Combination of antibody-drug conjugate and tubulin inhibitor

Abstract

To provide a pharmaceutical composition such that a specific antibody-drug conjugate and a tubulin inhibitor are administered in combination, and / or a method of treatment.SOLUTION: The present invention provides a pharmaceutical composition such that an antibody-drug conjugate in which a drug-linker represented by the following formula (where A represents a connecting position to an antibody) is conjugated to an antibody via a thioether bond, and a tubulin inhibitor are administered in combination, and a method of treatment.SELECTED DRAWING: Figure 9

Description

[Technical field]

[0001] The present invention relates to a method for administering a tubulin inhibitor in combination with a specific antibody-drug conjugate. and / or a pharmaceutical composition comprising a specific antibody-drug conjugate. The present invention relates to a method of treatment in which a combination of tubulin inhibitors is administered to an individual. do. [Background technology]

[0002] Tubulin inhibitors disrupt the G phase of the cell cycle by affecting microtubule dynamics. It arrests cell division at the 2 (pre-division) and / or M (division) phases and induces apoptosis. It is a drug that suppresses the proliferation of cancer cells by inducing cell death (Non-Patent Document 1, 2).

[0003] Tubulin inhibitors inhibit microtubule dynamics by promoting tubulin polymerization. Drugs that affect the tubulin polymerization (tubulin polymerization promoters) and drugs that inhibit the polymerization of tubulin There are drugs (tubulin polymerization inhibitors) that affect microtubule dynamics by .

[0004] Tubulin polymerization promoters include paclitaxel and docetaxel. Docetaxel and Cabazitaxel It is known that tubulin polymerization inhibitors include eribulin ), Vincristine, Vinblastine ne), Vinorelbine, Vindesine , monomethyl auristatin E (MM Brentuximab vedotin (B AE), an antibody-drug conjugate Renteximab Vedotin) and DM1-based antibody-drug complex Trastuzumab emtansine, a conjugate sine) are known.

[0005] The antibody that binds to an antigen that is expressed on the surface of cancer cells and can be internalized into the cells has cytotoxicity. Antibody-Drug Conjugates ADCs (antibody-derived jugates) are a promising candidate for the treatment of cancer by selectively delivering drugs to cancer cells. It is expected that drugs will accumulate inside cells and kill cancer cells (Non-Patent Documents 3-7). .

[0006] As one of the antibody-drug conjugates, we have developed a conjugate that combines an antibody and a topoisomerase I inhibitor called exon Antibody-drug conjugates that contain derivatives of Satecan as building blocks are known (see Patent Document 1-7, non-patent literature 8-11).

[0007] In addition, Patent Documents 1 to 7 disclose the use of the above antibody-drug conjugate in combination with various cancer therapeutic agents. It is described that the drug can be administered to

[0008] However, when the above antibody-drug conjugate was used in combination with a tubulin inhibitor, There are no test results showing the combined effect of these drugs or any scientific evidence suggesting such test results. Not yet. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2014 / 057687

Patent document 2

Patent document 3

Patent document 4

Patent document 5

Patent document 6

Patent document 7

Non-licensed literature

[0010] [Non-licensed document 1] Dumontet C, et al., Nat Rev Drug Discov. 2010 Oct;9(10): 790-803.

Non-licensed Document 2

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

[0011] The antibody-drug conjugates used in the present invention (which contain a derivative of exatecan as a component) It has been confirmed that antibody-drug conjugates that can be used alone exhibit excellent antitumor effects. However, when used in combination with other anticancer drugs that have different mechanisms of action, It is hoped that a treatment that can comprehensively suppress the proliferation of cancer cells and exert a more effective antitumor effect will be developed. Can be enjoyed.

[0012] The present invention relates to a method for administering a tubulin inhibitor in combination with a specific antibody-drug conjugate. and / or a pharmaceutical composition comprising a specific antibody-drug conjugate. The present invention provides a method of treatment in which a combination of tubulin inhibitors is administered to an individual. The objective of the project is to [Means for solving the problem]

[0013] The present inventors have conducted extensive research to solve the above problems, and have found that a specific antibody-drug combination The conjugate and tubulin inhibitor were administered in combination, providing excellent combination therapy. The present invention has been completed based on the findings.

[0014] That is, the present invention provides the following [1] to

[0344] . [1] The antibody-drug conjugate and the tubulin inhibitor are administered in combination. A pharmaceutical composition comprising: The antibody-drug conjugate has the formula

[0015] [ka]

[0016] (wherein A represents the binding site to the antibody) The antibody-drug conjugate is formed by binding the drug linker represented by the formula: The pharmaceutical composition is a jugate. [2] The antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TR antibody, [1] The antibody is an OP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody. The pharmaceutical composition described in [3] The method according to [2], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody. Pharmaceutical composition. [4] The anti-HER2 antibody comprises an amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO:1. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO:2. The pharmaceutical composition according to [3], wherein the antibody comprises a light chain consisting of [5] The anti-HER2 antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 1 and a heavy chain having the amino acid sequence shown in SEQ ID NO: 2. The pharmaceutical composition according to [3], wherein the antibody comprises a light chain having the amino acid sequence described above. [6] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to The pharmaceutical composition according to any one of [3] to [5], wherein the number of the active ingredients is in the range of 8. [7] The method according to [2], wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody. Pharmaceutical composition. [8] The anti-HER3 antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 3 and a heavy chain having the amino acid sequence shown in SEQ ID NO: 4. The pharmaceutical composition according to [7], wherein the antibody comprises a light chain having the amino acid sequence described above. [9] The anti-HER3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain, as described in [8]. A pharmaceutical composition comprising:

[10] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to The pharmaceutical composition according to any one of [7] to [9], wherein the number of the active ingredient is in the range of 8.

[0017]

[11] [2] The antibody in the antibody-drug conjugate is an anti-TROP2 antibody. Pharmaceutical compositions.

[12] The anti-TROP2 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO:5. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO:6. The pharmaceutical composition according to

[11] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[13] The anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain

[12] . The pharmaceutical composition described.

[14] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5 The pharmaceutical composition according to any one of

[11] to

[13] , wherein the molecular weight is in the range of from 1 to 4.5.

[15] [2] The antibody in the antibody-drug conjugate is an anti-B7-H3 antibody. Pharmaceutical compositions.

[16] 7. The anti-B7-H3 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO:7. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO:8. The pharmaceutical composition according to

[15] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[17] The anti-B7-H3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain

[16] . The pharmaceutical composition described.

[18] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5 The pharmaceutical composition according to any one of

[15] to

[17] , wherein the molecular weight is in the range of from 1 to 4.5.

[19] [2] The antibody in the antibody-drug conjugate is an anti-GPR20 antibody. Pharmaceutical compositions.

[20] The anti-GPR20 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 472 of SEQ ID NO:9. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 10. The pharmaceutical composition according to

[19] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[0018] [twenty one] The anti-GPR20 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain

[20] . The pharmaceutical composition described. [twenty two] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to The pharmaceutical composition according to any one of

[19] to

[21] , wherein the number of the active ingredient is in the range of 8. [twenty three] The method according to [2], wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody. Pharmaceutical composition. [twenty four] The anti-CDH6 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO:11. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO:12. The pharmaceutical composition according to

[23] , wherein the antibody comprises a light chain consisting of an amino acid sequence. [twenty five] The anti-CDH6 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain, as described in

[24] . The pharmaceutical composition described above.

[26] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to The pharmaceutical composition according to any one of

[23] to

[25] , wherein the number of the active ingredient is in the range of 8.

[27] The tubulin inhibitor is paclitaxel, docetaxel, cabazitaxel, or A pharmacologically acceptable salt thereof, or nab-paclitaxel, according to any one of [1] to

[26] . The pharmaceutical composition according to any one of claims 1 to 4.

[28] The pharmaceutical composition described in

[27] , wherein the tubulin inhibitor is paclitaxel.

[29] The tubulin inhibitor is eribulin or a pharmacologically acceptable salt thereof, or eribulin The pharmaceutical composition according to any one of [1] to

[0026] , which is an antibody-drug conjugate in which the antibody is linked via a linker.

[30] The pharmaceutical composition described in

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

[0019]

[31] Antibody-drug conjugates and tubulin inhibitors are active ingredients in different formulations. The pharmaceutical composition according to any one of [1] to

[0030] , characterized in that the pharmaceutical composition is contained as one or more of the following and is administered simultaneously or at different times.

[32] Breast cancer, stomach cancer, colon cancer, lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary Cancer of the bladder, prostate, uterine, and ovarian cancers, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, and uterine cancer Any of [1] to

[31] for the treatment of at least one selected from the group consisting of tumors, The pharmaceutical composition according to any one of claims 1 to 5.

[33] The pharmaceutical composition described in

[32] for the treatment of breast cancer.

[34] The pharmaceutical composition described in

[32] for the treatment of gastric cancer.

[35] The pharmaceutical composition described in

[32] for the treatment of lung cancer.

[36] The pharmaceutical composition described in

[32] for the treatment of ovarian cancer.

[37] The decrease in expression of drug susceptibility factors caused by administration of antibody-drug conjugates was evaluated using tube The pharmaceutical composition according to any one of [1] to

[36] , characterized in that the phosphorylation inhibitor inhibits Pharmaceutical composition.

[38] The pharmaceutical composition described in

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

[39] The increased expression of drug resistance factors caused by administration of antibody-drug conjugates was The pharmaceutical composition according to any one of [1] to

[36] , characterized in that the inhibitor inhibits composition.

[40] The pharmaceutical composition described in

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

[41] The antibody-drug conjugate and the tubulin inhibitor are administered in combination. A pharmaceutical composition comprising: The antibody-drug conjugate has the formula

[0020] [ka]

[0021] (wherein the drug linker is bonded to the antibody via a thioether bond, and n is the number of antibodies per (The average number of drug linkers bonded per A pharmaceutical composition comprising an antibody-drug conjugate represented by the formula:

[42] The antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TR antibody, The pharmaceutical composition described in

[0041] , which is an OP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[43]

[42] The method according to claim 42, wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody. Pharmaceutical compositions.

[44] The anti-HER2 antibody comprises an amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO:1. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO:2. The pharmaceutical composition according to

[43] , wherein the antibody comprises a light chain consisting of:

[45] The anti-HER2 antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 1 and a heavy chain having the amino acid sequence shown in SEQ ID NO: 2. The pharmaceutical composition according to

[43] , wherein the antibody comprises a light chain having the amino acid sequence set forth above.

[46] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to The pharmaceutical composition according to any one of

[43] to

[45] , wherein the number of active ingredients is in the range of 8.

[47]

[42] The antibody in the antibody-drug conjugate is an anti-HER3 antibody. Pharmaceutical compositions.

[48] The anti-HER3 antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 3 and a heavy chain having the amino acid sequence shown in SEQ ID NO: 4. The pharmaceutical composition according to

[47] , wherein the antibody comprises a light chain having the amino acid sequence set forth above.

[49] The anti-HER3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain, as described in

[48] . The pharmaceutical composition described above.

[50] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to The pharmaceutical composition according to any one of

[47] to

[49] , wherein the number of active ingredients is in the range of 8.

[0022]

[51]

[42] , in which the antibody in the antibody-drug conjugate is an anti-TROP2 antibody. A pharmaceutical composition comprising:

[52] The anti-TROP2 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO:5. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO:6. The pharmaceutical composition according to

[51] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[53] The anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain

[52] . The pharmaceutical composition described.

[54] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5 The pharmaceutical composition according to any one of

[51] to

[53] , wherein the molecular weight is in the range of from 1 to 4.5.

[55]

[42] , wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody. A pharmaceutical composition comprising:

[56] 7. The anti-B7-H3 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO:7. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO:8. The pharmaceutical composition according to

[55] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[57] The anti-B7-H3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain,

[56] The pharmaceutical composition described.

[58] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5 The pharmaceutical composition according to any one of

[55] to

[57] , wherein the molecular weight is in the range of from 1 to 4.5.

[59]

[42] , wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody. A pharmaceutical composition comprising:

[60] The anti-GPR20 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 472 of SEQ ID NO:9. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 10. The pharmaceutical composition according to

[59] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[0023]

[61] The anti-GPR20 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain

[60] . The pharmaceutical composition described.

[62] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to The pharmaceutical composition according to any one of

[59] to

[61] , wherein the number of active ingredients is in the range of 8.

[63]

[42] The antibody in the antibody-drug conjugate is an anti-CDH6 antibody. Pharmaceutical compositions.

[64] The anti-CDH6 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO:11. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO:12. The pharmaceutical composition according to

[63] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[65] The anti-CDH6 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain, as described in

[64] . The pharmaceutical composition described above.

[66] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to The pharmaceutical composition according to any one of

[63] to

[65] , wherein the number of active ingredients is in the range of 8.

[67] The tubulin inhibitor is paclitaxel, docetaxel, cabazitaxel, or or nab-paclitaxel,

[41] to

[66] The pharmaceutical composition according to any one of claims 1 to 5.

[68] The pharmaceutical composition described in

[67] , wherein the tubulin inhibitor is paclitaxel.

[69] The tubulin inhibitor is eribulin or a pharmacologically acceptable salt thereof, or eribulin The pharmaceutical composition according to any one of

[41] to

[0066] , which is an antibody-drug conjugate in which the antibody is linked via a linker.

[70] The pharmaceutical composition described in

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

[0024]

[71] Antibody-drug conjugates and tubulin inhibitors are active ingredients in different formulations. The pharmaceutical composition according to any one of

[41] to

[0070] , wherein the pharmaceutical composition is administered simultaneously or at different times.

[72] Breast cancer, stomach cancer, colon cancer, lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary Cancer of the bladder, prostate, uterine, and ovarian cancers, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, and uterine cancer Any of

[41] to

[71] for the treatment of at least one tumor selected from the group consisting of tumors and tumours. The pharmaceutical composition according to any one of claims 1 to 5.

[73] The pharmaceutical composition described in

[72] for the treatment of breast cancer.

[74] The pharmaceutical composition described in

[72] for the treatment of gastric cancer.

[75] The pharmaceutical composition described in

[72] for the treatment of lung cancer.

[76] The pharmaceutical composition described in

[72] for the treatment of ovarian cancer.

[77] The decrease in expression of drug susceptibility factors caused by administration of antibody-drug conjugates was evaluated using tube

[41] to

[76] , characterized in that the phosphorylation inhibitor inhibits Pharmaceutical compositions.

[78] The pharmaceutical composition described in

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

[79] The increased expression of drug resistance factors caused by administration of antibody-drug conjugates was The medical device according to any one of

[41] to

[76] , characterized in that the anti-inflammatory drug is an anti-inflammatory drug. Pharmaceutical composition.

[80] The pharmaceutical composition described in

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

[81] Antibody-drug conjugates and tubulin inhibitors are used in combination to treat 23. A method of treating a subject comprising administering to said subject a therapeutic agent ... The antibody-drug conjugate has the formula

[0025] [ka]

[0026] (wherein A represents the binding site to the antibody) The antibody-drug conjugate is formed by binding the drug linker represented by the formula: A method of treatment that is jugate.

[82] The antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TR antibody, The therapeutic method described in

[0081] , wherein the antibody is an OP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[83]

[82] The method according to

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

[84] The anti-HER2 antibody comprises an amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO:1. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO:2. The therapeutic method according to

[83] , wherein the antibody comprises a light chain consisting of:

[85] The anti-HER2 antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 1 and a heavy chain having the amino acid sequence shown in SEQ ID NO: 2. The therapeutic method according to

[83] , wherein the antibody comprises a light chain having the amino acid sequence listed above.

[86] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to A treatment method according to any one of

[83] to

[85] , wherein the number of the active ingredients is in the range of 8.

[87]

[82] The method according to

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

[88] The anti-HER3 antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 3 and a heavy chain having the amino acid sequence shown in SEQ ID NO: 4. The therapeutic method according to

[87] , wherein the antibody comprises a light chain having the amino acid sequence listed above.

[89] The anti-HER3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain, as described in

[88] . The treatment methods listed above.

[90] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to The treatment method according to any one of items

[87] to

[89] , wherein the number of the active ingredients is in the range of 8.

[0027]

[91]

[82] , in which the antibody in the antibody-drug conjugate is an anti-TROP2 antibody. Treatment methods.

[92] The anti-TROP2 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO:5. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO:6. The therapeutic method according to

[91] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[93] The anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain

[92] . The described method of treatment.

[94] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5 The method of any one of

[91] to

[93] , wherein the range is from 1 to 4.5.

[95]

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

[96] 7. The anti-B7-H3 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO:7. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO:8. The therapeutic method according to

[95] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[97] The anti-B7-H3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain,

[96] The described method of treatment.

[98] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5 The method of any one of

[95] to

[97] , wherein the range is from 1 to 4.5.

[99]

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

[0100] The anti-GPR20 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 472 of SEQ ID NO:9. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 10. The therapeutic method according to

[99] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[0028]

[0101] The anti-GPR20 antibody has a deletion of the lysine residue at the carboxyl terminus of the heavy chain. The treatment method described above.

