Use of antibody-drug conjugate

Abstract

A pharmaceutical composition characterized by administration of an antibody-drug conjugate and a tubulin inhibitor, wherein the antibody-drug conjugate is a drug linker of the following formula (where A represents the binding site with the antibody) and is bound to the antibody via a thioether bond; and / or a treatment method characterized by administration of the antibody-drug conjugate and the tubulin inhibitor to an individual.

Description

[Technical Field] This invention relates to a pharmaceutical composition characterized by the combination of a specific antibody-drug conjugate and a tubulin inhibitor for administration; and / or a treatment method characterized by the combination of a specific antibody-drug conjugate and a tubulin inhibitor for administration to an individual. [Previous Technology] Tubulin inhibitors are drugs that inhibit the proliferation of cancer cells by affecting microtubule dynamics, causing cell division to stop in the G2 phase (preparation phase) and / or M phase (mitosis phase) of the cell cycle, and inducing cell death through apoptosis (Non-Patent Literature 1, 2). Among tubulin inhibitors, there are agents that affect microtubule dynamics by promoting tubulin polymerization (tubulin polymerization promoters) and agents that affect microtubule dynamics by inhibiting tubulin polymerization (tubulin polymerization inhibitors). Regarding microtubule polymerization promoters, known examples include paclitaxel, docetaxel, and cabazitaxel. Regarding microtubule polymerization inhibitors, known examples include eribulin, vinblastine, vinorelbine, vindesine, brentuximab vedotin (an antibody-drug conjugate containing monomethyl auristatin E; MMAE), and trastuzumab emtansine (an antibody-drug conjugate containing DM1). Antibody-drug conjugates (ADCs), which bind antibodies that bind to antigens expressed on the surface of cancer cells and can be internalized into cells, can selectively deliver drugs to cancer cells, and are expected to accumulate drugs within cancer cells and destroy them (Non-Patent Literature 3-7). As one type of antibody-drug conjugate, antibody-drug conjugates with antibodies and derivatives of ethathecan, which are topoisomerase I inhibitors, as constituent elements are known (Patent Documents 1-7, Non-Patent Documents 8-11). Furthermore, as described in Patent Documents 1-7, the aforementioned antibody-drug conjugate can be administered together with various cancer therapeutic agents. However, no experimental results demonstrating superior combined efficacy of the aforementioned antibody-drug conjugates and microtubule inhibitors are documented, nor is there any scientific basis for such results. [Prior Art Documents] [Patent Documents] [Patent Document 1] International Publication No. 2014 / 057687 [Patent Document 2] International Publication No. 2014 / 061277 [Patent Document 3] International Publication No. 2015 / 098099 [Patent Document 4] International Publication No. 2015 / 115091 [Patent Document 5] International Publication No. 2015 / 146132 [Patent Document 6] International Publication No. 2015 / 155976 [Patent Document 7] International Publication No. 2015 / 155998 [Non-Patent Literature] [Non-Patent Literature 1] Dumontet C, et al., Nat Rev Drug Discov. 2010 Oct;9(10): 790-803. [Non-Patent Literature 2] Mukhtar E, et al., Mol Cancer Ther. 2014 Feb: 13(2): 275-284. [Non-Patent Literature 3] Ducry, L., et al., Bioconjugate Chem.(2010) 21, 5–13. [Non-Patent Literature 4] Alley, SC, et al., Current Opinion in Chemical Biology(2010) 14, 529–537. [Non-Patent Literature 5] Damle NK Expert Opin. Biol. Ther.(2004) 4, 1445-1452. [Non-Patent Literature 6] Senter PD, et al., Nature Biotechnology(2012) 30, 631-637. [Non-Patent Literature 7] Howard A. et al., J Clin Oncol 29: 398-405. [Non-Patent Literature 8] Ogitani Y. et al., Clinical Cancer Research (2016) 22(20), 5097-5108. [Non-Patent Literature 9] Ogitani Y. et al., Cancer Science (2016) 107, 1039-1046. [Non-Patent Literature 10] Doi T, et al., Lancet Oncol 2017; 18: 1512-22. [Non-Patent Literature 11] Takegawa N, et al., Int. J. Cancer: 141, 1682-1689 (2017) [Summary of the Invention] [Invention Summary] [Problem to be Solved by the Invention] The antibody-drug conjugates used in this invention (antibody-drug conjugates with ethathecan derivatives as constituent elements) have been shown to exhibit excellent antitumor effects even as a single agent. However, it is desirable to obtain a treatment method that can comprehensively inhibit the proliferation of cancer cells and exert a more superior antitumor effect by combining it with other anticancer agents with different mechanisms of action. This invention addresses the problem of providing a pharmaceutical composition and / or a treatment method, wherein the pharmaceutical composition is characterized by being administered in combination with a specific antibody-drug conjugate and a microtubule inhibitor, and the treatment method is characterized by being administered to an individual in combination with a specific antibody-drug conjugate and a microtubule inhibitor. [Means for solving the problem] The inventors, through dedicated research to solve the aforementioned problems, discovered that the combined administration of a specific antibody-drug conjugate and a microtubule inhibitor exhibited excellent synergistic effects, thus completing this invention. That is, the present invention provides the following [1] to

[344] . [1] A pharmaceutical composition characterized by being administered in combination with an antibody-drug conjugate and a tubulin inhibitor, wherein the antibody-drug conjugate is an antibody-drug conjugate in which a drug linker and an antibody are bound by a thioether bond as shown in the following formula, [Figure] (where A represents the binding position with the antibody). [2] The pharmaceutical composition as described in [1], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody. [3] The pharmaceutical composition as described in [2], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody. [4] A pharmaceutical composition as described in [3], wherein the anti-HER2 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 1 to 449 in sequence identification number 1 and a light chain composed of amino acid sequences numbered 1 to 214 in sequence identification number 2. [5] A pharmaceutical composition as described in [3], wherein the anti-HER2 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 1 in sequence identification number 1 and a light chain composed of amino acid sequences numbered 2 in sequence identification number 2. [6] A pharmaceutical composition as described in any one of [3] to [5], wherein the average number of drug linkers bound to each antibody in the antibody-drug conjugate is in the range of 7 to 8. [7] A pharmaceutical composition as described in [2], wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody. [8] A pharmaceutical composition as described in [7], wherein the anti-HER3 antibody system comprises an antibody consisting of a heavy chain composed of an amino acid sequence as described in Sequence Identification Number 3 and a light chain composed of an amino acid sequence as described in Sequence Identification Number 4. [9] A pharmaceutical composition as described in [8], wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-HER3 antibody is deleted.

[10] A pharmaceutical composition as described in any one of [7] to [9], wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[11] A pharmaceutical composition as described in [2], wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[12] The pharmaceutical composition described in

[11] , wherein the anti-TROP2 anti-system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 470 in sequence identification number 5 and a light chain composed of amino acid sequences numbered 21 to 234 in sequence identification number 6.

