Combination of antibody-drug conjugates and tubulin inhibitors

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] This invention involves the combination of a specific antibody-drug conjugate and a tubulin inhibitor. A pharmaceutical composition characterized by being provided, and / or a specific antibody-drug conjugate This invention relates to a therapeutic method characterized by the administration of a combination of tubulin inhibitors to an individual. ru. [Background technology]

[0002] Tubulin inhibitors affect the G1 cell cycle by influencing microtubule dynamics. Cell division is stopped in phase 2 (preparatory phase) and / or phase M (mitotic phase), and apoptosis occurs. It is a drug that suppresses the proliferation of cancer cells by inducing cell death (Non-Patent Document 1, 2).

[0003] Tubulin inhibitors work by promoting tubulin polymerization, thereby altering microtubule dynamics. Drugs that affect tubulin polymerization (tubulin polymerization promoters) and drugs that inhibit tubulin polymerization. There are drugs (tubulin polymerization inhibitors) that affect microtubule dynamics. .

[0004] Examples of tubulin polymerization promoters include paclitaxel and docetamol. Docetaxel and Cabazitaxel, etc. It is known. Also, as a tubulin polymerization inhibitor, there is eribulin. ), vincristine, vinblastine ne), vinorelbine, vindesine Monomethyl auristatin E (MM) Brentuximab vedotin (B) is an antibody-drug conjugate that has AE as a component. rentuximab Vedotin, and antibody-drug compounds containing DM1 Trastuzumab Emtansine is a drug adjugate. Examples include sine.

[0005] Antibodies that bind to antigens expressed on the surface of cancer cells and that can be internalized within the cells have cytotoxic properties. Antibody-drug conjugates are antibodies to which drugs are bound. Jugate (ADC) can selectively deliver drugs to cancer cells, thus treating cancer It is expected that the drug will accumulate inside the cells and kill the cancer cells (Non-patent documents 3-7). .

[0006] One example of an antibody-drug conjugate is one in which an antibody is combined with an antibody, which is a topoisomerase I inhibitor. Antibody-drug conjugates containing derivatives of satecan are known (Patent Document). 1-7, Non-patent documents 8-11).

[0007] Furthermore, Patent Documents 1 to 7 describe the above antibody-drug conjugates combined with various cancer treatment agents. It is stated that it can be administered to [the patient].

[0008] However, when the above antibody-drug conjugate is used in combination with a tubulin inhibitor, The results of tests demonstrating the combined effect, and the scientific evidence suggesting those results, are not included. I haven't done that. [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] Mukhtar E, et al., Mol Cancer Ther. 2014 Feb: 13(2): 275-284. [Non-licensed document 3] Ducry, L., et al., Bioconjugate Chem. (2010) 21, 5-13.

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

[0011] The antibody-drug conjugate used in this invention (containing a derivative of exatecan as a component) Antibody-drug conjugates have been shown to exhibit excellent antitumor effects even when used as monotherapy. However, by using it in combination with other anticancer drugs that have different mechanisms of action, There is a desire to acquire a treatment method that can comprehensively suppress the proliferation of cancer cells and exhibit superior antitumor effects. Born.

[0012] This invention involves the combination of a specific antibody-drug conjugate and a tubulin inhibitor. A pharmaceutical composition characterized by being provided, and / or a specific antibody-drug conjugate This provides a therapeutic method characterized by the administration of a combination of tubulin inhibitors to the individual. The task is to accomplish this. [Means for solving the problem]

[0013] The inventors of this invention conducted diligent research to solve the above problem and found that a specific antibody-drug The combination of a conjugate and a tubulin inhibitor provides superior efficacy. We discovered that it exhibits a beneficial effect, and thus completed the present invention.

[0014] In other words, the present invention provides the following [1] to

[0344] . [1] The combination of an antibody-drug conjugate and a tubulin inhibitor is administered. A pharmaceutical composition characterized by, The antibody-drug conjugate is,

[0015] [ka]