[0102] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to A treatment method described in any one of items

[99] to

[0101] , in the range of 8.

[0103]

[82] The antibody in the antibody-drug conjugate is an anti-CDH6 antibody. Treatment method.

[0104] The anti-CDH6 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO:11. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO:12. A therapeutic method described in

[0103] , wherein the antibody has a light chain consisting of an amino acid sequence.

[0105] The anti-CDH6 antibody has a deletion of the lysine residue at the carboxyl terminus of the heavy chain. The described method of treatment.

[0106] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to A treatment method described in any one of

[0103] to

[0105] , wherein the range is 8.

[0107] The tubulin inhibitor is paclitaxel, docetaxel, cabazitaxel, or The method for treatment according to any one of

[81] to

[0106] , wherein the compound is a pharmacologically acceptable salt thereof, or nab-paclitaxel.

[0108] A treatment method described in

[0107] , wherein the tubulin inhibitor is paclitaxel.

[0109] The tubulin inhibitor is eribulin or a pharmacologically acceptable salt thereof, or eribulin The therapeutic method according to any one of

[81] to

[0106] , wherein the antibody is an antibody-drug conjugate in which the antibody is linked via a linker.

[0110] A treatment method described in

[0109] , wherein the tubulin inhibitor is eribulin mesylate.

[0029]

[0111] Antibody-drug conjugates and tubulin inhibitors are active ingredients in different formulations. The method for treatment according to any one of

[81] to

[0110] , characterized in that the compounds are contained in the above-mentioned mixture and administered simultaneously or at different times.

[0112] Breast cancer, stomach cancer, colon cancer, lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary Cancer of the bladder, prostate, uterine, and ovarian cancers, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, and uterine cancer

[81] to

[0111] for the treatment of at least one selected from the group consisting of tumors and tumours. 13. The method of treatment according to any one of claims 1 to 12.

[0113] A therapeutic method described in

[0112] for treating breast cancer.

[0114] A therapeutic method described in

[0112] for treating gastric cancer.

[0115] A therapeutic method described in

[0112] for treating lung cancer.

[0116] A therapeutic method described in

[0112] for the treatment of ovarian cancer.

[0117] The decrease in expression of drug susceptibility factors caused by administration of antibody-drug conjugates was evaluated using tube The present invention relates to a method for treating a pulmonary circulation disorder, and a method for treating a pulmonary circulation disorder. Treatment methods.

[0118] A therapeutic method described in

[0117] , wherein the drug sensitivity factor is SLFN11.

[0119] The increased expression of drug resistance factors caused by administration of antibody-drug conjugates was The method according to any one of

[81] to

[0116] , characterized in that the inhibitor inhibits Treatment method.

[0120] A treatment method described in

[0119] , wherein the drug resistance factor is ABCG2.

[0121] Antibody-drug conjugates and tubulin inhibitors are used in combination to treat 23. A method of treating a subject comprising administering to said subject a therapeutic agent ... The antibody-drug conjugate has the formula

[0030] [ka]

[0031] (wherein the drug linker is bonded to the antibody via a thioether bond, and n is the number of antibodies per (The average number of drug linkers bonded per The therapeutic method comprises administering to the patient an antibody-drug conjugate as defined above.

[0122] The antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TR antibody, The therapeutic method described in

[0121] , wherein the antibody is an OP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[0123] The antibody in the antibody-drug conjugate is an anti-HER2 antibody. Treatment methods.

[0124] The anti-HER2 antibody comprises an amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO:1. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO:2. A therapeutic method described in

[0123] , wherein the antibody comprises a light chain consisting of:

[0125] The anti-HER2 antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 1 and a heavy chain having the amino acid sequence shown in SEQ ID NO: 2. The therapeutic method described in

[0123] , wherein the antibody has a light chain consisting of the amino acid sequence listed above.

[0126] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to A treatment method described in any one of

[0123] to

[0125] , wherein the range is 8.

[0127] The antibody in the antibody-drug conjugate is an anti-HER3 antibody. Treatment methods.

[0128] The anti-HER3 antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 3 and a heavy chain having the amino acid sequence shown in SEQ ID NO: 4. The therapeutic method described in

[0127] , wherein the antibody has a light chain consisting of the amino acid sequence listed above.

[0129] The anti-HER3 antibody has a deletion of the lysine residue at the carboxyl terminus of the heavy chain. The described method of treatment.

[0130] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to A treatment method described in any one of

[0127] to

[0129] , wherein the range is 8.

[0032]

[0131] The antibody in the antibody-drug conjugate is an anti-TROP2 antibody. The treatment methods listed above.

[0132] The anti-TROP2 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO:5. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO:6. A therapeutic method described in

[0131] , wherein the antibody has a light chain consisting of an amino acid sequence.

[0133] The anti-TROP2 antibody has a deletion of the lysine residue at the carboxyl terminus of the heavy chain. The treatment method described above.

[0134] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5 The method of any one of

[0131] to

[0133] , wherein the range is from 1 to 4.5. .

[0135] The antibody in the antibody-drug conjugate is an anti-B7-H3 antibody. The treatment methods listed above.

[0136] 7. The anti-B7-H3 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO:7. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO:8. A therapeutic method described in

[0135] , wherein the antibody has a light chain consisting of an amino acid sequence.

[0137] The anti-B7-H3 antibody has a deletion of the lysine residue at the carboxyl terminus of the heavy chain. The treatment method described above.

[0138] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5 The method of any one of

[0135] to

[0137] , wherein the range is from 1 to 4.5. .

[0139] The antibody in the antibody-drug conjugate is an anti-GPR20 antibody. The treatment methods listed above.

[0140] The anti-GPR20 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 472 of SEQ ID NO:9. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 10. The therapeutic method described in

[0139] , wherein the antibody has a light chain consisting of an amino acid sequence.

[0033]

[0141] The anti-GPR20 antibody has a deletion of the lysine residue at the carboxyl terminus of the heavy chain. The treatment method described above.

[0142] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to A treatment method described in any one of

[0139] to

[0141] , wherein the range is 8.

[0143] The antibody in the antibody-drug conjugate is an anti-CDH6 antibody. Treatment methods.

[0144] The anti-CDH6 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO:11. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO:12. The therapeutic method described in

[0143] , wherein the antibody has a light chain consisting of an amino acid sequence.

[0145] The anti-CDH6 antibody has a deletion of the lysine residue at the carboxyl terminus of the heavy chain. The described method of treatment.

[0146] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to A treatment method described in any one of

[0143] to

[0145] , wherein the range is 8.

[0147] The tubulin inhibitor is paclitaxel, docetaxel, cabazitaxel, or A treatment method described in any one of

[0121] to

[0146] , wherein the compound is a pharmacologically acceptable salt thereof, or nab-paclitaxel.

[0148] A treatment method described in

[0147] , wherein the tubulin inhibitor is paclitaxel.

[0149] The tubulin inhibitor is eribulin or a pharmacologically acceptable salt thereof, or eribulin and an antibody-drug conjugate in which the compound is linked to an antibody via a linker.

[0146] A treatment method described in any one of the above items.

[0150] A treatment method described in

[0149] , wherein the tubulin inhibitor is eribulin mesylate.

[0034]

[0151] Antibody-drug conjugates and tubulin inhibitors are active ingredients in different formulations. and are administered simultaneously or at different times.

[0150] A treatment method described in any one of the above items.

[0152] Breast cancer, stomach cancer, colon cancer, lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary Cancer of the bladder, prostate, uterine, and ovarian cancers, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, and uterine cancer

[0121] to

[0151] for the treatment of at least one selected from the group consisting of tumors, The method for treatment according to any one of the preceding claims.

[0153] A therapeutic method described in

[0152] for treating breast cancer.

[0154] A therapeutic method described in

[0152] for treating gastric cancer.

[0155] A therapeutic method described in

[0152] for treating lung cancer.

[0156] A therapeutic method described in

[0152] for the treatment of ovarian cancer.

[0157] The decrease in expression of drug susceptibility factors caused by administration of antibody-drug conjugates was evaluated using tube

[0121] to

[0156] , characterized in that the phosphorylation inhibitor inhibits The treatment methods listed above.

[0158] A therapeutic method described in

[0157] , wherein the drug sensitivity factor is SLFN11.

[0159] The increased expression of drug resistance factors caused by administration of antibody-drug conjugates was The present invention relates to a method for treating a pulmonary circulation disorder, and a method for treating a pulmonary circulation disorder. Treatment methods.

[0160] A treatment method described in

[0159] , wherein the drug resistance factor is ABCG2.

[0161] and administering the same in combination with a tubulin inhibitor to treat a disease. formula

[0035] [ka]

[0036] (wherein A represents the binding site to the antibody) The antibody-drug conjugate is formed by binding the drug linker represented by the formula: Jugate.

[0162] The antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TR antibody, The antibody-drug conjugate described in

[0161] , which is an OP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[0163] The antibody in the antibody-drug conjugate is an anti-HER2 antibody. Antibody-drug conjugates.

[0164] The anti-HER2 antibody comprises an amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO:1. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO:2. An antibody-drug conjugate according to

[0163] , which is an antibody comprising a light chain consisting of:

[0165] The anti-HER2 antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 1 and a heavy chain having the amino acid sequence shown in SEQ ID NO: 2. The antibody-drug according to

[0163] , which is an antibody having a light chain consisting of the amino acid sequence listed above. Conjugate.

[0166] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to 8 to 8 of the antibody-drug conjugate according to any one of

[0163] to

[0165] . ugate.

[0167] The antibody in the antibody-drug conjugate is an anti-HER3 antibody. Antibody-drug conjugates.

[0168] The anti-HER3 antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 3 and a heavy chain having the amino acid sequence shown in SEQ ID NO: 4. The antibody-drug according to

[0167] , which is an antibody having a light chain consisting of the amino acid sequence listed above. Conjugate.

[0169] The anti-HER3 antibody has a deletion of the lysine residue at the carboxyl terminus of the heavy chain. The antibody-drug conjugates described herein.

[0170] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to 8. The antibody-drug conjugate according to any one of

[0167] to

[0169] , gate.

[0037]

[0171] The antibody in the antibody-drug conjugate is an anti-TROP2 antibody. The antibody-drug conjugates described above.

[0172] The anti-TROP2 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO:5. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO:6. The antibody-drug conjugate according to

[0171] , which is an antibody having a light chain consisting of an amino acid sequence. Quote.

[0173] The anti-TROP2 antibody has a deletion of the lysine residue at the carboxyl terminus of the heavy chain. The antibody-drug conjugate according to claim 1,

[0174] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5

[0171] to

[0173] , wherein the antibody-drug Material conjugates.

[0175] The antibody in the antibody-drug conjugate is an anti-B7-H3 antibody. The antibody-drug conjugates described above.

[0176] 7. The anti-B7-H3 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO:7. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO:8. The antibody-drug conjugate according to

[0175] , which is an antibody having a light chain consisting of an amino acid sequence. Quote.

[0177] The anti-B7-H3 antibody has a deletion of the lysine residue at the carboxyl terminus of the heavy chain. The antibody-drug conjugate according to claim 1,

[0178] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5

[0175] to

[0177] , wherein the antibody-drug Material conjugates.

[0179] The antibody in the antibody-drug conjugate is an anti-GPR20 antibody. The antibody-drug conjugates described above.

[0180] The anti-GPR20 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 472 of SEQ ID NO:9. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 10. The antibody-drug conjugate according to

[0179] , which is an antibody having a light chain consisting of the amino acid sequence gate.

[0038]

[0181] The anti-GPR20 antibody has a deletion of the lysine residue at the carboxyl terminus of the heavy chain. The antibody-drug conjugate according to claim 1,

[0182] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to 8 to 8 of the antibody-drug conjugate according to any one of

[0179] to

[0181] . ugate.

[0183] The antibody in the antibody-drug conjugate is an anti-CDH6 antibody. Antibody-drug conjugates.

[0184] The anti-CDH6 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO:11. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO:12. The antibody-drug conjugate according to

[0183] , which is an antibody having a light chain consisting of the amino acid sequence gate.

[0185] The anti-CDH6 antibody has a deletion of the lysine residue at the carboxyl terminus of the heavy chain. The antibody-drug conjugates described herein.

[0186] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to 8 to 8 of the antibody-drug conjugate according to any one of

[0183] to

[0185] . ugate.

[0187] The tubulin inhibitor is paclitaxel, docetaxel, cabazitaxel, or The antibody-drug conjugate according to any one of

[0161] to

[0186] , which is a pharmacologically acceptable salt thereof, or nab-paclitaxel.

[0188] The antibody-drug conjugate according to

[0187] , wherein the tubulin inhibitor is paclitaxel. ugate.

[0189] The tubulin inhibitor is eribulin or a pharmacologically acceptable salt thereof, or eribulin and an antibody-drug conjugate in which the above is linked to an antibody via a linker.

[0186] An antibody-drug conjugate described in any one of the above.

[0190] The antibody-drug according to

[0189] , wherein the tubulin inhibitor is eribulin mesylate. Conjugate.

[0039]

[0191] Antibody-drug conjugates and tubulin inhibitors are active ingredients in different formulations. and are administered simultaneously or at different times.

[0190] An antibody-drug conjugate described in any one of the above.

[0192] Breast cancer, stomach cancer, colon cancer, lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary Cancer of the bladder, prostate, uterine, and ovarian cancers, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, and uterine cancer

[0161] to

[0191] for the treatment of at least one selected from the group consisting of tumors, The antibody-drug conjugate according to any one of claims 1 to 5.

[0193] An antibody-drug conjugate described in

[0192] for the treatment of breast cancer.

[0194] An antibody-drug conjugate described in

[0192] for the treatment of gastric cancer.

[0195] An antibody-drug conjugate described in

[0192] for the treatment of lung cancer.

[0196] An antibody-drug conjugate described in

[0192] for the treatment of ovarian cancer.

[0197] The decrease in expression of drug susceptibility factors caused by administration of antibody-drug conjugates was evaluated using tube

[0161] to

[0196] , characterized in that the phosphorylation inhibitor inhibits The antibody-drug conjugates described above.

[0198] The antibody-drug conjugate according to

[0197] , wherein the drug sensitivity factor is SLFN11. .

[0199] The increased expression of drug resistance factors caused by administration of antibody-drug conjugates was The method according to any one of

[0161] to

[0196] , characterized in that the inhibitor inhibits Antibody-drug conjugates.

[0200] An antibody-drug conjugate described in

[0199] , wherein the drug resistance factor is ABCG2.

[0201] and administering the same in combination with a tubulin inhibitor to treat a disease. formula

[0040] [ka]

[0041] (wherein the drug linker is bonded to the antibody via a thioether bond, and n is the number of antibodies per (The average number of drug linkers bonded per The antibody-drug conjugate shown in FIG.

[0202] The antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TR antibody, The antibody-drug conjugate described in

[0201] , which is an OP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[0203] The antibody in the antibody-drug conjugate is an anti-HER2 antibody. Antibody-drug conjugates.

[0204] The anti-HER2 antibody comprises an amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO:1. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO:2. An antibody-drug conjugate according to

[0203] , which is an antibody comprising a light chain consisting of:

[0205] The anti-HER2 antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 1 and a heavy chain having the amino acid sequence shown in SEQ ID NO: 2. The antibody-drug according to

[0203] , which is an antibody having a light chain consisting of the amino acid sequence listed above. Conjugate.

[0206] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to 8 to 8 of the antibody-drug conjugate according to any one of

[0203] to

[0205] . ugate.

[0207] The antibody in the antibody-drug conjugate is an anti-HER3 antibody. Antibody-drug conjugates.

[0208] The anti-HER3 antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 3 and a heavy chain having the amino acid sequence shown in SEQ ID NO: 4. The antibody-drug according to

[0207] , which is an antibody having a light chain consisting of the amino acid sequence listed above. Conjugate.

[0209] The anti-HER3 antibody has a deletion of the lysine residue at the carboxyl terminus of the heavy chain. The antibody-drug conjugates described herein.

[0210] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to 8. The antibody-drug conjugate according to any one of

[0207] to

[0209] , gate.

[0042]

[0211] The antibody in the antibody-drug conjugate is an anti-TROP2 antibody. The antibody-drug conjugates described above.

[0212] The anti-TROP2 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO:5. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO:6. The antibody-drug conjugate according to

[0211] , which is an antibody having a light chain consisting of an amino acid sequence. Quote.

[0213] The anti-TROP2 antibody has a deletion of the lysine residue at the carboxyl terminus of the heavy chain. The antibody-drug conjugate according to claim 1,

[0214] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5

[0211] to

[0213] , wherein the antibody-drug is in the range of 4.5 to 4.5. Material conjugates.

[0215] The antibody in the antibody-drug conjugate is an anti-B7-H3 antibody. The antibody-drug conjugates described above.

[0216] 7. The anti-B7-H3 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO:7. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO:8. The antibody-drug conjugate according to

[0215] , which is an antibody having a light chain consisting of an amino acid sequence. Quote.

