAY1125976, AZD5363, TAS-117, ONC201, BVD-523, CC-9%90003, GDC-0994, LY3214996, MK-8353, trametinib, binimetinib, selumetinib, refametinib, pimasertib, cobimetinib, E6201, PD-0325301, RO5126766, GDC-0623, regorafenib, sorafenib, vemurafenib, dabrafenib, encorafenib, RAF265, GDC-5573, LY3009120, dinaciclib, milciclib, seliciclib, alvocidib, roniciclib, voruciclib, AT7519, PHA-793887, CYC-065, MK- 8776, LY2606368, LY2603618, CBP501, GDC-0425, CCT245737, AZD1775, volasertib, alisertib, ilorasertib, ENMD-2076, AMG900, imatinib, dasatinib, bosutinib, nilotinib, ponatinib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, cabozantinib, tivozanib, brivanib, linifanib, lucitanib, ibrutinib, acalabrutinib, tirabrutinib, gilteritinib, quizartinib, midostaurin, brigatinib, crizotinib, ceritinib, alectinib, lorlatinib, ruxolitinib, tofacitinib, baricitinib, pacritinib, capmatinib, tepotinib, pexidartinib, BLZ-945, JNJ- 40346527, JNJ-28312141, entrectinib, GR-389988, gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, pyrotinib, poziotinib, tucatinib, and mubritinib, and pharmacologically acceptable salts thereof.

[0095]

[594] The method of treatment according to

[593] , wherein the kinase inhibitor is abemaciclib or a pharmacologically acceptable salt thereof.

[595] The method of treatment according to

[593] , wherein the kinase inhibitor is palbociclib or a pharmacologically acceptable salt thereof.

[596] The method of treatment according to

[593] , wherein the kinase inhibitor is everolimus or a pharmacologically acceptable salt thereof.

[597] The method of treatment according to

[593] , wherein the kinase inhibitor is taselisib or a pharmacologically acceptable salt thereof.

[598] The method of treatment according to

[593] , wherein the kinase inhibitor is alpelisib or a pharmacologically acceptable salt thereof. [59%] The method of treatment according to

[593] , wherein the kinase inhibitor is regorafenib or a pharmacologically acceptable salt thereof.

[600] The method of treatment according to

[593] , wherein the kinase inhibitor is cabozantinib or a pharmacologically acceptable salt thereof.

[0096]

[601] The method of treatment according to

[593] , wherein the kinase inhibitor is sunitinib or a pharmacologically acceptable salt thereof.

[602] The method of treatment according to

[593] , wherein the kinase inhibitor is nintedanib or a pharmacologically acceptable salt thereof.

[603] The method of treatment according to

[593] , wherein the kinase inhibitor is brigatinib or a pharmacologically acceptable salt thereof.

[604] The method of treatment according to

[593] , wherein the kinase inhibitor is erlotinib or a pharmacologically acceptable salt thereof.

[605] The method of treatment according to

[593] , wherein the kinase inhibitor is neratinib or a pharmacologically acceptable salt thereof.

[606] The method of treatment according to

[593] , wherein the kinase inhibitor is poziotinib or a pharmacologically acceptable salt thereof.

[607] The method of treatment according to

[593] , wherein the kinase inhibitor is tucatinib or a pharmacologically acceptable salt thereof.

[608] The method of treatment according to

[593] , wherein the kinase inhibitor is mubritinib or a pharmacologically acceptable salt thereof.

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

[593] to

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

[610] The method of treatment according to

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

[0097]

[611] The method of treatment according to

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

[612] The method of treatment according to

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

[613] The method of treatment according to

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

[614] The method of treatment according to

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

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

[610] to

[614] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[616] The method of treatment according to

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

[617] The method of treatment according to

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

[618] The method of treatment according to

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

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

[616] to

[618] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[620] The method of treatment according to

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

[0098]

[621] The method of treatment according to

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

[622] The method of treatment according to

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

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

[620] to

[622] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[624] The method of treatment according to

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

[625] The method of treatment according to

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

[626] The method of treatment according to

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

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

[624] to

[626] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[628] The method of treatment according to

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

[623] The method of treatment according to

[628] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 10.

[630] The method of treatment according to

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

[0099]

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

[628] to

[630] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

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

[593] to

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

[633] The pharmaceutical composition according to any one of

[593] to

[632] , wherein the pharmaceutical composition is for use in treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, endometrial cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.

[634] The method of treatment according to

[633] , wherein the method of treatment is for treating breast cancer.

[635] The method of treatment according to

[633] , wherein the method of treatment is for treating colorectal cancer.

[636] The method of treatment according to

[633] , wherein the method of treatment is for treating gastric cancer.

[637] The method of treatment according to

[633] , wherein the method of treatment is for treating lung cancer.

[638] The method of treatment according to

[633] , wherein the method of treatment is for treating pancreatic cancer.

[633] The method of treatment according to

[633] , wherein the method of treatment is for treating kidney cancer.

[640] The method of treatment according to

[633] , wherein the method of treatment is for treating ovarian cancer.

[641] A method of treatment, comprising administering an antibody-drug conjugate and a kinase inhibitor in combination to a subject in need of treatment, wherein the antibody-drug conjugate is an antibody-drug conjugate represented by the following formula:

[0100] [Formula 12] n

[0101] wherein a drug-linker is conjugated to an antibody via a thioether bond, and n is the average number of units of the drug-linker conjugated per antibody molecule, and the kinase inhibitor is at least one selected from the group consisting of abemaciclib, palbociclib, ribociclib, trilaciclib, G1T38, PF-06873600, TP-1287, FN- 1501, KRX-0601, everolimus, sirolimus, temsirolimus, TAK- 228, CC-223, AZD8055, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP-BGT226, PQR309, taselisib, alpelisib, TAK-117, GSK2636771, AZD8186, IPI-549, idelalisib, duvelisib, AMG319, buparlisib, pictilisib, pilaralisib, copanlisib, sonolisib, CH5132799, ZSTK474, GDC-0077, rigosertib, ipatasertib, uprosertib, MK-2206, BAY1125976, AZD5363, TAS-117, ONC201, BVD-523, CC-90003, GDC-0994, LY3214996, MK-8353, trametinib, binimetinib, selumetinib, refametinib, pimasertib, cobimetinib, E6201, PD-0325901, RO5126766, GDC-0623, regorafenib, sorafenib, vemurafenib, dabrafenib, encorafenib, RAF265, GDC-5573, LY3009120, dinaciclib, milciclib, seliciclib, alvocidib, roniciclib, voruciclib, AT7519, PHA-793887, CYC-065, MK- 8776, LY2606368, LY2603618, CBP501, GDC-0425, CCT245737, AZD1775, volasertib, alisertib, ilorasertib, ENMD-2076, AMG900, imatinib, dasatinib, bosutinib, nilotinib, ponatinib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, cabozantinib, tivozanib, brivanib, linifanib, lucitanib, ibrutinib, acalabrutinib, tirabrutinib, gilteritinib, quizartinib, midostaurin, brigatinib, crizotinib, ceritinib, alectinib, lorlatinib, ruxolitinib, tofacitinib, baricitinib, pacritinib, capmatinib, tepotinib, pexidartinib, BLZ-945, JNJ- 40346527, JNJ-28312141, entrectinib, GR-38%9988, gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, pyrotinib, poziotinib, tucatinib, and mubritinib, and pharmacologically acceptable salts thereof.

[0102]

[642] The method of treatment according to

[641] , wherein the kinase inhibitor is abemaciclib or a pharmacologically acceptable salt thereof.

[643] The method of treatment according to

[641] , wherein the kinase inhibitor is palbociclib or a pharmacologically acceptable salt thereof.

[644] The method of treatment according to

[641] , wherein the kinase inhibitor is everolimus or a pharmacologically acceptable salt thereof.

[645] The method of treatment according to

[641] , wherein the kinase inhibitor is taselisib or a pharmacologically acceptable salt thereof.

[646] The method of treatment according to

[641] , wherein the kinase inhibitor is alpelisib or a pharmacologically acceptable salt thereof.

[647] The method of treatment according to

[641] , wherein the kinase inhibitor is regorafenib or a pharmacologically acceptable salt thereof.

[648] The method of treatment according to

[641] , wherein the kinase inhibitor is cabozantinib or a pharmacologically acceptable salt thereof.

[649] The method of treatment according to

[641] , wherein the kinase inhibitor is sunitinib or a pharmacologically acceptable salt thereof.

[650] The method of treatment according to

[641] , wherein the kinase inhibitor is nintedanib or a pharmacologically acceptable salt thereof.

[0103]

[651] The method of treatment according to

[641] , wherein the kinase inhibitor is brigatinib or a pharmacologically acceptable salt thereof.

[652] The method of treatment according to

[641] , wherein the kinase inhibitor is erlotinib or a pharmacologically acceptable salt thereof.

[653] The method of treatment according to

[641] , wherein the kinase inhibitor is neratinib or a pharmacologically acceptable salt thereof.

[654] The method of treatment according to

[641] , wherein the kinase inhibitor is poziotinib or a pharmacologically acceptable salt thereof.

[655] The method of treatment according to

[641] , wherein the kinase inhibitor is tucatinib or a pharmacologically acceptable salt thereof.

[656] The method of treatment according to

[641] , wherein the kinase inhibitor is mubritinib or a pharmacologically acceptable salt thereof.

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

[641] to

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

[658] The method of treatment according to

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

[659] The method of treatment according to

[658] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 consisting of an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 consisting of an amino acid sequence consisting of amino acid residues 397 to 109 of SEQ ID NO: 1, and a light chain comprising CDRL1 consisting of an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 consisting of an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2.

[0104]

[660] The method of treatment according to

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

[661] The method of treatment according to

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

[662] The method of treatment according to

[658] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: . and a light chain consisting of an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 3.

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

[658] to

[662] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[664] The method of treatment according to

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

[665] The method of treatment according to

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

[666] The method of treatment according to

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

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

[664] to

[666] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[668] The method of treatment according to

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

[663] The method of treatment according to

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

[670] The method of treatment according to

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

[0105]

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

[668] to

[670] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[672] The method of treatment according to

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

[673] The method of treatment according to

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

[674] The method of treatment according to

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

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

[672] to

[674] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[676] The method of treatment according to

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

[677] The method of treatment according to

[676] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 10.

[678] The method of treatment according to

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

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

[676] to

[678] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

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

[641] to [67%], wherein the antibody-drug conjugate and the kinase inhibitor are separately contained as active components in different formulations, and are administered simultaneously or at different times.

[0106]

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

[641] to

[680] , wherein the method of treatment is for treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, endometrial cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.

[682] The method of treatment according to

[681] , wherein the method of treatment is for treating breast cancer.

[683] The method of treatment according to

[681] , wherein the method of treatment is for treating colorectal cancer.

[684] The method of treatment according to

[681] , wherein the method of treatment is for treating gastric cancer.

[685] The method of treatment according to

[681] , wherein the method of treatment is for treating lung cancer.

[686] The method of treatment according to

[681] , wherein the method of treatment is for treating pancreatic cancer.

[687] The method of treatment according to

[681] , wherein the method of treatment is for treating kidney cancer.

[688] The method of treatment according to

[681] , wherein the method of treatment is for treating ovarian cancer.

[683] An antibody-drug conjugate for use in treating a disease through being administered in combination with a kinase inhibitor, wherein a drug-linker represented by the following formula:

[0107] wherein A represents a connecting position to an antibody, is conjugated to the antibody via a thicether bond in the antibody-drug conjugate, and the kinase inhibitor is at least one selected from the group consisting of abemaciclib, palbociclib, ribociclib, trilaciclib, G1T38, PF-06873600, TP-1287, FN- 1501, KRX-0601, everolimus, sirolimus, temsirolimus, TAK- 228, CC-223, AZD8055, dactolisib, apitolisib, gedatolisib, 1LY3023414, PF-04691502, NVP-BGT226, PQR309, taselisib, alpelisib, TAK-117, GSK2636771, AZD8186, IPI-549, idelalisib, duvelisib, AMG319, buparlisib, pictilisib, pilaralisib, copanlisib, sonolisib, CH5132799, ZSTK474, GDC-0077, rigosertib, ipatasertib, uprosertib, MK-2206 BAY1125976, AZD5363, TAS-117, ONC201, BVD-523, CC-90003, GDC-0994, LY3214996, MK-8353, trametinib, binimetinib, selumetinib, refametinib, pimasertib, cobimetinib, E6201, PD-03253901, RO5126766, GDC-0623, regorafenib, sorafenib, vemurafenib, dabrafenib, encorafenib, RAF265, GDC-5573, LY3009120, dinaciclib, milciclib, seliciclib, alvocidib, roniciclib, voruciclib, AT7519, PHA-793887, CYC-065, MK- 8776, LY2606368, LY2603618, CBP501, GDC-0425, CCT245737, AZD1775, volasertib, alisertib, ilorasertib, ENMD-2076, AMG900, imatinib, dasatinib, bosutinib, nilotinib, ponatinib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, cabozantinib, tivozanib, brivanib, linifanib, lucitanib, ibrutinib, acalabrutinib, tirabrutinib, gilteritinib, quizartinib, midostaurin, brigatinib, crizotinib, ceritinib, alectinib, lorlatinib, ruxolitinib, tofacitinib, baricitinib, pacritinib, capmatinib, tepotinib, pexidartinib, BLZ-945, JNJ- 40346527, JNJ-28312141, entrectinib, GR-389988, gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, pyrotinib, poziotinib, tucatinib, and mubritinib, and pharmacologically acceptable salts thereof.

[0109]

[690] The antibody-drug conjugate according to

[683] , wherein the kinase inhibitor is abemaciclib or a pharmacologically acceptable salt thereof.

[691] The antibody-drug conjugate according to

[683] , wherein the kinase inhibitor is palbociclib or a pharmacologically acceptable salt thereof.

[692] The antibody-drug conjugate according to

[689] , wherein the kinase inhibitor is everolimus or a pharmacologically acceptable salt thereof.

[693] The antibody-drug conjugate according to

[683] , wherein the kinase inhibitor is taselisib or a pharmacologically acceptable salt thereof.

[694] The antibody-drug conjugate according to

[689] , wherein the kinase inhibitor is alpelisib or a pharmacologically acceptable salt thereof.

[695] The antibody-drug conjugate according to

[689] , wherein the kinase inhibitor is regorafenib or a pharmacologically acceptable salt thereof.

[696] The antibody-drug conjugate according to

[683] , wherein the kinase inhibitor is cabozantinib or a pharmacologically acceptable salt thereof.

[697] The antibody-drug conjugate according to

[689] , wherein the kinase inhibitor is sunitinib or a pharmacologically acceptable salt thereof.

[698] The antibody-drug conjugate according to

[683] , wherein the kinase inhibitor is nintedanib or a pharmacologically acceptable salt thereof.

[693] The antibody-drug conjugate according to

[683] , wherein the kinase inhibitor is brigatinib or a pharmacologically acceptable salt thereof.

[700] The antibody-drug conjugate according to

[683] , wherein the kinase inhibitor is erlotinib or a pharmacologically acceptable salt thereof.

[0110]

[701] The antibody-drug conjugate according to

[683] , wherein the kinase inhibitor is neratinib or a pharmacologically acceptable salt thereof.

[702] The antibody-drug conjugate according to

[689] , wherein the kinase inhibitor is poziotinib or a pharmacologically acceptable salt thereof.

[703] The antibody-drug conjugate according to

[683] , wherein the kinase inhibitor is tucatinib or a pharmacologically acceptable salt thereof.

[704] The antibody-drug conjugate according to

[689] , wherein the kinase inhibitor is mubritinib or a pharmacologically acceptable salt thereof.

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

[689] to

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

[706] The antibody-drug conjugate according to

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

[707] The antibody-drug conjugate according to

[706] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 consisting of an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 consisting of an amino acid sequence consisting of amino acid residues 397 to 109 of SEQ ID NO: 1, and a light chain comprising CDRL1 consisting of an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 consisting of an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2.

[708] The antibody-drug conjugate according to

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

[703] The antibody-drug conjugate according to

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

[0111]

[710] The antibody-drug conjugate according to

[706] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: . and a light chain consisting of an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 3.