[0016] (In the formula, A indicates the binding site with the antibody.) An antibody-drug linker, represented by the symbol, is linked to an antibody via a thioether bond. A pharmaceutical composition containing jugate. [2] In antibody-drug conjugates, the antibodies are anti-HER2 antibodies, anti-HER3 antibodies, and anti-TR antibodies. The antibody is an OP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody, [1] The pharmaceutical composition described above. [3] The antibody in the antibody-drug conjugate is an anti-HER2 antibody, as described in [2]. A pharmaceutical composition. [4] The anti-HER2 antibody has the amino acid combination described in SEQ ID NO: 1, from amino acid numbers 1 to 449. Heavy chain consisting of columns and amino acid sequences described in Sequence ID No. 2 for amino acid numbers 1 to 214 The pharmaceutical composition according to [3], comprising an antibody containing a light chain consisting of the above. [5] The anti-HER2 antibody consists of a heavy chain comprising the amino acid sequence described in SEQ ID NO: 1 and SEQ ID NO: 2 The pharmaceutical composition according to [3], comprising an antibody containing a light chain consisting of the amino acid sequence described above. [6] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. A pharmaceutical composition according to any one of the eight items, [3] to [5]. [7] The antibody in the antibody-drug conjugate is an anti-HER3 antibody, as described in [2]. A pharmaceutical composition. [8] The anti-HER3 antibody consists of a heavy chain comprising the amino acid sequence described in SEQ ID NO: 3 and SEQ ID NO: 4. The pharmaceutical composition according to [7], comprising an antibody containing a light chain consisting of the amino acid sequence described above. [9] The anti-HER3 antibody lacks a lysine residue at the heavy chain carboxyl terminus, as described in [8]. A pharmaceutical composition.

[10] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. A pharmaceutical composition according to any one of the eight items, [7] to [9].

[0017]

[11] The antibody in the antibody-drug conjugate is an anti-TROP2 antibody, as described in [2]. Pharmaceutical composition.

[12] The anti-TROP2 antibody is the amino acid described in SEQ ID NO: 5, amino acid numbers 20 to 470. A heavy chain consisting of an acid sequence and amino acids listed as 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 acid sequence.

[13] In anti-TROP2 antibodies, the lysine residue at the heavy chain carboxyl terminus is deleted,

[12] The pharmaceutical composition described.

[14] The average number of drug linkers bound per antibody in antibody-drug conjugates is 3.5. A pharmaceutical composition according to any one of items

[11] to

[13] , ranging from 4.5.

[15] The antibody in the antibody-drug conjugate is an anti-B7-H3 antibody, as described in [2]. Pharmaceutical composition.

[16] The anti-B7-H3 antibody is the amino acid described in SEQ ID NO: 7, amino acid numbers 20 to 471. A heavy chain consisting of an acid sequence and amino acids listed as 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 acid sequence.

[17] In the anti-B7-H3 antibody, the lysine residue at the heavy chain carboxyl terminus is deleted,

[16] The pharmaceutical composition described.

[18] The average number of drug linkers bound per antibody in antibody-drug conjugates is 3.5. A pharmaceutical composition according to any one of items

[15] to

[17] , ranging from 4.5.

[19] The antibody in the antibody-drug conjugate is an anti-GPR20 antibody, as described in [2]. Pharmaceutical composition.

[20] The anti-GPR20 antibody is the amino acid number 20 to 472 described in SEQ ID NO: 9. A heavy chain consisting of an acid sequence and the amino acids described in SEQ ID NO: 10, amino acid numbers 21 to 234. The pharmaceutical composition according to

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

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

[20] The pharmaceutical composition described. [twenty two] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. A pharmaceutical composition according to any one of the eight items,

[19] to

[21] . [twenty three] The antibody in the antibody-drug conjugate is an anti-CDH6 antibody, as described in [2]. A pharmaceutical composition. [twenty four] The anti-CDH6 antibody is the amino acid numbered 20 to 471 in SEQ ID NO: 11. A heavy chain consisting of an acid sequence and the amino acids described in SEQ ID NO: 12, amino acid numbers 21 to 233. The pharmaceutical composition according to

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

[24] . A listed pharmaceutical composition.

[26] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. A pharmaceutical composition according to any one of the eight items,

[23] to

[25] .

[27] Tubulin inhibitors include paclitaxel, docetaxel, cabazitaxel, or These are pharmacoacceptable salts, or nab-paclitaxel, [1] to

[26] A pharmaceutical composition as described in any one of the items.

[28] The pharmaceutical composition according to

[27] , wherein the tubulin inhibitor is paclitaxel.

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

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

[30] The pharmaceutical composition according to

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

[0019]

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

[0030] , characterized in that it is contained as and administered simultaneously or at different times.

[32] Breast cancer, stomach cancer, colorectal cancer, lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, bile duct cancer Cancers of the pelvis, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, and uterine cancer For at least one treatment selected from the group consisting of tumors, [1] to

[31] A pharmaceutical composition as described in item 1.

[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 the expression of drug sensitivity factors caused by the administration of antibody-drug conjugates is controlled by tubes. The medical device described in any one of [1] to

[36] , characterized in that it is suppressed by a phosphorus inhibitor. A pharmaceutical composition.

[38] The pharmaceutical composition according to

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

[39] The increased expression of drug resistance factors caused by the administration of antibody-drug conjugates is addressed by tubulo. The pharmaceutical product according to any one of items [1] to

[36] , characterized in that it is suppressed by an inhibitor. composition.