[13] The pharmaceutical composition described in

[12] wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-TROP2 antibody is deleted.

[14] The pharmaceutical composition described in any one of

[11] to

[13] wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[15] The pharmaceutical composition described in [2] wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[16] The pharmaceutical composition described in

[15] wherein the anti-B7-H3 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 471 in sequence identification number 7 and a light chain composed of amino acid sequences numbered 21 to 233 in sequence identification number 8.

[17] The pharmaceutical composition described in

[16] wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted.

[18] The pharmaceutical composition described in any one of

[15] to

[17] wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[19] The pharmaceutical composition described in [2] wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[20] A pharmaceutical composition as described in

[19] , wherein the anti-GPR20 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 472 in sequence identification number 9 and a light chain composed of amino acid sequences numbered 21 to 234 in sequence identification number 10.

[21] A pharmaceutical composition as described in

[20] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-GPR20 antibody is deleted.

[22] A pharmaceutical composition as described in any one of

[19] to

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

[23] A pharmaceutical composition as described in [2], wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[24] The pharmaceutical composition described in

[23] , wherein the anti-CDH6 anti-system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 471 in sequence identification number 11 and a light chain composed of amino acid sequences numbered 21 to 233 in sequence identification number 12.

[25] The pharmaceutical composition described in

[24] wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.

[26] The pharmaceutical composition described in any one of

[23] to

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

[27] The pharmaceutical composition described in any of [1] to

[26] wherein the tubulin inhibitor is paclitaxel, docetaxel, cabazitaxel, or a pharmacologically permissible salt thereof, or nab-paclitaxel.

[28] The pharmaceutical composition described in

[27] wherein the tubulin inhibitor is paclitaxel.

[29] The pharmaceutical composition described in any of [1] to

[26] wherein the tubulin inhibitor is eribulin or a pharmacologically permissible salt thereof, or an antibody-drug conjugate in which eribulin is bound to an antibody-mediated linker.

[30] A pharmaceutical composition as described in

[29] , wherein the tubulin inhibitor is eribulin mesylate.

[31] A pharmaceutical composition as described in any one of [1] to

[30] is characterized in that each individual formulation contains an antibody-drug conjugate and a tubulin inhibitor as active ingredients, and is administered simultaneously or at different times.

[32] A pharmaceutical composition as described in any one of [1] to

[31] is used for the treatment of at least one of the following groups: breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, and uterine carcinosarcoma.

[33] A pharmaceutical composition as described in

[32] is used for the treatment of breast cancer.

[34] A pharmaceutical composition as described in

[32] is used for the treatment of gastric cancer.

[35] A pharmaceutical composition as described in

[32] is used for the treatment of lung cancer.

[36] A pharmaceutical composition as described in

[32] is used for the treatment of ovarian cancer.

[37] A pharmaceutical composition as described in any one of [1] to

[36] is characterized in that a tubulin inhibitor inhibits the reduction in the expression of drug-sensing factors produced by administration of an antibody-drug conjugate.

[38] A pharmaceutical composition as described in

[37] wherein the drug-sensing factor is SLFN11.

[39] A pharmaceutical composition as described in any one of [1] to

[36] is characterized in that a tubulin inhibitor inhibits the increase in the expression of drug-sensing factors produced by administration of an antibody-drug conjugate.

[40] A pharmaceutical composition as described in

[39] wherein the drug-resistant factor is ABCG2.

[41] A pharmaceutical composition characterized by being administered in combination with an antibody-drug conjugate and a microtubule inhibitor, wherein the antibody-drug conjugate is an antibody-drug conjugate as shown in the following formula: [Figure] (wherein, the drug linker is bound to the antibody via a thioether bond, and n represents the average number of drug linkers bound per antibody).

[42] In the pharmaceutical composition described in

[41] , the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[43] In the pharmaceutical composition described in

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

[44] The pharmaceutical composition described in

[43] wherein the anti-HER2 anti-system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 1 to 449 in sequence identification number 1 and a light chain composed of amino acid sequences numbered 1 to 214 in sequence identification number 2.

[45] The pharmaceutical composition described in

[43] wherein the anti-HER2 anti-system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 1 and a light chain composed of amino acid sequences numbered 2.

[46] A pharmaceutical composition as described in any of

[43] to

[45] , wherein the average number of drug linkers in each antibody in the antibody-drug conjugate is in the range of 7 to 8.

[47] A pharmaceutical composition as described in

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

[48] A pharmaceutical composition as described in

[47] , wherein the anti-HER3 antibody system comprises an antibody consisting of a heavy chain composed of an amino acid sequence described in Sequence Identification Number 3 and a light chain composed of an amino acid sequence described in Sequence Identification Number 4.

[49] A pharmaceutical composition as described in

[48] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-HER3 antibody is deleted.

[50] A pharmaceutical composition as described in any of

[47] to

[49] , wherein the average number of drug linkers in each antibody in the antibody-drug conjugate is in the range of 7 to 8.

[51] The pharmaceutical composition described in

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

[52] The pharmaceutical composition described in

[51] wherein the anti-TROP2 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 470 in sequence identification number 5 and a light chain composed of amino acid sequences numbered 21 to 234 in sequence identification number 6.

[53] The pharmaceutical composition described in

[52] wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-TROP2 antibody is deleted.

[54] The pharmaceutical composition described in any one of

[51] to

[53] wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[55] The pharmaceutical composition described in

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

[56] The pharmaceutical composition described in

[55] , wherein the anti-B7-H3 anti-system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 471 in sequence identification number 7 and a light chain composed of amino acid sequences numbered 21 to 233 in sequence identification number 8.

[57] The pharmaceutical composition described in

[56] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted.

[58] The pharmaceutical composition described in any one of

[55] to

[57] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[59] The pharmaceutical composition described in

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

[60] The pharmaceutical composition described in

[59] contains an antibody comprising a heavy chain consisting of amino acid sequences numbered 20 to 472 in sequence identification number 9 and a light chain consisting of amino acid sequences numbered 21 to 234 in sequence identification number 10.

[61] A pharmaceutical composition as described in

[60] wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-GPR20 antibody is deleted.

[62] A pharmaceutical composition as described in any one of

[59] to

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

[63] A pharmaceutical composition as described in

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

[64] A pharmaceutical composition as described in

[63] wherein the anti-CDH6 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 471 in sequence identification number 11 and a light chain composed of amino acid sequences numbered 21 to 233 in sequence identification number 12.

[65] A pharmaceutical composition as described in

[64] wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.

[66] A pharmaceutical composition as described in any of

[63] to

[65] , wherein the average number of drug linkers bound to each antibody in the antibody-drug conjugate is in the range of 7 to 8.