[0217] The anti-B7-H3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain. The antibody-drug conjugate according to claim 1,

[0218] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5

[0215] to

[0217] , wherein the antibody-drug is in the range of 4.5 to 4.5. Material conjugates.

[0219] The antibody in the antibody-drug conjugate is an anti-GPR20 antibody. The antibody-drug conjugates described above.

[0220] The anti-GPR20 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 472 of SEQ ID NO:9. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 10. The antibody-drug conjugate according to

[0219] , which is an antibody having a light chain consisting of the amino acid sequence gate.

[0043]

[0221] The anti-GPR20 antibody has a deletion of the lysine residue at the carboxyl terminus of the heavy chain. The antibody-drug conjugate according to claim 1,

[0222] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to 8 to 8 of the antibody-drug conjugate according to any one of

[0219] to

[0221] . ugate.

[0223] The antibody in the antibody-drug conjugate is an anti-CDH6 antibody. Antibody-drug conjugates.

[0224] The anti-CDH6 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO:11. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO:12. The antibody-drug conjugate according to

[0223] , which is an antibody having a light chain consisting of the amino acid sequence gate.

[0225] The anti-CDH6 antibody has a deletion of the lysine residue at the carboxyl terminus of the heavy chain. The antibody-drug conjugates described herein.

[0226] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to 8 to 8 of the antibody-drug conjugate according to any one of

[0223] to

[0225] . ugate.

[0227] The tubulin inhibitor is paclitaxel, docetaxel, cabazitaxel, or The antibody-drug conjugate described in any one of

[0201] to

[0226] , which is a pharmacologically acceptable salt thereof, or nab-paclitaxel.

[0228] The antibody-drug conjugate according to

[0227] , wherein the tubulin inhibitor is paclitaxel. ugate.

[0229] The tubulin inhibitor is eribulin or a pharmacologically acceptable salt thereof, or eribulin and an antibody-drug conjugate in which the compound is linked to an antibody via a linker.

[0226] An antibody-drug conjugate described in any one of the above.

[0230] The antibody-drug according to

[0229] , wherein the tubulin inhibitor is eribulin mesylate. Conjugate.

[0044]

[0231] Antibody-drug conjugates and tubulin inhibitors are active ingredients in different formulations. and are administered simultaneously or at different times.

[0230] An antibody-drug conjugate described in any one of the above.

[0232] Breast cancer, stomach cancer, colon cancer, lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary Cancer of the bladder, prostate, uterine, and ovarian cancers, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, and uterine cancer

[0201] to

[0231] for the treatment of at least one selected from the group consisting of tumors, The antibody-drug conjugate according to any one of claims 1 to 5.

[0233] An antibody-drug conjugate described in

[0232] for the treatment of breast cancer.

[0234] An antibody-drug conjugate described in

[0232] for the treatment of gastric cancer.

[0235] An antibody-drug conjugate described in

[0232] for the treatment of lung cancer.

[0236] An antibody-drug conjugate described in

[0232] for the treatment of ovarian cancer.

[0237] The decrease in expression of drug susceptibility factors caused by administration of antibody-drug conjugates was evaluated using tube

[0201] to

[0236] , characterized in that the phosphorylation inhibitor inhibits The antibody-drug conjugates described above.

[0238] The antibody-drug conjugate according to

[0237] , wherein the drug sensitivity factor is SLFN11. .

[0239] The increased expression of drug resistance factors caused by administration of antibody-drug conjugates was The present invention relates to a method for treating a cancer, comprising the steps of: Antibody-drug conjugates.

[0240] The antibody-drug conjugate described in

[0239] , wherein the drug resistance factor is ABCG2.

[0241] and administering the same in combination with a tubulin inhibitor to treat a disease. For the manufacture of medicines formula

[0045] [ka]

[0046] (wherein A represents the binding site to the antibody) The antibody-drug conjugate is formed by binding the drug linker represented by the formula: Use of Jugate.

[0242] The antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TR antibody, The use described in

[0241] , wherein the antibody is an OP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[0243] The antibody in the antibody-drug conjugate is an anti-HER2 antibody. Use of.

[0244] The anti-HER2 antibody comprises an amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO:1. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO:2. The use described in

[0243] , wherein the antibody comprises a light chain consisting of:

[0245] The anti-HER2 antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 1 and a heavy chain having the amino acid sequence shown in SEQ ID NO: 2. The use described in

[0243] , wherein the antibody comprises a light chain having the amino acid sequence listed above.

[0246] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to The use described in any one of

[0243] to

[0245] , which is in the range of 8.

[0247] The antibody in the antibody-drug conjugate is an anti-HER3 antibody. Use of.

[0248] The anti-HER3 antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 3 and a heavy chain having the amino acid sequence shown in SEQ ID NO: 4. The use described in

[0247] , wherein the antibody comprises a light chain having the amino acid sequence listed above.

[0249] The anti-HER3 antibody has a deletion of the lysine residue at the carboxyl terminus of the heavy chain. Use as described.

[0250] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to The use described in any one of

[0247] to

[0249] , wherein the range is 8.

[0047]

[0251] The antibody in the antibody-drug conjugate is an anti-TROP2 antibody. Use of the above.

[0252] The anti-TROP2 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO:5. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO:6. The use described in

[0251] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[0253] The anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain. The use described in.

[0254] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5 The use described in any one of

[0251] to

[0253] , wherein the range is from 1 to 4.5.

[0255] The antibody in the antibody-drug conjugate is an anti-B7-H3 antibody. Use of the above.

[0256] 7. The anti-B7-H3 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO:7. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO:8. The use described in

[0255] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[0257] The anti-B7-H3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain. The use described in.

[0258] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5 The use described in any one of

[0255] to

[0257] , wherein the range is from 1 to 4.5.

[0259] The antibody in the antibody-drug conjugate is an anti-GPR20 antibody. Use of the above.

[0260] The anti-GPR20 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 472 of SEQ ID NO:9. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 10. The use described in

[0259] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[0048]

[0261] The anti-GPR20 antibody has a deletion of the lysine residue at the carboxyl terminus of the heavy chain. The use described in.

[0262] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to The use described in any one of items

[0259] to

[0261] , which is in the range of 8.

[0263] The antibody in the antibody-drug conjugate is an anti-CDH6 antibody. Use of.

[0264] The anti-CDH6 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO:11. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO:12. The use described in

[0263] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[0265] The anti-CDH6 antibody has a deletion of the lysine residue at the carboxyl terminus of the heavy chain. Use as described.

[0266] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to The use described in any one of

[0263] to

[0265] , which is in the range of 8.

[0267] The tubulin inhibitor is paclitaxel, docetaxel, cabazitaxel, or The use described in any one of

[0241] to

[0266] , wherein the compound is a pharmacologically acceptable salt thereof, or nab-paclitaxel.

[0268] The use described in

[0267] , wherein the tubulin inhibitor is paclitaxel.

[0269] The tubulin inhibitor is eribulin or a pharmacologically acceptable salt thereof, or eribulin and an antibody-drug conjugate in which the above is linked to an antibody via a linker.

[0266] The use described in any one of the above items.

[0270] The use described in

[0269] , wherein the tubulin inhibitor is eribulin mesylate.

[0049]

[0271] Antibody-drug conjugates and tubulin inhibitors are active ingredients in different formulations. and are administered simultaneously or at different times.

[0270] The use described in any one of the above.

[0272] Breast cancer, stomach cancer, colon cancer, lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary Cancer of the bladder, prostate, uterine, and ovarian cancers, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, and uterine cancer

[0241] to

[0271] for the treatment of at least one selected from the group consisting of tumors, 2. The use according to any one of claims 1 to 11.

[0273] The use described in

[0272] for the treatment of breast cancer.

[0274] The use described in

[0272] for the treatment of gastric cancer.

[0275] The use described in

[0272] for the treatment of lung cancer.

[0276] The use described in

[0272] for the treatment of ovarian cancer.

[0277] The decrease in expression of drug susceptibility factors caused by administration of antibody-drug conjugates was evaluated using tube

[0241] to

[0276] , characterized in that the phosphorylation inhibitor inhibits Use of the above.

[0278] The use described in

[0277] , wherein the drug sensitivity factor is SLFN11.

[0279] The increased expression of drug resistance factors caused by administration of antibody-drug conjugates was The method according to any one of

[0241] to

[0276] , characterized in that the inhibitor inhibits Use of.

[0280] The use described in

[0279] , wherein the drug resistance factor is ABCG2.

[0281] and administering the same in combination with a tubulin inhibitor to treat a disease. For the manufacture of medicines formula

[0050] [ka]

[0051] (wherein the drug linker is bonded to the antibody via a thioether bond, and n is the number of antibodies per (The average number of drug linkers bonded per The use of an antibody-drug conjugate as shown in

[0282] The antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TR antibody, The use described in

[0281] , wherein the antibody is an OP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[0283] The antibody in the antibody-drug conjugate is an anti-HER2 antibody. Use of.

[0284] The anti-HER2 antibody comprises an amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO:1. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO:2. The use described in

[0283] , wherein the antibody comprises a light chain consisting of:

[0285] The anti-HER2 antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 1 and a heavy chain having the amino acid sequence shown in SEQ ID NO: 2. The use described in

[0283] , wherein the antibody comprises a light chain having the amino acid sequence listed above.

[0286] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to The use described in any one of items

[0283] to

[0285] , which is in the range of 8.

[0287] The antibody in the antibody-drug conjugate is an anti-HER3 antibody. Use of.

[0288] The anti-HER3 antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 3 and a heavy chain having the amino acid sequence shown in SEQ ID NO: 4. The use described in

[0287] , wherein the antibody comprises a light chain having the amino acid sequence listed above.

[0289] The anti-HER3 antibody has a deletion of the lysine residue at the carboxyl terminus of the heavy chain. Use as described.

[0290] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to The use described in any one of

[0287] to

[0289] , wherein the range is 8.

[0052]

[0291] The antibody in the antibody-drug conjugate is an anti-TROP2 antibody. Use of the above.

[0292] The anti-TROP2 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO:5. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO:6. The use described in

[0291] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[0293] The anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain. The use described in.

[0294] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5 The use described in any one of

[0291] to

[0293] , wherein the range is from 1 to 4.5.

[0295] The antibody in the antibody-drug conjugate is an anti-B7-H3 antibody. Use of the above.

[0296] 7. The anti-B7-H3 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO:7. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO:8. The use described in

[0295] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[0297] The anti-B7-H3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain. The use described in.

[0298] The average number of drug linkers per antibody in the antibody-drug conjugate is 3.5 The use described in any one of

[0295] to

[0297] , wherein the range is from 1 to 4.5.

[0299] The antibody in the antibody-drug conjugate is an anti-GPR20 antibody. Use of the above.

[0300] The anti-GPR20 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 472 of SEQ ID NO:9. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 10. The use described in

[0299] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[0053]

[0301] The anti-GPR20 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain. The use described in.

[0302] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to The use described in any one of items

[0299] to

[0301] , which is in the range of 8.

[0303] The antibody in the antibody-drug conjugate is an anti-CDH6 antibody. Use of.

[0304] The anti-CDH6 antibody comprises the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO:11. and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO:12. The use described in

[0303] , wherein the antibody comprises a light chain consisting of an amino acid sequence.

[0305] The anti-CDH6 antibody has a deletion of the lysine residue at the carboxyl terminus of the heavy chain. Use as described.

[0306] The average number of drug linkers per antibody in antibody-drug conjugates ranged from 7 to The use described in any one of

[0303] to

[0305] , wherein the range is 8.

[0307] The tubulin inhibitor is paclitaxel, docetaxel, cabazitaxel, or The use described in any one of

[0281] to

[0306] , wherein the compound is a pharmacologically acceptable salt thereof, or nab-paclitaxel.

[0308] The use described in

[0307] , wherein the tubulin inhibitor is paclitaxel.

[0309] The tubulin inhibitor is eribulin or a pharmacologically acceptable salt thereof, or eribulin and an antibody-drug conjugate in which the above is linked to an antibody via a linker.

[0306] The use described in any one of the above items.

[0310] The use described in

[0309] , wherein the tubulin inhibitor is eribulin mesylate.

[0054]

[0311] Antibody-drug conjugates and tubulin inhibitors are active ingredients in different formulations. and are administered simultaneously or at different times.

[0310] The use described in any one of the above items.

[0312] Breast cancer, stomach cancer, colon cancer, lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary Cancer of the bladder, prostate, uterine, and ovarian cancers, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, and uterine cancer

[0281] to

[0311] for the treatment of at least one selected from the group consisting of tumors, The use according to any one of claims 1 to 5.

[0313] The use described in

[0312] for the treatment of breast cancer.

[0314] The use described in

[0312] for the treatment of gastric cancer.

[0315] The use described in

[0312] for the treatment of lung cancer.

[0316] The use described in

[0312] for the treatment of ovarian cancer.

[0317] The decrease in expression of drug susceptibility factors caused by administration of antibody-drug conjugates was evaluated using tube

[0281] to

[0316] , characterized in that the phosphorylation inhibitor inhibits Use of the above.

[0318] The use described in

[0317] , wherein the drug sensitivity factor is SLFN11.

[0319] The increased expression of drug resistance factors caused by administration of antibody-drug conjugates was The present invention relates to a method for treating a cancer, comprising the steps of: Use of.

[0320] The use described in

[0319] , wherein the drug resistance factor is ABCG2.

[0055]

[0321] The antibody-drug conjugate and the tubulin inhibitor are administered in combination. A pharmaceutical composition comprising: 1) The decrease in expression of drug sensitivity factors caused by administration of the antibody-drug conjugate is and / or 2) detecting an increase in expression of drug resistance factors caused by administration of the antibody-drug conjugate in the culture medium; The inhibitors of rabulin suppress A pharmaceutical composition comprising:

[0322] The pharmaceutical composition described in

[0321] , wherein the drug sensitivity factor is SLFN11.

[0323] A pharmaceutical composition described in

[0321] or

[0322] , wherein the drug resistance factor is ABCG2.

[0324] A pharmaceutical composition described in any one of

[0321] to

[0323] , wherein the drug in the antibody-drug conjugate has a topoisomerase I inhibitory effect.

[0325] The antibody-drug conjugate has the formula

[0056] [ka]

[0057] (wherein A represents the binding site to the antibody) The antibody-drug conjugate is formed by binding the drug linker represented by the formula: A pharmaceutical composition described in any one of

[0321] to

[0323] , which is a jugate.

[0326] The antibody-drug conjugate has the formula

[0058] [ka]

[0059] (wherein the drug linker is bonded to the antibody via a thioether bond, and n is the number of antibodies per (The average number of drug linkers bonded per Any one of

[0321] to

[0323] , which is an antibody-drug conjugate represented by the formula: The pharmaceutical composition described in

[0327] Antibody-drug conjugates and tubulin inhibitors are used in combination to treat 23. A method of treating a subject comprising administering to said subject a therapeutic agent ... 1) The decrease in expression of drug sensitivity factors caused by administration of the antibody-drug conjugate is and / or 2) detecting an increase in expression of drug resistance factors caused by administration of the antibody-drug conjugate in the culture medium; The inhibitors of rabulin suppress A method of treatment, characterized by:

[0328] A treatment method described in

[0327] , wherein the drug sensitivity factor is SLFN11.

[0329] A treatment method described in

[0327] or

[0328] , wherein the drug resistance factor is ABCG2.

[0330] A therapeutic method described in any one of

[0327] to

[0329] , wherein the drug in the antibody-drug conjugate has a topoisomerase I inhibitory effect.

[0331] The antibody-drug conjugate has the formula

[0060] [ka]

[0061] (wherein A represents the binding site to the antibody) The antibody-drug conjugate is formed by binding the drug linker represented by the formula: A treatment method described in any one of

[0327] to

[0329] , wherein the compound is a jugate.

[0332] The antibody-drug conjugate has the formula

[0062] [ka]

[0063] (wherein the drug linker is bonded to the antibody via a thioether bond, and n is the number of antibodies per (The average number of drug linkers bonded per Any one of

[0327] to

[0329] , which is an antibody-drug conjugate represented by the formula: The treatment method described above.

[0333] and administering the same in combination with a tubulin inhibitor to treat a disease. 1. An antibody-drug conjugate comprising: 1) The decrease in expression of drug sensitivity factors caused by administration of the antibody-drug conjugate is and / or 2) detecting an increase in expression of drug resistance factors caused by administration of the antibody-drug conjugate in the culture medium; The inhibitors of rabulin suppress An antibody-drug conjugate, comprising:

[0334] The antibody-drug conjugate according to

[0333] , wherein the drug sensitivity factor is SLFN11. .

[0335] The antibody-drug conjugate according to

[0333] or

[0334] , wherein the drug resistance factor is ABCG2. Jugate.

[0336] An antibody-drug conjugate described in any one of

[0333] to

[0335] , wherein the drug in the antibody-drug conjugate has a topoisomerase I inhibitory effect.

[0337] The antibody-drug conjugate has the formula

[0064] [ka]

[0065] (wherein A represents the binding site to the antibody) The antibody-drug conjugate is formed by binding the drug linker represented by the formula:

[0333] to

[0335] , which is an antibody-drug conjugate. ugate.