[40] The pharmaceutical composition according to

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

[41] The combination of an antibody-drug conjugate and a tubulin inhibitor is administered. A pharmaceutical composition characterized by, The antibody-drug conjugate is,

[0020] [ka]

[0021] (In the formula, the drug linker is bound to the antibody by a thioether bond, and n is per antibody) (This shows the average number of linkers in each drug.) A pharmaceutical composition which is an antibody-drug conjugate represented by [the formula shown].

[42] In antibody-drug conjugates, the antibodies are anti-HER2 antibodies, anti-HER3 antibodies, and anti-TR antibodies. The pharmaceutical composition according to

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

[43] The antibody in the antibody-drug conjugate is an anti-HER2 antibody, as described in

[42] . Pharmaceutical composition.

[44] The anti-HER2 antibody has the amino acid combination described in SEQ ID NO: 1, from amino acid numbers 1 to 449. Heavy chain consisting of columns and amino acid sequences described in Sequence ID No. 2 for amino acid numbers 1 to 214 The pharmaceutical composition according to

[43] , comprising an antibody containing a light chain consisting of the above.

[45] The anti-HER2 antibody consists of a heavy chain comprising the amino acid sequence described in SEQ ID NO: 1 and SEQ ID NO: 2 The pharmaceutical composition according to

[43] , comprising an antibody containing a light chain consisting of the amino acid sequence described above.

[46] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. A pharmaceutical composition according to any one of the eight items,

[43] to

[45] .

[47] The antibody in the antibody-drug conjugate is an anti-HER3 antibody, as described in

[42] . Pharmaceutical composition.

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

[47] , comprising an antibody containing a light chain consisting of the amino acid sequence described above.

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

[48] . A listed pharmaceutical composition.

[50] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. A pharmaceutical composition according to any one of the eight items,

[47] to

[49] .

[0022]

[51] The antibody in the antibody-drug conjugate is an anti-TROP2 antibody, as described in

[42] . A pharmaceutical composition.

[52] The anti-TROP2 antibody is the amino acid described in SEQ ID NO: 5, amino acid numbers 20 to 470. A heavy chain consisting of an acid sequence and amino acids listed as 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 acid sequence.

[53] In the anti-TROP2 antibody, the lysine residue at the heavy chain carboxyl terminus is deleted,

[52] The pharmaceutical composition described.

[54] The average number of drug linkers bound per antibody in antibody-drug conjugates is 3.5. A pharmaceutical composition according to any one of items

[51] to

[53] , ranging from 4.5.

[55] The antibody in the antibody-drug conjugate is an anti-B7-H3 antibody, as described in

[42] . A pharmaceutical composition.

[56] The anti-B7-H3 antibody is the amino acid described in SEQ ID NO: 7, amino acid numbers 20 to 471. A heavy chain consisting of an acid sequence and amino acids listed as 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 acid sequence.

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

[56] The pharmaceutical composition described.

[58] The average number of drug linkers bound per antibody in antibody-drug conjugates is 3.5. A pharmaceutical composition according to any one of items

[55] to

[57] , ranging from 4.5.

[59] The antibody in the antibody-drug conjugate is an anti-GPR20 antibody, as described in

[42] . A pharmaceutical composition.

[60] The anti-GPR20 antibody is the amino acid number 20 to 472 described in SEQ ID NO: 9. A heavy chain consisting of an acid sequence and the amino acids described in SEQ ID NO: 10, amino acid numbers 21 to 234. The pharmaceutical composition according to

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

[0023]

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

[60] The pharmaceutical composition described.

[62] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. A pharmaceutical composition according to any one of the eight items,

[59] to

[61] .

[63] The antibody in the antibody-drug conjugate is an anti-CDH6 antibody, as described in

[42] . Pharmaceutical composition.

[64] The anti-CDH6 antibody is the amino acid numbered 20 to 471 in SEQ ID NO: 11. A heavy chain consisting of an acid sequence and the amino acids described in SEQ ID NO: 12, amino acid numbers 21 to 233. The pharmaceutical composition according to

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

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

[64] . A listed pharmaceutical composition.

[66] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. A pharmaceutical composition according to any one of the eight items,

[63] to

[65] .

[67] Tubulin inhibitors include paclitaxel, docetaxel, cabazitaxel, or These are pharmacopoecilistically acceptable salts, or nab-paclitaxel,

[41] to

[66] A pharmaceutical composition as described in any one of the items.

[68] The pharmaceutical composition according to

[67] , wherein the tubulin inhibitor is paclitaxel.

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

[41] to

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

[70] The pharmaceutical composition according to

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

[0024]

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

[41] to

[0070] , characterized in that it is contained as and administered simultaneously or at different times.

[72] Breast cancer, stomach cancer, colorectal cancer, lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, bile duct cancer Cancers of the pelvis, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, and uterine cancer For at least one treatment selected from the group consisting of tumors,

[41] to

[71] Any of the pharmaceutical compositions described in item 1.