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

[706] to

[710] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[712] The antibody-drug conjugate according to

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

[713] The antibody-drug conjugate according to

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

[714] The antibody-drug conjugate according to

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

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

[712] to

[714] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[716] The antibody-drug conjugate according to

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

[717] The antibody-drug conjugate according to

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

[718] The antibody-drug conjugate according to

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

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

[716] to

[718] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[720] The antibody-drug conjugate according to

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

[0112]

[721] The antibody-drug conjugate according to

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

[722] The antibody-drug conjugate according to

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

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

[720] to

[722] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[724] The antibody-drug conjugate according to

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

[725] The antibody-drug conjugate according to

[724] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 10.

[726] The antibody-drug conjugate according to

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

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

[724] to

[726] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

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

[689] to

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

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

[689] to

[728] , wherein the antibody-drug conjugate is for use in treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, endometrial cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.

[0113]

[730] The antibody-drug conjugate according to

[729] , wherein the antibody-drug conjugate is for use in treating breast cancer.

[731] The antibody-drug conjugate according to

[729] , wherein the antibody-drug conjugate is for use in treating colorectal cancer.

[732] The antibody-drug conjugate according to

[729] , wherein the antibody-drug conjugate is for use in treating gastric cancer.

[733] The antibody-drug conjugate according to

[729] , wherein the antibody-drug conjugate is for use in treating lung cancer.

[734] The antibody-drug conjugate according to

[729] , wherein the antibody-drug conjugate is for use in treating pancreatic cancer.

[735] The antibody-drug conjugate according to

[729] , wherein the antibody-drug conjugate is for use in treating kidney cancer.

[736] The antibody-drug conjugate according to

[729] , wherein the antibody-drug conjugate is for use in treating ovarian cancer.

[737] An antibody-drug conjugate for use in treating a disease through being administered in combination with a kinase inhibitor, wherein the antibody-drug conjugate is an antibody-drug conjugate represented by the following formula:

[0114] [Formula 14] Antibody n

[0115] wherein a drug-linker is conjugated to an antibody via a thioether bond, and n is the average number of units of the drug-linker conjugated per antibody molecule, and the kinase inhibitor is at least one selected from the group consisting of abemaciclib, palbociclib, ribociclib, trilaciclib, G1T38, PF-06873600, TP-1287, FN- 1501, KRX-0601, everolimus, sirolimus, temsirolimus, TAK- 228, CC-223, AZD8055, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP-BGT226, PQR309, taselisib, alpelisib, TAK-117, GSK2636771, AZD8186, IPI-549, idelalisib, duvelisib, AMG3193, buparlisib, pictilisib, pilaralisib, copanlisib, sonolisib, CH5132799, ZSTK474, GDC-0077, rigosertib, ipatasertib, uprosertib, MK-2206, BAY1125976, AZD5363, TAS-117, ONC201, BVD-523, CC-9%90003, GDC-0994, LY3214996, MK-8353, trametinib, binimetinib, selumetinib, refametinib, pimasertib, cobimetinib, E6201, PD-0325301, RO5126766, GDC-0623, regorafenib, sorafenib, vemurafenib, dabrafenib, encorafenib, RAF265, GDC-5573, LY3009120, dinaciclib, milciclib, seliciclib, alvocidib, roniciclib, voruciclib, AT7519, PHA-793887, CYC-065, MK- 8776, LY2606368, LY2603618, CBP501, GDC-0425, CCT245737, AZD1775, volasertib, alisertib, ilorasertib, ENMD-2076, AMG900, imatinib, dasatinib, bosutinib, nilotinib, ponatinib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, cabozantinib, tivozanib, brivanib, linifanib, lucitanib, ibrutinib, acalabrutinib, tirabrutinib, gilteritinib, quizartinib, midostaurin, brigatinib, crizotinib, ceritinib, alectinib, lorlatinib, ruxolitinib, tofacitinib, baricitinib, pacritinib, capmatinib, tepotinib, pexidartinib, BLZ-945, JNJ- 40346527, JNJ-28312141, entrectinib, GR-389988, gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, pyrotinib, poziotinib, tucatinib, and mubritinib, and pharmacologically acceptable salts thereof.

[0116]

[738] The antibody-drug conjugate according to

[737] , wherein the kinase inhibitor is abemaciclib or a pharmacologically acceptable salt thereof. [73%] The antibody-drug conjugate according to

[737] , wherein the kinase inhibitor is palbociclib or a pharmacologically acceptable salt thereof.

[740] The antibody-drug conjugate according to

[737] , wherein the kinase inhibitor is everolimus or a pharmacologically acceptable salt thereof.

[741] The antibody-drug conjugate according to

[737] , wherein the kinase inhibitor is taselisib or a pharmacologically acceptable salt thereof.

[742] The antibody-drug conjugate according to

[737] , wherein the kinase inhibitor is alpelisib or a pharmacologically acceptable salt thereof.

[743] The antibody-drug conjugate according to

[737] , wherein the kinase inhibitor is regorafenib or a pharmacologically acceptable salt thereof.

[744] The antibody-drug conjugate according to

[737] , wherein the kinase inhibitor is cabozantinib or a pharmacologically acceptable salt thereof.

[745] The antibody-drug conjugate according to

[737] , wherein the kinase inhibitor is sunitinib or a pharmacologically acceptable salt thereof.

[746] The antibody-drug conjugate according to

[737] , wherein the kinase inhibitor is nintedanib or a pharmacologically acceptable salt thereof.

[747] The antibody-drug conjugate according to

[737] , wherein the kinase inhibitor is brigatinib or a pharmacologically acceptable salt thereof.

[748] The antibody-drug conjugate according to

[737] , wherein the kinase inhibitor is erlotinib or a pharmacologically acceptable salt thereof.

[749] The antibody-drug conjugate according to

[737] , wherein the kinase inhibitor is neratinib or a pharmacologically acceptable salt thereof.

[750] The antibody-drug conjugate according to

[737] , wherein the kinase inhibitor is poziotinib or a pharmacologically acceptable salt thereof.

[0117]

[751] The antibody-drug conjugate according to

[737] , wherein the kinase inhibitor is tucatinib or a pharmacologically acceptable salt thereof.

[752] The antibody-drug conjugate according to

[737] , wherein the kinase inhibitor is mubritinib or a pharmacologically acceptable salt thereof.

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

[737] to

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

[754] The antibody-drug conjugate according to

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

[755] The antibody-drug conjugate according to

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

[756] The antibody-drug conjugate according to

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

[757] The antibody-drug conjugate according to

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

[758] The antibody-drug conjugate according to

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

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

[754] to

[758] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[760] The antibody-drug conjugate according to

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

[0118]

[761] The antibody-drug conjugate according to

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

[762] The antibody-drug conjugate according to

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

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

[760] to

[762] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[764] The antibody-drug conjugate according to

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

[765] The antibody-drug conjugate according to

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

[766] The antibody-drug conjugate according to

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

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

[764] to

[766] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[768] The antibody-drug conjugate according to

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

[763] The antibody-drug conjugate according to

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

[770] The antibody-drug conjugate according to

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

[0119]

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

[768] to

[770] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.58.

[772] The antibody-drug conjugate according to

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

[773] The antibody-drug conjugate according to

[772] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 10.

[774] The antibody-drug conjugate according to

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

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

[772] to

[774] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

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

[737] to

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

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

[737] to

[776] , wherein the antibody-drug conjugate is for use in treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, endometrial cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.

[778] The antibody-drug conjugate according to

[777] , wherein the antibody-drug conjugate is for use in treating breast cancer. [77%] The antibody-drug conjugate according to

[777] , wherein the antibody-drug conjugate is for use in treating colorectal cancer.

[780] The antibody-drug conjugate according to

[777] , wherein the antibody-drug conjugate is for use in treating gastric cancer.

[0120]

[781] The antibody-drug conjugate according to

[777] , wherein the antibody-drug conjugate is for use in treating lung cancer.

[782] The antibody-drug conjugate according to

[777] , wherein the antibody-drug conjugate is for use in treating pancreatic cancer.

[783] The antibody-drug conjugate according to

[777] , wherein the antibody-drug conjugate is for use in treating kidney cancer.

[784] The antibody-drug conjugate according to

[777] , wherein the antibody-drug conjugate is for use in treating ovarian cancer.

[785] Use of an antibody-drug conjugate for the manufacture of a medicament for treating a disease through being administered in combination with a kinase inhibitor, wherein a drug-linker represented by the following formula:

[0121] wherein A represents a connecting position to an antibody, is conjugated to the antibody via a thicether bond in the antibody-drug conjugate, and the kinase inhibitor is at least one selected from the group consisting of abemaciclib, palbociclib, ribociclib, trilaciclib, G1T38, PF-06873600, TP-1287, FN- 1501, KRX-0601, everolimus, sirolimus, temsirolimus, TAK- 228, CC-223, AZD8055, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP-BGT226, PQR309, taselisib, alpelisib, TAK-117, GSK2636771, AZD8186, IPI-549, idelalisib, duvelisib, AMG3193, buparlisib, pictilisib, pilaralisib, copanlisib, sonolisib, CH5132799, ZSTK474, GDC-0077, rigosertib, ipatasertib, uprosertib, MK-2206, BAY1125976, AZD5363, TAS-117, ONC201, BVD-523, CC-9%90003, GDC-0994, LY3214996, MK-8353, trametinib, binimetinib, selumetinib, refametinib, pimasertib, cobimetinib, E6201, PD-0325901, RO5126766, GDC-0623, regorafenib, sorafenib, vemurafenib, dabrafenib, encorafenib, RAF265, GDC-5573, LY3009120, dinaciclib, milciclib, seliciclib, alvocidib, roniciclib, voruciclib, AT7519, PHA-793887, CYC-065, MK- 8776, LY2606368, LY2603618, CBP501, GDC-0425, CCT245737, AZD1775, volasertib, alisertib, ilorasertib, ENMD-2076, AMG900, imatinib, dasatinib, bosutinib, nilotinib, ponatinib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, cabozantinib, tivozanib, brivanib, linifanib, lucitanib, ibrutinib, acalabrutinib, tirabrutinib, gilteritinib, quizartinib, midostaurin, brigatinib, crizotinib, ceritinib, alectinib, lorlatinib, ruxolitinib, tofacitinib, baricitinib, pacritinib, capmatinib, tepotinib, pexidartinib, BLZ-945, JNJ- 40346527, JNJ-28312141, entrectinib, GR-389988, gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, pyrotinib, poziotinib, tucatinib, and mubritinib, and pharmacologically acceptable salts thereof.

[786] The use according to

[785] , wherein the kinase inhibitor is abemaciclib or a pharmacologically acceptable salt thereof.

[787] The use according to

[785] , wherein the kinase inhibitor is palbociclib or a pharmacologically acceptable salt thereof.

[788] The use according to

[785] , wherein the kinase inhibitor is everolimus or a pharmacologically acceptable salt thereof.

[783] The use according to

[785] , wherein the kinase inhibitor is taselisib or a pharmacologically acceptable salt thereof.

[790] The use according to

[785] , wherein the kinase inhibitor is alpelisib or a pharmacologically acceptable salt thereof.

[0123]

[791] The use according to

[785] , wherein the kinase inhibitor is regorafenib or a pharmacologically acceptable salt thereof.

[792] The use according to

[785] , wherein the kinase inhibitor is cabozantinib or a pharmacologically acceptable salt thereof.

[793] The use according to

[785] , wherein the kinase inhibitor is sunitinib or a pharmacologically acceptable salt thereof.

[794] The use according to

[785] , wherein the kinase inhibitor is nintedanib or a pharmacologically acceptable salt thereof.

[795] The use according to

[785] , wherein the kinase inhibitor is brigatinib or a pharmacologically acceptable salt thereof.

[796] The use according to

[785] , wherein the kinase inhibitor is erlotinib or a pharmacologically acceptable salt thereof.

[797] The use according to

[785] , wherein the kinase inhibitor is neratinib or a pharmacologically acceptable salt thereof.

[798] The use according to

[785] , wherein the kinase inhibitor is poziotinib or a pharmacologically acceptable salt thereof.

[799] The use according to

[785] , wherein the kinase inhibitor is tucatinib or a pharmacologically acceptable salt thereof.

[800] The use according to

[785] , wherein the kinase inhibitor is mubritinib or a pharmacologically acceptable salt thereof.

[0124]

[801] The use according to any one of

[785] to

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

[802] The use according to

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

[803] The use according to

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

[804] The pharmaceutical composition according to

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

[805] The use according to

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

[806] The use according to

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

[807] The use according to any one of

[802] to

[806] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[808] The use according to

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

[808] The use according to

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

[810] The use according to

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

[0125]

[811] The use according to any one of

[808] to

[810] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[812] The use according to

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

[813] The use according to

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

[814] The use according to

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

[815] The use according to any one of

[812] to

[814] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[816] The use according to

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

[817] The use according to

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

[818] The use according to

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

[813] The use according to any one of

[816] to

[818] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[820] The use according to

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

[0126]

[821] The use according to

[820] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 10.

[822] The use according to

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

[823] The use according to any one of

[820] to

[822] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[824] The use according to any one of

[785] to

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

[825] The use according to any one of

[785] to

[824] , wherein the use is for treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, endometrial cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.

[826] The use according to

[825] , wherein the use is for treating breast cancer.

[827] The use according to

[825] , wherein the use is for treating colorectal cancer.

[828] The use according to

[825] , wherein the use is for treating gastric cancer.

[828] The use according to

[825] , wherein the use is for treating lung cancer.

[830] The use according to

[825] , wherein the use is for treating pancreatic cancer.

[831] The use according to

[825] , wherein the use is for treating kidney cancer.

[832] The use according to

[825] , wherein the use is for treating ovarian cancer.

[833] Use of an antibody-drug conjugate for the manufacture of a medicament for treating a disease through being administered in combination with a kinase inhibitor, wherein the antibody-drug conjugate is an antibody-drug conjugate represented by the following formula:

[0127] [Formula 16] Antibody n

[0128] wherein a drug-linker is conjugated to an antibody via a thioether bond, and n is the average number of units of the drug-linker conjugated per antibody molecule, and the kinase inhibitor is at least one selected from the group consisting of abemaciclib, palbociclib, ribociclib, trilaciclib, G1T38, PF-06873600, TP-1287, FN- 1501, KRX-0601, everolimus, sirolimus, temsirolimus, TAK- 228, CC-223, AZD8055, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP-BGT226, PQR309, taselisib, alpelisib, TAK-117, GSK2636771, AZD8186, IPI-549, idelalisib, duvelisib, AMG319, buparlisib, pictilisib, pilaralisib, copanlisib, sonolisib, CH5132799, ZSTK474, GDC-0077, rigosertib, ipatasertib, uprosertib, MK-2206, BAY1125976, AZD5363, TAS-117, ONC201, BVD-523, CC-90003, GDC-0994, LY3214996, MK-8353, trametinib, binimetinib, selumetinib, refametinib, pimasertib, cobimetinib, E6201, PD-0325901, RO5126766, GDC-0623, regorafenib, sorafenib, vemurafenib, dabrafenib, encorafenib, RAF265, GDC-5573, LY3009120, dinaciclib, milciclib, seliciclib, alvocidib, roniciclib, voruciclib, AT7519, PHA-793887, CYC-065, MK- 8776, LY2606368, LY2603618, CBP501, GDC-0425, CCT245737, AZD1775, volasertib, alisertib, ilorasertib, ENMD-2076, AMG900, imatinib, dasatinib, bosutinib, nilotinib, ponatinib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, cabozantinib, tivozanib, brivanib, linifanib, lucitanib, ibrutinib, acalabrutinib, tirabrutinib, gilteritinib, quizartinib, midostaurin, brigatinib, crizotinib, ceritinib, alectinib, lorlatinib, ruxolitinib, tofacitinib, baricitinib, pacritinib, capmatinib, tepotinib, pexidartinib, BLZ-3945, JNJ- 40346527, JNJ-28312141, entrectinib, GR-389988, gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, pyrotinib, poziotinib, tucatinib, and mubritinib, and pharmacologically acceptable salts thereof.

[0129]

[834] The use according to

[833] , wherein the kinase inhibitor is abemaciclib or a pharmacologically acceptable salt thereof.

[835] The use according to

[833] , wherein the kinase inhibitor is palbociclib or a pharmacologically acceptable salt thereof.