[0338] The antibody-drug conjugate has the formula

[0066] [ka]

[0067] (wherein the drug linker is bonded to the antibody via a thioether bond, and n is the number of antibodies per (The average number of drug linkers bonded per Any one of

[0333] to

[0335] , which is an antibody-drug conjugate represented by the formula: The antibody-drug conjugate according to claim 1,

[0339] and administering the same in combination with a tubulin inhibitor to treat a disease. 1. Use of an antibody-drug conjugate for the manufacture of a medicament, comprising: 1) The decrease in expression of drug sensitivity factors caused by administration of the antibody-drug conjugate is and / or 2) detecting an increase in expression of drug resistance factors caused by administration of the antibody-drug conjugate in the culture medium; The inhibitors of rabulin suppress Characterized by, use.

[0340] The use described in

[0339] , wherein the drug sensitivity factor is SLFN11.

[0341] The use described in

[0339] or

[0340] , wherein the drug resistance factor is ABCG2.

[0342] The use described in any one of

[0339] to

[0341] , wherein the drug in the antibody-drug conjugate has a topoisomerase I inhibitory effect.

[0343] The antibody-drug conjugate has the formula

[0068] [ka]

[0069] (wherein A represents the binding site to the antibody) The antibody-drug conjugate is formed by binding the drug linker represented by the formula: The use of any one of

[0339] to

[0341] , which is a jugate.

[0344] The antibody-drug conjugate has the formula

[0070] [ka]

[0071] (wherein the drug linker is bonded to the antibody via a thioether bond, and n is the number of antibodies per (The average number of drug linkers bonded per Any one of

[0339] to

[0341] , which is an antibody-drug conjugate represented by the formula: The use described in. Effect of the Invention

[0072] According to the present invention, a specific antibody-drug conjugate and a tubulin inhibitor are combined. The pharmaceutical composition and / or specific antibody-drug conjugates are characterized in that they are administered in a single dose. A method of treatment comprising administering a combination of a gate and a tubulin inhibitor to an individual. The law can be provided. [Brief description of the drawings]

[0073] [Figure 1] FIG. 1 shows the amino acid sequence of the anti-HER2 antibody heavy chain (SEQ ID NO:1). [Diagram 2] FIG. 2 shows the amino acid sequence of the anti-HER2 antibody light chain (SEQ ID NO:2). [Diagram 3] FIG. 2 shows the amino acid sequence of the anti-HER3 antibody heavy chain (SEQ ID NO: 3). [Figure 4] FIG. 1 shows the amino acid sequence of the anti-HER3 antibody light chain (SEQ ID NO: 4). [Diagram 5] FIG. 1 shows the amino acid sequence of the anti-TROP2 antibody heavy chain (SEQ ID NO:5). [Figure 6] FIG. 1 shows the amino acid sequence of the anti-TROP2 antibody light chain (SEQ ID NO: 6). [Figure 7] FIG. 7 shows the amino acid sequence of the anti-B7-H3 antibody heavy chain (SEQ ID NO:7). [Figure 8] FIG. 1 shows the amino acid sequence of the anti-B7-H3 antibody light chain (SEQ ID NO: 8). [Figure 9] FIG. 1 shows the tumor growth inhibitory effects of the antibody-drug conjugate (1) and Paclitaxel single-agent administration groups, and the antibody-drug conjugate (1) and Paclitaxel combined administration group in mice subcutaneously implanted with KPL-4 cells. [Figure 10] FIG. 1 shows the tumor growth inhibitory effects in the antibody-drug conjugate (1) and Eribulin mesylate single-agent administration groups, and in the antibody-drug conjugate (1) and Eribulin mesylate combined administration group, in mice subcutaneously implanted with KPL-4 cells. [Figure 11] FIG. 1 shows the tumor growth inhibitory effects of the antibody-drug conjugate (1) and Paclitaxel single-agent administration groups, and the antibody-drug conjugate (1) and Paclitaxel combined administration group in mice subcutaneously implanted with JIMT-1 cells. [Figure 12]FIG. 1 shows the tumor growth inhibitory effects of the antibody-drug conjugate (1) and Eribulin mesylate single-agent administration groups, as well as the antibody-drug conjugate (1) and Eribulin mesylate combined administration group, in mice subcutaneously implanted with JIMT-1 cells. [Figure 13] FIG. 1 shows the tumor growth inhibitory effects of the antibody-drug conjugate (1) and Paclitaxel single-agent administration groups, and the antibody-drug conjugate (1) and Paclitaxel combined administration group in mice subcutaneously implanted with NCI-N87 cells. [Figure 14] FIG. 1 shows the tumor growth inhibitory effects of the antibody-drug conjugate (1) and Eribulin mesylate single-agent administration groups, as well as the antibody-drug conjugate (1) and Eribulin mesylate combined administration group, in mice subcutaneously implanted with NCI-N87 cells. [Figure 15] FIG. 1 shows the tumor growth inhibitory effects of antibody-drug conjugate (1) and Paclitaxel alone, as well as the antibody-drug conjugate (1) and Paclitaxel combined administration group in mice subcutaneously implanted with MDA-MB-453 cells. [Figure 16] FIG. 1 shows the tumor growth inhibitory effects of the antibody-drug conjugate (1) and Paclitaxel single-agent administration groups, and the antibody-drug conjugate (1) and Paclitaxel combined administration group in mice subcutaneously implanted with SNU-1 cells. [Figure 17] FIG. 1 shows the tumor growth inhibitory effects of the antibody-drug conjugate (1) and Paclitaxel single-agent administration groups, and the antibody-drug conjugate (1) and Paclitaxel combined administration group in mice subcutaneously implanted with NCI-H441 cells. [Figure 18] FIG. 1 shows the amino acid sequence of the anti-GPR20 antibody heavy chain (SEQ ID NO: 9). [Figure 19] FIG. 1 shows the amino acid sequence of the anti-GPR20 antibody light chain (SEQ ID NO: 10). [Figure 20]FIG. 1 shows the amino acid sequence of the anti-CDH6 antibody heavy chain (SEQ ID NO: 11). [Figure 21] FIG. 1 shows the amino acid sequence of the anti-CDH6 antibody light chain (SEQ ID NO: 12). [Figure 22] This figure shows the tumor growth inhibitory effects of the antibody-drug conjugate (2) and Paclitaxel single-agent administration group, and the antibody-drug conjugate (2) and Paclitaxel combined administration group in mice subcutaneously implanted with JIMT-1 cells. [Diagram 23] FIG. 1 shows the tumor growth inhibitory effects of the antibody-drug conjugate (3) and Paclitaxel single-agent administration groups, and the antibody-drug conjugate (3) and Paclitaxel combined administration group in mice subcutaneously implanted with OV-90 cells. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0074] A preferred embodiment of the present invention will be described below. The embodiment shows an example of a typical embodiment of the present invention, and the present invention The scope will not be interpreted narrowly.

[0075] 1. Antibody-drug conjugates The antibody-drug conjugate used in the present invention has the formula

[0076] [ka]

[0077] (wherein A represents the binding site to the antibody) The antibody-drug complex is formed by binding the drug linker represented by the formula: It is a njugate.

[0078] In the present invention, the portion of the antibody-drug conjugate consisting of a linker and a drug The structure is called a "drug linker." This drug linker is a drug that binds to the disulfide bond between the antibody chains. Thiol groups (in other words) generated at the positions (two heavy chain-heavy chain positions and two heavy chain-light chain positions) in other words, it is bound to the sulfur atom of a cysteine ​​residue.

[0079] The drug linker of the present invention is a topoisomerase I inhibitor, exatecan (IUPAC Name: (1S,9S)-1-amino-9-ethyl-5-fluoro-1,2,3,9,12, 15-Hexahydro-9-hydroxy-4-methyl-10H,13H-benzo[de]pi Lano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione Chemical name: (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro 9-Hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4': 6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione and Exatecan is a compound of the formula

[0080] [ka]

[0081] It is a camptothecin derivative having an antitumor effect, represented by the following formula:

[0082] The antibody-drug conjugate used in the present invention may also be represented by the following formula:

[0083] [ka]

[0084] Here, the drug linker is bound to the antibody via a thioether bond. The so-called average drug binding ratio (DAR; Drug-to-Antibody Ratio) and Synonymous with the average number of drug linkers bound per antibody.

[0085] The antibody-drug conjugate used in the present invention is transferred into cancer cells and then binds to the linker. The part is cut off, formula

[0086] [ka]

[0087] This liberates a compound represented by the formula:

[0088] The above compound is the main component of the antitumor activity of the antibody-drug conjugate used in the present invention. It is believed to have a topoisomerase I inhibitory effect (Ogitani Y. et al., Clinical Cancer Research, 2016, Oct 15;22(20):5097-5108, Epub 2016 Mar 29).

[0089] Topoisomerase I breaks and rejoins single strands of DNA, which causes the higher order structure of DNA. It is an enzyme that converts topoisomerase I structures and is involved in DNA synthesis. Drugs that inhibit DNA synthesis stop cells in the S phase of the cell cycle (the DNA synthesis phase). It inhibits the proliferation of cancer cells by halting cell division and inducing apoptotic cell death. can be suppressed.

[0090] On the other hand, tubulin inhibitors affect the microtubule dynamics and thus regulate the cell periphery. It stops cell division at the G2 phase (preparatory phase for division) and / or the M phase (division phase) of the cell cycle, resulting in apoptosis. By inducing cell death by oxidative stress, it is possible to suppress the proliferation of cancer cells (Dumont et C, et al., Nat Rev Drug Discov. 2010 Oct;9(10): 790-803.)(Mukhtar E, et al. , Mol Cancer Ther. 2014 Feb: 13(2): 275-284.).

[0091] Therefore, the antibody-drug conjugate (which has a topoisomerase I inhibitory effect) used in the present invention The agent having the antitumor activity is administered in combination with a tubulin inhibitor. By this, cell division is induced in the S phase and the G2 and / or M phase of the cell cycle. This allows for excellent combined effects (antitumor effects) to be achieved.

[0092] The antibody-drug conjugate used in the present invention has a bystander effect. It is also known that cancer cells have a role in the regulation of immune function (Ogitani Y. et al., Cancer Science (2016) 107, 1039-1046).

[0093] This bystander effect is believed to be due to the fact that the antibody-drug conjugates used in the present invention inhibit the expression of the target After internalization into the cancer cells, the compounds are released and transported to nearby cancer cells that do not express the target. It also exerts an antitumor effect on the tumor cells.

[0094] This bystander effect is due to the fact that the antibody-drug conjugate of the present invention Even when used in combination with tumor inhibitors, it exerts an excellent antitumor effect. .

[0095] 2. Antibodies in antibody-drug conjugates The antibody in the antibody-drug conjugate used in the present invention may be derived from any species. The antibodies may be derived from any source, but are preferably derived from humans, rats, mice, and rabbits. If derived from a species other than human, it is preferred to chimerize or humanize it using well-known techniques. The antibody of the present invention may be a polyclonal antibody or a monoclonal antibody. Although antibodies may be used, monoclonal antibodies are preferred.

[0096] The antibody in the antibody-drug conjugate used in the present invention preferably targets cancer cells. It has the property of being able to recognize cancer cells and bind to them. the ability to be taken up and internalized into cancer cells, and / or the ability to kill cancer cells It is preferable that the material has properties such as

[0097] The binding of the antibody to the cancer cells can be confirmed using flow cytometry. Antibody uptake into the cell can be achieved by (1) intracellularly delivering a secondary antibody (fluorescently labeled) that binds to the therapeutic antibody. A Cell Death and Differentiation Assay (CDA) to visualize the antibodies incorporated into the on (2008) 15, 751-761), (2) using a secondary antibody (fluorescently labeled) that binds to the therapeutic antibody to detect the cell Assay to measure the amount of fluorescence taken up into the vesicles (Molecular Biology of the Cell Vol. 1 5, 5268-5282, December 2004), or (3) using immunotoxins that bind to therapeutic antibodies. When the drug is taken up into cells, it releases toxins and inhibits cell proliferation. This can be confirmed using the P assay (BioTechniques 28:162-165, January 2000). The toxin is a recombinant complex protein consisting of the catalytic domain of diphtheria toxin and protein G. White matter can also be used.

[0098] Anti-tumor activity of antibodies can be evaluated in vitro by measuring their ability to inhibit cell proliferation. For example, a cancer cell line that overexpresses the antibody's target protein can be cultured and Antibodies were added at various concentrations to the cells, and the effects on focus formation, colony formation, and spheroid growth were evaluated. In vivo, for example, the inhibitory activity of a target protein can be measured. The antibody is administered to nude mice transplanted with a cancer cell line expressing the antibody, and changes in the cancer cells are measured. By this, antitumor activity can be confirmed.

[0099] It is preferable that the antibody itself has an antitumor effect, but the antibody-drug conjugate may have an antitumor effect. Since a compound that exerts an antitumor effect is bound to the antibody, the antibody itself does not necessarily have an antitumor effect. For the purpose of specifically and selectively exerting the cytotoxicity of antitumor compounds on cancer cells, It is important, and preferred, that the antibody has the property of being internalized and transported into cancer cells.

[0100] The antibody in the antibody-drug conjugate used in the present invention can be obtained by known means. For example, antigenic polysaccharides can be obtained by using methods commonly used in the art. It is obtained by immunizing an animal with the peptide and collecting and purifying the antibodies produced in the body. The origin of the antigen is not limited to humans, but can be derived from animals other than humans, such as mice and rats. Alternatively, animals can be immunized with an antigen that binds to the heterologous antigen obtained. By testing the cross-reactivity of antibodies with human antigens, we select antibodies that can be applied to human diseases. can.

[0101] Also, known methods (e.g., Kohler and Milstein, Nature (1975) 256, p. 495-497; ennet, R. ed., Monoclonal Antibodies, p.365-367, Plenum Press, NY (1980)). Therefore, the antibody-producing cells that produce antibodies against the antigen are fused with myeloma cells. Therefore, it is also possible to establish hybridomas and obtain monoclonal antibodies.

[0102] The antigen is produced by genetically engineering the gene encoding the antigen protein in the host cell. Specifically, a vector capable of expressing an antigen gene is prepared. This can then be introduced into a host cell to express the gene, and the expressed antigen can be purified. Immunizing an animal with the antigen-expressing cells or cell lines expressing the antigen by the above genetic manipulation. The antibodies can also be obtained by using the method.

[0103] The antibody in the antibody-drug conjugate used in the present invention is a heterologous antigen for humans. Recombinant antibodies that have been artificially modified to reduce their affinity, for example, Preferably, the antibody is a chimeric antibody or a humanized antibody. Alternatively, it is preferable that the antibody is an antibody having only the gene sequence of an antibody derived from a human, i.e., a human antibody. These antibodies can be produced using known methods.

[0104] Chimeric antibodies include antibodies in which the variable and constant regions of the antibody are of different species, such as mouse antibodies. Chimeric antibodies in which the variable regions of a mouse or rat-derived antibody are joined to constant regions of human origin are also included. (Proc. Natl. Acad. Sci. USA, 81, 6851-6855, (1984)).

[0105] Humanized antibodies are characterized by the complementarity determining regions (CDRs) of heterologous antibodies. The antibody was developed by incorporating only the ity determining region (IL-1) of human-derived antibodies. (Nature (1986) 321, p.522-525), and the CDR grafting method is used to graft the CDR sequences of heterologous antibodies. In addition, some of the framework amino acid residues of the heterologous antibody were also transplanted into a human antibody ( WO 90 / 07861, gene conversion mutagenesis Antibodies humanized using a cytotoxic ion mutagenesis strategy (U.S. Patent No. 5,333,411). No. 821337).

[0106] Human antibodies include those derived from human antibodies having a human chromosome fragment containing the genes for the heavy and light chains of human antibodies. Antibodies generated using antibody-producing mice (Tomizuka, K. et al., Nature Genetics (1997) 1 6, 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(K itagawa, Y., Matsuda, T. and Iijima, S. eds.), Kluwer Academic Publishers, 1999; See Tomizuka, K. et. al., Proc. Natl. Acad. Sci. USA (2000) 97, p.722-727. Alternatively, a phage display selected from a human antibody library can be used. The antibody obtained by the method described in Wormstone, IM et al., Investigative Ophthalmology & Vis (2002)43 (7), p.2301-2308;Carmen, S. et. al., Briefings in Functio nal Genomics and Proteomics(2002), 1(2), p.189-203;Siriwardena, D. et. al., Opht halmology (2002) 109(3), p.427-431, etc.) can also be mentioned.

[0107] The antibody in the antibody-drug conjugate used in the present invention also includes modified antibodies. The modified form is an antibody according to the present invention that has been chemically or biologically modified. Chemical modifications include the attachment of chemical moieties to the amino acid backbone, N- or O-linkages. - Chemical modifications including the attachment of chemical moieties to the bound carbohydrate chain. The organism may also contain post-translational modifications (e.g., addition of N-linked or O-linked glycosylation, N- or C-terminal Processing, deamidation, isomerization of aspartic acid, oxidation of methionine, etc. By expressing this in a prokaryotic host cell, a methionine residue was added to the N-terminus. Also, in order to enable detection or isolation of the antibody or antigen according to the present invention, Such modifications include those labeled with an enzyme label, a fluorescent label, and an affinity label. Such modified antibodies according to the present invention are included in the meaning of the term "antibody." These are useful for improving affinity, reducing antigenicity, detecting or isolating antibodies or antigens, and the like.