[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 the expression of drug sensitivity factors caused by the administration of antibody-drug conjugates is controlled by tubes. The method described in any one of

[41] to

[76] , characterized in that a phosphorus inhibitor is suppressed. Pharmaceutical composition.

[78] The pharmaceutical composition according to

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

[79] The increased expression of drug resistance factors caused by the administration of antibody-drug conjugates is addressed by tubulo. The drug according to any one of

[41] to

[76] , characterized in that the drug inhibitor suppresses the drug A pharmaceutical composition.

[80] The pharmaceutical composition according to

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

[81] Antibody-drug conjugates and tubulin inhibitors are used in combination to treat conditions requiring treatment. A treatment method characterized by being administered to an individual, The antibody-drug conjugate is,

[0025] [ka]

[0026] (In the formula, A indicates the binding site with the antibody.) An antibody-drug linker, represented by the symbol, is linked to an antibody via a thioether bond. A treatment method called Jugate.

[82] In antibody-drug conjugates, the antibodies are anti-HER2 antibodies, anti-HER3 antibodies, and anti-TR antibodies. The treatment 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] The antibody in the antibody-drug conjugate is an anti-HER2 antibody, as described in

[82] . Treatment method.

[84] The anti-HER2 antibody has the amino acid combination described in SEQ ID NO: 1, from amino acid numbers 1 to 449. Heavy chain consisting of columns and amino acid sequences described in Sequence ID No. 2 for amino acid numbers 1 to 214 The therapeutic method described in

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

[85] The anti-HER2 antibody consists of a heavy chain comprising the amino acid sequence described in SEQ ID NO: 1 and SEQ ID NO: 2 The therapeutic method described in

[83] , wherein the antibody comprises a light chain consisting of the amino acid sequence described above.

[86] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. A treatment method described in any one of the eight ranges,

[83] to

[85] .

[87] The antibody in the antibody-drug conjugate is an anti-HER3 antibody, as described in

[82] . Treatment method.

[88] The anti-HER3 antibody consists of a heavy chain comprising the amino acid sequence described in SEQ ID NO: 3 and SEQ ID NO: 4. The therapeutic method described in

[87] , wherein the antibody comprises a light chain consisting of the amino acid sequence described above.

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

[88] . Treatment methods listed.

[90] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. A treatment method described in any one of the eight ranges,

[87] to

[89] .

[0027]

[91] The antibody in the antibody-drug conjugate is an anti-TROP2 antibody, as described in

[82] . Treatment methods.

[92] The anti-TROP2 antibody is the amino acid described in SEQ ID NO: 5, amino acid numbers 20 to 470. A heavy chain consisting of an acid sequence and amino acids listed as amino acid numbers 21 to 234 in SEQ ID NO: 6 The therapeutic method described in

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

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

[92] The treatment methods described.

[94] The average number of drug linkers bound per antibody in antibody-drug conjugates is 3.5. A treatment method described in any one of items

[91] to

[93] , within the range of 4.5.

[95] The antibody in the antibody-drug conjugate is an anti-B7-H3 antibody, as described in

[82] . Treatment methods.

[96] The anti-B7-H3 antibody is the amino acid described in SEQ ID NO: 7, amino acid numbers 20 to 471. A heavy chain consisting of an acid sequence and amino acids listed as amino acid numbers 21 to 233 in SEQ ID NO: 8 The therapeutic method described in

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

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

[96] The treatment methods described.

[98] The average number of drug linkers bound per antibody in antibody-drug conjugates is 3.5. A treatment method described in any one of the items from

[95] to

[97] , within the range of 4.5.

[99] The antibody in the antibody-drug conjugate is an anti-GPR20 antibody, as described in

[82] . Treatment methods.

[0100] The anti-GPR20 antibody is the amino acid number 20 to 472 described in SEQ ID NO: 9. A heavy chain consisting of an acid sequence and the amino acids described in SEQ ID NO: 10, amino acid numbers 21 to 234. The therapeutic method described in

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

[0028]

[0101] The anti-GPR20 antibody lacks a lysine residue at the heavy chain carboxyl terminus,

[0100] The treatment methods described.

[0102] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. A treatment method described in any one of the eight ranges, from

[99] to

[0101] .

[0103] The antibody in the antibody-drug conjugate is an anti-CDH6 antibody, as described in

[82] . Treatment method.

[0104] The anti-CDH6 antibody is the amino acid numbered 20 to 471 in SEQ ID NO: 11. A heavy chain consisting of an acid sequence and the amino acids described in SEQ ID NO: 12, amino acid numbers 21 to 233. The therapeutic method described in

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

[0105] The anti-CDH6 antibody lacks a lysine residue at the heavy chain carboxyl terminus,

[0104] The treatment methods described.

[0106] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. A treatment method described in any one of the eight ranges, from

[0103] to

[0105] .