[836] The use according to

[833] , wherein the kinase inhibitor is everolimus or a pharmacologically acceptable salt thereof.

[837] The use according to

[833] , wherein the kinase inhibitor is taselisib or a pharmacologically acceptable salt thereof.

[838] The use according to

[833] , wherein the kinase inhibitor is alpelisib or a pharmacologically acceptable salt thereof.

[833] The use according to

[833] , wherein the kinase inhibitor is regorafenib or a pharmacologically acceptable salt thereof.

[840] The use according to

[833] , wherein the kinase inhibitor is cabozantinib or a pharmacoclogically acceptable salt thereof.

[0130]

[841] The use according to

[833] , wherein the kinase inhibitor is sunitinib or a pharmacologically acceptable salt thereof.

[842] The use according to

[833] , wherein the kinase inhibitor is nintedanib or a pharmacologically acceptable salt thereof.

[843] The use according to

[833] , wherein the kinase inhibitor is brigatinib or a pharmacologically acceptable salt thereof.

[844] The use according to

[833] , wherein the kinase inhibitor is erlotinib or a pharmacologically acceptable salt thereof.

[845] The use according to

[833] , wherein the kinase inhibitor is neratinib or a pharmacologically acceptable salt thereof.

[846] The use according to

[833] , wherein the kinase inhibitor is poziotinib or a pharmacologically acceptable salt thereof.

[847] The use according to

[833] , wherein the kinase inhibitor is tucatinib or a pharmacologically acceptable salt thereof.

[848] The use according to

[833] , wherein the kinase inhibitor is mubritinib or a pharmacologically acceptable salt thereof.

[8439] The use according to any one of

[833] to

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

[850] The use according to [84%], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[0131]

[851] The use according to

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

[852] The use according to

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

[853] The use according to

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

[854] The use according to

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

[855] The use according to any one of

[850] to

[854] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[856] The use according to [84%], wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[857] The use according to

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

[858] The use according to

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

[853] The use according to any one of

[856] to

[858] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[860] The use according to

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

[0132]

[861] The use according to

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

[862] The use according to

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

[863] The use according to any one of

[860] to

[862] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[864] The use according to [84%], wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[865] The use according to

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

[866] The use according to

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

[867] The use according to any one of

[864] to

[866] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.5.

[868] The use according to

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

[869] The use according to

[868] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 10.

[870] The use according to

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

[0133]

[871] The use according to any one of

[868] to

[870] , wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

[872] The use according to any one of

[833] to

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

[873] The use according to any one of

[833] to

[872] , wherein the use is for treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, endometrial cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.

[874] The use according to

[873] , wherein the use is for treating breast cancer.

[875] The use according to

[873] , wherein the use is for treating colorectal cancer.

[876] The use according to

[873] , wherein the use is for treating gastric cancer.

[877] The use according to

[873] , wherein the use is for treating lung cancer.

[878] The use according to

[873] , wherein the use is for treating pancreatic cancer.

[873] The use according to

[873] , wherein the use is for treating kidney cancer.

[880] The use according to

[873] , wherein the use is for treating ovarian cancer.

[881] A pharmaceutical composition wherein an anti- cancer agent and a kinase inhibitor are administered in combination, and the anti-cancer agent releases a drug represented by the following formula:

[0134] in a tumor, and the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an AKT inhibitor, an ERK inhibitor, an MEK inhibitor, an RAF inhibitor, a CDK1 inhibitor, a CDK2 inhibitor, a CHK1l inhibitor, a WEEl inhibitor, a PLK1l inhibitor, an Aurora kinase inhibitor, a Bcr-Abl inhibitor, an Src inhibitor, an EPH inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, a BTK inhibitor, an FLT3 inhibitor, an ALK inhibitor, a JAK inhibitor, an MET inhibitor, a CSF-1R inhibitor, an NTRK inhibitor, an EGFR inhibitor, and an HER2 inhibitor.

[0136]

[882] The pharmaceutical composition according to

[881] , wherein the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an RAF inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, an FLT3 inhibitor, an ALK inhibitor, a CSF-1R inhibitor, an EGFR inhibitor, and an HER2 inhibitor.

[883] The pharmaceutical composition according to

[882] , wherein the kinase inhibitor is a CDK4 / 6 inhibitor.

[884] The pharmaceutical composition according to

[883] , wherein the CDK4 / 6 inhibitor is abemaciclib, palbociclib, ribociclib, trilaciclib, G1T38, PF-06873600, TP-1287, FN- 1501, or KRX-0601, or a pharmacologically acceptable salt thereof.

[885] The pharmaceutical composition according to

[882] , wherein the kinase inhibitor is an mTOR inhibitor.

[886] The pharmaceutical composition according to

[885] , wherein the mTOR inhibitor is everolimus, sirolimus, temsirolimus, TAK-228, CC-223, AZD8055, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP- BGT226, or PQR309, or a pharmacologically acceptable salt thereof.

[887] The pharmaceutical composition according to

[882] , wherein the kinase inhibitor is a PI3K inhibitor.

[888] The pharmaceutical composition according to

[887] , wherein the PI3K inhibitor is taselisib, alpelisib, TAK- 117, GSK2636771, AZD8186, IPI-549, idelalisib, duvelisib, AMG319, buparlisib, pictilisib, pilaralisib, copanlisib, sonolisib, CH5132799, ZSTK474, GDC-0077, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP- BGT226, PQR309, KRX-0601, or rigosertib, or a pharmacologically acceptable salt thereof.

[0137]

[883] The pharmaceutical composition according to

[882] , wherein the kinase inhibitor is an RAF inhibitor.

[890] The pharmaceutical composition according to

[889] , wherein the RAF inhibitor is regorafenib, sorafenib, vemurafenib, dabrafenib, encorafenib, RAF265, GDC-5573, LY3009120, or RO5126766, or a pharmacologically acceptable salt thereof.

[891] The pharmaceutical composition according to

[882] , wherein the kinase inhibitor is a VEGFR inhibitor.

[892] The pharmaceutical composition according to

[891] , wherein the VEGFR inhibitor is regorafenib, sorafenib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, cabozantinib, tivozanib, brivanib, linifanib, lucitanib, ilorasertib, or ENMD-2076, or a pharmacologically acceptable salt thereof.

[893] The pharmaceutical composition according to

[882] , wherein the kinase inhibitor is a KIT inhibitor.

[894] The pharmaceutical composition according to

[893] , wherein the KIT inhibitor is regorafenib, sorafenib, imatinib, ilorasertib, sunitinib, pazopanib, lenvatinib, or dasatinib, or a pharmacologically acceptable salt thereof.

[895] The pharmaceutical composition according to

[882] , wherein the kinase inhibitor is an RET inhibitor.

[896] The pharmaceutical composition according to

[895] , wherein the RET inhibitor is regorafenib, sorafenib, vandetanib, lenvatinib, or sunitinib, or a pharmacologically acceptable salt thereof.

[897] The pharmaceutical composition according to

[882] , wherein the kinase inhibitor is a PDGFR inhibitor.

[898] The pharmaceutical composition according to

[897] , wherein the PDGFR inhibitor is regorafenib, sorafenib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, ilorasertib, imatinib, nilotinib, or dasatinib, or a pharmacologically acceptable salt thereof.

[899] The pharmaceutical composition according to

[882] , wherein the kinase inhibitor is an FGFR inhibitor.

[900] The pharmaceutical composition according to

[897] , wherein the FGFR inhibitor is regorafenib, sorafenib, lenvatinib, nintedanib, axitinib, or pazopanib, or a pharmacologically acceptable salt thereof.

[0138]

[901] The pharmaceutical composition according to

[882] , wherein the kinase inhibitor is an FLT3 inhibitor.

[902] The pharmaceutical composition according to

[901] , wherein the FLT3 inhibitor is gilteritinib, quizartinib, midostaurin, sorafenib, ilorasertib, ENMD-2076, or sunitinib, or a pharmacologically acceptable salt thereof.

[903] The pharmaceutical composition according to

[882] , wherein the kinase inhibitor is an ALK inhibitor.

[904] The pharmaceutical composition according to

[903] , wherein the ALK inhibitor is brigatinib, crizotinib, ceritinib, alectinib, or lorlatinib, or a pharmacologically acceptable salt thereof.

[905] The pharmaceutical composition according to

[882] , wherein the kinase inhibitor is a CSF-1R inhibitor.

[906] The pharmaceutical composition according to

[905] , wherein the CSF-1R inhibitor is pexidartinib, BLZ-945, JNJ-40346527, JNJ-28312141, ilorasertib, imatinib, sunitinib, or axitinib, or a pharmacologically acceptable salt thereof.

[907] The pharmaceutical composition according to

[882] , wherein the kinase inhibitor is an EGFR inhibitor.

[908] The pharmaceutical composition according to

[907] , wherein the EGFR inhibitor is gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

[903] The pharmaceutical composition according to

[882] , wherein the kinase inhibitor is an HER2 inhibitor.

[910] The pharmaceutical composition according to

[909] , wherein the HER2 inhibitor is tucatinib, neratinib, mubritinib, lapatinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

[0139]

[911] The pharmaceutical composition according to any one of

[881] to

[910] , wherein the pharmaceutical composition is for use in treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, endometrial cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.

[912] A method of treatment comprising administering an anti-cancer agent and a kinase inhibitor in combination to a subject in need of treatment, wherein the anti- cancer agent releases a drug represented by the following formula:

[0140] in a tumor, and the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an AKT inhibitor, an ERK inhibitor, an MEK inhibitor, an RAF inhibitor, a CDK1l inhibitor, a CDK2 inhibitor, a CHK1l inhibitor, a WEEl inhibitor, a PLKl inhibitor, an Aurora kinase inhibitor, a Bcr-Abl inhibitor, an Src inhibitor, an EPH inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, a BTK inhibitor, an FLT3 inhibitor, an ALK inhibitor, a JAK inhibitor, an MET inhibitor, a CSF-1R inhibitor, an NTRK inhibitor, an EGFR inhibitor, and an HER2 inhibitor.

[913] The method of treatment according to

[912] , wherein the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an RAF inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, an FLT3 inhibitor, an ALK inhibitor, a CSF-1R inhibitor, an EGFR inhibitor, and an HER2 inhibitor.

[914] The method of treatment according to

[913] , wherein the kinase inhibitor is a CDK4 / 6 inhibitor.

[915] The method of treatment according to

[914] , wherein the CDK4 / 6 inhibitor is abemaciclib, palbociclib, ribociclib, trilaciclib, G1T38, PF-06873600, TP-1287, FN- 1501, or KRX-0601, or a pharmacologically acceptable salt thereof.

[916] The method of treatment according to

[913] , wherein the kinase inhibitor is an mTOR inhibitor.

[917] The method of treatment according to

[916] , wherein the mTOR inhibitor is everolimus, sirolimus, temsirolimus, TAK-228, CC-223, AZD8055, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP- BGT226, or PQR309, or a pharmacologically acceptable salt thereof.

[918] The method of treatment according to

[913] , wherein the kinase inhibitor is a PI3K inhibitor. [91%] The method of treatment according to

[918] , wherein the PI3K inhibitor is taselisib, alpelisib, TAK- 117, GSK2636771, AZD8186, IPI-549, idelalisib, duvelisib, AMG319, buparlisib, pictilisib, pilaralisib, copanlisib, sonolisib, CH5132799, ZSTK474, GDC-0077, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP- BGT226, PQR309, KRX-0601, or rigosertib, or a pharmacologically acceptable salt thereof.

[920] The method of treatment according to

[913] , wherein the kinase inhibitor is an RAF inhibitor.

[0142]

[921] The method of treatment according to

[920] , wherein the RAF inhibitor is regorafenib, sorafenib, vemurafenib, dabrafenib, encorafenib, RAF265, GDC-5573, LY3009120, or RO5126766, or a pharmacologically acceptable salt thereof.

[922] The method of treatment according to

[913] , wherein the kinase inhibitor is a VEGFR inhibitor.

[923] The method of treatment according to

[922] , wherein the VEGFR inhibitor is regorafenib, sorafenib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, cabozantinib, tivozanib, brivanib, linifanib, lucitanib, ilorasertib, or ENMD-2076, or a pharmacologically acceptable salt thereof.

[924] The method of treatment according to

[913] , wherein the kinase inhibitor is a KIT inhibitor.

[925] The method of treatment according to

[924] , wherein the KIT inhibitor is regorafenib, sorafenib, imatinib, ilorasertib, sunitinib, pazopanib, lenvatinib, or dasatinib, or a pharmacologically acceptable salt thereof.

[926] The method of treatment according to

[913] , wherein the kinase inhibitor is an RET inhibitor.

[927] The method of treatment according to

[926] , wherein the RET inhibitor is regorafenib, sorafenib, vandetanib, lenvatinib, or sunitinib, or a pharmacologically acceptable salt thereof.

[928] The method of treatment according to

[913] , wherein the kinase inhibitor is a PDGFR inhibitor.

[929] The method of treatment according to

[928] , wherein the PDGFR inhibitor is regorafenib, sorafenib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, ilorasertib, imatinib, nilotinib, or dasatinib, or a pharmacologically acceptable salt thereof.

[930] The method of treatment according to

[913] , wherein the kinase inhibitor is an FGFR inhibitor.

[0143]

[931] The method of treatment according to

[930] , wherein the FGFR inhibitor is regorafenib, sorafenib, lenvatinib, nintedanib, axitinib, or pazopanib, or a pharmacologically acceptable salt thereof.

[932] The method of treatment according to

[913] , wherein the kinase inhibitor is an FLT3 inhibitor.

[933] The method of treatment according to

[932] , wherein the FLT3 inhibitor is gilteritinib, quizartinib, midostaurin, sorafenib, ilorasertib, ENMD-2076, or sunitinib, or a pharmacologically acceptable salt thereof.

[934] The method of treatment according to

[913] , wherein the kinase inhibitor is an ALK inhibitor.

[935] The method of treatment according to

[934] , wherein the ALK inhibitor is brigatinib, crizotinib, ceritinib, alectinib, or lorlatinib, or a pharmacologically acceptable salt thereof.

[936] The method of treatment according to

[913] , wherein the kinase inhibitor is a CSF-1R inhibitor.

[937] The method of treatment according to

[936] , wherein the CSF-1R inhibitor is pexidartinib, BLZ-945, JNJ-40346527, JINJ-28312141, ilorasertib, imatinib, sunitinib, or axitinib, or a pharmacologically acceptable salt thereof.

[938] The method of treatment according to

[913] , wherein the kinase inhibitor is an EGFR inhibitor.

[933] The method of treatment according to

[938] , wherein the EGFR inhibitor is gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

[940] The method of treatment according to

[913] , wherein the kinase inhibitor is an HER2 inhibitor.

[0144]

[941] The method of treatment according to

[940] , wherein the HER2 inhibitor is tucatinib, neratinib, mubritinib, lapatinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

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

[912] to

[941] , wherein the method of treatment is for treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, endometrial cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.

[943] An anti-cancer agent for use in treating a disease through being administered in combination with a kinase inhibitor, wherein the anti-cancer agent releases a drug represented by the following formula:

[0145] in a tumor, and the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an AKT inhibitor, an ERK inhibitor, an MEK inhibitor, an RAF inhibitor, a CDK1l inhibitor, a CDK2 inhibitor, a CHK1l inhibitor, a WEE1l inhibitor, a PLK1l inhibitor, an Aurora kinase inhibitor, a Bcr-Abl inhibitor, an Src inhibitor, an EPH inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, a BTK inhibitor, an FLT3 inhibitor, an ALK inhibitor, a JAK inhibitor, an MET inhibitor, a CSF-1R inhibitor, an NTRK inhibitor, an EGFR inhibitor, and an HER2 inhibitor.

[944] The anti-cancer agent according to

[943] , wherein the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an RAF inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, an FLT3 inhibitor, an ALK inhibitor, a CSF-1R inhibitor, an EGFR inhibitor, and an HER2 inhibitor.

[0147]

[945] The anti-cancer agent according to

[944] , wherein the kinase inhibitor is a CDK4 / 6 inhibitor.

[946] The anti-cancer agent according to

[945] , wherein the CDK4 / 6 inhibitor is abemaciclib, palbociclib, ribociclib, trilaciclib, G1T38, PF-06873600, TP-1287, FN- 1501, or KRX-0601, or a pharmacologically acceptable salt thereof.