[67] A pharmaceutical composition as described in any of

[41] to

[66] , wherein the tubulin inhibitor is paclitaxel, European paclitaxel, cabazitaxel, or a pharmacologically permissible salt thereof, or nab-paclitaxel.

[68] A pharmaceutical composition as described in

[67] , wherein the tubulin inhibitor is paclitaxel.

[69] A pharmaceutical composition as described in any of

[41] to

[66] , wherein the tubulin inhibitor is eribulin or a pharmacologically permissible salt thereof, or an antibody-drug conjugate in which eribulin is bound to an antibody-mediated linker.

[70] A pharmaceutical composition as described in

[69] , wherein the tubulin inhibitor is eribulin mesylate.

[71] A pharmaceutical composition as described in any of

[41] to

[70] is characterized in that each individual formulation contains an antibody-drug conjugate and a microtubule inhibitor as active ingredients, and is administered simultaneously or at different times.

[72] A pharmaceutical composition as described in any of

[41] to

[71] is used for the treatment of at least one of the following groups: breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, and uterine carcinosarcoma.

[73] A pharmaceutical composition as described in

[72] is used for the treatment of breast cancer.

[74] A pharmaceutical composition as described in

[72] is used for the treatment of gastric cancer.

[75] A pharmaceutical composition as described in

[72] is used for the treatment of lung cancer.

[76] A pharmaceutical composition as described in

[72] is used for the treatment of ovarian cancer.

[77] Any pharmaceutical composition described in any of

[41] to

[76] is characterized by a microtubule inhibitor that inhibits the reduction in the expression of drug-sensing factors produced by administration of an antibody-drug conjugate.

[78] A pharmaceutical composition as described in

[77] , wherein the drug-sensitizing factor is SLFN11.

[79] A pharmaceutical composition as described in any of

[41] to

[76] , characterized in that the tubulin inhibitor inhibits the increase in the expression of the drug-sensitizing factor produced by administration of the antibody-drug conjugate.

[80] A pharmaceutical composition as described in

[79] , wherein the drug-resistant factor is ABCG2.

[81] A treatment method characterized in that an antibody-drug conjugate is combined with a tubulin inhibitor and administered to an individual in need of treatment, wherein the antibody-drug conjugate is an antibody-drug conjugate in which a drug linker and an antibody are bound by a thioether bond as shown in the following formula, [Figure] (where A represents the binding site with the antibody).

[82] A treatment method as described in

[81] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[83] The treatment method described in

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

[84] The treatment method described in

[83] , wherein the anti-HER2 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 1 to 449 in sequence identification number 1 and a light chain composed of amino acid sequences numbered 1 to 214 in sequence identification number 2.

[85] The treatment method described in

[83] , wherein the anti-HER2 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 1 in sequence identification number 1 and a light chain composed of amino acid sequences numbered 2 in sequence identification number 2.

[86] The treatment method described in any one of

[83] to

[85] , wherein the average number of drug linkers bound to each antibody in the antibody-drug conjugate is in the range of 7 to 8.

[87] The treatment method described in

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

[88] The treatment method described in

[87] , wherein the anti-HER3 antibody system comprises an antibody consisting of a heavy chain composed of an amino acid sequence described in Sequence Identification Number 3 and a light chain composed of an amino acid sequence described in Sequence Identification Number 4.

[89] The treatment method described in

[88] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-HER3 antibody is deleted.

[90] The treatment method described in any one of

[87] to

[89] , wherein the average number of drug linkers bound to each antibody in the antibody-drug conjugate is in the range of 7 to 8.

[91] The treatment method described in

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

[92] The treatment method described in

[91] , wherein the anti-TROP2 antibody system comprises an antibody consisting of a heavy chain composed of an amino acid sequence described in Sequence Identification Number 5, amino acid numbers 20 to 470, and a light chain composed of an amino acid sequence described in Sequence Identification Number 6, amino acid numbers 21 to 234.

[93] The treatment method described in

[92] wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-TROP2 antibody is deleted.

[94] The treatment method described in any one of

[91] to

[93] wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[95] The treatment method described in

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

[96] The treatment method described in

[95] wherein the anti-B7-H3 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 471 in sequence identification number 7 and a light chain composed of amino acid sequences numbered 21 to 233 in sequence identification number 8.

[97] The treatment method described in

[96] wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted.

[98] A treatment method as described in any of

[95] to

[97] , wherein the average number of drug linkers bound to each antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[99] A treatment method as described in

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

[100] A treatment method as described in

[99] , wherein the anti-GPR20 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 472 in sequence identification number 9 and a light chain composed of amino acid sequences numbered 21 to 234 in sequence identification number 10.

[101] A treatment method as described in

[100] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-GPR20 antibody is deleted.

[102] The treatment method described in any of

[99] to

[101] , wherein the average number of drug linkers bound to each antibody in the antibody-drug conjugate is in the range of 7 to 8.

[103] The treatment method described in

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

[104] The treatment method described in

[103] , wherein the anti-CDH6 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 471 in sequence identification number 11 and a light chain composed of amino acid sequences numbered 21 to 233 in sequence identification number 12.

[105] The treatment method described in

[104] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.

[106] The treatment method described in any of

[103] to

[105] , wherein the average number of drug linkers bound to each antibody in the antibody-drug conjugate is in the range of 7 to 8.

[107] The treatment method described in any of

[81] to

[106] , wherein the tubulin inhibitor is paclitaxel, European paclitaxel, cabazitaxel, or a pharmacologically permissible salt of the like, or nab-paclitaxel.

[108] The treatment method described in

[107] wherein the tubulin inhibitor is paclitaxel.

[109] The treatment method described in any one of

[81] to

[106] wherein the tubulin inhibitor is eribulin or a pharmacologically permissible salt thereof, or an antibody-drug conjugate in which eribulin is bound to an antibody-mediated linker.

[110] The treatment method described in

[109] wherein the tubulin inhibitor is eribulin mesylate.

[111] The treatment method described in any one of

[81] to

[110] is characterized in that an individual formulation contains an antibody-drug conjugate and a tubulin inhibitor as active ingredients, and is administered simultaneously or at different times.

[112] The treatment method described in any one of

[81] to

[111] is for the treatment of at least one of the group comprising breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, and uterine carcinosarcoma.

[113] The treatment method described in

[112] is for the treatment of breast cancer.

[114] The treatment method described in

[112] is for the treatment of gastric cancer.

[115] The treatment method described in

[112] is for the treatment of lung cancer.

[116] The treatment method described in

[112] is for the treatment of ovarian cancer.

[117] The treatment method described in any one of

[81] to

[116] is characterized in that the microtubule inhibitor inhibits the reduction in the expression of drug-sensitizing factors produced by administration of the antibody-drug conjugate.