[0107] Tubulin inhibitors include paclitaxel, docetaxel, cabazitaxel, or The treatment method described in any one of paragraphs

[81] to

[0106] , wherein the pharmacoposityally acceptable salts thereof or nab-paclitaxel.

[0108] The treatment method described in

[0107] , wherein the tubulin inhibitor is paclitaxel.

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

[81] to

[0106] , wherein the antibody-drug conjugate is obtained by linking an antibody via a linker.

[0110] The 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. A therapeutic method according to any one of

[81] to

[0110] , characterized in that it is contained as and administered simultaneously or at different times.

[0112] Breast cancer, stomach cancer, colorectal cancer, lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, bile duct cancer Cancers of the pelvis, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, and uterine cancer For at least one treatment selected from the group consisting of tumors,

[81] to

[0111] The treatment method described in any one of the items.

[0113] Treatment methods described in

[0112] for the treatment of breast cancer.

[0114] The treatment method described in

[0112] for the treatment of gastric cancer.

[0115] The treatment method described in

[0112] for the treatment of lung cancer.

[0116] The treatment method described in

[0112] for the treatment of ovarian cancer.

[0117] The decrease in the expression of drug sensitivity factors caused by the administration of antibody-drug conjugates is controlled by tubes. The present invention is characterized by being suppressed by a phosphorus inhibitor, as described in any one of items

[81] to

[0116] . Treatment methods.

[0118] The treatment method described in

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

[0119] The increased expression of drug resistance factors caused by the administration of antibody-drug conjugates is addressed by tubulo. The following is characterized by being suppressed by an inhibitor, as described in any one of items

[81] to

[0116] . Treatment method.

[0120] The 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 conditions requiring treatment. A treatment method characterized by being administered to an individual, The antibody-drug conjugate is,

[0030] [ka]

[0031] (In the formula, the drug linker is bound to the antibody by a thioether bond, and n is per antibody) (This shows the average number of linkers in each drug.) A treatment method that involves an antibody-drug conjugate, as shown by [the formula / symbol].

[0122] In antibody-drug conjugates, the antibodies are anti-HER2 antibodies, anti-HER3 antibodies, and anti-TR antibodies. The treatment 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, as described in

[0122] . Treatment methods.

[0124] The anti-HER2 antibody has the amino acid combination described in SEQ ID NO: 1, from amino acid numbers 1 to 449. Heavy chain consisting of columns and amino acid sequences described in Sequence ID No. 2 for amino acid numbers 1 to 214 The therapeutic method described in

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

[0125] The anti-HER2 antibody consists of a heavy chain comprising the amino acid sequence described in SEQ ID NO: 1 and SEQ ID NO: 2 The therapeutic method described in

[0123] , wherein the antibody comprises a light chain consisting of the amino acid sequence described.

[0126] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. A treatment method described in any one of the eight ranges, from

[0123] to

[0125] .

[0127] The antibody in the antibody-drug conjugate is an anti-HER3 antibody, as described in

[0122] . Treatment methods.

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

[0127] , wherein the antibody comprises a light chain consisting of the amino acid sequence described.

[0129] In the anti-HER3 antibody, the lysine residue at the heavy chain carboxyl terminus is deleted,

[0128] The treatment methods described.

[0130] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. A treatment method described in any one of the eight ranges,

[0127] to

[0129] .

[0032]

[0131] The antibody in the antibody-drug conjugate is an anti-TROP2 antibody, as described in

[0122] . Treatment methods listed.

[0132] The anti-TROP2 antibody is the amino acid described in SEQ ID NO: 5, amino acid numbers 20 to 470. A heavy chain consisting of an acid sequence and amino acids listed as amino acid numbers 21 to 234 in SEQ ID NO: 6 The therapeutic method described in

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

[0133] The anti-TROP2 antibody lacks a lysine residue at the heavy chain carboxyl terminus,

[0132] The treatment methods described.

[0134] The average number of drug linkers bound per antibody in antibody-drug conjugates is 3.5. A treatment method described in any one of the items

[0131] to

[0133] , which is within the range of 4.5 items. .

[0135] In the antibody-drug conjugate, the antibody is an anti-B7-H3 antibody, as described in

[0122] . Treatment methods listed.

[0136] The anti-B7-H3 antibody is the amino acid described in SEQ ID NO: 7, amino acid numbers 20 to 471. A heavy chain consisting of an acid sequence and amino acids listed as amino acid numbers 21 to 233 in SEQ ID NO: 8 The therapeutic method described in

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

[0137] The anti-B7-H3 antibody lacks a lysine residue at the heavy chain carboxyl terminus,

[0136] The treatment methods described.

[0138] The average number of drug linkers bound per antibody in antibody-drug conjugates is 3.5. A treatment method described in any one of items

[0135] to

[0137] , within a range of 4.5. .