[0108] In addition, it is possible to regulate the sugar chain modification (glycosylation, deglycosylation, etc.) of the antibody of the present invention. It is possible to enhance antibody-dependent cellular cytotoxicity by glycosylation of antibodies. Techniques for adjusting chain modification include those described in International Publication No. 99 / 54342 and International Publication No. 00 / 6173. 9, WO 02 / 31140, WO 2007 / 133855, and WO 2007 / 133856. Publication No. 2013 / 120066 and the like are known, but are not limited thereto. The antibodies according to the present invention also include those in which the glycosylation has been regulated.

[0109] In addition, antibodies produced in cultured mammalian cells have a lysine residue at the carboxyl terminus of the heavy chain. It is known that the nucleotide group is deleted (Journal of Chromatography A, 705: 129-134 (1995) ), and also has two amino acid residues, glycine and lysine, deleted from the carboxyl terminus of the heavy chain. It is now known that the proline residue located at the carboxyl terminus is amidated ( Analytical Biochemistry, 360: 75-83(2007)). However, the deletion and Modifications affect the antigen-binding ability and effector functions of antibodies (such as complement activation and antibody-dependent cellular cytotoxicity). Therefore, the antibody of the present invention does not have any effect on the antibody's function (use, etc.). Also included are antibodies and functional fragments of such antibodies, each of which has one or two amino acids at the carboxyl terminus of the heavy chain. Deletions of the amino acid sequence and amidated versions of the amino acid sequence (e.g., However, the antigen-binding ability and the effector - As long as the function is maintained, the carboxyl-terminal deletions of the heavy chains of the antibodies according to the invention are The two heavy chains constituting the antibody of the present invention may be full-length or the above-mentioned deletions. The heavy chain may be any one of the heavy chains selected from the group consisting of the fusion proteins, or a combination of any two of the heavy chains. The ratio of the amounts of each deletion body may be determined based on the amount of the mammalian culture medium producing the antibody according to the present invention. Although the type of culture cell and culture conditions may affect the antibody of the present invention, the antibody preferably has two List those in which one amino acid residue is deleted at the carboxyl terminus of both heavy chains. can be done.

[0110] The isotype of the antibody according to the present invention may be, for example, IgG (IgG1, IgG2, Ig Examples of the antibody include IgG1 and IgG2. It is possible.

[0111] The antibody in the antibody-drug conjugate used in the present invention is not particularly limited. For example, For example, anti-HER2 antibody, anti-HER3 antibody, anti-TROP2 antibody, anti-B7-H3 antibody, anti-CD 3 antibodies, anti-CD30 antibody, anti-CD33 antibody, anti-CD37 antibody, anti-CD56 antibody, anti-CD9 8 antibody, anti-DR5 antibody, anti-EGFR antibody, anti-EPHA2 antibody, anti-FGFR2 antibody, anti-FG FR4 antibody, anti-FOLR1 antibody, anti-VEGF antibody, anti-CD20 antibody, anti-CD22 antibody, anti- CD70 antibody, anti-PSMA antibody, anti-CEA antibody, anti-Mesothelin antibody, anti-A33 Antibodies, anti-CanAg antibody, anti-Cripto antibody, anti-G250 antibody, anti-MUC1 antibody, anti-G PNMB antibody, anti-Integrin antibody, anti-Tenascin-C antibody, anti-SLC44A Examples of the antibody include anti-HE4 antibody, anti-GPR20 antibody, and anti-CDH6 antibody. R2 antibody, anti-HER3 antibody, anti-TROP2 antibody, anti-B7-H3 antibody, anti-GPR20 antibody, and anti-CDH6 antibodies.

[0112] In the present invention, the term "anti-HER2 antibody" refers to an antibody that binds to HER2 (Human Epidermal Growth Factor (HER2) l Growth Factor Receptor Type 2; ErbB-2) and preferably binds to HER2 and thereby enters HER2-expressing cells. The antibodies shown have localizing activity.

[0113] Examples of anti-HER2 antibodies include trastuzumab (US Patent No. 5821337), Pertuzumab (International Publication No. 01 / No. 00245), and preferably trastuzumab.

[0114] In the present invention, the term "anti-HER3 antibody" refers to an antibody that binds to HER3 (Human Epidermal Growth Factor (HER3) l Growth Factor Receptor Type 3; ErbB-3) and preferably binds to HER3 and thereby enters HER3-expressing cells. The antibodies shown have localizing activity.

[0115] Examples of anti-HER3 antibodies include Patritumab (U3-1 287), U1-59 (International Publication No. 2007 / 077028), MM-121 (Ser ibantumab), the anti-ERBB3 antibody described in WO 2008 / 100624, G-7116 (Lumretuzumab) and LJM-716 (Elgemtumab) b) can be mentioned, and preferably, can be mentioned patritumab and U1-59. do.

[0116] In the present invention, the term "anti-TROP2 antibody" refers to an antibody that specifically binds to TROP2 (TACSTD2: Tumor r-associated calcium signal transducer 2 ; EGP-1) and preferably binds to TROP2, thereby 1 shows antibodies having the activity of being internalized into ROP2-expressing cells.

[0117] As an anti-TROP2 antibody, for example, hTINA1-H1L1 (International Publication No. 2015 / 013366) No. 098099).

[0118] In the present invention, the term "anti-B7-H3 antibody" refers to a B7-H3 (B cell antibody PD-L3; CD276; and Preferably, the antibody has an activity of being internalized into B7-H3 expressing cells by binding to B7-H3. The antibodies shown are:

[0119] As an anti-B7-H3 antibody, for example, M30-H1-L4 (International Publication No. 2014 / 05 No. 7687).

[0120] In the present invention, the term "anti-GPR20 antibody" refers to an antibody that binds to GPR20 (G Protein-CoA). Specifically binds to GPR20, preferably GPR20. The figures show antibodies that have the activity of being internalized into GPR20-expressing cells when combined with GPR20.

[0121] As an anti-GPR20 antibody, for example, h046-H4e / L7 (International Publication No. 2018 / 013366) No. 135501).

[0122] In the present invention, an "anti-CDH6 antibody" refers to an antibody specific to CDH6 (Cadherin-6). and preferably binds to CDH6 and is internalized into CDH6-expressing cells. The antibodies shown have the activity.

[0123] Examples of anti-CDH6 antibodies include H01L02 (International Publication No. 2018 / 212136 No.) can be mentioned.

[0124] 3. Preparation of Antibody-drug Conjugates The drug linker intermediate used in the production of the antibody-drug conjugate of the present invention is as follows: This is shown in the formula:

[0125] [ka]

[0126] The drug linker intermediate shown above is N-[6-(2,5-dioxo-2,5-dihydro-1 H-Pyrrol-1-yl)hexanoyl]glycylglycyl-L-phenylalanyl-N -[(2-{[(1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl Ru-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12 H-Benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline The chemical name is glycine amide. The present invention can be represented by International Publication No. 2014 / 057687 and International Publication No. 2015 / 0980. 99, International Publication No. 2015 / 115091, International Publication No. 2015 / 155998, The composition can be produced by referring to the descriptions in International Publication No. 2019 / 044947 and the like.

[0127] The antibody-drug conjugate used in the present invention comprises the above-mentioned drug linker intermediate and a thiol linker intermediate. It is produced by reacting an antibody having a carboxyl group (also called a sulfhydryl group) with the antibody. It is possible.

[0128] Antibodies having sulfhydryl groups can be obtained by methods well known in the art (Hermanson, G. T, Bioconjugate Techniques, pp.56-136, pp.456-493, Academic Press (1996)). For example, a reducing agent such as tris(2-carboxyethyl)phosphine hydrochloride (TCEP) is used. 0.3 to 3 molar equivalents per intrachain disulfide of the antibody are used. By reacting with the antibody in a buffer containing a chelating agent such as EDTA, Antibodies with partially or completely reduced intrachain disulfides and sulfhydryl groups can be obtained.

[0129] In addition, 2 to 20 molar equivalents of a drug linker per antibody having a sulfhydryl group are - Using the intermediate, antibody-drug conjugates with 2 to 8 drugs bound to each antibody are prepared. Gates can be manufactured.

[0130] The average number of drugs bound per antibody molecule of the produced antibody-drug conjugate can be calculated using, for example, For example, the antibody-drug conjugate and its conjugate at two wavelengths of 280 nm and 370 nm The UV method is a method of calculating the UV absorbance of the jugation precursor (UV method), and the The drug-substance conjugate was treated with a reducing agent, and each of the resulting fragments was analyzed by HPLC. This can be done by a quantitative determination and calculation method (HPLC method).

[0131] Conjugation of the antibody to the drug linker intermediate and the antibody-drug conjugate The average number of drugs bound per molecule was calculated according to the method described in WO 2014 / 057687 and WO 2014 / 057687. Publication No. 2015 / 098099, International Publication No. 2015 / 115091, International Publication No. 015 / 155998, WO 2018 / 135501, and WO 201 This can be implemented by referring to the descriptions in No. 8 / 212136 etc.

[0132] In the present invention, the term "anti-HER2 antibody-drug conjugate" refers to the antibody- The present invention provides an antibody-drug conjugate in which the antibody in the drug conjugate is an anti-HER2 antibody. vinegar.

[0133] The anti-HER2 antibody is preferably a polypeptide comprising the amino acid sequence set forth in SEQ ID NO:1, which is selected from the group consisting of amino acids 1 to 449. A heavy chain consisting of the amino acid sequence of SEQ ID NO:2 and an amino acid sequence as set forth in SEQ ID NO:2, or an antibody comprising a light chain consisting of the amino acid sequence set forth in SEQ ID NO:1. and a light chain consisting of the amino acid sequence set forth in SEQ ID NO:2.

[0134] The average number of drug linkers bound per antibody in the anti-HER2 antibody-drug conjugate is Preferably, it is 2 to 8, more preferably, it is 3 to 8, and even more preferably, it is 7 to 8. More preferably, the ratio is from 7.5 to 8, and even more preferably, the ratio is about 8.

[0135] The anti-HER2 antibody-drug conjugate is described in WO 2015 / 115091 and the like. The above can be used as a reference for manufacturing.

[0136] In the present invention, the term "anti-HER3 antibody-drug conjugate" refers to the antibody- The present invention provides an antibody-drug conjugate in which the antibody in the drug conjugate is an anti-HER3 antibody. vinegar.

[0137] The anti-HER3 antibody is preferably a polypeptide comprising the amino acid sequence set forth in SEQ ID NO:3, amino acid number 26 to 35. CDRH1 consisting of the amino acid sequence set forth in amino acid numbers 50 to 65 of SEQ ID NO:3 and CDRH2 consisting of the amino acid sequence of amino acid numbers 98 to 10 in SEQ ID NO:3. 6, and a heavy chain comprising CDRH3 having the amino acid sequence set forth in SEQ ID NO: 4. CDRL1 consisting of the amino acid sequence set forth in amino acid numbers 24 to 39 in SEQ ID NO: 4 CDRL2 consisting of the amino acid sequence set forth in amino acid numbers 56 to 62, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO:4. A light chain comprising CDRL3 having the amino acid sequence set forth in amino acid numbers 95 to 103 in the above. and wherein the antibody comprises More preferably, the amino acid sequence of SEQ ID NO:3, which is set forth as amino acid numbers 1 to 117, is and a heavy chain comprising a heavy chain variable region comprising the amino acid sequence represented by amino acid numbers 1 to 113 in SEQ ID NO:4. a light chain comprising a light chain variable region having the amino acid sequence set forth above, Even more preferably, the heavy chain comprises the amino acid sequence set forth in SEQ ID NO:3 and the or the carboxyl terminus of the heavy chain of said antibody, It is an antibody in which the lysine residues are deleted.

[0138] The average number of drug linkers bound per antibody in the anti-HER3 antibody-drug conjugate is Preferably, it is 2 to 8, more preferably, it is 3 to 8, and even more preferably, it is 7 to 8. More preferably, the ratio is from 7.5 to 8, and even more preferably, the ratio is about 8.

[0139] The anti-HER3 antibody-drug conjugate is described in WO 2015 / 155998 and the like. The above can be used as a reference for manufacturing.

[0140] In the present invention, the term "anti-TROP2 antibody-drug conjugate" refers to the antibody of the present invention. -An antibody-drug conjugate, wherein the antibody in the drug conjugate is an anti-TROP2 antibody Shows.

[0141] The anti-TROP2 antibody preferably comprises the amino acid sequence set forth in SEQ ID NO:5, from amino acid number 50 to amino acid number 54. CDRH1 consisting of the amino acid sequence represented by amino acid numbers 69 to 85 in SEQ ID NO:5 and CDRH2 consisting of the amino acid sequence set forth above, and the amino acid sequence from amino acid number 118 to amino acid number 119 in SEQ ID NO:5. 129, and a heavy chain comprising CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO:6. CDRL1 consisting of the amino acid sequence set forth in amino acid numbers 44 to 54; CDRL2 consisting of the amino acid sequence set forth in amino acid numbers 70 to 76 in SEQ ID NO: 6, comprising a CDRL3 consisting of the amino acid sequence set forth in amino acid numbers 109 to 117. a light chain comprising a mitogen-activated receptor agonist (MTA), More preferably, the amino acid sequence set forth in amino acid numbers 20 to 140 in SEQ ID NO:5. and a heavy chain comprising a heavy chain variable region consisting of amino acid numbers 21 to 129 in SEQ ID NO:6. a light chain comprising a light chain variable region having an amino acid sequence according to Even more preferably, the amino acid sequence set forth in SEQ ID NO:5, from amino acid number 20 to amino acid number 470 and a heavy chain consisting of the amino acids set forth in SEQ ID NO:6, amino acids 21 to 234. or a lysine residue at the carboxyl terminus of the heavy chain of said antibody. It is an antibody that is deficient in

[0142] The average number of drug linkers per antibody in anti-TROP2 antibody-drug conjugates is , preferably 2 to 8, more preferably 3 to 5, and even more preferably 3.5 to 4.5, and even more preferably about 4.

[0143] The anti-TROP2 antibody-drug conjugate can be prepared according to the method described in WO 2015 / 098099, etc. The preparation can be carried out by referring to the description.

[0144] In the present invention, the term "anti-B7-H3 antibody-drug conjugate" refers to the antibody of the present invention. -An antibody-drug conjugate, wherein the antibody in the drug conjugate is an anti-B7-H3 antibody Shows.

[0145] The anti-B7-H3 antibody preferably comprises the amino acid sequence set forth in SEQ ID NO:7, from amino acid number 50 to amino acid number 54. CDRH1 consisting of the amino acid sequence represented by amino acid numbers 69 to 85 in SEQ ID NO:7 CDRH2 consisting of the amino acid sequence set forth above, and the amino acid sequence from amino acid number 118 to amino acid number 119 in SEQ ID NO:7. 130, and a heavy chain comprising CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 8. CDRL1 consisting of the amino acid sequence set forth in amino acid numbers 44 to 53; CDRL2 consisting of the amino acid sequence set forth in amino acid numbers 69 to 75 of SEQ ID NO: 8, comprising a CDRL3 consisting of the amino acid sequence set forth in amino acid numbers 108 to 116. a light chain comprising a mitogen-activated receptor agonist (MTA), More preferably, the amino acid sequence set forth in amino acid numbers 20 to 141 in SEQ ID NO:7. and a heavy chain comprising a heavy chain variable region consisting of amino acid numbers 21 to 128 in SEQ ID NO:8. a light chain comprising a light chain variable region having an amino acid sequence according to Even more preferably, the amino acids set forth in SEQ ID NO:7 at amino acid numbers 20 to 471 and a heavy chain consisting of the amino acids set forth in SEQ ID NO:8, amino acids 21 to 233. or a lysine residue at the carboxyl terminus of the heavy chain of said antibody. It is an antibody that is deficient in

[0146] The average number of drug linkers per antibody in anti-B7-H3 antibody-drug conjugates is , preferably 2 to 8, more preferably 3 to 5, and even more preferably 3.5 to 4.5, and even more preferably about 4.

[0147] The anti-B7-H3 antibody-drug conjugate used in the present invention is The present invention can be produced by referring to the description in US Pat. No. 5,999,333, issued Dec. 14, 2004, and the like.

[0148] In the present invention, an "anti-GPR20 antibody-drug conjugate" refers to an antibody according to the present invention. -An antibody-drug conjugate, wherein the antibody in the drug conjugate is an anti-GPR20 antibody Shows.