[947] The anti-cancer agent according to

[944] , wherein the kinase inhibitor is an mTOR inhibitor.

[948] The anti-cancer agent according to

[947] , wherein the mTOR inhibitor is everolimus, sirolimus, temsirolimus, TAK-228, CC-223, AZD8055, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP-BGT226, or PQR309, or a pharmacologically acceptable salt thereof.

[949] The anti-cancer agent according to

[944] , wherein the kinase inhibitor is a PI3K inhibitor.

[950] The anti-cancer agent according to

[949] , wherein the PI3K inhibitor is taselisib, alpelisib, TAK-117, GSK2636771, AzD8186, IPI-549, idelalisib, duvelisib, AMG319, buparlisib, pictilisib, pilaralisib, copanlisib, sonolisib, CH5132799, ZSTK474, GDC-0077, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP- BGT226, PQR309, KRX-0601, or rigosertib, or a pharmacologically acceptable salt thereof.

[951] The anti-cancer agent according to

[944] , wherein the kinase inhibitor is an RAF inhibitor.

[952] The anti-cancer agent according to

[951] , wherein the RAF inhibitor is regorafenib, sorafenib, vemurafenib, dabrafenib, encorafenib, RAF265, GDC-5573, LY3009120, or RO5126766, or a pharmacologically acceptable salt thereof.

[953] The anti-cancer agent according to

[944] , wherein the kinase inhibitor is a VEGFR inhibitor.

[954] The anti-cancer agent according to

[953] , wherein the VEGFR inhibitor is regorafenib, sorafenib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, cabozantinib, tivozanib, brivanib, linifanib, lucitanib, ilorasertib, or ENMD-2076, or a pharmacologically acceptable salt thereof.

[955] The anti-cancer agent according to

[944] , wherein the kinase inhibitor is a KIT inhibitor.

[956] The anti-cancer agent according to

[955] , wherein the KIT inhibitor is regorafenib, sorafenib, imatinib, ilorasertib, sunitinib, pazopanib, lenvatinib, or dasatinib, or a pharmacologically acceptable salt thereof.

[957] The anti-cancer agent according to

[944] , wherein the kinase inhibitor is an RET inhibitor.

[958] The anti-cancer agent according to

[957] , wherein the RET inhibitor is regorafenib, sorafenib, vandetanib, lenvatinib, or sunitinib, or a pharmacologically acceptable salt thereof.

[959] The anti-cancer agent according to

[944] , wherein the kinase inhibitor is a PDGFR inhibitor.

[960] The anti-cancer agent according to

[959] , wherein the PDGFR inhibitor is regorafenib, sorafenib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, ilorasertib, imatinib, nilotinib, or dasatinib, or a pharmacoclogically acceptable salt thereof.

[0148]

[961] The anti-cancer agent according to

[944] , wherein the kinase inhibitor is an FGFR inhibitor.

[962] The anti-cancer agent according to

[961] , wherein the FGFR inhibitor is regorafenib, sorafenib, lenvatinib, nintedanib, axitinib, or pazopanib, or a pharmacologically acceptable salt thereof.

[963] The anti-cancer agent according to

[944] , wherein the kinase inhibitor is an FLT3 inhibitor.

[964] The anti-cancer agent according to

[963] , wherein the FLT3 inhibitor is gilteritinib, quizartinib, midostaurin, sorafenib, ilorasertib, ENMD-2076, or sunitinib, or a pharmacologically acceptable salt thereof.

[965] The anti-cancer agent according to

[944] , wherein the kinase inhibitor is an ALK inhibitor.

[966] The anti-cancer agent according to

[965] , wherein the ALK inhibitor is brigatinib, crizotinib, ceritinib, alectinib, or lorlatinib, or a pharmacologically acceptable salt thereof.

[967] The anti-cancer agent according to

[944] , wherein the kinase inhibitor is a CSF-1R inhibitor.

[968] The anti-cancer agent according to

[967] , wherein the CSF-1R inhibitor is pexidartinib, BLZ-945, JNJ- 40346527, JINJ-28312141, ilorasertib, imatinib, sunitinib, or axitinib, or a pharmacologically acceptable salt thereof.

[969] The anti-cancer agent according to

[944] , wherein the kinase inhibitor is an EGFR inhibitor.

[970] The anti-cancer agent according to

[969] , wherein the EGFR inhibitor is gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

[0149]

[971] The anti-cancer agent according to

[944] , wherein the kinase inhibitor is an HER? inhibitor.

[972] The anti-cancer agent according to

[971] , wherein the HERZ2 inhibitor is tucatinib, neratinib, mubritinib, lapatinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

[973] The anti-cancer agent according to any one of

[943] to

[972] , wherein the anti-cancer agent is for use in treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, endometrial cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.

[974] Use of an anti-cancer agent for the manufacture of a medicament for treating a disease through being administered in combination with a kinase inhibitor, wherein the anti-cancer agent releases a drug represented by the following formula:

[0150] in a tumor, and the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an AKT inhibitor, an ERK inhibitor, an MEK inhibitor, an RAF inhibitor, a CDK1l inhibitor, a CDK2 inhibitor, a CHK1l inhibitor, a WEEl inhibitor, a PLKl inhibitor, an Aurora kinase inhibitor, a Bcr-Abl inhibitor, an Src inhibitor, an EPH inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, a BTK inhibitor, an FLT3 inhibitor, an ALK inhibitor, a JAK inhibitor, an MET inhibitor, a CSF-1R inhibitor, an NTRK inhibitor, an EGFR inhibitor, and an HER2 inhibitor.

[975] The use according to

[974] , wherein the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an RAF inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, an FLT3 inhibitor, an ALK inhibitor, a CSF-1R inhibitor, an EGFR inhibitor, and an HER2 inhibitor.

[976] The use according to

[975] , wherein the kinase inhibitor is a CDK4 / 6 inhibitor.

[977] The use according to

[976] , wherein the CDK4 / 6 inhibitor is abemaciclib, palbociclib, ribociclib, trilaciclib, G1T38, PF-06873600, TP-1287, FN-1501, or KRX-0601, or a pharmacologically acceptable salt thereof.

[978] The use according to

[975] , wherein the kinase inhibitor is an mTOR inhibitor.

[978] The use according to

[978] , wherein the mTOR inhibitor is everolimus, sirolimus, temsirolimus, TAK-228, CC-223, AZD8055, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP-BGT226, or PQR309, or a pharmacologically acceptable salt thereof.

[980] The use according to

[975] , wherein the kinase inhibitor is a PI3K inhibitor.

[0152]

[981] The use according to

[980] , wherein the PI3K inhibitor is taselisib, alpelisib, TAK-117, GSK2636771, AZD8186, IPI-549, idelalisib, duvelisib, AMG319, buparlisib, pictilisib, pilaralisib, copanlisib, sonolisib, CH5132799, ZSTK474, GDC-0077, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP- BGT226, PQR309, KRX-0601, or rigosertib, or a pharmacologically acceptable salt thereof.

[982] The use according to

[975] , wherein the kinase inhibitor is an RAF inhibitor.

[983] The use according to

[982] , wherein the RAF inhibitor is regorafenib, sorafenib, vemurafenib, dabrafenib, encorafenib, RAF265, GDC-5573, LY3009120, or RO5126766, or a pharmacologically acceptable salt thereof.

[984] The use according to

[975] , wherein the kinase inhibitor is a VEGFR inhibitor.

[0153]

[985] The use according to

[984] , wherein the VEGFR inhibitor is regorafenib, sorafenib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, cabozantinib, tivozanib, brivanib, linifanib, lucitanib, ilorasertib, or ENMD-2076, or a pharmacologically acceptable salt thereof.

[986] The use according to

[975] , wherein the kinase inhibitor is a KIT inhibitor.

[987] The use according to

[986] , wherein the KIT inhibitor is regorafenib, sorafenib, imatinib, ilorasertib, sunitinib, pazopanib, lenvatinib, or dasatinib, or a pharmacologically acceptable salt thereof.

[988] The use according to

[975] , wherein the kinase inhibitor is an RET inhibitor.

[988] The use according to

[988] , wherein the RET inhibitor is regorafenib, sorafenib, vandetanib, lenvatinib, or sunitinib, or a pharmacoclogically acceptable salt thereof.

[990] The use according to

[975] , wherein the kinase inhibitor is a PDGFR inhibitor.

[991] The use according to

[990] , wherein the PDGFR inhibitor is regorafenib, sorafenib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, ilorasertib, imatinib, nilotinib, or dasatinib, or a pharmacologically acceptable salt thereof.

[992] The use according to

[975] , wherein the kinase inhibitor is an FGFR inhibitor.

[993] The use according to

[992] , wherein the FGFR inhibitor is regorafenib, sorafenib, lenvatinib, nintedanib, axitinib, or pazopanib, or a pharmacologically acceptable salt thereof.

[994] The use according to

[975] , wherein the kinase inhibitor is an FLT3 inhibitor.

[995] The use according to

[994] , wherein the FLT3 inhibitor is gilteritinib, quizartinib, midostaurin, sorafenib, ilorasertib, ENMD-2076, or sunitinib, or a pharmacologically acceptable salt thereof.

[996] The use according to

[975] , wherein the kinase inhibitor is an ALK inhibitor.

[997] The use according to

[996] , wherein the ALK inhibitor is brigatinib, crizotinib, ceritinib, alectinib, or lorlatinib, or a pharmacologically acceptable salt thereof.

[998] The use according to

[975] , wherein the kinase inhibitor is a CSF-1R inhibitor. [99%] The use according to

[998] , wherein the CSF-1R inhibitor is pexidartinib, BLZ-945, JNJ-40346527, JNJ- 28312141, ilorasertib, imatinib, sunitinib, or axitinib, or a pharmacologically acceptable salt thereof.

[1000] The use according to

[975] , wherein the kinase inhibitor is an EGFR inhibitor.

[0154]

[1001] The use according to

[1000] , wherein the EGFR inhibitor is gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

[1002] The use according to

[975] , wherein the kinase inhibitor is an HER? inhibitor.

[1003] The use according to

[1002] , wherein the HER2 inhibitor is tucatinib, neratinib, mubritinib, lapatinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

[1004] The use according to any one of

[974] to

[1003] , wherein the use is for treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, endometrial cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.

[1005] A pharmaceutical composition wherein an anti- cancer agent and a kinase inhibitor are administered in combination, and the anti-cancer agent releases a drug represented by the following formula:

[0155] in a tumor, and the kinase inhibitor is at least one selected from the group consisting of abemaciclib, palbociclib, ribociclib, trilaciclib, G1T38, PF-06873600, TP-1287, FN- 1501, KRX-0601, everolimus, sirolimus, temsirolimus, TAK- 228, CC-223, AZD8055, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP-BGT226, PQR309, taselisib, alpelisib, TAK-117, GSK2636771, AZD8186, IPI-549, idelalisib, duvelisib, AMG319, buparlisib, pictilisib, pilaralisib, copanlisib, sonolisib, CH5132799, ZSTK474, GDC-0077, rigosertib, ipatasertib, uprosertib, MK-2206, BAY1125976, AZD5363, TAS-117, ONC201, BVD-523, CC-90003, GDC-0994, LY3214996, MK-8353, trametinib, binimetinib, selumetinib, refametinib, pimasertib, cobimetinib, E6201, PD-0325901, RO5126766, GDC-0623, regorafenib, sorafenib, vemurafenib, dabrafenib, encorafenib, RAF265, GDC-5573, LY3009120, dinaciclib, milciclib, seliciclib, alvocidib, roniciclib, voruciclib, AT7519, PHA-793887, CYC-065, MK- 8776, LY2606368, LY2603618, CBP501, GDC-0425, CCT245737, AZD1775, volasertib, alisertib, ilorasertib, ENMD-2076, AMG900, imatinib, dasatinib, bosutinib, nilotinib, ponatinib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, cabozantinib, tivozanib, brivanib, linifanib, lucitanib, ibrutinib, acalabrutinib, tirabrutinib, gilteritinib, quizartinib, midostaurin, brigatinib, crizotinib, ceritinib, alectinib, lorlatinib, ruxolitinib, tofacitinib, baricitinib, pacritinib, capmatinib, tepotinib, pexidartinib, BLZ-3945, JNJ- 40346527, JNJ-28312141, entrectinib, GR-389988, gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, pyrotinib, poziotinib, tucatinib, and mubritinib, and pharmacologically acceptable salts thereof.

[1006] The pharmaceutical composition according to

[1005] , wherein the kinase inhibitor is abemaciclib or a pharmacologically acceptable salt thereof.

[1007] The pharmaceutical composition according to

[1005] , wherein the kinase inhibitor is palbociclib or a pharmacologically acceptable salt thereof.

[1008] The pharmaceutical composition according to

[1005] , wherein the kinase inhibitor is everolimus or a pharmacologically acceptable salt thereof.

[1009] The pharmaceutical composition according to

[1005] , wherein the kinase inhibitor is taselisib or a pharmacologically acceptable salt thereof.

[1010] The pharmaceutical composition according to

[1005] , wherein the kinase inhibitor is alpelisib or a pharmacologically acceptable salt thereof.

[1011] The pharmaceutical composition according to

[1005] , wherein the kinase inhibitor is regorafenib or a pharmacologically acceptable salt thereof.

[1012] The pharmaceutical composition according to

[1005] , wherein the kinase inhibitor is cabozantinib or a pharmacologically acceptable salt thereof.

[1013] The pharmaceutical composition according to

[1005] , wherein the kinase inhibitor is sunitinib or a pharmacologically acceptable salt thereof.

[1014] The pharmaceutical composition according to

[1005] , wherein the kinase inhibitor is nintedanib or a pharmacologically acceptable salt thereof.

[1015] The pharmaceutical composition according to

[1005] , wherein the kinase inhibitor is brigatinib or a pharmacologically acceptable salt thereof.

[1016] The pharmaceutical composition according to

[1005] , wherein the kinase inhibitor is erlotinib or a pharmacologically acceptable salt thereof.

[1017] The pharmaceutical composition according to

[1005] , wherein the kinase inhibitor is neratinib or a pharmacologically acceptable salt thereof.

[1018] The pharmaceutical composition according to

[1005] , wherein the kinase inhibitor is poziotinib or a pharmacologically acceptable salt thereof.

[1019] The pharmaceutical composition according to

[1005] , wherein the kinase inhibitor is tucatinib or a pharmacologically acceptable salt thereof.

[1020] The pharmaceutical composition according to

[1005] , wherein the kinase inhibitor is mubritinib or a pharmacologically acceptable salt thereof.

[0157]

[1021] The pharmaceutical composition according to any one of

[1005] to

[1020] , wherein the pharmaceutical composition is for use in treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, endometrial cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.

[1022] A method of treatment comprising administering an anti-cancer agent and a kinase inhibitor in combination to a subject in need of treatment, wherein the anti- cancer agent releases a drug represented by the following formula:

[0158] in a tumor, and the kinase inhibitor is at least one selected from the group consisting of abemaciclib, palbociclib, ribociclib, trilaciclib, G1T38, PF-06873600, TP-1287, FN- 1501, KRX-0601, everolimus, sirolimus, temsirolimus, TAK- 228, CC-223, AZD8055, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP-BGT226, PQR309, taselisib, alpelisib, TAK-117, GSK2636771, AZD8186, IPI-549, idelalisib, duvelisib, AMG319, buparlisib, pictilisib, pilaralisib, copanlisib, sonolisib, CH5132799, ZSTK474, GDC-0077, rigosertib, ipatasertib, uprosertib, MK-2206, BAY1125976, AZD5363, TAS-117, ONC201, BVD-523, CC-90003, GDC-0994, LY3214996, MK-8353, trametinib, binimetinib, selumetinib, refametinib, pimasertib, cobimetinib, E6201, PD-0325901, RO5126766, GDC-0623, regorafenib, sorafenib, vemurafenib, dabrafenib, encorafenib, RAF265, GDC-5573, LY3009120, dinaciclib, milciclib, seliciclib, alvocidib, roniciclib, voruciclib, AT7519, PHA-793887, CYC-065, MK- 8776, LY2606368, LY2603618, CBP501, GDC-0425, CCT245737, AZD1775, volasertib, alisertib, ilorasertib, ENMD-2076, AMG900, imatinib, dasatinib, bosutinib, nilotinib, ponatinib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, cabozantinib, tivozanib, brivanib, linifanib, lucitanib, ibrutinib, acalabrutinib, tirabrutinib, gilteritinib, quizartinib, midostaurin, brigatinib, crizotinib, ceritinib, alectinib, lorlatinib, ruxolitinib, tofacitinib, baricitinib, pacritinib, capmatinib, tepotinib, pexidartinib, BLZ-3945, JNJ- 40346527, JNJ-28312141, entrectinib, GR-389988, gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, pyrotinib, poziotinib, tucatinib, and mubritinib, and pharmacologically acceptable salts thereof.