[0139] The antibody in the antibody-drug conjugate is an anti-GPR20 antibody, as described in

[0122] . Treatment methods listed.

[0140] The anti-GPR20 antibody is the amino acid number 20 to 472 described in SEQ ID NO: 9. A heavy chain consisting of an acid sequence and the amino acids described in SEQ ID NO: 10, amino acid numbers 21 to 234. The therapeutic method described in

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

[0033]

[0141] The anti-GPR20 antibody lacks a lysine residue at the heavy chain carboxyl terminus,

[0140] The treatment methods described.

[0142] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. A treatment method described in any one of the eight ranges, from

[0139] to

[0141] .

[0143] The antibody in the antibody-drug conjugate is an anti-CDH6 antibody, as described in

[0122] . Treatment methods.

[0144] The anti-CDH6 antibody is the amino acid numbered 20 to 471 in SEQ ID NO: 11. A heavy chain consisting of an acid sequence and the amino acids described in SEQ ID NO: 12, amino acid numbers 21 to 233. The therapeutic method described in

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

[0145] The anti-CDH6 antibody lacks a lysine residue at the heavy chain carboxyl terminus,

[0144] The treatment methods described.

[0146] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. A treatment method described in any one of the eight ranges, from

[0143] to

[0145] .

[0147] Tubulin inhibitors include paclitaxel, docetaxel, cabazitaxel, or The treatment method described in any one of paragraphs

[0121] to

[0146] , wherein the pharmacologically acceptable salts thereof, or nab-paclitaxel, are used.

[0148] The treatment method described in

[0147] , wherein the tubulin inhibitor is paclitaxel.

[0149] The tubulin inhibitor is eribulin or a pharmacoacceptable salt thereof, or eribulin An antibody-drug conjugate is formed by linking an antibody to a drug via a linker, from

[0121] The treatment method described in any one of the items in

[0146] .

[0150] The 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. It is characterized by being contained as and administered simultaneously or at different times, from

[0121] A treatment method described in any one of the items in

[0150] .

[0152] Breast cancer, stomach cancer, colorectal cancer, lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, bile duct cancer Cancers of the pelvis, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, and uterine cancer For at least one treatment selected from the group consisting of tumors,

[0121] to

[0151] A treatment method described in any one of the following items.

[0153] Treatment method described in

[0152] for the treatment of breast cancer.

[0154] The treatment method described in

[0152] for the treatment of gastric cancer.

[0155] The treatment method described in

[0152] for the treatment of lung cancer.

[0156] The treatment method described in

[0152] for the treatment of ovarian cancer.

[0157] The decrease in the expression of drug sensitivity factors caused by the administration of antibody-drug conjugates is controlled by tubes. A phosphorus inhibitor is characterized by suppression, as described in any one of items

[0121] to

[0156] . Treatment methods listed.

[0158] The treatment method described in

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

[0159] The increased expression of drug resistance factors caused by the administration of antibody-drug conjugates is addressed by tubulo. The following is characterized by being suppressed by an inhibitor, as described in any one of items

[0121] to

[0156] . Treatment methods.

[0160] The treatment method described in

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

[0161] When administered in combination with tubulin inhibitors, it is used to treat the disease. formula

[0035] [ka]

[0036] (In the formula, A indicates the binding site with the antibody.) An antibody-drug linker, represented by the symbol, is linked to an antibody via a thioether bond. Jugate.

[0162] In antibody-drug conjugates, the antibodies are anti-HER2 antibodies, anti-HER3 antibodies, and anti-TR antibodies. An antibody-drug conjugate as 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, as described in

[0162] . Antibody-drug conjugates.

[0164] The anti-HER2 antibody has the amino acid combination described in SEQ ID NO: 1, from amino acid numbers 1 to 449. Heavy chain consisting of columns and amino acid sequences described in Sequence ID No. 2 for amino acid numbers 1 to 214 The antibody-drug conjugate described in

[0163] is an antibody comprising a light chain consisting of the above.

[0165] The anti-HER2 antibody consists of a heavy chain comprising the amino acid sequence described in SEQ ID NO: 1 and SEQ ID NO: 2 The antibody-drug described in

[0163] is an antibody comprising a light chain consisting of the amino acid sequence shown. Conjugate.

[0166] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. Antibody-drug condyloma described in any one of the eight ranges from

[0163] to

[0165] Gate.

[0167] The antibody in the antibody-drug conjugate is an anti-HER3 antibody, as described in

[0162] . Antibody-drug conjugates.

[0168] The anti-HER3 antibody consists of a heavy chain comprising the amino acid sequence described in SEQ ID NO: 3 and SEQ ID NO: 4. The antibody-drug described in

[0167] is an antibody comprising a light chain consisting of the amino acid sequence shown. Conjugate.