[118] A treatment method as described in

[117] , wherein the drug-sensitizing factor is SLFN11.

[119] A treatment method as described in any of

[81] to

[116] , characterized in that a tubulin inhibitor inhibits the increase in the expression of the drug-sensitizing factor produced by administration of an antibody-drug conjugate.

[120] A treatment method as described in

[119] , wherein the drug-resistant factor is ABCG2.

[121] A treatment method characterized in that an antibody-drug conjugate and a tubulin inhibitor are combined and administered to an individual in need of treatment, wherein the antibody-drug conjugate is an antibody-drug conjugate as shown in the following formula [Figure] (wherein, the drug linker is bound to the antibody by a thioether bond, and n represents the average number of drug linkers bound per antibody).

[122] A treatment method as described in

[121] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[123] The treatment method described in

[122] is an anti-HER2 antibody in the antibody-drug conjugate.

[124] The treatment method described in

[123] , wherein the anti-HER2 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 1 to 449 in sequence identification number 1 and a light chain composed of amino acid sequences numbered 1 to 214 in sequence identification number 2.

[125] The treatment method described in

[123] , wherein the anti-HER2 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 1 in sequence identification number 1 and a light chain composed of amino acid sequences numbered 2 in sequence identification number 2.

[126] The treatment method described in any one of

[123] to

[125] , wherein the average number of drug linkers bound to each antibody in the antibody-drug conjugate is in the range of 7 to 8.

[127] The treatment method described in

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

[128] The treatment method described in

[127] , wherein the anti-HER3 antibody system comprises an antibody consisting of a heavy chain composed of an amino acid sequence described in Sequence Identification Number 3 and a light chain composed of an amino acid sequence described in Sequence Identification Number 4.

[129] The treatment method described in

[128] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-HER3 antibody is deleted.

[130] The treatment method described in any one of

[127] to

[129] , wherein the average number of drug linkers bound to each antibody in the antibody-drug conjugate is in the range of 7 to 8.

[131] The treatment method described in

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

[132] The treatment method described in

[131] , wherein the anti-TROP2 anti-system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 470 in sequence identification number 5 and a light chain composed of amino acid sequences numbered 21 to 234 in sequence identification number 6.

[133] The treatment method described in

[132] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-TROP2 antibody is deleted.

[134] The treatment method described in any one of

[131] to

[133] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[135] The treatment method described in

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

[136] The treatment method described in

[135] wherein the anti-B7-H3 anti-system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 471 in sequence identification number 7 and a light chain composed of amino acid sequences numbered 21 to 233 in sequence identification number 8.

[137] The treatment method described in

[136] wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted.

[138] The treatment method described in any of

[135] to

[137] , wherein the average number of drug linkers bound to each antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[139] The treatment method described in

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

[140] The treatment method described in

[139] , wherein the anti-GPR20 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 472 in sequence identification number 9 and a light chain composed of amino acid sequences numbered 21 to 234 in sequence identification number 10.

[141] The treatment method described in

[140] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-GPR20 antibody is deleted.

[142] The treatment method described in any of

[139] to

[141] , wherein the average number of drug linkers bound to each antibody in the antibody-drug conjugate is in the range of 7 to 8.

[143] The treatment method described in

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

[144] The treatment method described in

[143] , wherein the anti-CDH6 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 471 in sequence identification number 11 and a light chain composed of amino acid sequences numbered 21 to 233 in sequence identification number 12.

[145] The treatment method described in

[144] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.

[146] The treatment method described in any of

[143] to

[145] , wherein the average number of drug linkers bound to each antibody in the antibody-drug conjugate is in the range of 7 to 8.

[147] The treatment method described in any of

[121] to

[146] , wherein the tubulin inhibitor is paclitaxel, European paclitaxel, cabazitaxel, or a pharmacologically permissible salt thereof, or nab-paclitaxel.

[148] The treatment method described in

[147] , wherein the tubulin inhibitor is paclitaxel.

[149] The treatment method described in any of

[121] to

[146] , wherein the tubulin inhibitor is eribulin or a pharmacologically permissible salt thereof, or an antibody-drug conjugate in which eribulin is bound to an antibody-mediated linker.

[150] The treatment method described in

[149] , wherein the tubulin inhibitor is eribulin mesylate.

[151] The treatment method described in any of

[121] to

[150] is characterized by containing an antibody-drug conjugate and a microtubule inhibitor as active ingredients in individual formulations, and being administered at the same or different times.

[152] The treatment method described in any one of

[121] to

[151] is for the treatment of at least one of the group comprising breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, and uterine carcinosarcoma.

[153] The treatment method described in

[152] is for the treatment of breast cancer.

[154] The treatment method described in

[152] is for the treatment of gastric cancer.

[155] The treatment method described in

[152] is for the treatment of lung cancer.

[156] The treatment method described in

[152] is for the treatment of ovarian cancer.

[157] The treatment method described in any one of

[121] to

[156] is characterized in that the microtubule inhibitor inhibits the reduction in the expression of drug-sensitizing factors produced by administration of an antibody-drug conjugate.

[158] A treatment method as described in

[157] , wherein the drug-sensitizing factor is SLFN11.

[159] A treatment method as described in any of

[121] to

[156] , characterized in that the tubulin inhibitor inhibits the increase in the expression of the drug-sensitizing factor produced by administration of the antibody-drug conjugate.

[160] A treatment method as described in

[159] , wherein the drug-resistant factor is ABCG2.

[161] An antibody-drug conjugate for treating a disease by administration in combination with a tubulin inhibitor, the antibody-drug conjugate being an antibody-drug conjugate with a drug linker and an antibody bound by a thioether bond as shown in the following formula, [Figure] (where A represents the binding site with the antibody).

[162] An antibody-drug conjugate as described in

[161] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[163] An antibody-drug conjugate as described in

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

[164] An antibody-drug conjugate as described in

[163] , wherein the anti-HER2 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 1 to 449 in sequence identification number 1 and a light chain composed of amino acid sequences numbered 1 to 214 in sequence identification number 2.

[165] An antibody-drug conjugate as described in

[163] , wherein the anti-HER2 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 1 in sequence identification number 1 and a light chain composed of amino acid sequences numbered 2 in sequence identification number 2.

[166] An antibody-drug conjugate as described in any one of

[163] to

[165] , wherein the average number of drug linkers bound to each antibody in the antibody-drug conjugate is in the range of 7 to 8.

[167] An antibody-drug conjugate as described in

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

[168] An antibody-drug conjugate as described in

[167] , wherein the anti-HER3 antibody system comprises an antibody consisting of a heavy chain composed of an amino acid sequence as described in Sequence Identification Number 3 and a light chain composed of an amino acid sequence as described in Sequence Identification Number 4.

[169] An antibody-drug conjugate as described in

[168] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-HER3 antibody is deleted.