[1023] The method of treatment according to

[1022] , wherein the kinase inhibitor is abemaciclib or a pharmacologically acceptable salt thereof.

[1024] The method of treatment according to

[1022] , wherein the kinase inhibitor is palbociclib or a pharmacologically acceptable salt thereof.

[1025] The method of treatment according to

[1022] , wherein the kinase inhibitor is everolimus or a pharmacologically acceptable salt thereof.

[1026] The method of treatment according to

[1022] , wherein the kinase inhibitor is taselisib or a pharmacologically acceptable salt thereof.

[1027] The method of treatment according to

[1022] , wherein the kinase inhibitor is alpelisib or a pharmacologically acceptable salt thereof.

[1028] The method of treatment according to

[1022] , wherein the kinase inhibitor is regorafenib or a pharmacologically acceptable salt thereof.

[10298] The method of treatment according to

[1022] , wherein the kinase inhibitor is cabozantinib or a pharmacologically acceptable salt thereof.

[1030] The method of treatment according to

[1022] , wherein the kinase inhibitor is sunitinib or a pharmacologically acceptable salt thereof.

[1031] The method of treatment according to

[1022] , wherein the kinase inhibitor is nintedanib or a pharmacologically acceptable salt thereof.

[1032] The method of treatment according to

[1022] , wherein the kinase inhibitor is brigatinib or a pharmacologically acceptable salt thereof.

[1033] The method of treatment according to

[1022] , wherein the kinase inhibitor is erlotinib or a pharmacologically acceptable salt thereof.

[1034] The method of treatment according to

[1022] , wherein the kinase inhibitor is neratinib or a pharmacologically acceptable salt thereof.

[1035] The method of treatment according to

[1022] , wherein the kinase inhibitor is poziotinib or a pharmacologically acceptable salt thereof.

[1036] The method of treatment according to

[1022] , wherein the kinase inhibitor is tucatinib or a pharmacologically acceptable salt thereof.

[1037] The method of treatment according to

[1022] , wherein the kinase inhibitor is mubritinib or a pharmacologically acceptable salt thereof.

[1038] The pharmaceutical composition according to any one of

[1022] to

[1037] , wherein the pharmaceutical composition is for use in treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, endometrial cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma. [103%] An anti-cancer agent for use in treating a disease through being administered in combination with a kinase inhibitor, wherein the anti-cancer agent releases a drug represented by the following formula:

[0160] in a tumor, and the kinase inhibitor is at least one selected from the group consisting of abemaciclib, palbociclib, ribociclib, trilaciclib, G1T38, PF-06873600, TP-1287, FN- 1501, KRX-0601, everolimus, sirolimus, temsirolimus, TAK- 228, CC-223, AZD8055, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP-BGT226, PQR309, taselisib, alpelisib, TAK-117, GSK2636771, AZD8186, IPI-549, idelalisib, duvelisib, AMG319, buparlisib, pictilisib, pilaralisib, copanlisib, sonolisib, CH5132799, ZSTK474, GDC-0077, rigosertib, ipatasertib, uprosertib, MK-2206, BAY1125976, AZD5363, TAS-117, ONC201, BVD-523, CC-90003, GDC-0994, LY3214996, MK-8353, trametinib, binimetinib, selumetinib, refametinib, pimasertib, cobimetinib, E6201, PD-03253901, RO5126766, GDC-0623, regorafenib, sorafenib, vemurafenib, dabrafenib, encorafenib, RAF265, GDC-5573, LY3009120, dinaciclib, milciclib, seliciclib, alvocidib, roniciclib, voruciclib, AT7519, PHA-793887, CYC-065, MK- 8776, LY2606368, LY2603618, CBP501, GDC-0425, CCT245737, AZD1775, volasertib, alisertib, ilorasertib, ENMD-2076, AMG900, imatinib, dasatinib, bosutinib, nilotinib, ponatinib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, cabozantinib, tivozanib, brivanib, linifanib, lucitanib, ibrutinib, acalabrutinib, tirabrutinib, gilteritinib, quizartinib, midostaurin, brigatinib, crizotinib, ceritinib, alectinib, lorlatinib, ruxolitinib, tofacitinib, baricitinib, pacritinib, capmatinib, tepotinib, pexidartinib, BLZ-3945, JNJ- 40346527, JNJ-28312141, entrectinib, GR-38%9988, gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, pyrotinib, poziotinib, tucatinib, and mubritinib, and pharmacologically acceptable salts thereof.

[1040] The anti-cancer agent according to

[1039] , wherein the kinase inhibitor is abemaciclib or a pharmacologically acceptable salt thereof.

[1041] The anti-cancer agent according to

[1033] , wherein the kinase inhibitor is palbociclib or a pharmacologically acceptable salt thereof.

[1042] The anti-cancer agent according to

[1033] , wherein the kinase inhibitor is everolimus or a pharmacologically acceptable salt thereof.

[1043] The anti-cancer agent according to

[1039] , wherein the kinase inhibitor is taselisib or a pharmacologically acceptable salt thereof.

[1044] The anti-cancer agent according to

[1033] , wherein the kinase inhibitor is alpelisib or a pharmacologically acceptable salt thereof.

[1045] The anti-cancer agent according to

[1039] , wherein the kinase inhibitor is regorafenib or a pharmacologically acceptable salt thereof.

[1046] The anti-cancer agent according to

[1039] , wherein the kinase inhibitor is cabozantinib or a pharmacologically acceptable salt thereof.

[1047] The anti-cancer agent according to

[1033] , wherein the kinase inhibitor is sunitinib or a pharmacologically acceptable salt thereof.

[1048] The anti-cancer agent according to

[1033] , wherein the kinase inhibitor is nintedanib or a pharmacologically acceptable salt thereof.

[1048] The anti-cancer agent according to

[1033] , wherein the kinase inhibitor is brigatinib or a pharmacologically acceptable salt thereof.

[1050] The anti-cancer agent according to

[1039] , wherein the kinase inhibitor is erlotinib or a pharmacologically acceptable salt thereof.

[0162]

[1051] The anti-cancer agent according to

[1039] , wherein the kinase inhibitor is neratinib or a pharmacologically acceptable salt thereof.

[1052] The anti-cancer agent according to

[1033] , wherein the kinase inhibitor is poziotinib or a pharmacologically acceptable salt thereof.

[1053] The anti-cancer agent according to

[1039] , wherein the kinase inhibitor is tucatinib or a pharmacologically acceptable salt thereof.

[1054] The anti-cancer agent according to

[1033] , wherein the kinase inhibitor is mubritinib or a pharmacologically acceptable salt thereof.

[1055] The anti-cancer agent according to any one of [103%] to

[1054] , wherein the anti-cancer agent is for use in treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, endometrial cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, and melanoma.

[1056] Use of an anti-cancer agent for the manufacture of a medicament for treating a disease through being administered in combination with a kinase inhibitor, wherein the anti-cancer agent releases a drug represented by the following formula:

[0163] in a tumor, and the kinase inhibitor is at least one selected from the group consisting of abemaciclib, palbociclib, ribociclib, trilaciclib, G1T38, PF-06873600, TP-1287, FN- 1501, KRX-0601, everolimus, sirolimus, temsirolimus, TAK- 228, CC-223, AZD8055, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP-BGT226, PQR309, taselisib, alpelisib, TAK-117, GSK2636771, AZD8186, IPI-549, idelalisib, duvelisib, AMG319, buparlisib, pictilisib, pilaralisib, copanlisib, sonolisib, CH5132799, ZSTK474, GDC-0077, rigosertib, ipatasertib, uprosertib, MK-2206, BAY1125976, AZD5363, TAS-117, ONC201, BVD-523, CC-90003, GDC-0994, LY3214996, MK-8353, trametinib, binimetinib, selumetinib, refametinib, pimasertib, cobimetinib, E6201, PD-0325901, RO5126766, GDC-0623, regorafenib, sorafenib, vemurafenib, dabrafenib, encorafenib, RAF265, GDC-5573, LY3009120, dinaciclib, milciclib, seliciclib, alvocidib, roniciclib, voruciclib, AT7519, PHA-793887, CYC-065, MK- 8776, LY2606368, LY2603618, CBP501, GDC-0425, CCT245737, AZD1775, volasertib, alisertib, ilorasertib, ENMD-2076, AMG900, imatinib, dasatinib, bosutinib, nilotinib, ponatinib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, cabozantinib, tivozanib, brivanib, linifanib, lucitanib, ibrutinib, acalabrutinib, tirabrutinib, gilteritinib, quizartinib, midostaurin, brigatinib, crizotinib, ceritinib, alectinib, lorlatinib, ruxolitinib, tofacitinib, baricitinib, pacritinib, capmatinib, tepotinib, pexidartinib, BLZ-3945, JNJ- 40346527, JNJ-28312141, entrectinib, GR-389988, gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, pyrotinib, poziotinib, tucatinib, and mubritinib, and pharmacologically acceptable salts thereof.

[1057] The use according to

[1056] , wherein the kinase inhibitor is abemaciclib or a pharmacologically acceptable salt thereof.

[1058] The use according to

[1056] , wherein the kinase inhibitor is palbociclib or a pharmacologically acceptable salt thereof.

[1058] The use according to

[1056] , wherein the kinase inhibitor is everolimus or a pharmacologically acceptable salt thereof.

[1060] The use according to

[1056] , wherein the kinase inhibitor is taselisib or a pharmacologically acceptable salt thereof.

[1061] The use according to

[1056] , wherein the kinase inhibitor is alpelisib or a pharmacologically acceptable salt thereof.

[1062] The use according to

[1056] , wherein the kinase inhibitor is regorafenib or a pharmacologically acceptable salt thereof.

[1063] The use according to

[1056] , wherein the kinase inhibitor is cabozantinib or a pharmacologically acceptable salt thereof.

[1064] The use according to

[1056] , wherein the kinase inhibitor is sunitinib or a pharmacologically acceptable salt thereof.

[1065] The use according to

[1056] , wherein the kinase inhibitor is nintedanib or a pharmacologically acceptable salt thereof.

[1066] The use according to

[1056] , wherein the kinase inhibitor is brigatinib or a pharmacologically acceptable salt thereof.

[1067] The use according to

[1056] , wherein the kinase inhibitor is erlotinib or a pharmacologically acceptable salt thereof.

[1068] The use according to

[1056] , wherein the kinase inhibitor is neratinib or a pharmacologically acceptable salt thereof.

[1069] The use according to

[1056] , wherein the kinase inhibitor is poziotinib or a pharmacologically acceptable salt thereof.

[1070] The use according to

[1056] , wherein the kinase inhibitor is tucatinib or a pharmacologically acceptable salt thereof.

[0165]

[1071] The use according to

[1056] , wherein the kinase inhibitor is mubritinib or a pharmacologically acceptable salt thereof.

[1072] The use according to any one of

[1056] to

[1071] , wherein the use is for treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, endometrial cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma. Advantageous Effects of Invention

[0166] The present invention can provide a pharmaceutical composition wherein a specific antibody-drug conjugate and a kinase inhibitor are administered in combination, and / or a method of treatment wherein a specific antibody- drug conjugate and a kinase inhibitor are administered in combination to a subject. Brief Description of Drawings

[0167] [Figure 1] Figure 1 is a diagram showing the amino acid sequence of a heavy chain of an anti-HER2 antibody (SEQ ID NO: 1). [Figure 2] Figure 2 is a diagram showing the amino acid sequence of a light chain of an anti-HER2 antibody (SEQ ID NO: 2). [Figure 3] Figure 3 is a diagram showing the amino acid sequence of a heavy chain of an anti-HER3 antibody (SEQ ID NO: 3). [Figure 4] Figure 4 is a diagram showing the amino acid sequence of a light chain of an anti-HER3 antibody (SEQ ID NO: 4). [Figure 5] Figure 5 is a diagram showing the amino acid sequence of a heavy chain of an anti-TROP2 antibody (SEQ ID NO: 5). [Figure 6] Figure 6 is a diagram showing the amino acid sequence of a light chain of an anti-TROP2 antibody (SEQ ID NO: 6). [Figure 7] Figure 7 is a diagram showing the amino acid sequence of a heavy chain of an anti-B7-H3 antibody (SEQ ID NO: 7). [Figure 8] Figure 8 is a diagram showing the amino acid sequence of a light chain of an anti-B7-H3 antibody (SEQ ID NO: 8). [Figure 9] Figure 9 is a diagram showing the amino acid sequence of a heavy chain of an anti-CDH6 antibody (SEQ ID NO: 9). [Figure 10] Figure 10 is a diagram showing the amino acid sequence of a light chain of an anti-CDH6 antibody (SEQ ID NO: 10). [Figure 11] Figure 11 is a diagram showing tumor growth inhibitory effects on mice with subcutaneously transplanted MDA-MB-453 cells for a single administration group with an antibody-drug conjugate (1) and that with everolimus, and for a combined administration group with the antibody-drug conjugate (1) and everolimus. [Figure 12] Figure 12 is a diagram showing tumor growth inhibitory effects on mice with subcutaneously transplanted MDA-MB-453 cells for a single administration group with an antibody-drug conjugate (1) and that with taselisib, and for a combined administration group with the antibody-drug conjugate (1) and taselisib. [Figure 13] Figure 13 is a diagram showing tumor growth inhibitory effects on mice with subcutaneously transplanted MDA-MB-453 cells for a single administration group with an antibody-drug conjugate (1) and that with abemaciclib, and for a combined administration group with the antibody-drug conjugate (1) and abemaciclib. [Figure 14] Figure 14 is a diagram showing tumor growth inhibitory effects on mice with subcutaneously transplanted JIMT-1 cells for a single administration group with an antibody-drug conjugate (1) and that with everolimus, and for a combined administration group with the antibody-drug conjugate (1) and everolimus. [Figure 15] Figure 15 is a diagram showing tumor growth inhibitory effects on mice with subcutaneously transplanted COLO201 cells for a single administration group with an antibody-drug conjugate (1) and that with regorafenib, and for a combined administration group with the antibody-drug conjugate (1) and regorafenib. [Figure 16] Figure 16 is a diagram showing tumor growth inhibitory effects on mice with subcutaneously transplanted KPL-4 cells for a single administration group with an antibody-drug conjugate (1) and that with tucatinib, and for a combined administration group with the antibody-drug conjugate (1) and tucatinib. [Figure 17] Figure 17 is a diagram showing tumor growth inhibitory effects on mice with subcutaneously transplanted MDA-MB-453 cells for a single administration group with an antibody-drug conjugate (1) and that with tucatinib, and for a combined administration group with the antibody-drug conjugate (1) and tucatinib. [Figure 18] Figure 18 is a diagram showing tumor growth inhibitory effects on mice with subcutaneously transplanted NCI-N87 cells for a single administration group with an antibody-drug conjugate (1) and that with tucatinib, and for a combined administration group with the antibody-drug conjugate (1) and tucatinib. [Figure 18] Figure 19 is a diagram showing tumor growth inhibitory effects on mice with subcutaneously transplanted KPL-4 cells for a single administration group with an antibody-drug conjugate (2) and that with neratinib, and for a combined administration group with the antibody-drug conjugate (2) and neratinib. [Figure 20] Figure 20 is a diagram showing tumor growth inhibitory effects on mice with subcutaneously transplanted 786-0 cells for a single administration group with an antibody-drug conjugate (3) and that with cabozantinib, and for a combined administration group with the antibody-drug conjugate (3) and cabozantinib. [Figure 21] Figure 21 is a diagram showing tumor growth inhibitory effects on mice with subcutaneously transplanted MDA-MB-453 cells for a single administration group with an antibody-drug conjugate (2) and that with palbociclib, and for a combined administration group with the antibody-drug conjugate (2) and palbociclib. [Figure 22] Figure 22 is a diagram showing tumor growth inhibitory effects on mice with subcutaneously transplanted MDA-MB-453 cells for a single administration group with an antibody-drug conjugate (2) and that with alpelisib, and for a combined administration group with the antibody-drug conjugate (2) and alpelisib. Description of Embodiments

[0168] Hereinafter, preferred modes for carrying out the present invention are described. The embodiments described below are given merely for illustrating one example of a typical embodiment of the present invention and are not intended to limit the scope of the present invention.