[0169] In the anti-HER3 antibody, the lysine residue at the heavy chain carboxyl terminus is deleted,

[0168] The antibody-drug conjugate described.

[0170] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. The antibody-drug conjugate described in any one of the eight ranges

[0167] to

[0169] gate.

[0037]

[0171] The antibody in the antibody-drug conjugate is an anti-TROP2 antibody, as described in

[0162] . The antibody-drug conjugates listed.

[0172] The anti-TROP2 antibody is the amino acid described in SEQ ID NO: 5, amino acid numbers 20 to 470. A heavy chain consisting of an acid sequence and amino acids listed as amino acid numbers 21 to 234 in SEQ ID NO: 6 An antibody comprising a light chain consisting of an acid sequence, the antibody-drug conjugate described in

[0171] . .

[0173] The anti-TROP2 antibody lacks a lysine residue at the heavy chain carboxyl terminus,

[0172] Antibody-drug conjugate as described above.

[0174] The average number of drug linkers bound per antibody in antibody-drug conjugates is 3.5. The antibody-drug described in any one of items

[0171] to

[0173] , which is in the range of 4.5 from

[0171] to

[0173] . Object conjugate.

[0175] In the antibody-drug conjugate, the antibody is an anti-B7-H3 antibody, as described in

[0162] . The antibody-drug conjugates listed.

[0176] The anti-B7-H3 antibody is the amino acid described in SEQ ID NO: 7, amino acid numbers 20 to 471. A heavy chain consisting of an acid sequence and amino acids listed as amino acid numbers 21 to 233 in SEQ ID NO: 8 An antibody comprising a light chain consisting of an acid sequence, the antibody-drug conjugate described in

[0175] . .

[0177] The anti-B7-H3 antibody lacks a lysine residue at the heavy chain carboxyl terminus,

[0176] Antibody-drug conjugate as described above.

[0178] The average number of drug linkers bound per antibody in antibody-drug conjugates is 3.5. The antibody-drug described in any one of items

[0175] to

[0177] , which is in the range of 4.5 from

[0175] to

[0177] . Object conjugate.

[0179] The antibody in the antibody-drug conjugate is an anti-GPR20 antibody, as described in

[0162] . The antibody-drug conjugates listed.

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

[0179] . The antibody-drug conjugate described in

[0180] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-GPR20 antibody is deleted. The antibody-drug conjugate described in

[0179] , wherein the average number of drug linkers per antibody in the antibody-drug conjugate ranges from 7 to 8. The antibody-drug conjugate described in

[0162] , wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[0038] <00,00881> The anti-CDH6 antibody has a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO: 11 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 12, and is the antibody-drug conjugate described in

[0183] . The antibody-drug conjugate described in

[0184] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.

[0182] The antibody-drug conjugate described in any one of

[0183] to

[0185] , wherein the average number of drug linkers per antibody in the antibody-drug conjugate ranges from 7 to 8. The antibody-drug conjugate described in any one of

[0179] to

[0181] , wherein the average number of drug linkers per antibody in the antibody-drug conjugate ranges from 7 to 8. The antibody-drug conjugate described in

[0183] , wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[0183] The antibody-drug conjugate described in

[0162] , wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody. The antibody-drug conjugate described in

[0183] , wherein the anti-CDH6 antibody has a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO: 11 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 12.

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

[0183] . The anti-CDH6 antibody has a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO: 11 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 12, and is the antibody-drug conjugate described in

[0183] . The anti-CDH6 antibody has a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO: 11 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 12, and is the antibody-drug conjugate described in

[0183] . The antibody-drug conjugate described in

[0183] , wherein the anti-CDH6 antibody has a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO: 11 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 12.

[0185] The antibody-drug conjugate described in

[0184] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted. The antibody-drug conjugate described in

[0184] , wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.

[0186] The antibody-drug conjugate described in any one of

[0183] to

*0185

[0183] to

[0185] , wherein the average number of drug linkers per antibody in the antibody-drug conjugate ranges from 7 to 8. Hugate.

[0187] The tubulin inhibitor is paclitaxel, docetaxel, cabazitaxel, or one of their pharmacologically acceptable salts, or nab-paclitaxel, the antibody-drug conjugate according to any one of

[0161] to

[0186] .

[0188] The tubulin inhibitor is paclitaxel, the antibody-drug conju gate according to

[0187] .

[0189] The tubulin inhibitor is eribulin or its pharmacologically acceptable salt, or an antibody-drug conjugate in which eribulin is conjugated to an antibody via a linker, the antibody-drug conjugate according to any one of

[0161] to

[0186] .

[0190] The tubulin inhibitor is eribulin mesylate, the antibody-drug conjugate according to

[0189] .