[170] An antibody-drug conjugate as described in any one of

[167] to

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

[171] An antibody-drug conjugate as described in

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

[172] An antibody-drug conjugate as described in

[171] , wherein the anti-TROP2 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 470 in sequence identification number 5 and a light chain composed of amino acid sequences numbered 21 to 234 in sequence identification number 6.

[173] An antibody-drug conjugate as described in

[172] wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-TROP2 antibody is deleted.

[174] An antibody-drug conjugate as described in any one of

[171] to

[173] wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[175] An antibody-drug conjugate as described in

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

[176] An antibody-drug conjugate as described in

[175] , wherein the anti-B7-H3 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 471 in sequence identification number 7 and a light chain composed of amino acid sequences numbered 21 to 233 in sequence identification number 8.

[177] An antibody-drug conjugate as described in

[176] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted.

[178] An antibody-drug conjugate as described in any one of

[175] to

[177] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[179] An antibody-drug conjugate as described in

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

[180] The antibody-drug conjugate described in

[179] , wherein the anti-GPR20 anti-system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 472 in sequence identification number 9 and a light chain composed of amino acid sequences numbered 21 to 234 in sequence identification number 10.

[181] An antibody-drug conjugate as described in

[180] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-GPR20 antibody is deleted.

[182] An antibody-drug conjugate as described in any one of

[179] to

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

[183] ​​An antibody-drug conjugate as described in

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

[184] An antibody-drug conjugate as described in

[183] , wherein the anti-CDH6 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 471 in sequence identification number 11 and a light chain composed of amino acid sequences numbered 21 to 233 in sequence identification number 12.

[185] An antibody-drug conjugate as described in

[184] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.

[186] An antibody-drug conjugate as described in any one of

[183] ​​to

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

[187] An antibody-drug conjugate as described in any one of

[161] to

[186] , wherein the tubulin inhibitor is paclitaxel, European paclitaxel, cabazitaxel, or a pharmacologically permissible salt thereof, or nab-paclitaxel.

[188] An antibody-drug conjugate as described in

[187] , wherein the tubulin inhibitor is paclitaxel.

[189] An antibody-drug conjugate as described in any of

[161] to

[186] , wherein the tubulin inhibitor is eribulin or a pharmacologically permissible salt thereof, or an antibody-drug conjugate in which eribulin is bound to an antibody-drug linker.

[190] An antibody-drug conjugate as described in

[189] , wherein the tubulin inhibitor is eribulin mesylate.

[191] An antibody-drug conjugate as described in any of

[161] to

[190] , characterized in that each individual formulation contains an antibody-drug conjugate and a tubulin inhibitor as active ingredients, and is administered simultaneously or at different times.

[192] The antibody-drug conjugate described in any one of

[161] to

[191] is used for the treatment of at least one of the group comprising breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, and uterine carcinosarcoma.

[193] The antibody-drug conjugate described in

[192] is used for the treatment of breast cancer.

[194] The antibody-drug conjugate described in

[192] is used for the treatment of gastric cancer.

[195] The antibody-drug conjugate described in

[192] is used for the treatment of lung cancer.

[196] The antibody-drug conjugate described in

[192] is used for the treatment of ovarian cancer.

[197] An antibody-drug conjugate as described in any of

[161] to

[196] , characterized in that the tubulin inhibitor inhibits the decrease in the expression of the drug-sensitivity factor produced by administration of the antibody-drug conjugate.

[198] An antibody-drug conjugate as described in

[197] , wherein the drug-sensitivity factor is SLFN11.

[199] An antibody-drug conjugate as described in any of

[161] to

[196] , characterized in that the tubulin inhibitor inhibits the increase in the expression of the drug-sensitivity factor produced by administration of the antibody-drug conjugate.

[200] An antibody-drug conjugate as described in

[199] , wherein the drug resistance factor is ABCG2.

[201] An antibody-drug conjugate shown in the following formula, which is administered in combination with a tubulin inhibitor for the treatment of a disease, [Figure] (wherein, the drug linker is bound to the antibody by a thioether bond, and n represents the average number of drug linkers bound per antibody).

[202] The antibody-drug conjugate as described in

[201] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[203] The antibody-drug conjugate as described in

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

[204] The antibody-drug conjugate as described in

[203] , wherein the anti-HER2 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 1 to 449 in sequence identification number 1 and a light chain composed of amino acid sequences numbered 1 to 214 in sequence identification number 2.

[205] The antibody-drug conjugate as described in

[203] , wherein the anti-HER2 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 1 in sequence identification number 1 and a light chain composed of amino acid sequences numbered 2 in sequence identification number 2.

[206] An antibody-drug conjugate as described in any of

[203] to

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

[207] An antibody-drug conjugate as described in

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

[208] An antibody-drug conjugate as described in

[207] , wherein the anti-HER3 antibody system comprises an antibody consisting of a heavy chain composed of an amino acid sequence described in Sequence Identification Number 3 and a light chain composed of an amino acid sequence described in Sequence Identification Number 4.

[209] An antibody-drug conjugate as described in

[208] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-HER3 antibody is deleted.

[210] An antibody-drug conjugate as described in any of

[207] to

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

[211] An antibody-drug conjugate as described in

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

[212] An antibody-drug conjugate as described in

[211] , wherein the anti-TROP2 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 470 in sequence identification number 5 and a light chain composed of amino acid sequences numbered 21 to 234 in sequence identification number 6.

[213] An antibody-drug conjugate as described in

[212] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-TROP2 antibody is deleted.

[214] An antibody-drug conjugate as described in any one of

[211] to

[213] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[215] An antibody-drug conjugate as described in

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

[216] An antibody-drug conjugate as described in

[215] , wherein the anti-B7-H3 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 471 in sequence identification number 7 and a light chain composed of amino acid sequences numbered 21 to 233 in sequence identification number 8.

[217] An antibody-drug conjugate as described in

[216] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted.

[218] An antibody-drug conjugate as described in any one of

[215] to

[217] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[219] An antibody-drug conjugate as described in

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

[220] An antibody-drug conjugate as described in

[219] , wherein the anti-GPR20 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 472 in sequence identification number 9 and a light chain composed of amino acid sequences numbered 21 to 234 in sequence identification number 10.

[221] An antibody-drug conjugate as described in

[220] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-GPR20 antibody is deleted.

[222] An antibody-drug conjugate as described in any one of

[219] to

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

[223] As described in

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

[224] An antibody-drug conjugate as described in

[223] , wherein the anti-CDH6 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 471 in sequence identification number 11 and a light chain composed of amino acid sequences numbered 21 to 233 in sequence identification number 12.

[225] An antibody-drug conjugate as described in

[224] wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.