[0169] 1. Antibody-drug conjugate The antibody-drug conjugate used in the present invention is an antibody-drug conjugate in which a drug- linker represented by the following formula:

[0170] wherein A represents the connecting position to an antibody, is conjugated to the antibody via a thioether bond. 10172] In the present invention, the partial structure consisting of a linker and a drug in the antibody-drug conjugate is referred to as a "drug-linker". The drug- linker is connected to a thiol group (in other words, the sulfur atom of a cysteine residue) formed at an interchain disulfide bond site (two sites between heavy chains, and two sites between a heavy chain and a light chain) in the antibody.

[0173] The drug-linker of the present invention includes exatecan (IUPAC name: (1S,9S)-l-amino-9-ethyl-5-fluoro- 1,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H, 13H~- benzo[de]pyrano[3',4':6,7]indolizino([1,2-b]quinolin- 10,13-dione, (also expressed as chemical name: (1S,9S)-1- amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl- 1H, 12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2~ blquinolin-10,13 (9H, 15H) -dione)), which is a topoisomerase 1 inhibitor, as a component. Exatecan is a camptothecin derivative having an antitumor effect, represented by the following formula:

[0174]

[0175]

[0176] The antibody-drug conjugate used in the present invention can be also represented by the following formula:

[0177] [Formula 27] Antibody

[0178] ’ wherein, the drug-linker is conjugated to an antibody via a thioether bond. The meaning of n is the same as that of what is called the average number of conjugated drug molecules (DAR; Drug-to-Antibody Ratio), and indicates the average number of units of the drug-linker conjugated per antibody molecule. After migrating into cancer cells, the antibody-drug conjugate used in the present invention is cleaved at the linker portion to release the compound represented by the following formula.

[0179]

[0180]

[0181] The aforementioned compound is inferred to be the original source of the antitumor activity of the antibody-drug conjugate used in the present invention, and has been confirmed to have a topoisomerase 1 inhibitory effect (Ogitani Y. et al., Clinical Cancer Research, 2016, Oct 15;22(20):5097-5108, Epub 2016 Mar 29).

[0182] The antibody-drug conjugate used in the present invention is known to have a bystander effect (Ogitani Y. et al., Cancer Science (2016) 107, 1039-1046).

[0183] The bystander effect is exerted through a process such that the antibody-drug conjugate used in the present invention is internalized in cancer cells expressing a target and the aforementioned compound is released then exerts an antitumor effect also on cancer cells which are present therearound and not expressing the target.

[0184] This bystander effect is exerted as an excellent antitumor effect even when the antibody-drug conjugate is used in combination with a kinase inhibitor according to the present invention.

[0185] 2. Antibody in antibody-drug conjugate The antibody in the antibody-drug conjugate used in the present invention may be derived from any species, and is preferably an antibody derived from a human, a rat, a mouse, or a rabbit. In cases when the antibody is derived from species other than human species, it is preferably chimerized or humanized using a well known technique. The antibody of the present invention may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody.

[0186] The antibody in the antibody-drug conjugate used in the present invention is an antibody preferably having a characteristic of being capable of targeting cancer cells, and is preferably an antibody possessing, for example, a property of recognizing a cancer cell, a property of binding to a cancer cell, a property of internalizing in a cancer cell, and / or cytocidal activity against cancer cells.

[0187] The binding activity of the antibody against cancer cells can be confirmed using flow cytometry. The internalization of the antibody into cancer cells can be confirmed using (1) an assay of visualizing an antibody incorporated in cells under a fluorescence microscope using a secondary antibody (fluorescently labeled) binding to the therapeutic antibody (Cell Death and Differentiation (2008) 15, 751-761), (2) an assay of measuring a fluorescence intensity incorporated in cells using a secondary antibody (fluorescently labeled) binding to the therapeutic antibody (Molecular Biology of the Cell, Vol. 15, 5268-5282, December 2004), or (3) a Mab-ZAP assay using an immunotoxin binding to the therapeutic antibody wherein the toxin is released upon incorporation into cells to inhibit cell growth (Bio Techniques 28: 162-165, January 2000). As the immunotoxin, a recombinant complex protein of a diphtheria toxin catalytic domain and protein G may be used.

[0188] The antitumor activity of the antibody can be confirmed in vitro by determining inhibitory activity against cell growth. For example, a cancer cell line overexpressing a target protein for the antibody is cultured, and the antibody is added at varying concentrations into the culture system to determine inhibitory activity against focus formation, colony formation, and spheroid growth. The antitumor activity can be confirmed in vivo, for example, by administering the antibody to a nude mouse with a transplanted cancer cell line highly expressing the target protein, and determining change in the cancer cell.

[0189] Since the compound conjugated in the antibody-drug conjugate exerts an antitumor effect, it is preferred but not essential that the antibody itself should have an antitumor effect. For the purpose of specifically and selectively exerting the cytotoxic activity of the antitumor compound against cancer cells, it is important and also preferred that the antibody should have the property of internalizing to migrate into cancer cells.

[0190] The antibody in the antibody-drug conjugate used in the present invention can be obtained by a procedure known in the art. For example, the antibody of the present invention can be obtained using a method usually carried out in the art, which involves immunizing animals with an antigenic polypeptide and collecting and purifying antibodies produced in vivo. The origin of the antigen is not limited to humans, and the animals may be immunized with an antigen derived from a non-human animal such as a mouse, a rat and the like. In this case, the cross-reactivity of antibodies binding to the obtained heterologous antigen with human antigens can be tested to screen for an antibody applicable to a human disease.

[0191] Alternatively, antibody-producing cells which produce antibodies against the antigen are fused with myeloma cells according to a method known in the art (e.g., Kohler and Milstein, Nature (1975) 256, p. 495- 497; and Kennet, R. ed., Monoclonal Antibodies, p. 365- 367, Plenum Press, N.Y. (1980)) to establish hybridomas, from which monoclonal antibodies can in turn be obtained.

[0192] The antigen can be obtained by genetically engineering host cells to produce a gene encoding the antigenic protein. Specifically, vectors that permit expression of the antigen gene are prepared and transferred to host cells so that the gene is expressed. The antigen thus expressed can be purified. The antibody can also be obtained by a method of immunizing animals with the above-described genetically engineered antigen- expressing cells or a cell line expressing the antigen.

[0193] The antibody in the antibody-drug conjugate used in the present invention is preferably a recombinant antibody obtained by artificial modification for the purpose of decreasing heterologous antigenicity to humans such as a chimeric antibody or a humanized antibody, or is preferably an antibody having only the gene sequence of an antibody derived from a human, that is, a human antibody. These antibodies can be produced using a known method.

[0194] As the chimeric antibody, an antibody in which antibody variable and constant regions are derived from different species, for example, a chimeric antibody in which a mouse- or rat-derived antibody variable region is connected to a human-derived antibody constant region can be exemplified (Proc. Natl. Acad. Sci. USA, 81, 6851-6855, (1984)).

[0195] As the humanized antibody, an antibody obtained by integrating only the complementarity determining region (CDR) of a heterologous antibody into a human-derived antibody (Nature (1986) 321, pp. 522-525), and an antibody obtained by grafting a part of the amino acid residues of the framework of a heterologous antibody as well as the CDR sequence of the heterologous antibody to a human antibody by a CDR-grafting method (International Publication No. WO 90 / 07861), and an antibody humanized using a gene conversion mutagenesis strategy (U.S. Patent No. 5821337) can be exemplified.

[0196] As the human antibody, an antibody generated by using a human antibody-producing mouse having a human chromosome fragment including genes of a heavy chain and light chain of a human antibody (see Tomizuka, K. et al., Nature Genetics (1997) 16, p.133-143; Kuroiwa, Y. et. al., Nucl. Acids Res. (1998) 26, p.3447-3448; Yoshida, H. et. al., Animal Cell Technology:Basic and Applied Aspects vol.10, p.69-73 (Kitagawa, Y., Matsuda, T. and Iijima, S. eds.), Kluwer Academic Publishers, 1999; Tomizuka, K. et. al., Proc. Natl. Acad. Sci. USA (2000) 97, p.722-727, etc.) can be exemplified. As an alternative, an antibody obtained by phage display, the antibody being selected from a human antibody library (see Wormstone, I. M. et. al, Investigative Ophthalmology & Visual Science. (2002)43 (7), p.2301-2308; Carmen, S. et. al., Briefings in Functional Genomics and Proteomics (2002), 1(2), p.189-203; Siriwardena, D. et. al., Ophthalmology (2002) 109(3), p.427-431, etc.) can be exemplified.

[0197] In the antibody in the antibody-drug conjugate used in present invention, modified variants of the antibody are also included. The modified variant refers to a variant obtained by subjecting the antibody according to the present invention to chemical or biological modification. Examples of the chemically modified variant include variants including a linkage of a chemical moiety to an amino acid skeleton, variants including a linkage of a chemical moiety to an N-linked or O-linked carbohydrate chain, etc. Examples of the biologically modified variant include variants obtained by post-translational modification (such as N-linked or O-linked glycosylation, N- or C-terminal processing, deamidation, isomerization of aspartic acid, or oxidation of methionine), and variants in which a methionine residue has been added to the N terminus by being expressed in a prokaryotic host cell. Further, an antibody labeled so as to enable the detection or isolation of the antibody or an antigen according to the present invention, for example, an enzyme-labeled antibody, a fluorescence-labeled antibody, and an affinity-labeled antibody are also included in the meaning of the modified variant. Such a modified variant of the antibody according to the present invention is useful for improving the stability and blood retention of the antibody, reducing the antigenicity thereof, detecting or isolating an antibody or an antigen, and so on.

[0198] Further, by regulating the modification of a glycan which is linked to the antibody according to the present invention (glycosylation, defucosylation, etc.), it is possible to enhance antibody-dependent cellular cytotoxic activity. As the technique for regulating the modification of a glycan of antibodies, International Publication No. WO 99 / 54342, International Publication No. WO 00 / 61739, International Publication No. WO 02 / 31140, International Publication No. WO 2007 / 133855, International Publication No. WO 2013 / 120066, etc. are known. However, the technique is not limited thereto. In the antibody according to the present invention, antibodies in which the modification of a glycan is regulated are also included.

[0199] It is known that a lysine residue at the carboxyl terminus of the heavy chain of an antibody produced in a cultured mammalian cell is deleted (Journal of Chromatography A, 705: 129-134 (1995)), and it is also known that two amino acid residues (glycine and lysine) at the carboxyl terminus of the heavy chain of an antibody produced in a cultured mammalian cell are deleted and a proline residue newly located at the carboxyl terminus is amidated (Analytical Biochemistry, 360: 75-83 (2007)). However, such deletion and modification of the heavy chain sequence do not affect the antigen-binding affinity and the effector function (the activation of complement, antibody-dependent cellular cytotoxicity, etc.) of the antibody. Therefore, in the antibody according to the present invention, antibodies subjected to such modification and functional fragments of the antibody are also included, and deletion variants in which one or two amino acids have been deleted at the carboxyl terminus of the heavy chain, variants obtained by amidation of deletion variants (for example, a heavy chain in which the carboxyl terminal proline residue has been amidated), and the like are also included. The type of deletion variant having a deletion at the carboxyl terminus of the heavy chain of the antibody according to the present invention is not limited to the above variants as long as the antigen- binding affinity and the effector function are conserved. The two heavy chains constituting the antibody according to the present invention may be of one type selected from the group consisting of a full-length heavy chain and the above-described deletion variant, or may be of two types in combination selected therefrom. The ratio of the amount of each deletion variant can be affected by the type of cultured mammalian cells which produce the antibody according to the present invention and the culture conditions. However, an antibody in which one amino acid residue at the carboxyl terminus has been deleted in both of the two heavy chains in the antibody according to the present invention can be preferably exemplified.

[0200] As isotypes of the antibody according to the present invention, for example, IgG (IgGl, IgG2, IgG3, IgG4) can be exemplified. Preferably, IgGl or IgG2 can be exemplified.

[0201] Examples of antibodies in the antibody-drug conjugate used in the present invention include, but are not limited to, an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-CDH6 antibody, an anti-CD3 antibody, an anti-CD30 antibody, an anti-CD33 antibody, an anti-CD37 antibody, an anti-CD56 antibody, an anti-CD98 antibody, an anti-DR5 antibody, an anti-EGFR antibody, an anti-EPHA2 antibody, an anti-FGFR2 antibody, an anti-FGFR4 antibody, an anti- FOLR1 antibody, an anti-VEGF antibody, an anti-CD20 antibody, an anti-CD22 antibody, an anti-CD70 antibody, an anti-PSMA antibody, an anti-CEA antibody, an anti- Mesothelin antibody, an anti-A33 antibody, an anti-CanAg antibody, an anti-Cripto antibody, an anti-G250 antibody, an anti-MUCl antibody, an anti-GPNMB antibody, an anti- Integrin antibody, an anti-Tenascin-C antibody, and an anti-SLC44A4 antibody. Further an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, and an anti-CDH6 antibody can be preferably exemplified.

[0202] In the present invention, the term "anti-HER2 antibody" refers to an antibody which binds specifically to HER2 (Human Epidermal Growth Factor Receptor Type 2; ErbB-2), and preferably has an activity of internalization in HER2-expressing cells by binding to HERZ.

[0203] Examples of the anti-HER2 antibody include trastuzumab (U.S. Patent No. 5821337) and pertuzumab (International Publication No. WO 01 / 00245). Preferably, trastuzumab can be exemplified.

[0204] In the present invention, the term "anti-HER3 antibody" refers to an antibody which binds specifically to HER3 (Human Epidermal Growth Factor Receptor Type 3; ErbB-3), and preferably has an activity of internalization in HER3-expressing cells by binding to HERZ.

[0205] Examples of the anti-HER3 antibody include patritumab (U3-1287), Ul-59 (International Publication No. WO 2007 / 077028), MM-121 (seribantumab), an anti-ERBB3 antibody described in International Publication No. WO 2008 / 100624, RG-7116 (lumretuzumab), and LJIM-716 (elgemtumab). Preferably, patritumab and Ul-59 can be exemplified.

[0206] In the present invention, the term "anti-TROP2 antibody" refers to an antibody which binds specifically to TROP2 (TACSTD2: Tumor-associated calcium signal transducer 2; EGP-1), and preferably has an activity of internalization in TROP2-expressing cells by binding to TROP2.

[0207] Examples of the anti-TROP2 antibody include hTINAl- H1Ll (International Publication No. WO 2015 / 098099).

[0208] In the present invention, the term "anti-B7-H3 antibody" refers to an antibody which binds specifically to B7-H3 (B cell antigen #7 homolog 3; PD-L3; CD276), and preferably has an activity of internalization in B7-H3- expressing cells by binding to B7-H3.

[0209] Examples of the anti-B7-H3 antibody include M30-H1l- L4 (International Publication No. WO 2014 / 057687).

[0210] In the present invention, the term "anti-CDH6 antibody" refers to an antibody which binds specifically to CDH6 (Cadherin-6), and preferably has an activity of internalization in CDH6-expressing cells by binding to CDH6.

[0211] Examples of the anti-CDH6 antibody include HO1LO02 (International Publication No. WO 2018 / 212136).

[0212] 3. Production of antibody-drug conjugate A drug-linker intermediate for use in production of the antibody-drug conjugate according to the present invention is represented by the following formula.

[0213] The drug-linker intermediate can be expressed as the chemical name N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl) hexanoyl]lglycylglycyl-L-phenylalanyl-N-[ (2-{[(1S,98)- 9-ethyl-5-fluoro-9-hydroxy-4-methyl-10, 13-dioxo- 2,3,9,10,13,15-hexahydro-1H, 12H- benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1- yllamino}-2-oxoethoxy)methyl]lglycinamide, and can be produced with reference to descriptions in International Publication No. WO 2014 / 057687, International Publication No. WO 2015 / 098099, International Publication No. WO 2015 / 115091, International Publication No. WO 2015 / 155998, International Publication No. WO 2019 / 044947, and so on.