[0149] The anti-GPR20 antibody preferably comprises the sequence set forth in amino acids 45 to 54 of SEQ ID NO:9. CDRH1 consisting of the amino acid sequence represented by amino acid numbers 69 to 78 in SEQ ID NO:9 and CDRH2 consisting of the amino acid sequence set forth above, and the amino acid sequence from amino acid number 118 to amino acid number 119 in SEQ ID NO:9. 131, and a heavy chain comprising CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 10. CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 44 to 54, CDRL2 consisting of the amino acid sequence set forth in amino acid numbers 70 to 76 in the sequence A CDRL consisting of the amino acid sequence set forth in amino acid numbers 109 to 117 in number 10. a light chain comprising: More preferably, the amino acid sequence set forth in amino acid numbers 20 to 142 in SEQ ID NO:9. and a heavy chain comprising a heavy chain variable region consisting of amino acid numbers 21 to 12 in SEQ ID NO: 10. 9. A light chain comprising a light chain variable region having the amino acid sequence according to claim 9, Even more preferably, the amino acids set forth in SEQ ID NO:9 at amino acid numbers 20 to 472 and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO: 10. or a light chain of said antibody comprising a lysine residue at the carboxyl terminus of said heavy chain. It is an antibody in which a base is deleted.

[0150] The average number of drug linkers per antibody in anti-GPR20 antibody-drug conjugates is , preferably 2 to 8, more preferably 3 to 8, and even more preferably 7 to 8. , even more preferably from 7.5 to 8, and even more preferably about 8.

[0151] The anti-GPR20 antibody-drug conjugate can be prepared according to the method described in WO 2018 / 135501, etc. The preparation can be carried out by referring to the description.

[0152] In the present invention, the term "anti-CDH6 antibody-drug conjugate" refers to the antibody- The present invention provides an antibody-drug conjugate in which the antibody in the drug conjugate is an anti-CDH6 antibody. vinegar.

[0153] The anti-CDH6 antibody preferably comprises the sequence set forth in amino acids 45 to 54 of SEQ ID NO:11. CDRH1 consisting of the amino acid sequence of amino acid 69 to 78 in SEQ ID NO:11 CDRH2 consisting of the amino acid sequence shown in SEQ ID NO:11, and amino acid number 118 in SEQ ID NO:11 A heavy chain comprising a CDRH3 consisting of the amino acid sequence set forth in any one of SEQ ID NO: 12 to 130, CDRL1 consisting of the amino acid sequence set forth in amino acid numbers 44 to 54 in SEQ ID NO: CDRL2 consisting of the amino acid sequence set forth in amino acid numbers 70 to 76 in paragraph 12; and A CD450 consisting of the amino acid sequence set forth in amino acid numbers 109 to 116 in SEQ ID NO: 12. a light chain comprising RL3, More preferably, the amino acid sequence set forth in amino acid numbers 20 to 141 in SEQ ID NO:11 is and a heavy chain comprising a heavy chain variable region consisting of amino acid numbers 21 to 1 in SEQ ID NO:12. 28. An antibody comprising a light chain comprising a light chain variable region consisting of the amino acid sequence set forth in 29. Even more preferably, the amino acids set forth in SEQ ID NO:11 at amino acid numbers 20 to 471 are and a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO:12. or a light chain of said antibody comprising a carboxyl-terminal lysine of said heavy chain. An antibody in which residues have been deleted.

[0154] The average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is Preferably, it is 2 to 8, more preferably, it is 3 to 8, and even more preferably, it is 7 to 8. More preferably, the ratio is from 7.5 to 8, and even more preferably, the ratio is about 8.

[0155] The anti-CDH6 antibody-drug conjugate is described in WO 2018 / 212136 and the like. The above can be used as a reference for manufacturing.

[0156] 4. Tubulin Inhibitors In the present invention, a "tubulin inhibitor" refers to an agent that affects microtubule dynamics. This causes cell division to be arrested in the G2 (preparatory phase) and / or M (mitotic phase) phases of the cell cycle. It is a drug that suppresses the proliferation of cancer cells by inducing cell death through apoptosis. (Dumontet C, et al., Nat Rev Drug Discov. 2010 Oct;9(10): 790-803.)(Mukht ar E, et al., Mol Cancer Ther. 2014 Feb: 13(2): 275-284.).

[0157] Tubulin inhibitors inhibit microtubule dynamics by promoting tubulin polymerization. A drug that affects the tubulin polymerization (referred to as a "tubulin polymerization promoter" in the present invention) and a tubulin polymerization promoter Agents that affect microtubule dynamics by inhibiting the polymerization of purine (in the present invention) There are drugs called "tubulin polymerization inhibitors" for this purpose.

[0158] Tubulin polymerization promoters include taxanes (paclitaxel, docetaxel, and , cabazitaxel, etc.) are known. Halichondro is a tubulin polymerization inhibitor. Phosphorus compounds (eribulin, etc.), vinca alkaloids (vincristine, vinblastine, norelbine, vindesine, etc.), dolastatins (MMAE and MMAF, etc.), and meitanthin These drugs and their pharmacological properties are well known. Such acceptable salts can be used as the tubulin inhibitors of the present invention. Conjugates of any of the drugs with albumin (e.g., conjugates of paclitaxel with albumin) and nab-paclitaxel, which is a cytotoxic antibody. Antibody-drug conjugates linked via a carboxyl group (e.g., MMAE and an anti-CD30 antibody) brentuximab vedotin, an antibody-drug conjugate attached via a linker; It is an antibody-drug conjugate in which DM1 and an anti-HER2 antibody are linked via a linker. Trastuzumab emtansine, MMAE and anti-GPMNB antibody linked via a linker CDX-011 (International Publication No. WO 2006 / 071441) is an antibody-drug conjugate No. 6,333,666, and an antibody-drug conjugate in which DM4 and an anti-FOLR1 antibody are linked via a linker. IMGN-853, an anti-MMAE drug (International Publication No. WO 2017 / 049149, etc.), RG-7 is an antibody-drug conjugate that is linked to the CD79b antibody via a linker. 596 (U.S. Publication No. 2017 / 304438, etc.), DM4 and anti-CD19 antibody linked SAR-3419 (U.S. Publication No. 2013 / 013366), an antibody-drug conjugate linked via a β-linker, 15 / 071949, etc.), an antibody that combines MMAE and an anti-PSMA antibody via a linker The PSMA-ADC, a substance-drug conjugate (WO 2007 / 002222), etc.), and an antibody-drug conjugate in which DM4 and an anti-CD138 antibody are linked via a linker. BT-062 (U.S. Publication No. 2007 / 183971, etc.), DM4 and anti-meso BAY is an antibody-drug conjugate that is linked to thelin antibody via a linker. -94-9343 (International Publication No. 2010 / 124797, etc.), MMAF and anti-CD19 antibody SGN-CD19A ( (International Publication No. WO 2009 / 052431, etc.), MMAF and anti-ENPP3 antibody are linked via a linker The antibody-drug conjugate AGS-16C3F, which is an antibody-drug conjugate bound via a cytochrome P450 antibody, is also included in the present invention. It can be used as a tubulin inhibitor.

[0159] Among the tubulin inhibitors preferably used in the present invention, The present invention relates to a pharmaceutical composition comprising a taxane or a pharmacologically acceptable salt thereof, or a compound comprising a taxane and albumin. Conjugates of the formula (I) may include, more preferably, paclitaxel, docetaxel, cabazitaxel, or a pharmacologically acceptable salt thereof, or nab-paclitaxel. and even more preferably, paclitaxel, docetaxel trihydrate, or cabazitaxel. and more preferably, paclitaxel acetone solvate or nab-paclitaxel. More preferably, paclitaxel can be mentioned.

[0160] Among the tubulin inhibitors preferably used in the present invention, The present invention relates to a compound comprising halichondrins or a pharmacologically acceptable salt thereof, or an anticancer agent having an anticancer effect against halichondrins. More preferred examples of the antibody-drug conjugate include an antibody-drug conjugate in which the antibody is linked to the drug via a linker. Preferably, eribulin or a pharmacologically acceptable salt thereof, or a linker between eribulin and an antibody. Antibody-drug conjugates linked via a fusion protein (e.g., eribulin and anti-FOLR1 antibody) MORAb-202 (USA) is an antibody-drug conjugate that combines Patent Publication No. 2017 / 252458, etc.), and more preferably, One example is eribulin mesylate.

[0161] In the present invention, the "pharmacologically acceptable salt" refers to either an acid addition salt or a base addition salt. Examples of acid addition salts include camsylate (camphorsulfonate), methacrylate, etc. Silyl salt (methanesulfonate), trifluoromethanesulfonate, and ethanesulfonate lower alkanesulfonates such as phosphates; tosylates (p-toluenesulfonates); Arylsulfonates such as benzenesulfonates; phosphates, nitrates, perchlorates, and Inorganic acid salts such as sulfates; hydrochlorides, hydrobromides, hydroiodides, and hydrofluorides; Hydrohalides; acetates, malates, fumarates, succinates, citrates, tartrates salts of organic acids such as phosphates, oxalates, and maleates; and salts of ornithine and glutamate. Examples of base addition salts include amino acid salts such as benzoyl peroxide and aspartic acid salts. For example, alkali metal salts such as sodium salts, potassium salts, and lithium salts; calcium salts, magnesium salts, etc. alkaline earth metal salts such as sodium salts; inorganic salts such as ammonium salts; dibenzylamine salts, molybdenum salts, etc. phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglycine diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, diethanolamine salt , N-benzyl-N-(2-phenylethoxy)amine salt, piperazine salt, tetramethyl Ammonium salts, tris(hydroxymethyl)aminomethane salts and other organic amine salts; Examples of the salts include amino acid salts such as guanidine salts.

[0162] In addition, pharmacologically acceptable salts may exist as solvates, and these solvates are also included in the "pharmacologically acceptable salts" of the present invention. Examples of such solvates include , hydrates (e.g., 0.5 hydrate, 1 hydrate, 2 hydrate, 3 hydrate), ethanol solvates, and acetone solvates.

[0163] 5. Pharmaceuticals The antibody-drug conjugate according to the present invention and a tubulin inhibitor are combined as follows: Pharmaceutical compositions and methods of treatment that are administered are described.

[0164] The pharmaceutical compositions and treatment methods of the present invention comprise an antibody-drug conjugate and a tubulin inhibitor. The drugs are contained as active ingredients in different preparations and administered simultaneously or at different times. or a combination of an antibody-drug conjugate and tubulin. The inhibitor is contained as an active ingredient in a single preparation and administered. This is also possible.

[0165] The pharmaceutical composition and treatment method of the present invention can be used for the treatment of cancer, and is preferably are breast cancer, stomach cancer (sometimes called gastric adenocarcinoma), and colon cancer (sometimes called colorectal cancer). including colon and rectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), esophageal cancer, head and neck cancer (including salivary gland cancer and pharyngeal cancer), gastroesophageal junction adenocarcinoma, Biliary tract cancer (including bile duct cancer), Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urinary Urinary tract cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal Cancer, liver cancer, hepatocellular carcinoma, uterine cancer, kidney cancer, vulva cancer, thyroid cancer, and penile cancer Cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, and melanoma and more preferably, Preferably, the cancer is selected from the group consisting of breast cancer, stomach cancer, colon cancer, lung cancer, esophageal cancer, salivary gland cancer, and gastroesophageal junction cancer. Cancer, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, and pediatric cancer Use for the treatment of at least one cancer selected from the group consisting of uterine carcinosarcoma and sarcoma. and more preferably, the cancer is selected from the group consisting of breast cancer, gastric cancer, lung cancer, and ovarian cancer. The present invention can be used to treat at least one cancer that is

[0166] Among the antibody-drug conjugates used in the present invention, what kind of antibody is particularly The suitability of the body-drug conjugate will depend on the type of cancer and tumor markers tested. For example, if HER2 expression is confirmed in the cancer, The HER2 antibody-drug conjugate can be preferably used to treat cancer with HER3 expression. If this is confirmed, the anti-HER3 antibody-drug conjugate can be suitably used. If TROP2 expression is confirmed in the cancer, anti-TROP2 antibody-drug conjugates If B7-H3 expression is confirmed in the cancer, anti-B7-H 3. Antibody-drug conjugates can be used effectively, and GPR20 expression in cancer has been confirmed. If this is confirmed, the anti-GPR20 antibody-drug conjugate can be preferably used, If CDH6 expression is confirmed in the cancer, anti-CDH6 antibody-drug conjugates are preferred. can be used for.

[0167] HER2, HER3, TROP2, B7-H3, GPR20, and CDH6 and their The presence or absence of other tumor markers can be determined, for example, by collecting tumor tissue from a cancer patient and analyzing it with formalin-fixed plaque. FFPE specimens can be used for immunohistochemistry (IHC) and flow cytometry. Examination at the gene product (protein) level using the Western blot method, etc., The method is based on in situ hybridization (ISH) and quantitative PCR (q-PCR). R) and can be confirmed by testing at the gene transcription level using microarray analysis, etc. Alternatively, cell-free circulating tumor DNA (ctDNA) can be collected from cancer patients and used for next-generation It can also be confirmed by testing using methods such as sequencing (NGS).

[0168] The pharmaceutical composition and treatment method of the present invention can be suitably used for mammals. , and more preferably for use in humans.

[0169] The antitumor effect of the pharmaceutical composition and treatment method of the present invention can be evaluated by, for example, transplanting cancer cells into a test animal. A model was created, and the reduction in tumor volume was observed by administering the pharmaceutical composition and treatment method of the present invention. The effect of the antibody used in the present invention can be confirmed by measuring the effect of the antibody or the life-prolonging effect. The antitumor effects of the drug-drug conjugate and the tubulin inhibitor administered alone were compared. By comparing the antibody-drug conjugates used in the present invention and tubulin inhibition The combined effect of the drugs can be confirmed.

[0170] In addition, the antitumor effects of the pharmaceutical composition and treatment method of the present invention have been demonstrated in clinical trials. onse Evaluation Criteria in Solid Tumors RECIST evaluation method, WHO evaluation method, Macdonald evaluation method, weight measurement, and other Complete response was confirmed by other methods. CR), Partial response (PR), Progression (PR), PD, Objective Response Rate ORR, Duration of response (DoR) ), Progression-Free Survival (PFS) The outcome will be assessed based on indicators such as overall survival (OS). can be done.

[0171] Furthermore, the combined effect of the pharmaceutical composition and treatment method of the present invention is enhanced by the incorporation of drug susceptibility factors and / or drugs. For example, the test subject may be treated with the drug of the present invention. When the antibody-drug conjugate and the tubulin inhibitor were administered alone, The drug susceptibility factors and and / or the expression level of drug resistance factors. Tubulin inhibitors suppress the decrease in expression of drug sensitivity factors caused by administration of tubulin. If this can be confirmed, the combined effect of the antibody-drug conjugate and tubulin inhibitor will be confirmed. Such a drug sensitivity factor can be determined, for example, by detecting SLFN11. SLFN11 is known to be a sensitivity factor for topoisomerase I inhibitors. It is known that (Zoppoli G. et al., Proc Natl Acad Sci US A. 2012;109(39): 150 30-5). Alternatively, the drug produced by administration of the antibody-drug conjugate used in the present invention If it can be confirmed that tubulin inhibitors suppress the increased expression of drug resistance factors, It can be determined that there is an effect of combining the compound conjugate with a tubulin inhibitor. An example of such a drug resistance factor is ABCG2. Resistance factors (transporters) of drugs released from the antibody-drug conjugates of the present invention (Nagai Y. et al., Xenobiotica. 2019;49(9):1086-96) In addition, drug sensitivity factors and / or drug resistance factors are expressed at the gene (RNA, etc.) level. The amount can be compared, and the expression levels at the protein level can also be compared.

[0172] By the above-mentioned method, the antitumor effect of the pharmaceutical composition and the treatment method of the present invention can be confirmed by comparing the existing It is possible to confirm the superiority of the pharmaceutical composition and method for treating cancer.

[0173] The pharmaceutical compositions and treatment methods of the present invention slow the growth of cancer cells, inhibit their proliferation, and These actions can destroy cancer cells. It is possible to achieve relief from symptoms and improve quality of life, and it is possible to achieve therapeutic effects while preserving the lives of cancer patients. Even if it does not destroy cancer cells, it may suppress or control their proliferation. This will enable cancer patients to achieve a higher quality of life and longer survival. It is possible.

[0174] The pharmaceutical composition of the present invention can be applied to patients as a systemic therapy, and also can be applied locally to cancer tissues. It can be expected to have a therapeutic effect when applied to the following:

[0175] The pharmaceutical compositions of the present invention may be administered containing one or more pharma- ceutical compatible ingredients. The components compatible with the antibody-drug conjugates and tubulin inhibitors used in the present invention Depending on the dosage and concentration of the drug, additives and other ingredients commonly used in this field may be used. For example, the antibody-drug conjugate used in the present invention may be appropriately selected and applied. The gates may contain buffers, such as histidine buffers, excipients, such as sucrose or trehalose, and The present invention can be administered in a pharmaceutical composition containing a surfactant such as polysorbate 80 or 20. The pharmaceutical composition containing the antibody-drug conjugate used in the present invention is preferably administered as an injection. It can be used as an aqueous injection or a freeze-dried injection, more preferably. More preferably, it can be used as a freeze-dried injection.