[226] An antibody-drug conjugate as described in any one of

[223] to

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

[227] An antibody-drug conjugate as described in any of

[201] to

[226] , wherein the tubulin inhibitor is paclitaxel, European paclitaxel, cabazitaxel, or a pharmacologically permissible salt thereof, or nab-paclitaxel.

[228] An antibody-drug conjugate as described in

[227] , wherein the tubulin inhibitor is paclitaxel.

[229] An antibody-drug conjugate as described in any of

[201] to

[226] , wherein the tubulin inhibitor is eribulin or a pharmacologically permissible salt thereof, or an antibody-drug conjugate in which eribulin is bound to an antibody-mediated linker.

[230] An antibody-drug conjugate as described in

[229] , wherein the tubulin inhibitor is eribulin mesylate.

[231] An antibody-drug conjugate as described in any of

[201] to

[230] is characterized in that each individual formulation contains an antibody-drug conjugate and a microtubule inhibitor as active ingredients, and is administered simultaneously or at different times.

[232] An antibody-drug conjugate as described in any of

[201] to

[231] is used for the treatment of at least one of the following cancers: breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, and uterine carcinosarcoma.

[233] An antibody-drug conjugate as described in

[232] is used for the treatment of breast cancer.

[234] An antibody-drug conjugate as described in

[232] is used for the treatment of gastric cancer.

[235] An antibody-drug conjugate as described in

[232] is used for the treatment of lung cancer.

[236] An antibody-drug conjugate as described in

[232] is used for the treatment of ovarian cancer.

[237] An antibody-drug conjugate as described in any of

[201] to

[236] is characterized by a microtubule inhibitor inhibiting the reduction in the expression of drug-sensing factors produced by administration of the antibody-drug conjugate.

[238] An antibody-drug conjugate as described in

[237] wherein the drug-sensing factor is SLFN11.

[239] An antibody-drug conjugate as described in any of

[201] to

[236] , characterized in that the tubulin inhibitor inhibits the increase in the expression of the drug-sensitivity factor produced by administration of the antibody-drug conjugate.

[240] An antibody-drug conjugate as described in

[239] , wherein the drug resistance factor is ABCG2.

[241] Use of an antibody-drug conjugate for manufacturing a medicine for treating a disease by administration in combination with a tubulin inhibitor, wherein the antibody-drug conjugate is an antibody-drug conjugate in which a drug linker and an antibody are bound by a thioether bond as shown in the following formula, [Figure] (where A represents the binding site with the antibody).

[242] Use as described in

[241] , wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[243] As described in

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

[244] As described in

[243] , wherein the anti-HER2 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 1 to 449 in Sequence Identification Number 1 and a light chain composed of amino acid sequences numbered 1 to 214 in Sequence Identification Number 2.

[245] As described in

[243] , wherein the anti-HER2 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 1 in Sequence Identification Number 1 and a light chain composed of amino acid sequences numbered 2 in Sequence Identification Number 2.

[246] As described in any one of

[243] to

[245] , wherein the average number of drug linkers bound to each antibody in the antibody-drug conjugate is in the range of 7 to 8.

[247] As described in

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

[248] As described in

[247] , the anti-HER3 antibody system comprises an antibody consisting of a heavy chain composed of an amino acid sequence described in Sequence Identification Number 3 and a light chain composed of an amino acid sequence described in Sequence Identification Number 4.

[249] As described in

[248] , the lysine residue at the carboxyl terminus of the heavy chain of the anti-HER3 antibody is deleted.

[250] As described in any one of

[247] to

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

[251] As described in

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

[252] As described in

[251] , the anti-TROP2 anti-system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 470 in sequence identification number 5 and a light chain composed of amino acid sequences numbered 21 to 234 in sequence identification number 6.

[253] As described in

[252] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-TROP2 antibody is deleted.

[254] As described in any one of

[251] to

[253] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[255] As described in

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

[256] As described in

[255] , wherein the anti-B7-H3 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 471 in sequence identification number 7 and a light chain composed of amino acid sequences numbered 21 to 233 in sequence identification number 8.

[257] As described in

[256] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted.

[258] As described in any of

[255] to

[257] , wherein the average number of drug linkers bound to each antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[259] As described in

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

[260] As described in

[259] , wherein the anti-GPR20 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 472 in sequence identification number 9 and a light chain composed of amino acid sequences numbered 21 to 234 in sequence identification number 10.

[261] As described in

[260] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-GPR20 antibody is deleted.

[262] As described in any of

[259] to

[261] , wherein the average number of drug linkers bound to each antibody in the antibody-drug conjugate is in the range of 7 to 8.

[263] As described in

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

[264] As described in

[263] , wherein the anti-CDH6 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 471 in sequence identification number 11 and a light chain composed of amino acid sequences numbered 21 to 233 in sequence identification number 12.

[265] As described in

[264] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is missing.

[266] As described in any of

[263] to

[265] , wherein the average number of drug linkers bound to each antibody in the antibody-drug conjugate is in the range of 7 to 8.

[267] As described in any of

[241] to

[266] , wherein the tubulin inhibitor is paclitaxel, European paclitaxel, cabazitaxel, or a pharmacologically permissible salt of the like, or nab-paclitaxel.

[268] As described in

[267] , wherein the tubulin inhibitor is paclitaxel.

[269] The use described in any of

[241] to

[266] , wherein the tubulin inhibitor is eribulin or a pharmacologically permissible salt thereof, or an antibody-drug conjugate in which eribulin is bound to an antibody-mediated linker.

[270] The use described in

[269] , wherein the tubulin inhibitor is eribulin mesylate.

[271] The use described in any of

[241] to

[270] , characterized in that each individual formulation contains an antibody-drug conjugate and a tubulin inhibitor as active ingredients, and is administered simultaneously or at different times.

[272] The use described in any of

[241] to

[271] is for the treatment of at least one of the following groups: breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, and uterine carcinosarcoma.

[273] As described in

[272] , it is used for the treatment of breast cancer.

[274] As described in

[272] , it is used for the treatment of gastric cancer.

[275] As described in

[272] , it is used for the treatment of lung cancer.

[276] As described in

[272] , it is used for the treatment of ovarian cancer.

[277] As described in any one of

[241] to

[276] , it is characterized in that the tubulin inhibitor inhibits the decrease in the expression of drug-sensitivity factors produced by administration of antibody-drug conjugates.

[278] As described in

[277] , wherein the drug-sensitivity factor is SLFN11.

[279] As described in any one of

[241] to

[276] , it is characterized in that the tubulin inhibitor inhibits the increase in the expression of drug-sensitivity factors produced by administration of antibody-drug conjugates.

[280] As described in

[279] , wherein the drug resistance factor is ABCG2.

[281] Use of an antibody-drug conjugate as shown in the following formula, for use in the manufacture of a medicine for treating a disease by administration in combination with a tubulin inhibitor, [Figure] (wherein, the drug linker is bound to the antibody by a thioether bond, and n represents the average number of drug linkers bound per antibody).