[0215] The antibody-drug conjugate used in the present invention can be produced by reacting the above-described drug-linker intermediate and an antibody having a thiol group (alternatively referred to as a sulfhydryl group).

[0216] The antibody having a sulfhydryl group can be obtained by a method well known in the art (Hermanson, G. T, Bioconjugate Techniques, pp. 56-136, pp. 456-493, Academic Press (1996)). For example, by using 0.3 to 3 molar equivalents of a reducing agent such as tris (2- carboxyethyl) phosphine hydrochloride (TCEP) per interchain disulfide within the antibody and reacting with the antibody in a buffer solution containing a chelating agent such as ethylenediamine tetraacetic acid (EDTA), an antibody having a sulfhydryl group with partially or completely reduced interchain disulfides within the antibody can be obtained.

[0217] Further, by using 2 to 20 molar equivalents of the drug-linker intermediate per the antibody having a sulfhydryl group, an antibody-drug conjugate in which 2 to 8 drug molecules are conjugated per antibody molecule can be produced.

[0218] The average number of conjugated drug molecules per antibody molecule of the antibody-drug conjugate produced can be determined, for example, by a method of calculation based on measurement of UV absorbance for the antibody-drug conjugate and the conjugation precursor thereof at two wavelengths of 280 nm and 370 nm (UV method), or a method of calculation based on quantification through HPLC measurement for fragments obtained by treating the antibody-drug conjugate with a reducing agent (HPLC method).

[0219] Conjugation between the antibody and the drug-linker intermediate and calculation of the average number of conjugated drug molecules per antibody molecule of the antibody-drug conjugate can be performed with reference to descriptions in International Publication No. WO 2014 / 057687, International Publication No. WO 2015 / 098099, International Publication No. WO 2015 / 115091, International Publication No. WO 2015 / 155998, International Publication No. WO 2017 / 002776, International Publication No. WO 2018 / 212136, and so on.

[0220] In the present invention, the term "anti-HER2 antibody-drug conjugate" refers to an antibody-drug conjugate such that the antibody in the antibody-drug conjugate according to the present invention is an anti- HER2 antibody.

[0221] The anti-HER2 antibody is preferably an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 consisting of an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 consisting of an amino acid sequence consisting of amino acid residues 97 to 109 of SEQ ID NO: 1, and a light chain comprising CDRL1 consisting of an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 consisting of an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2; more preferably an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 120 of SEQ ID NO: .. and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 107 of SEQ ID NO: 2; and even more preferably an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: . and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 2, or an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: .. and a light chain consisting of an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2.

[0222] The average number of units of the drug-linker conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 8, even more preferably 7 to 8, even more preferably 7.5 to 8, and even more preferably about 8.

[0223] The anti-HER2 antibody-drug conjugate used in the present invention can be produced with reference to descriptions in International Publication No. WO 2015 / 115091 and so on.

[0224] In the present invention, the term "anti-HER3 antibody-drug conjugate" refers to an antibody-drug conjugate such that the antibody in the antibody-drug conjugate according to the present invention is an anti- HER3 antibody.

[0225] The anti-HER3 antibody is preferably an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence consisting of amino acid residues 26 to 35 of SEQ ID NO: 3, CDRH2 consisting of an amino acid sequence consisting of amino acid residues 50 to 65 of SEQ ID NO: 3, and CDRH3 consisting of an amino acid sequence consisting of amino acid residues 98 to 106 of SEQ ID NO: 3, and a light chain comprising CDRL1 consisting of an amino acid sequence consisting of amino acid residues 24 to 39 of SEQ ID NO: 4, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 56 to 62 of SEQ ID NO: 4, and CDRL3 consisting of an amino acid sequence consisting of amino acid residues 95 to 103 of SEQ ID NO: 4; more preferably an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 117 of SEQ ID NO: 3 and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 113 of SEQ ID NO: 4; and even more preferably an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 3 and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 4, or a variant of the antibody in which the lysine residue at the carboxyl terminus of the heavy chain is deleted.

[0226] The average number of units of the drug-linker conjugated per antibody molecule in the anti-HER3 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 8, even more preferably 7 to 8, even more preferably 7.5 to 8, and even more preferably about 8.

[0227] The anti-HER3 antibody-drug conjugate can be produced with reference to descriptions in International Publication No. WO 2015 / 155998 and so on.

[0228] In the present invention, the term "anti-TROP2 antibody-drug conjugate" refers to an antibody-drug conjugate such that the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[0229] The anti-TROP2 antibody is preferably an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence consisting of amino acid residues 50 to 54 of SEQ ID NO: 5, CDRH2 consisting of an amino acid sequence consisting of amino acid residues 69 to 85 of SEQ ID NO: 5, and CDRH3 consisting of an amino acid sequence consisting of amino acid residues 118 to 129 of SEQ ID NO: 5, and a light chain comprising CDRL1 consisting of an amino acid sequence consisting of amino acid residues 44 to 54 of SEQ ID NO: 6, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 70 to 76 of SEQ ID NO: 6, and CDRL3 consisting of an amino acid sequence consisting of amino acid residues 109 to 117 of SEQ ID NO: 6; more preferably an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 140 of SEQ ID NO: 5 and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 129 of SEQ ID NO: 6; and even more preferably an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 5 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 6, or a variant of the antibody in which the lysine residue at the carboxyl terminus of the heavy chain is deleted.

[0230] The average number of units of the drug-linker conjugated per antibody molecule in the anti-TROP2 antibody-drug conjugate used in the present invention is preferably 2 to 8, more preferably 3 to 5, even more preferably 3.5 to 4.5, and even more preferably about 4.

[0231] The anti-TROP2 antibody-drug conjugate can be produced with reference to descriptions in International Publication No. WO 2015 / 098099, International Publication No. WO 2017 / 002776, and so on.

[0232] In the present invention, the term "anti-B7-H3 antibody-drug conjugate" refers to an antibody-drug conjugate such that the antibody in the antibody-drug conjugate according to the present invention is an anti- B7-H3 antibody.

[0233] The anti-B7-H3 antibody is preferably an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence consisting of amino acid residues 50 to 54 of SEQ ID NO: 7, CDRH2 consisting of an amino acid sequence consisting of amino acid residues 69 to 85 of SEQ ID NO: 7, and CDRH3 consisting of an amino acid sequence consisting of amino acid residues 118 to 130 of SEQ ID NO: 7, and a light chain comprising CDRL1 consisting of an amino acid sequence consisting of amino acid residues 44 to 53 of SEQ ID NO: 8, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 69 to 75 of SEQ ID NO: 8, and CDRL3 consisting of an amino acid sequence consisting of amino acid residues 108 to 116 of SEQ ID NO: 8; more preferably an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 141 of SEQ ID NO: 7 and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 128 of SEQ ID NO: 8; and even more preferably an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 7 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 8, or a variant of the antibody in which the lysine residue at the carboxyl terminus of the heavy chain is deleted.

[0234] The average number of units of the drug-linker conjugated per antibody molecule in the anti-B7-H3 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 5, even more preferably 3.5 to 4.5, and even more preferably about 4.

[0235] The anti-B7-H3 antibody-drug conjugate used in the present invention can be produced with reference to descriptions in International Publication No. WO 2014 / 057687, International Publication No. WO 2017 / 002776, and so on.

[0236] In the present invention, the term "anti-CDH6 antibody-drug conjugate" refers to an antibody-drug conjugate such that the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[0237] The anti-CDH6 antibody is preferably an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence consisting of amino acid residues 45 to 54 of SEQ ID NO: 9, CDRH2 consisting of an amino acid sequence consisting of amino acid residues 69 to 78 of SEQ ID NO: 9, and CDRH3 consisting of an amino acid sequence consisting of amino acid residues 118 to 130 of SEQ ID NO: 9, and a light chain comprising CDRL1 consisting of an amino acid sequence consisting of amino acid residues 44 to 54 of SEQ ID NO: 10, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 70 to 76 of SEQ ID NO: 10, and CDRL3 consisting of an amino acid sequence consisting of amino acid residues 109 to 116 of SEQ ID NO: 10; more preferably an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 141 of SEQ ID NO: 9 and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 128 of SEQ ID NO: 10; and even more preferably an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 10, or a variant of the antibody in which the lysine residue at the carboxyl terminus of the heavy chain is deleted.

[0238] The average number of units of the drug-linker conjugated per antibody molecule in the anti-CDH6 antibody-drug conjugate used in the present invention is preferably 2 to 8, more preferably 3 to 8, even more preferably 7.5 to 8, and even more preferably about 8.

[0239] The anti-CDH6 antibody-drug conjugate used in the present invention can be produced with reference to descriptions in International Publication No. WO 2018 / 212136 and so on.

[0240] 4. Kinase inhibitor In the present invention, the term "kinase inhibitor" refers to an agent that inhibits a kinase involved in cancer cell growth and tumor angiogenesis. As the kinase inhibitor in the present invention, at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an AKT inhibitor, an ERK inhibitor, an MEK inhibitor, an RAF inhibitor, a CDKl inhibitor, a CDK2 inhibitor, a CHK1 inhibitor, a WEEl inhibitor, a PLKl inhibitor, an Aurora kinase inhibitor, a Bcr-Abl inhibitor, an Src inhibitor, an EPH inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, a BTK inhibitor, an FLT3 inhibitor, an ALK inhibitor, a JAK inhibitor, an MET inhibitor, a CSF-1R inhibitor, an NTRK inhibitor, an EGFR inhibitor, and an HERZ2 inhibitor can be exemplified.

[0241] The term "pharmacologically acceptable salt" of the kinase inhibitor used in the present invention may be either an acid addition salt or a base addition salt. Examples of the acid addition salt can include lower alkanesulfonates such as camsylate (camphorsulfonate), mesylate (methanesulfonate), trifluoromethanesulfonate, and ethanesulfonate; arylsulfonates such as tosylate (p- toluenesulfonate) and benzenesulfonate; inorganic acid salts such as phosphate, nitrate, perchlorate, and sulfate; hydrogen halide salts such as hydrochloride, hydrobromide, hydroiodide, and hydrofluoride; organic acid salts such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalate, and maleate; and amino acid salts such as ornithinate, glutamate, and aspartate. Examples of the base addition salt can include alkali metal salts such as sodium salt, potassium salt, and lithium salt; alkali earth metal salts such as calcium salt and magnesium salt; inorganic salts such as ammonium salt; organic amine salts such as dibenzylamine salt, morpholine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N,N'- dibenzylethylenediamine salt, diethanolamine salt, N- benzyl-N- (2-phenylethoxy) amine salt, piperazine salt, tetramethylammonium salt, and tris (hydroxymethyl)aminomethane salt; and amino acid salts such as alginate.

[0242] The kinase inhibitor and pharmacologically acceptable salts thereof used in the present invention may each exist as a solvate, and solvates of them are also included in the meaning of the kinase inhibitor and pharmacologically acceptable salts thereof used in the present invention.

[0243] In the present invention, the term "CDK4 / 6 inhibitor" refers to an agent that inhibits cyclin dependent kinase 4 (CDK4) and inhibits cyclin dependent kinase 6 (CDK6). The CDK4 / 6 inhibitor in the present invention may have an effect of inhibiting a kinase other than CDK4 / 6. The CDK4 / 6 inhibitor in the present invention is not particularly limited as long as it is an agent that has the described characteristics, and preferred examples thereof can include abemaciclib (U.S. Patent No. 7855211), palbociclib (U.S. Patent No. 6936612), ribociclib (U.S. Patent No. 91393732), trilaciclib (International Publication No. WO 2012 / 061156), G1T38 (Oncotarget 2017, 8(26): 42343-42358), PF-06873600 (International Publication No. WO 2018 / 033815), TP-1287 (International Publication No. WO 2016 / 187316), FN-1501 (J Med Chem 2018, 61(4): 1499-1518), and KRX-0601 (International Publication No. WO 1989 / 007105), and pharmacologically acceptable salts thereof.

[0244] PF-06873600 and FN-1501 and pharmacologically acceptable salts thereof are each also known as a CDK2 inhibitor. TP-1287 and pharmacologically acceptable salts thereof are each also known as a CDKl inhibitor and a CDK2 inhibitor. KRX-0601 and pharmacologically acceptable salts thereof are each also known as a PI3K inhibitor, a CDKl inhibitor, a CDK2 inhibitor, and a CHK1 inhibitor.

[0245] In the present invention, the term "mTOR inhibitor" refers to an agent that inhibits mTOR (Mammalian target of Rapamycin), one of the serine / threonine kinases. The mTOR inhibitor in the present invention may have an effect of inhibiting a kinase other than mTOR. The mTOR inhibitor in the present invention is not particularly limited as long as it is an agent that has the described characteristics, and preferred examples thereof can include everolimus (U.S. Patent No. 5665772), sirolimus (U.S. Patent No. 5989591), temsirolimus (U.S. Patent No. 5362718), TAK-228 (Cancer Chemother Pharmacol 2017, 80(2): 261-273), CC-223 (J Med Chem 2015, 58(13): 5323- 5333), AZD8055 (Cancer Res 2010, 70(1l): 288-98), dactolisib (Invest New Drugs 2015, 33(2): 463-71), apitolisib (International Publication No. WO 2008 / 070740), gedatolisib (International Publication No. WO 2009 / 143313), LY3023414 (Mol Cancer Ther 2016, 15(10): 2344-2356), PF-04691502 (Mol Cancer Ther 2011, 10(11): 2189-99), NVP-BGT226 (Ann Oncol 2012, 23(9): 2399-408), and PQR30% (J Med Chem 2017, 60(17): 7524-7538), and pharmacologically acceptable salts thereof.

[0246] Dactolisib, apitolisib,...

Claims

Claims

1. A pharmaceutical composition wherein an antibody- drug conjugate and a kinase inhibitor are administered in combination, and the antibody-drug conjugate is an antibody-drug conjugate in which a drug-linker represented by the following formula: wherein A represents a connecting position to an antibody, is conjugated to the antibody via a thiocether bond, and the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an AKT inhibitor, an ERK inhibitor, an MEK inhibitor, an RAF inhibitor, a CDK1l inhibitor, a CDK2 inhibitor, a CHK1l inhibitor, a WEEl inhibitor, a PLK1l inhibitor, an Aurora kinase inhibitor, a Bcr-Abl inhibitor, an Src inhibitor, an EPH inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, a BTK inhibitor, an FLT3 inhibitor, an ALK inhibitor, a JAK inhibitor, an MET inhibitor, a CSF-1R inhibitor, an NTRK inhibitor, an EGFR inhibitor, and an HER2 inhibitor.

2. The pharmaceutical composition according to claim 1, wherein the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an RAF inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, an FLT3 inhibitor, an ALK inhibitor, a CSF-1R inhibitor, an EGFR inhibitor, and an HER2 inhibitor.

3. The pharmaceutical composition according to claim 2, wherein the kinase inhibitor is a CDK4 / 6 inhibitor.

4. The pharmaceutical composition according to claim 3, wherein the CDK4 / 6 inhibitor is abemaciclib, palbociclib, ribociclib, trilaciclib, G1T38, PF-06873600, TP-1287, FN- 1501, or KRX-0601, or a pharmacologically acceptable salt thereof.

5. The pharmaceutical composition according to claim 2, wherein the kinase inhibitor is an mTOR inhibitor.

6. The pharmaceutical composition according to claim 5, wherein the mTOR inhibitor is everolimus, sirolimus, temsirolimus, TAK-228, CC-223, AzZD8055, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP- BGT226, or PQR309, or a pharmacologically acceptable salt thereof.

7. The pharmaceutical composition according to claim 2, wherein the kinase inhibitor is a PI3K inhibitor.

8. The pharmaceutical composition according to claim 7, wherein the PI3K inhibitor is taselisib, alpelisib, TAK- 117, GSK2636771, AzZD8186, IPI-549, idelalisib, duvelisib, AMG319, buparlisib, pictilisib, pilaralisib, copanlisib, sonolisib, CH5132799, ZSTK474, GDC-0077, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP- BGT226, PQR309, KRX-0601, or rigosertib, or a pharmacologically acceptable salt thereof.