[0176] When the pharmaceutical composition containing the antibody-drug conjugate used in the present invention is an aqueous injection, In this case, it can be preferably diluted with an appropriate diluent and then administered intravenously by drip infusion. Examples of the liquid include glucose solution and physiological saline solution. Preferably, the liquid is glucose solution. A preferred example is a 5% glucose solution.

[0177] The pharmaceutical composition containing the antibody-drug conjugate used in the present invention is a freeze-dried injection. In the case of injection, it is preferable to dissolve the drug in water for injection, dilute the required amount with a suitable diluent, and then inject the drug. It can be administered intravenously. Diluents include glucose solution and saline solution. Examples of the solution include glucose solution, and more preferably 5% glucose solution. Examples include sugar solutions.

[0178] Routes of introduction that can be used to administer the pharmaceutical composition of the present invention include, for example, intravenous These include intradermal, subcutaneous, intramuscular and intraperitoneal routes, and preferably intravenous routes. Examples include:

[0179] The antibody-drug conjugate used in the present invention is administered to humans once every 1 to 180 days. The dose may be administered at intervals of once every week, preferably once every 1, 2, 3, or 4 weeks. It may be administered at intervals of once every three weeks, and even more preferably. The antibody-drug conjugate used in the present invention is about 0.001 to 10 The dosage can be 0.0 mg / kg, and preferably 0.8 to 12.4 mg / kg per administration. The antibody-drug conjugates used in the present invention can be administered at a dose of 100 mg / kg. When the drug is an anti-ER2 antibody-drug conjugate, the amount is preferably 0.8 mg per dose. / kg, 1.6mg / kg, 3.2mg / kg, 5.4mg / kg, 6.4mg / kg, Doses of 7.4 mg / kg or 8 mg / kg can be administered at intervals of once every 3 weeks. The antibody-drug conjugate used in the present invention is an anti-HER3 antibody-drug conjugate. In the case of a single dose, the preferred dose is 1.6 mg / kg, 3.2 mg / kg, or 4.8 mg / kg. g / kg, 5.6mg / kg, 6.4mg / kg, 8.0mg / kg, 9.6mg / kg or 12.8 mg / kg at a dose of once every 3 weeks. The antibody-drug conjugate used in the method is an anti-TROP2 antibody-drug conjugate. In this case, the preferred dose is 0.27 mg / kg, 0.5 mg / kg, or 1.0 mg / kg per dose. g, 2.0 mg / kg, 4.0 mg / kg, 6.0 mg / kg, or 8.0 mg / kg Doses can be administered at intervals of once every three weeks.

[0180] The tubulin inhibitor according to the present invention is administered to humans once every 1 to 180 days. The dose can be administered at intervals of once every week, once every two weeks, once every three weeks, or once every four weeks. In addition, the tubulin inhibitor according to the present invention can be administered at a dose of about 0.001 to 100 The tubulin inhibitor of the present invention can be administered in a dose of 100 mg / kg. In the case of ritaxel, it is preferably 100, 125, 135, 175, or 2 60 mg / m 2 The dose is given intravenously once every week or once every three weeks (points). Intravenous drip infusion) can be used (if administered once a week, it should be administered for three consecutive weeks). The tubulin inhibitor of the present invention is eribulin mesylate. In some cases, preferably 1.4 mg / m per dose 2 (body surface area) dose once a week It can be given intravenously at intervals of 10-20 weeks (2 consecutive weeks followed by a 3rd week off).

[0181] The pharmaceutical compositions and treatment methods of the present invention comprise the antibody-drug conjugates and tu The pharmaceutical composition and treatment of the present invention may further comprise a cancer therapeutic agent other than a rabulin inhibitor. The method can also be administered in combination with other cancer therapeutic agents, thereby enhancing the antitumor effect. Other cancer therapeutic agents that can be used for such purposes include the pharmaceutical composition of the present invention. They may be administered simultaneously, separately, or sequentially to an individual, or at different intervals between administrations. Such a cancer therapeutic agent may be administered as long as it has antitumor activity. Although not specified, examples include irinotecan (CPT-11) , Cisplatin, Carboplatin, Oxaliplatin, Fluorouracil cil, 5-FU), Gemcitabine, Capecitabine ecitabine, doxorubicin, epirubicin pirubicin, cyclophosphamide, Mitomycin C, Tegafur, Gimera Gimeracil / Oteracil combination drug, cetuximab ( Cetuximab, Panitumumab, Bevacizumab vacizumab, ramucirumab, regorafenib egorafenib), trifluridine and tipiracil Tipiracil combination drug, Gefitinib, Erlotinib rlotinib), afatinib, methotrexate otrexate, pemetrexed, tamoxifen moxifen, toremifene, fulvestrant vestrant, leuprorelin, goserelin serelin, letrozole, anastrozole trozole, progesterone formulation ion), trastuzumab, pertuzumab, and lapatinib. I can name at least one.

[0182] The pharmaceutical compositions and treatment methods of the present invention can also be used in combination with radiation therapy. For example, a cancer patient may be treated with the pharmaceutical composition of the present invention before and / or after the treatment. receive radiation therapy at the same time.

[0183] The pharmaceutical compositions and methods of treatment of the present invention are used as adjuvant chemotherapy in combination with surgery. The pharmaceutical composition of the present invention can also be used for the purpose of reducing tumor size prior to surgery. It may be administered before or after surgery (called neoadjuvant chemotherapy) or after surgery. It may be administered after surgery to prevent tumor recurrence (adjuvant chemotherapy, or adjuvant chemotherapy). This is called steroid therapy. EXAMPLES

[0184] The present invention will be described in detail with reference to the following examples, but the present invention is not limited thereto. Furthermore, these are not to be construed as limiting in any way.

[0185] Example 1: Preparation of antibody-drug conjugates A humanized anti-HER2 antibody was prepared according to the method of manufacture described in WO 2015 / 115091. A heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1, and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO:2. The antibody is

[0186] [ka]

[0187] (wherein A represents the binding site to the antibody) and an anti-HER2 antibody linked via a thioether bond. -drug conjugate (hereinafter referred to as "antibody-drug conjugate (1)") The DAR of the antibody-drug conjugate (1) is 7.7 or 7.8.

[0188] Example 2: Antitumor Test (1) Mice: 5-6 week-old female BALB / c nude mice (Charles River Laboratories Japan, Inc.) It was used in the experiment.

[0189] Measurements and calculations: In all studies, the major and minor diameters of the tumor were measured using electronic digital calipers. (CD-15CX, Mitutoyo Corp.) was measured twice a week, and tumor volume ( mm 3 ) was calculated using the following formula: Tumor volume (mm 3 ) = 1 / 2 x major axis (mm) x [minor axis (mm)] 2 The antibody-drug conjugate (1) was dissolved in ABS buffer (10 mM acetate buffer ( The solution was diluted with 10 mL / kg of ethanol (pH 5.5, 5% sorbitol) and administered into the tail vein. Paclitaxel was dissolved in Cremophor and ethanol (1:1) and diluted with saline. After dilution with water, the solution was administered into the tail vein at a volume of 10 or 20 mL / kg. In mesylate, the drug was diluted with saline and administered into the tail vein at a volume of 10 mL / kg. Ta.

[0190] Kawasaki Medical School, Professor Junichi Kurebayashi (British Journal of Cancer, (1999) 79 (5 / 6). 707-717) KPL-4 cells, a human breast cancer line obtained from the University of Tokyo, were suspended in saline and 1.5 × 10 7 The cells were subcutaneously transplanted into the right flank of female nude mice, and 17 days after transplantation, the mice were randomly assigned to groups. Antibody-drug conjugate (1) (DAR: 7.8) was Paclitaxel was administered intravenously into the tail vein at a dose of 7.5 mg / kg on Day 0 and Day 1. On day 7, 15 mg / kg of eribulin mesylate was administered via the tail vein. The drugs were administered at a dose of 0.8 mg / kg via the tail vein on Day 0 and Day 4. A group administered the same drug as the rat and a solvent-administered group were set as a control group.

[0191] The results of combined use of antibody-drug conjugate (1) and Paclitaxel are shown in FIG. Tumor growth inhibition rate (Tumor Gr) on the final day of the study after administration of paclitaxel alone The total inhibition (TGI) rate was 48%. The TGI of the antibody-drug conjugate (1) was 87%. 1) Combined administration of and Paclitaxel was more effective than Paclitaxel alone A significantly superior tumor growth inhibitory effect was observed (P<0.01 (Dunnett's test t. The same applies below.)) and from the single administration of antibody-drug conjugate (1) A significantly superior tumor growth inhibitory effect was also observed (P<0.05), and the combined effect was observed in all cases. The tumor was eliminated, which was extremely strong (TGI, 100%). The vertical axis indicates the number of days after cell transplantation, and the vertical axis indicates the tumor volume. No significant findings, such as weight loss, were observed. In the evaluation examples shown, unless otherwise specified, the tests were performed using the methods used in these evaluation examples. do.

[0192] Combined use of antibody-drug conjugate (1) and eribulin mesylate The results are shown in Figure 10. The TGI with single administration of eribulin mesylate was 91%. The TGI with single administration of the antibody-drug conjugate (1) was 87%. On the other hand, coadministration of antibody-drug conjugate (1) and eribulin mesylate The combination of eribulin mesylate and eribulin mesylate showed significantly greater tumor growth inhibition than eribulin mesylate alone. In addition, the antibody-drug conjugate (1) alone had a significant inhibitory effect (P<0.05). A significantly greater tumor growth inhibitory effect was observed than that of the control (P<0.05), and the combined effect was The disappearance of the tumor was very strong (TGI, 100%). The horizontal axis indicates the number of days after cell transplantation, and the vertical axis indicates the tumor volume. No significant findings such as weight loss were observed.

[0193] Example 3: Antitumor Test (2) DSMZ(Deutsche Sammlung von Mikroorganism) The human breast cancer line JIMT-1 was purchased from the 1. Suspend cells in saline at 5 x 10 6 The cells were injected subcutaneously into the right flank of female nude mice. The mice were randomly assigned to each group 13 days after transplantation (Day 0). The drug (1) (DAR: 7.7) was administered intravenously into the tail vein at a dose of 10 mg / kg on day 0. Paclitaxel was administered at a dose of 15 mg / kg on days 0, 7, and 14. Eribulin mesylate was administered at 0.8 μg / kg on Day 0 and Day 3. The mice were administered the drug alone or in combination with the control group. A solvent-administered group was set up.

[0194] The results of combined use of antibody-drug conjugate (1) and Paclitaxel are shown in Figure 11. The TGI rate with paclitaxel alone was 30%. The TGI of gate (1) by single agent administration was 73%. The combination of methadone (1) and paclitaxel was more effective than the monotherapy with paclitaxel. The tumor growth inhibitory effect was significantly superior to that of the antibody-drug combination (P<0.001). The tumor growth inhibitory effect was significantly superior to that of the single agent Conjugate (1) (P<0.05). The TGI was 97%. No particularly notable findings such as weight loss were observed.

[0195] Combined use of antibody-drug conjugate (1) and eribulin mesylate The results are shown in Figure 12. The TGI with single administration of eribulin mesylate was 73%. The TGI with single administration of the antibody-drug conjugate (1) was 73%. On the other hand, coadministration of antibody-drug conjugate (1) and eribulin mesylate The combination of eribulin mesylate and eribulin mesylate showed significantly greater tumor growth inhibition than eribulin mesylate alone. In addition, the antibody-drug conjugate (1) alone had a significant inhibitory effect (P<0.05). The tumor growth inhibition effect was significantly superior to that of the control (P<0.001), with a TGI of 97%. In addition, there were no particularly notable findings such as weight loss in either the single drug or combination drug administration groups. It was not approved.

[0196] Example 4: Antitumor Test (3) ATCC (American Type Culture Collection)? Human gastric cancer cell line NCI-N87 cells purchased from 7 cell The mice were subcutaneously transplanted into the right flank of female nude mice, and randomized to groups 6 days after transplantation ( Antibody-drug conjugate (1) (DAR: 7.8) was administered at 1 mg / mL on Day 0. Paclitaxel was administered intravenously at a dose of 15 mg / kg on Day 0 and Day 7. Eribulin mesylate was administered at a dose of 0.01 mg / kg via the tail vein. The mice were administered 0.4 mg / kg of each drug via the tail vein. The control group was a solvent-administered group.

[0197] The results of combined use of antibody-drug conjugate (1) and Paclitaxel are shown in Figure 13. The TGI rate with paclitaxel alone was 50%. The TGI of gate (1) by single agent administration was 45%. The combination of methadone (1) and paclitaxel was more effective than the monotherapy with paclitaxel. The tumor growth inhibitory effect was significantly superior to that of the antibody-drug combination (P<0.001). The tumor growth inhibitory effect was significantly superior to that of the single agent Conjugate (1) (P<0.05). The TGI was 82%. No particularly notable findings such as weight loss were observed.

[0198] Combined use of antibody-drug conjugate (1) and eribulin mesylate The results are shown in Figure 14. The TGI with single administration of eribulin mesylate was 64%. The TGI with single administration of the antibody-drug conjugate (1) was 45%. On the other hand, coadministration of antibody-drug conjugate (1) and eribulin mesylate The combination of eribulin mesylate and eribulin mesylate showed significantly greater tumor growth inhibition than eribulin mesylate alone. The inhibitory effect was observed (P<0.01), and the single administration of the antibody-drug conjugate (1) The tumor growth inhibition effect was significantly superior to that of the control group (P<0.001), and the TGI was 77%. In addition, there were no particularly notable findings such as weight loss in either the single drug or combination drug administration groups. It was not approved.

[0199] Example 5: Antitumor Test (4) Human breast cancer cell line MDA-MB-453 cells purchased from ATCC were cultured in a matrigel basement membrane matrix. Suspended in 1x10 7 The cells were placed on the right flank of a female nude mouse. The mice were subcutaneously implanted, and randomized to groups 7 days after implantation (Day 0). Gate (1) (DAR: 7.8) is a mouse model of mice administered 0.5 mg / kg intravenously on Day 0. Paclitaxel was administered via the tail vein at a dose of 15 mg / kg on days 0 and 7. Each drug was administered alone or in combination with other drugs, and a vehicle-administered control group was also included.

[0200] The results of combined use of antibody-drug conjugate (1) and Paclitaxel are shown in FIG. The TGI rate with paclitaxel alone was 96%. The TGI of gate (1) by single agent administration was 75%. In the combined administration of antibody-drug conjugate (1) and paclitaxel, A significantly superior tumor growth inhibitory effect was observed compared with single-agent administration (P<0.01), and the TGI was 1 In addition, no significant adverse events such as weight loss were observed in either the single agent or combination therapy groups. No other findings were noted.

[0201] Example 6: Antitumor Test (5) Human gastric cancer cell line SNU-1 cells purchased from ATCC were suspended in Matrigel at 1 × 10 7 The cells were subcutaneously transplanted into the right flank of female nude mice, and 28 days after transplantation, the mice were randomly assigned to groups. Antibody-drug conjugate (1) (DAR: 7.8) was Paclitaxel was administered intravenously into the tail vein at a dose of 10 mg / kg on Day 0 and Day 1. The mice were administered 15 mg / kg of each drug via the tail vein at 7 days after the administration. The roll group was set as a solvent-administered group.

[0202] The results of combined use of antibody-drug conjugate (1) and Paclitaxel are shown in FIG. The TGI rate with paclitaxel alone was 58%. The TGI for gate (1) was 79% for single agent administration. The combination of methadone (1) and paclitaxel was more effective than the monotherapy with paclitaxel. The tumor growth inhibition effect was significantly superior to that of the control group (P<0.01), with a TGI of 87%. In addition, no particularly notable findings such as weight loss were observed in either the single drug or combination treatment groups. I couldn't.

[0203] Example 7: Antitumor Test (6) Human lung cancer cell line NCI-H441 cells purchased from ATCC were suspended in Matrigel for 5× 10 6 The cells were subcutaneously transplanted into the right flank of female nude mice, and 7 days after transplantation, the mice were randomly assigned to groups. The antibody-drug conjugate (1) (DAR: 7.8) was Paclitaxel was administered intravenously at a dose of 10 mg / kg on Day 0 and Day 1. The mice were administered 15 mg / kg of the drug via the tail vein on ay7. A vehicle-administered group was set as a control group.

[0204] The results of combined use of antibody-drug conjugate (1) and Paclitaxel are shown in FIG. The TGI rate with paclitaxel alone was 55%. The TGI of gate (1) by single agent administration was 92%. The combination of methadone (1) and paclitaxel was more effective than the monotherapy with paclitaxel. The tumor growth inhibitory effect was significantly superior to that of the antibody-drug combination (P<0.001). The tumor growth inhibitory effect was significantly superior to that of the single agent Conjugate (1) (P<0.05). .01), and the TGI was 99%. There was no significant effect such as weight loss in either the single-agent or combination administration groups. No particularly notable findings were observed.