[282] As described in

[281] , the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[283] As described in

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

[284] As described in

[283] , the anti-HER2 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 1 to 449 in sequence identification number 1 and a light chain composed of amino acid sequences numbered 1 to 214 in sequence identification number 2.

[285] As described in

[283] , the anti-HER2 antibody system comprises an antibody consisting of a heavy chain composed of an amino acid sequence described in Sequence Identification Number 1 and a light chain composed of an amino acid sequence described in Sequence Identification Number 2.

[286] As described in any one of

[283] to

[285] , the average number of drug linkers bound to each antibody in the antibody-drug conjugate is in the range of 7 to 8.

[287] As described in

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

[288] As described in

[287] , the anti-HER3 antibody system comprises an antibody consisting of a heavy chain composed of an amino acid sequence described in Sequence Identification Number 3 and a light chain composed of an amino acid sequence described in Sequence Identification Number 4.

[289] As described in

[288] , the lysine residue at the carboxyl terminus of the heavy chain of the anti-HER3 antibody is deleted.

[290] As described in any of

[287] to

[289] , wherein the average number of drug linkers bound to each antibody in the antibody-drug conjugate is in the range of 7 to 8.

[291] As described in

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

[292] As described in

[291] , wherein the anti-TROP2 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 470 in sequence identification number 5 and a light chain composed of amino acid sequences numbered 21 to 234 in sequence identification number 6.

[293] As described in

[292] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-TROP2 antibody is deleted.

[294] As described in any of

[291] to

[293] , wherein the average number of drug linkers bound to each antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[295] As described in

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

[296] As described in

[295] , wherein the anti-B7-H3 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 471 in sequence identification number 7 and a light chain composed of amino acid sequences numbered 21 to 233 in sequence identification number 8.

[297] As described in

[296] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted.

[298] As described in any of

[295] to

[297] , wherein the average number of drug linkers bound to each antibody in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[299] As described in

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

[300] As described in

[299] , the anti-GPR20 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 472 in sequence identification number 9 and a light chain composed of amino acid sequences numbered 21 to 234 in sequence identification number 10.

[301] As described in

[300] , the lysine residue at the carboxyl terminus of the heavy chain of the anti-GPR20 antibody is deleted.

[302] As described in any one of

[299] to

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

[303] As described in

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

[304] As described in

[303] , the anti-CDH6 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 20 to 471 in sequence identification number 11 and a light chain composed of amino acid sequences numbered 21 to 233 in sequence identification number 12.

[305] As described in

[304] , the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.

[306] As described in any one of

[303] to

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

[307] As described in any one of

[281] to

[306] , the tubulin inhibitor is paclitaxel, European paclitaxel, cabazitaxel, or a pharmacologically permissible salt of the like, or nab-paclitaxel.

[308] As described in

[307] , wherein the tubulin inhibitor is paclitaxel.

[309] As described in any one of

[281] to

[306] , wherein the tubulin inhibitor is eribulin or a pharmacologically permissible salt thereof, or an antibody-drug conjugate formed by eribulin and an antibody-drug linker.

[310] As described in

[309] , wherein the tubulin inhibitor is eribulin mesylate.

[311] As described in any one of

[281] to

[310] , characterized in that each individual formulation contains an antibody-drug conjugate and a tubulin inhibitor as active ingredients, and is administered simultaneously or at different times.

[312] The use described in any of

[281] to

[311] is for the treatment of at least one of the group comprising breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, and uterine carcinosarcoma.

[313] The use described in

[312] is for the treatment of breast cancer.

[314] The use described in

[312] is for the treatment of gastric cancer.

[315] The use described in

[312] is for the treatment of lung cancer.

[316] The use described in

[312] is for the treatment of ovarian cancer.

[317] The use as described in any of

[281] to

[316] is characterized in that the tubulin inhibitor inhibits the decrease in the expression of the drug-sensitivity factor produced by administration of the antibody-drug conjugate.

[318] The use as described in

[317] , wherein the drug-sensitivity factor is SLFN11.

[319] The use as described in any of

[281] to

[316] is characterized in that the tubulin inhibitor inhibits the increase in the expression of the drug-sensitivity factor produced by administration of the antibody-drug conjugate.

[320] The use as described in

[319] , wherein the drug resistance factor is ABCG2.

[321] A pharmaceutical composition characterized in that it is a pharmaceutical composition administered in combination with an antibody-drug conjugate and a tubulin inhibitor, characterized in that: 1) the tubulin inhibitor inhibits the decrease in the expression of the drug-sensitivity factor produced by administration of the antibody-drug conjugate, and / or 2) the tubulin inhibitor inhibits the increase in the expression of the drug-sensitivity factor produced by administration of the antibody-drug conjugate.

[322] A pharmaceutical composition as described in

[321] , wherein the drug sensitivity factor is SLFN11.

[323] A pharmaceutical composition as described in

[321] or

[322] , wherein the drug tolerance factor is ABCG2.

[324] A pharmaceutical composition as described in any one of

[321] to

[323] , wherein the drug in the antibody-drug conjugate has topoisomerase I inhibitory activity.

[325] A pharmaceutical composition as described in any one of

[321] to

[323] , wherein the antibody-drug conjugate is an antibody-drug conjugate in which the drug linker shown in the following formula is bound to the antibody via a thioether bond, [Figure] (where A represents the binding site with the antibody).

[326] A pharmaceutical composition as described in any of

[321] to

[323] , wherein the antibody-drug conjugate is an antibody-drug conjugate as shown in the following formula, [Figure] (wherein, the drug linker is bound to the antibody via a thioether bond, and n represents the average number of drug linkers bound per antibody).

[327] A treatment method characterized by combining an antibody-drug conjugate with a tubulin inhibitor and administering it to an individual in need of treatment, characterized in that: 1) the tubulin inhibitor inhibits the decrease in the expression of the drug-sensitivity factor produced by the administration of the antibody-drug conjugate, and / or 2) the tubulin inhibitor inhibits the increase in the expression of the drug-sensitivity factor produced by the administration of the antibody-drug conjugate.

[328] A treatment method as described in

[327] , wherein the drug-sensitivity factor is SLFN11.

[329] A treatment method as described in

[327] or

[328] , wherein the drug resistance factor is ABCG2.

[330] The treatment method described in any of

[327] to

[329] , wherein the drug in the antibody-drug conjugate has topoisomerase I inhibitory activity.

[331] A treatment method as described in any of

[327] to

[329] , wherein the antibody-drug conjugate is an antibody-drug conjugate in which a drug linker and an antibody are bound by a thioether bond as shown in the following formula, [Figure] (where A represents the binding position with the antibody).