9. The pharmaceutical composition according to claim 2, wherein the kinase inhibitor is an RAF inhibitor.

10. The pharmaceutical composition according to claim 9, wherein the RAF inhibitor is regorafenib, sorafenib, vemurafenib, dabrafenib, encorafenib, RAF265, GDC-5573, LY3009120, or RO5126766, or a pharmacologically acceptable salt thereof.

11. The pharmaceutical composition according to claim 2, wherein the kinase inhibitor is a VEGFR inhibitor.

12. The pharmaceutical composition according to claim 11, wherein the VEGFR inhibitor is regorafenib, sorafenib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, cabozantinib, tivozanib, brivanib, linifanib, lucitanib, ilorasertib, or ENMD-2076, or a pharmacologically acceptable salt thereof.

13. The pharmaceutical composition according to claim 2, wherein the kinase inhibitor is a KIT inhibitor.

14. The pharmaceutical composition according to claim 13, wherein the KIT inhibitor is regorafenib, sorafenib, imatinib, ilorasertib, sunitinib, pazopanib, lenvatinib, or dasatinib, or a pharmacologically acceptable salt thereof.

15. The pharmaceutical composition according to claim 2, wherein the kinase inhibitor is an RET inhibitor.

16. The pharmaceutical composition according to claim 15, wherein the RET inhibitor is regorafenib, sorafenib, vandetanib, lenvatinib, or sunitinib, or a pharmacologically acceptable salt thereof.

17. The pharmaceutical composition according to claim 2, wherein the kinase inhibitor is a PDGFR inhibitor.

18. The pharmaceutical composition according to claim 17, wherein the PDGFR inhibitor is regorafenib, sorafenib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, ilorasertib, imatinib, nilotinib, or dasatinib, or a pharmacologically acceptable salt thereof.

19. The pharmaceutical composition according to claim 2, wherein the kinase inhibitor is an FGFR inhibitor.

20. The pharmaceutical composition according to claim 19, wherein the FGFR inhibitor is regorafenib, sorafenib, lenvatinib, nintedanib, axitinib, or pazopanib, or a pharmacologically acceptable salt thereof.

21. The pharmaceutical composition according to claim 2, wherein the kinase inhibitor is an FLT3 inhibitor.

22. The pharmaceutical composition according to claim 21, wherein the FLT3 inhibitor is gilteritinib, quizartinib, midostaurin, sorafenib, ilorasertib, ENMD-2076, or sunitinib, or a pharmacologically acceptable salt thereof.

23. The pharmaceutical composition according to claim 2, wherein the kinase inhibitor is an ALK inhibitor.

24. The pharmaceutical composition according to claim 23, wherein the ALK inhibitor is brigatinib, crizotinib, ceritinib, alectinib, or lorlatinib, or a pharmacologically acceptable salt thereof.

25. The pharmaceutical composition according to claim 2, wherein the kinase inhibitor is a CSF-1R inhibitor.

26. The pharmaceutical composition according to claim 25, wherein the CSF-1R inhibitor is pexidartinib, BLZ-945, JNJ-40346527, JINJ-28312141, ilorasertib, imatinib, sunitinib, or axitinib, or a pharmacologically acceptable salt thereof.

27. The pharmaceutical composition according to claim 2, wherein the kinase inhibitor is an EGFR inhibitor.

28. The pharmaceutical composition according to claim 27, wherein the EGFR inhibitor is gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

29. The pharmaceutical composition according to claim 2, wherein the kinase inhibitor is an HER2 inhibitor.

30. The pharmaceutical composition according to claim 29, wherein the HER2 inhibitor is tucatinib, neratinib, mubritinib, lapatinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

31. The pharmaceutical composition according to any one of claims 1 to 30, wherein the antibody in the antibody- drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, or an anti-CDH6é antibody.

32. The pharmaceutical composition according to claim 31, wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

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

2.

34. The pharmaceutical composition according to claim 32, wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 120 of SEQ ID NO: . and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 107 of SEQ ID NO:

2.

35. The pharmaceutical composition according to claim 32, wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: .. and a light chain consisting of an amino acid sequence represented by SEQ ID NO:

2.

36. The pharmaceutical composition according to claim 32, wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: and a light chain consisting of an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: beam

37. The pharmaceutical composition according to any one of claims 32 to 36, wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

38. The pharmaceutical composition according to claim 31, wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

39. The pharmaceutical composition according to claim 38, wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 3 and a light chain consisting of the amino acid sequence represented by SEQ ID NO:

4.

40. The pharmaceutical composition according to claim 39, wherein the anti-HER3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

41. The pharmaceutical composition according to any one of claims 38 to 40, wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

42. The pharmaceutical composition according to claim 31, wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

43. The pharmaceutical composition according to claim 42, wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 5 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO:

6.

44. The pharmaceutical composition according to claim 43, wherein the anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

45. The pharmaceutical composition according to any one of claims 42 to 44, wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.

5.

46. The pharmaceutical composition according to claim 31, wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

47. The pharmaceutical composition according to claim 46, wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 7 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO:

8.

48. The pharmaceutical composition according to claim 47, wherein the anti-B7-H3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

49. The pharmaceutical composition according to any one of claims 46 to 48, wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.

5.

50. The pharmaceutical composition according to claim 31, wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

51. The pharmaceutical composition according to claim 50, wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO:

10.

52. The pharmaceutical composition according to claim 51, wherein the anti-CDH6 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

53. The pharmaceutical composition according to any one of claims 50 to 52, wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

54. The pharmaceutical composition according to any one of claims 1 to 53, wherein the antibody-drug conjugate and the kinase inhibitor are separately contained as active components in different formulations, and are administered simultaneously or at different times.

55. The pharmaceutical composition according to any one of claims 1 to 54, wherein the pharmaceutical composition is for use in treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head- and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, endometrial cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.

56. The pharmaceutical composition according to claim 55, wherein the pharmaceutical composition is for use in treating breast cancer.

57. The pharmaceutical composition according to claim 55, wherein the pharmaceutical composition is for use in treating colorectal cancer.

58. The pharmaceutical composition according to claim 55, wherein the pharmaceutical composition is for use in treating gastric cancer.

59. The pharmaceutical composition according to claim 55, wherein the pharmaceutical composition is for use in treating lung cancer.

60. The pharmaceutical composition according to claim 55, wherein the pharmaceutical composition is for use in treating pancreatic cancer.

61. The pharmaceutical composition according to claim 55, wherein the pharmaceutical composition is for use in treating kidney cancer.

62. The pharmaceutical composition according to claim 55, wherein the pharmaceutical composition is for use in treating ovarian cancer.

63. A pharmaceutical composition wherein an antibody- drug conjugate and a kinase inhibitor are administered in combination, and the antibody-drug conjugate is an antibody-drug conjugate represented by the following formula: [Formula 2] n wherein a drug-linker is conjugated to an antibody via a thioether bond, and n indicates the average number of units of the drug-linker conjugated per antibody molecule, and the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an AKT inhibitor, an ERK inhibitor, an MEK inhibitor, an RAF inhibitor, a CDK1l inhibitor, a CDK2 inhibitor, a CHK1 inhibitor, a WEEl inhibitor, a PLKl inhibitor, an Aurora kinase inhibitor, a Bcr-Abl inhibitor, an Src inhibitor, an EPH inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, a BTK inhibitor, an FLT3 inhibitor, an ALK inhibitor, a JAK inhibitor, an MET inhibitor, a CSF-1R inhibitor, an NTRK inhibitor, an EGFR inhibitor, and an HER2 inhibitor.

64. The pharmaceutical composition according to claim 63, wherein the kinase inhibitor is at least one selected from the group consisting of a CDK4 / 6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an RAF inhibitor, a VEGFR inhibitor, a KIT inhibitor, an RET inhibitor, a PDGFR inhibitor, an FGFR inhibitor, an FLT3 inhibitor, an ALK inhibitor, a CSF-1R inhibitor, an EGFR inhibitor, and an HERZ? inhibitor.

65. The pharmaceutical composition according to claim 64, wherein the kinase inhibitor is a CDK4 / 6 inhibitor.

66. The pharmaceutical composition according to claim 65, wherein the CDK4 / 6 inhibitor is abemaciclib, palbociclib, ribociclib, trilaciclib, G1T38, PF-06873600, TP-1287, FN- 1501, or KRX-0601, or a pharmacologically acceptable salt thereof.

67. The pharmaceutical composition according to claim 64, wherein the kinase inhibitor is an mTOR inhibitor.

68. The pharmaceutical composition according to claim 67, wherein the mTOR inhibitor is everolimus, sirolimus, temsirolimus, TAK-228, CC-223, AzZD8055, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP- BGT226, or PQR309, or a pharmacologically acceptable salt thereof.

69. The pharmaceutical composition according to claim 64, wherein the kinase inhibitor is a PI3K inhibitor.

70. The pharmaceutical composition according to claim 69, wherein the PI3K inhibitor is taselisib, alpelisib, TAK- 117, GSK2636771, AZD8186, IPI-549, idelalisib, duvelisib, AMG319, buparlisib, pictilisib, pilaralisib, copanlisib, sonolisib, CH5132799, ZSTK474, GDC-0077, dactolisib, apitolisib, gedatolisib, LY3023414, PF-04691502, NVP- BGT226, PQR309, KRX-0601, or rigosertib, or a pharmacologically acceptable salt thereof.

71. The pharmaceutical composition according to claim 64, wherein the kinase inhibitor is an RAF inhibitor.

72. The pharmaceutical composition according to claim 71, wherein the RAF inhibitor is regorafenib, sorafenib, vemurafenib, dabrafenib, encorafenib, RAF265, GDC-5573, LY3009120, or RO5126766, or a pharmacologically acceptable salt thereof.

73. The pharmaceutical composition according to claim 64, wherein the kinase inhibitor is a VEGFR inhibitor.

74. The pharmaceutical composition according to claim 73, wherein the VEGFR inhibitor is regorafenib, sorafenib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, cabozantinib, tivozanib, brivanib, linifanib, lucitanib, ilorasertib, or ENMD-2076, or a pharmacologically acceptable salt thereof.

75. The pharmaceutical composition according to claim 64, wherein the kinase inhibitor is a KIT inhibitor.

76. The pharmaceutical composition according to claim 75, wherein the KIT inhibitor is regorafenib, sorafenib, imatinib, ilorasertib, sunitinib, pazopanib, lenvatinib, or dasatinib, or a pharmacologically acceptable salt thereof. [Claim 77) The pharmaceutical composition according to claim 64, wherein the kinase inhibitor is an RET inhibitor.

78. The pharmaceutical composition according to claim 77, wherein the RET inhibitor is regorafenib, sorafenib, vandetanib, lenvatinib, or sunitinib, or a pharmacologically acceptable salt thereof.

79. The pharmaceutical composition according to claim 64, wherein the kinase inhibitor is a PDGFR inhibitor.

80. The pharmaceutical composition according to claim 79, wherein the PDGFR inhibitor is regorafenib, sorafenib, sunitinib, axitinib, pazopanib, lenvatinib, nintedanib, ilorasertib, imatinib, nilotinib, or dasatinib, or a pharmacologically acceptable salt thereof.

81. The pharmaceutical composition according to claim 64, wherein the kinase inhibitor is an FGFR inhibitor.

82. The pharmaceutical composition according to claim 81, wherein the FGFR inhibitor is regorafenib, sorafenib, lenvatinib, nintedanib, axitinib, or pazopanib, or a pharmacologically acceptable salt thereof.

83. The pharmaceutical composition according to claim 64, wherein the kinase inhibitor is an FLT3 inhibitor.

84. The pharmaceutical composition according to claim 83, wherein the FLT3 inhibitor is gilteritinib, quizartinib, midostaurin, sorafenib, ilorasertib, ENMD-2076, or sunitinib, or a pharmacologically acceptable salt thereof.

85. The pharmaceutical composition according to claim 64, wherein the kinase inhibitor is an ALK inhibitor.

86. The pharmaceutical composition according to claim 85, wherein the ALK inhibitor is brigatinib, crizotinib, ceritinib, alectinib, or lorlatinib, or a pharmacologically acceptable salt thereof.

87. The pharmaceutical composition according to claim 64, wherein the kinase inhibitor is a CSF-1R inhibitor.

88. The pharmaceutical composition according to claim 87, wherein the CSF-1R inhibitor is pexidartinib, BLZ-945, JNJ-40346527, JINJ-28312141, ilorasertib, imatinib, sunitinib, or axitinib, or a pharmacologically acceptable salt thereof.

89. The pharmaceutical composition according to claim 64, wherein the kinase inhibitor is an EGFR inhibitor.

90. The pharmaceutical composition according to claim 89, wherein the EGFR inhibitor is gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

91. The pharmaceutical composition according to claim 64, wherein the kinase inhibitor is an HER2 inhibitor.

92. The pharmaceutical composition according to claim 91, wherein the HER2 inhibitor is tucatinib, neratinib, mubritinib, lapatinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.

93. The pharmaceutical composition according to any one of claims 63 to 92, wherein the antibody in the antibody- drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, or an anti-CDH6 antibody.

94. The pharmaceutical composition according to claim 93, wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

95. The pharmaceutical composition according to claim 94, wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 consisting of an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 consisting of an amino acid sequence consisting of amino acid residues 97 to 109 of SEQ ID NO: 1, and a light chain comprising CDRL1 consisting of an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 consisting of an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO:

2.

96. The pharmaceutical composition according to claim 94, wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 120 of SEQ ID NO: . and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 107 of SEQ ID NO:

2.

97. The pharmaceutical composition according to claim 94, wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: .. and a light chain consisting of an amino acid sequence represented by SEQ ID NO:

2.

98. The pharmaceutical composition according to claim 94, wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: . and a light chain consisting of an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO:

2.

99. The pharmaceutical composition according to any one of claims 94 to 98, wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

100. The pharmaceutical composition according to claim 93, wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

101. The pharmaceutical composition according to claim 100, wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 3 and a light chain consisting of the amino acid sequence represented by SEQ ID NO:

4.

102. The pharmaceutical composition according to claim 101, wherein the anti-HER3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

103. The pharmaceutical composition according to any one of claims 100 to 102, wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

104. The pharmaceutical composition according to claim 93, wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

105. The pharmaceutical composition according to claim 104, wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 5 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO:

6.

106. The pharmaceutical composition according to claim 105, wherein the anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

107. The pharmaceutical composition according to any one of claims 104 to 106, wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.

5.

108. The pharmaceutical composition according to claim 93, wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

109. The pharmaceutical composition according to claim 108, wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 7 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO:

8.

110. The pharmaceutical composition according to claim 109, wherein the anti-B7-H3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

111. The pharmaceutical composition according to any one of claims 108 to 110, wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.

5.

112. The pharmaceutical composition according to claim 93, wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

113. The pharmaceutical composition according to claim 112, wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO:

10.

114. The pharmaceutical composition according to claim 113, wherein the anti-CDH6 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

115. The pharmaceutical composition according to any one of claims 112 to 114, wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range of from 7 to 8.

116. The pharmaceutical composition according to any one of claims 63 to 115, wherein the antibody-drug conjugate and the kinase inhibitor are separately contained as active components in different formulations, and are administered simultaneously or at different times.

117. The pharmaceutical composition according to any one of claims 63 to 116, wherein the pharmaceutical composition is for use in treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, endometrial cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.

118. The pharmaceutical composition according to claim 117, wherein the pharmaceutical composition is for use in treating breast cancer.

119. The pharmaceutical composition according to claim 117, wherein the pharmaceutical composition is for use in treating colorectal cancer.

120. The pharmaceutical composition according to claim 117, wherein the pharmaceutical composition is for use in treating gastric cancer.

121. The pharmaceutical composition according to claim 117, wherein the pharmaceutical composition is for use in treating lung cancer.

122. The pharmaceutical composition according to claim 117, wherein the pharmaceutical composition is for use in treating pancreatic cancer.

123. The pharmaceutical composition according to claim 117, wherein the pharmaceutical composition is for use treating kidney cancer.

124. The pharmaceutical composition according to claim 117, wherein the pharmaceutical composition is for use treating ovarian cancer.

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