[0205] Example 8: Preparation of antibody-drug conjugate (2) According to the production method described in WO 2015 / 155998, an anti-HER3 antibody (sequence number: 155998) was produced. A heavy chain consisting of the amino acid sequence set forth in SEQ ID NO:3 and a (an antibody comprising a light chain having a structure similar to that of the antibody of formula

[0206] [ka]

[0207] (wherein A represents the binding site to the antibody) and an anti-HER3 antibody linked via a thioether bond. -drug conjugate (hereinafter referred to as "antibody-drug conjugate (2)") The DAR of the antibody-drug conjugate (2) is 7.6.

[0208] Example 9: Preparation of antibody-drug conjugate (3) According to the production method described in WO 2018 / 212136, an anti-CDH6 antibody (sequence A heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in sequence number 11; A light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 12. An antibody comprising the formula

[0209] [ka]

[0210] (wherein A represents the binding site to the antibody) and an anti-CDH6 antibody bound via a thioether bond. - preparing a drug conjugate (hereinafter referred to as "antibody-drug conjugate (3)"); The DAR of the antibody-drug conjugate (3) is 7.8.

[0211] Example 10: Antitumor test (7) Human breast cancer cell line JIMT-1 cells purchased from DSMZ were suspended in saline at 5 × 10 6 The cells were subcutaneously transplanted into the right flank of female nude mice, and 10 days after transplantation, the mice were randomly assigned to groups. Antibody-drug conjugate (2) (DAR: 7.6) was Paclitaxel was administered intravenously at a dose of 10 mg / kg on Day 0, Day 7, and Day 14. Taxel was administered at a dose of 15 mg / kg via the tail vein on days 0 and 7. There were groups administered the single agent and the combination agent, and a vehicle-administered control group.

[0212] The results of combined use of antibody-drug conjugate (2) and Paclitaxel are shown in FIG. The TGI rate with paclitaxel alone was 36%. The TGI for gate (2) was 69% for single agent administration. The combination of methadone (2) and paclitaxel was more effective than the monotherapy with paclitaxel. The tumor growth inhibitory effect was significantly superior to that of the antibody-drug combination (P<0.001). The tumor growth inhibitory effect was significantly superior to that of the single agent Conjugate (2) (P<0.05). The TGI was 97%. There was no significant weight loss in either the single-agent or combination treatment groups. No particularly notable findings were observed.

[0213] Example 11: Antitumor Test (8) Human ovarian cancer line OV-90 cells purchased from ATCC were suspended in Matrigel for 2.5 h. ×10 6 The cells were subcutaneously transplanted into the right flank of female nude mice, and 15 days after transplantation, the mice were randomly assigned to Grouping was performed (Day 0). Antibody-drug conjugate (3) (DAR: 7.8) On Day 0, paclitaxel was administered intravenously at a dose of 10 mg / kg into the tail vein. The drug was administered via the tail vein at a dose of 15 mg / kg on Days 1, 2, 3, and 7, and Day 14. A group administered the compound in combination with the compound and a group administered the solvent as a control group were also set up.

[0214] The results of combined use of antibody-drug conjugate (3) and Paclitaxel are shown in Figure 23. On day 17, the TGI with paclitaxel alone was 80%, while that with antibody-drug The TGI of the antibody-drug conjugate (3) alone was 97%, and that of the antibody-drug conjugate ( 3) The TGI achieved by the combined administration of EGFR and paclitaxel was 99%. In the case of combined administration of drug conjugate (3) and Paclitaxel, The tumor growth inhibitory effect was significantly superior to that of paclitaxel alone. P<0.001). Furthermore, on Day 38, the antibody-drug conjugate (3) alone The tumor growth inhibitory effect was significantly superior to that of the control group (P<0.01(Student Calculated by t-test.) In addition, in both the single drug and combination drug groups, No particularly notable findings such as weight loss were observed.

[0215] Example 12: RNA Expression Analysis Human breast cancer cell line JIMT-1 cells were transplanted into nude mice, and antibody-drug conjugates ( 1) Paclitaxel or Eribulin mesylate Single administration group, antibody-drug conjugate (1) and Paclitaxel, or antibody- A group administered the drug conjugate (1) in combination with eribulin mesylate, and A control group was set up. Tumor samples were taken before and after drug administration, and RNA expression was analyzed. The tumors were weighed and then incubated with RNAlater RNA Stabilization Kit. n Incubate in Reagent overnight, remove RNAlater, and then store at -80°C. RNA was purified by QIA using the RNeasy Mini Kit (QIAGEN). NEBNext Poly(A)mRNA was extracted using Cube and then extracted from the resulting RNA. Magnetic Module and NEBNext Ultra RNA Libra Prepare libraries using the Illumina Library Prep Kit. The library is Illmina NextSeq500 / 550 High Output Illmina NextSeq500 or 550 sequencing using Kit v2.5 The resulting base call file is Convert to fastq file using cl2fastq ver.2.20.0.422 The reads in the fastq files are based on the human reference genome GRCh37 assembly. The transcripts were aligned against the reference sequences using STAR ver.2.5.3a15. The number of reads for each gene was estimated using RSEM ver.1.3.016. Gene expression levels were analyzed across samples using EBSeq ver.1.22.0. Normalized Transcripts Per Ki using the Median Ratio Normalization Method The values ​​are expressed as total base million (TPM).

[0216] The mean TPM value of the SLFN11 gene in tumors from the control group was higher than that of the antibody-drug group. The mean TPM value of the SLFN11 gene after administration of the monotherapy conjugate (1) was In addition, antibody-drug conjugate (1) and Paclitaxel After co-administration of xel or antibody-drug conjugate (1) and Eribulin me The mean TPM value of the SLFN11 gene after coadministration of sylate was significantly higher than that after antibody- TPM of the SLFN11 gene after administration of the drug conjugate (1) alone was higher than the average Verify that it shows a high value.

[0217] Furthermore, the mean TPM value of the ABCG2 gene in tumors from the control group was significantly higher than that in the control group. The mean TPM value of the ABCG2 gene after single administration of the antibody-drug conjugate (1) The antibody-drug conjugate (1) and Pacl After coadministration of itaxel or antibody-drug conjugate (1) and Eribulin The mean TPM value of the ABCG2 gene after coadministration of mesylate was higher than that after coadministration of The mean TPM of the ABCG2 gene after single administration of the antibody-drug conjugate (1) was Verify that the value is lower than the

[0218] Example 13: Protein Expression Analysis Human breast cancer cell line JIMT-1 cells were transplanted into nude mice, and antibody-drug conjugates ( 1) Paclitaxel or Eribulin mesylate Single administration group, antibody-drug conjugate (1) and Paclitaxel, or antibody- A group administered the drug conjugate (1) in combination with eribulin mesylate, and A control group was set up. Tumor samples were taken before and after drug administration, and protein expression was measured. The tumors excised from the mice were crushed and dissolved in RIPA buffer. After centrifugation, the supernatant was collected as a tumor lysate. FN11 protein expression and β-Actin expression were measured using the Simple Western System (WSSS). es or Peggy Sue) and Compass for SW v Calculate the peak area using ER.4.0.0. SLFN11 of each tumor lysate The protein expression level ratio is calculated by the following formula:

[0219] SLFN11 protein expression level ratio = (peak expression level of SLFN11 protein at each time point) (SLFN11 protein area at Day 0) / (β-Actin peak area at each time point) Peak area value of protein / peak area value of β-Actin on Day 0) SLFN11 protein expression levels in the monotherapy group of antibody-drug conjugate (1) The combination of antibody-drug conjugate (1) and paclitaxel was more effective than the baseline. or combination of antibody-drug conjugate (1) and eribulin mesylate Confirm that the SLFN11 protein expression level is higher in the treated group . [Sequence List Free Text]

[0220] SEQ ID NO: 1: Amino acid sequence of the anti-HER2 antibody heavy chain SEQ ID NO: 2: Amino acid sequence of the anti-HER2 antibody light chain SEQ ID NO: 3: Amino acid sequence of the heavy chain of the anti-HER3 antibody SEQ ID NO: 4: Amino acid sequence of the light chain of the anti-HER3 antibody SEQ ID NO: 5: Amino acid sequence of the anti-TROP2 antibody heavy chain SEQ ID NO: 6: Amino acid sequence of the anti-TROP2 antibody light chain SEQ ID NO: 7: Amino acid sequence of the anti-B7-H3 antibody heavy chain SEQ ID NO: 8: Amino acid sequence of the anti-B7-H3 antibody light chain SEQ ID NO: 9: Amino acid sequence of the anti-GPR20 antibody heavy chain SEQ ID NO: 10: Amino acid sequence of the anti-GPR20 antibody light chain SEQ ID NO: 11: Amino acid sequence of the anti-CDH6 antibody heavy chain SEQ ID NO: 12: Amino acid sequence of the anti-CDH6 antibody light chain

Claims

1. 1. A pharmaceutical composition comprising an antibody-drug conjugate for use in combination with a tubulin inhibitor, comprising: The antibody-drug conjugate has the formula 【Chemistry 1】 (In the formula, A represents the binding site with the anti-CDH6 antibody.) and an anti-CDH6 antibody-drug conjugate in which the drug linker represented by the formula: the tubulin inhibitor is paclitaxel, docetaxel, cabazitaxel, or a pharmacologically acceptable salt thereof, nab-paclitaxel, eribulin or a pharmacologically acceptable salt thereof, or an antibody-drug conjugate in which eribulin is bound to the antibody via a linker, or an antibody-drug conjugate in which DM4 is bound to the antibody via a linker; Pharmaceutical compositions.

2. A pharmaceutical composition comprising a tubulin inhibitor for use in combination with an antibody-drug conjugate, comprising: The antibody-drug conjugate has the formula 【Chemistry 2】 (In the formula, A represents the binding site with the anti-CDH6 antibody.) and an anti-CDH6 antibody-drug conjugate in which the drug linker represented by the formula: the tubulin inhibitor is paclitaxel, docetaxel, cabazitaxel, or a pharmacologically acceptable salt thereof, nab-paclitaxel, eribulin or a pharmacologically acceptable salt thereof, or an antibody-drug conjugate in which eribulin is bound to the antibody via a linker, or an antibody-drug conjugate in which DM4 is bound to the antibody via a linker; Pharmaceutical compositions.

3. 1. A pharmaceutical composition comprising an antibody-drug conjugate, the antibody-drug conjugate and the tubulin inhibitor are administered in combination; The antibody-drug conjugate has the formula 【Chemistry 3】 (In the formula, A represents the binding site with the anti-CDH6 antibody.) and an anti-CDH6 antibody-drug conjugate in which the drug linker represented by the formula: the tubulin inhibitor is paclitaxel, docetaxel, cabazitaxel, or a pharmacologically acceptable salt thereof, nab-paclitaxel, eribulin or a pharmacologically acceptable salt thereof, or an antibody-drug conjugate in which eribulin is bound to the antibody via a linker, or an antibody-drug conjugate in which DM4 is bound to the antibody via a linker; Pharmaceutical compositions.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the anti-CDH6 antibody-drug conjugate and the tubulin inhibitor are contained as active ingredients in different formulations and are administered simultaneously or at different times.

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein the anti-CDH6 antibody-drug conjugate and the tubulin inhibitor are contained as active ingredients in a single formulation.

6. A pharmaceutical composition comprising an antibody-drug conjugate and a tubulin inhibitor in a single formulation, The antibody-drug conjugate has the formula 【Chemistry 4】 (In the formula, A represents the binding site with the anti-CDH6 antibody.) and an anti-CDH6 antibody-drug conjugate in which the drug linker represented by the formula: the tubulin inhibitor is paclitaxel, docetaxel, cabazitaxel, or a pharmacologically acceptable salt thereof, nab-paclitaxel, eribulin or a pharmacologically acceptable salt thereof, or an antibody-drug conjugate in which eribulin is bound to the antibody via a linker, or an antibody-drug conjugate in which DM4 is bound to the antibody via a linker; Pharmaceutical compositions.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO: 11 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 of SEQ ID NO:

12.

8. The pharmaceutical composition according to claim 7, wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.

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

10. The anti-CDH6 antibody-drug conjugate has the formula 【Chemistry 5】 (In the formula, the antibody is an anti-CDH6 antibody, the drug linker is bound to the antibody via a thioether bond, and n represents the average number of drug linkers bound per antibody.) The pharmaceutical composition according to any one of claims 1 to 8, wherein

11. The anti-CDH6 antibody-drug conjugate has the formula 【Chemistry 6】 (wherein the antibody is an anti-CDH6 antibody, the drug linker is bound to the antibody via a thioether bond, and n represents the drug-antibody ratio). The pharmaceutical composition according to any one of claims 1 to 8, wherein

12. 12. The pharmaceutical composition according to claim 10 or 11, wherein n is in the range of 7 to 8.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the tubulin inhibitor is paclitaxel, docetaxel, cabazitaxel, or a pharmacologically acceptable salt thereof, or nab-paclitaxel.

14. 13. The pharmaceutical composition of any one of claims 1 to 12, wherein the tubulin inhibitor is paclitaxel.

15. The pharmaceutical composition according to any one of claims 1 to 12, wherein the tubulin inhibitor is eribulin or a pharmacologically acceptable salt thereof, or an antibody-drug conjugate in which eribulin is linked to the antibody via a linker.

16. 13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the tubulin inhibitor is eribulin mesylate.

17. The pharmaceutical composition according to any one of claims 1 to 12, wherein the tubulin inhibitor is MORAb-202.

18. The pharmaceutical composition according to any one of claims 1 to 12, wherein the tubulin inhibitor is an antibody-drug conjugate in which DM4 and the antibody are linked via a linker.

19. The pharmaceutical composition according to any one of claims 1 to 12, wherein the tubulin inhibitor is IMGN-853.

20. 20. A pharmaceutical composition according to any one of claims 1 to 19 for the treatment of cancer.

21. The pharmaceutical composition according to any one of claims 1 to 19, for the treatment of 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, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, uterine cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, and melanoma.

22. 20. A pharmaceutical composition according to any one of claims 1 to 19 for the treatment of breast cancer.

23. 20. A pharmaceutical composition according to any one of claims 1 to 19 for the treatment of gastric cancer.

24. 20. A pharmaceutical composition according to any one of claims 1 to 19 for the treatment of lung cancer.

25. The pharmaceutical composition of claim 24, wherein the lung cancer is non-small cell lung cancer.

26. 20. A pharmaceutical composition according to any one of claims 1 to 19 for the treatment of esophageal cancer.

27. 20. A pharmaceutical composition according to any one of claims 1 to 19 for the treatment of head and neck cancer.

28. 20. A pharmaceutical composition according to any one of claims 1 to 19 for the treatment of ovarian cancer.

29. 20. A pharmaceutical composition according to any one of claims 1 to 19 for the treatment of cervical cancer.

30. A pharmaceutical composition according to any one of claims 1 to 19 for the treatment of endometrial cancer.

31. A pharmaceutical combination comprising an antibody-drug conjugate and a tubulin inhibitor, the antibody-drug conjugate and the tubulin inhibitor are administered in combination; The antibody-drug conjugate has the formula 【Chemistry 7】 (In the formula, A represents the binding site with the anti-CDH6 antibody.) and an anti-CDH6 antibody-drug conjugate in which the drug linker represented by the formula: the tubulin inhibitor is paclitaxel, docetaxel, cabazitaxel, or a pharmacologically acceptable salt thereof, nab-paclitaxel, eribulin or a pharmacologically acceptable salt thereof, or an antibody-drug conjugate in which eribulin is bound to the antibody via a linker, or an antibody-drug conjugate in which DM4 is bound to the antibody via a linker; Pharmaceutical combinations.

32. The pharmaceutical combination according to claim 31 , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO: 11 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 of SEQ ID NO:

12.

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

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

35. 35. A pharmaceutical combination according to any one of claims 31 to 34, wherein the tubulin inhibitor is paclitaxel.

36. 35. The pharmaceutical combination according to any one of claims 31 to 34, wherein the tubulin inhibitor is eribulin mesylate.

37. The pharmaceutical combination according to any one of claims 31 to 34, wherein the tubulin inhibitor is MORAb-202.

38. The pharmaceutical combination according to any one of claims 31 to 34, wherein the tubulin inhibitor is IMGN-853.

39. The pharmaceutical combination according to any one of claims 31 to 38, wherein the anti-CDH6 antibody-drug conjugate and the tubulin inhibitor are contained as active ingredients in different formulations and are administered simultaneously or at different times.

40. The pharmaceutical combination according to any one of claims 31 to 38, wherein the anti-CDH6 antibody-drug conjugate and the tubulin inhibitor are contained as active ingredients in a single formulation.

41. 41. A pharmaceutical combination according to any one of claims 31 to 40 for the treatment of cancer.

42. 41. The pharmaceutical combination of any one of claims 31 to 40, for the treatment of 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, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, uterine cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, and melanoma.

43. The pharmaceutical combination according to any one of claims 31 to 40, for the treatment of at least one cancer selected from the group consisting of breast cancer, gastric cancer, lung cancer, esophageal cancer, head and neck cancer, ovarian cancer, cervical cancer, and uterine cancer.

44. 41. A pharmaceutical combination according to any one of claims 31 to 40 for the treatment of ovarian cancer.

Images