[332] A treatment method as described in any of

[327] to

[329] , wherein the antibody-drug conjugate is an antibody-drug conjugate in which the drug linker is bound by a thioether bond as shown in the following formula [Figure] (where the drug linker is bound to the antibody by a thioether bond, and n represents the average number of drug linkers bound per antibody).

[333] An antibody-drug conjugate for treating a disease by administration in combination with a tubulin inhibitor, characterized in that: 1) the tubulin inhibitor inhibits the decrease in the expression of drug-sensitivity factors produced by administration of the antibody-drug conjugate, and / or 2) the tubulin inhibitor inhibits the increase in the expression of drug-sensitivity factors produced by administration of the antibody-drug conjugate.

[334] An antibody-drug conjugate as described in

[333] , wherein the drug sensitivity factor is SLFN11.

[335] An antibody-drug conjugate as described in

[333] or

[334] , wherein the drug resistance factor is ABCG2.

[336] An antibody-drug conjugate as described in any one of

[333] to

[335] , wherein the drug in the antibody-drug conjugate has topoisomerase I inhibitory activity.

[337] An antibody-drug conjugate as described in any one of

[333] to

[335] , wherein the antibody-drug conjugate is an antibody-drug conjugate in which the drug linker shown in the following formula is bound to the antibody via a thioether bond, [Figure] (where A represents the binding site with the antibody).

[338] An antibody-drug conjugate as described in any of

[333] to

[335] , wherein the antibody-drug conjugate is an antibody-drug conjugate as shown in the following formula, [Figure] (wherein, the drug linker is bound to the antibody via a thioether bond, and n represents the average number of drug linkers bound per antibody).

[339] An use of the antibody-drug conjugate for manufacturing a medicine for treating a disease by administration in combination with a tubulin inhibitor, characterized in that: 1) the tubulin inhibitor inhibits the decrease in the expression of the drug-sensitivity factor produced by administration of the antibody-drug conjugate, and / or 2) the tubulin inhibitor inhibits the increase in the expression of the drug-sensitivity factor produced by administration of the antibody-drug conjugate.

[340] The use as described in

[339] , wherein the drug-sensitivity factor is SLFN11.

[341] The use as described in

[339] or

[340] , wherein the drug resistance factor is ABCG2.

[342] The use described in any of

[339] to

[341] , wherein the drug in the antibody-drug conjugate has topoisomerase I inhibitory activity.

[343] The use described in any of

[339] to

[341] , wherein the antibody-drug conjugate is an antibody-drug conjugate in which the drug linker shown in the following formula is bound to the antibody via a thioether bond, [Figure] (where A represents the binding site with the antibody).

[344] The use described in any of

[339] to

[341] , wherein the antibody-drug conjugate is an antibody-drug conjugate in which the following formula is bound to the antibody via a thioether bond, [Figure] (where the drug linker is bound to the antibody via a thioether bond, and n represents the average number of drug linkers bound to each antibody). [Effects of the Invention] According to the present invention, a pharmaceutical composition and / or a treatment method may be provided, wherein the pharmaceutical composition is characterized by administration of a specific combination of an antibody-drug conjugate and a microtubule inhibitor, and the treatment method is characterized by administration of a specific combination of an antibody-drug conjugate and a microtubule inhibitor to an individual.

Implementation Method

Claims

1. Use of an antibody-drug conjugate for manufacturing a medicine for treating cancer, wherein the antibody-drug conjugate is combined with a tubulin inhibitor for administration, and wherein the antibody-drug conjugate is an antibody-drug conjugate in which a drug linker represented by the following formula is bound to an antibody via a thioether bond.

1. Among them, A indicates the binding site of the antibody; wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody; wherein the anti-HER2 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences numbered 1 to 449 in Sequence Identification No. 1 and a light chain composed of amino acid sequences numbered 1 to 214 in Sequence Identification No. 2, or wherein the anti-HER2 antibody system comprises an antibody consisting of a heavy chain composed of amino acid sequences recorded in Sequence Identification No. 1 and a light chain composed of amino acid sequences recorded in Sequence Identification No. 2; and wherein the tubulin inhibitor is paclitaxel, docetaxel, cabazitaxel, or a pharmacologically permissible salt thereof; nab-paclitaxel; eribulin or a pharmacologically permissible salt thereof; or an antibody-drug conjugate in which an eribulin mediator binds to the antibody.

2. As claimed in claim 1, wherein the anti-HER2 anti-system comprises an antibody consisting of a heavy chain composed of an amino acid sequence consisting of amino acids numbered 1 to 449 in sequence identification number 1, and a light chain composed of an amino acid sequence consisting of amino acids numbered 1 to 214 in sequence identification number 2.

3. As claimed in claim 1, wherein the anti-HER2 anti-system comprises an antibody consisting of a heavy chain composed of an amino acid sequence recorded in sequence identification number 1 and a light chain composed of an amino acid sequence recorded in sequence identification number 2.

4. As claimed in claim 1, wherein the average number of drug linkers bound to each antibody in the antibody-drug conjugate is in the range of 7 to 8.

5. As claimed in claim 1, wherein the tubulin inhibitor is paclitaxel, European paclitaxel, cabazitaxel, or a pharmacologically permissible salt of the like, or nab-paclitaxel.

6. As claimed in claim 5, wherein the tubulin inhibitor is paclitaxel.

7. As claimed in claim 1, wherein the tubulin inhibitor is eribulin or a pharmacologically permissible salt thereof, or an antibody-drug conjugate in which an eribulin mediator is bound to an antibody.

8. As claimed in claim 7, wherein the tubulin inhibitor is eribulin mesylate.

9. The use as claimed in claim 1, wherein the antibody-drug conjugate and the microtubule inhibitor are contained as active ingredients in individual formulations and administered simultaneously or at different times.

10. The use of any one of claims 2 to 4, wherein the tubulin inhibitor is paclitaxel, European paclitaxel, cabazitaxel, or a pharmacologically permissible salt of the like, or nab-paclitaxel.

11. As claimed in claim 10, wherein the tubulin inhibitor is paclitaxel.

12. The use as claimed in any of claims 2 to 4, wherein the tubulin inhibitor is eribulin or a pharmacologically permissible salt thereof, or an antibody-drug conjugate in which eribulin is bound to an antibody via a linker.

13. As claimed in claim 12, wherein the tubulin inhibitor is eribulin mesylate.

14. As claimed in any of claims 1 to 9, wherein the cancer is selected from at least one of the group consisting of breast cancer, stomach cancer, colorectal cancer, lung cancer, esophageal cancer, salivary gland cancer, esophagogastric junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, and uterine carcinoma.

15. As used in claim 14, wherein the cancer is breast cancer.

16. As used in claim 14, wherein the cancer is stomach cancer.

17. As used in claim 14, wherein the cancer is lung cancer.

18. As used in claim 14, wherein the cancer is ovarian cancer.

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