[0039]

[0191] The antibody-drug conjugate and the tubulin inhibitor are each contained as an active ingredient in a different formulation and are administered simultaneously or at different times, the antibody-drug conjugate according to any one of

[0161] to

[0190] . The antibody-drug conjugate for the treatment of at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary

[0192] tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, and uterine cancer sarcoma, the antibody-drug conjugate according to any one of

[0161] to

[0191]

[0193] ​​ An antibody-drug conjugate as described in

[0192] for the treatment of breast cancer.

[0194] An antibody-drug conjugate as described in

[0192] for the treatment of gastric cancer.

[0195] An antibody-drug conjugate as described in

[0192] for the treatment of lung cancer.

[0196] An antibody-drug conjugate as described in

[0192] for the treatment of ovarian cancer.

[0197] The decrease in the expression of a drug sensitivity factor caused by the administration of an antibody-drug conjugate is inhibited by a tubulin inhibitor, and the antibody-drug conjugate according to any one of

[0161] to

[0196] . The decrease in the expression of a drug sensitivity factor caused by the administration of an antibody-drug conjugate is inhibited by a tubulin inhibitor, and the antibody-drug conjugate according to any one of

[0161] to

[0196] . The antibody-drug conjugate described in any one of

[0161] to

[0196] .

[0198] The antibody-drug conjugate described in

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

[0199] The increase in the expression of a drug resistance factor caused by the administration of an antibody-drug conjugate is inhibited by a tubulin inhibitor, and the antibody-drug conjugate according to any one of

[0161] to

[0196] . The increase in the expression of a drug resistance factor caused by the administration of an antibody-drug conjugate is inhibited by a tubulin inhibitor, and the antibody-drug conjugate according to any one of

[0161] to

[0196] . 0000963The antibody-drug conjugate described in any one of

[0161] to

[0196] .

[0200] The antibody-drug conjugate described in

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

[0201] When administered in combination with a tubulin inhibitor, for treating a disease, the formula Formula

[0040]

Chemical formula

[0202] In antibody-drug conjugates, the antibodies are anti-HER2 antibodies, anti-HER3 antibodies, and anti-TR antibodies. An antibody-drug conjugate as 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, as described in

[0202] . Antibody-drug conjugates.

[0204] The anti-HER2 antibody has the amino acid combination described in SEQ ID NO: 1, from amino acid numbers 1 to 449. Heavy chain consisting of columns and amino acid sequences described in Sequence ID No. 2 for amino acid numbers 1 to 214 The antibody-drug conjugate described in

[0203] is an antibody comprising a light chain consisting of the above.

[0205] The anti-HER2 antibody consists of a heavy chain comprising the amino acid sequence described in SEQ ID NO: 1 and SEQ ID NO: 2 The antibody-drug described in

[0203] is an antibody comprising a light chain consisting of the amino acid sequence shown. Conjugate.

[0206] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. Antibody-drug condyloma described in any one of the eight ranges from

[0203] to

[0205] Gate.

[0207] The antibody in the antibody-drug conjugate is an anti-HER3 antibody, as described in

[0202] . Antibody-drug conjugates.

[0208] The anti-HER3 antibody consists of a heavy chain comprising the amino acid sequence described in SEQ ID NO: 3 and SEQ ID NO: 4. The antibody-drug described in

[0207] is an antibody comprising a light chain consisting of the amino acid sequence shown. Conjugate.

[0209] The anti-HER3 antibody has a deletion of the lysine residue at the heavy chain carboxyl terminus,

[0208] The antibody-drug conjugate described.

[0210] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. The antibody-drug conjugate described in any one of the eight ranges

[0207] to

[0209] gate.

[0042]

[0211] In the antibody-drug conjugate, the antibody is an anti-TROP2 antibody, as described in

[0202] . The antibody-drug conjugates listed.

[0212] The anti-TROP2 antibody is the amino acid described in SEQ ID NO: 5, amino acid numbers 20 to 470. A heavy chain consisting of an acid sequence and amino acids listed as amino acid numbers 21 to 234 in SEQ ID NO: 6 An antibody comprising a light chain consisting of an acid sequence, the antibody-drug conjugate described in

[0211] . .

[0213] The anti-TROP2 antibody lacks a lysine residue at the heavy chain carboxyl terminus,

[0212] Antibody-drug conjugate as described above.

[0214] The average number of drug linkers bound per antibody in antibody-drug conjugates is 3.5. The antibody-drug described in any one of the items

[0211] to

[0213] , which is in the range of 4.5 from

[0211] to

[0213] . Object conjugate.

[0215] In the antibody-drug conjugate, the antibody is an anti-B7-H3 antibody, as described in

[0202] . The antibody-drug conjugates listed.

[0216] The anti-B7-H3 antibody is the amino acid described in SEQ ID NO: 7, amino acid numbers 20 to 471. A heavy chain consisting of an acid sequence and amino acids listed as amino acid numbers 21 to 233 in SEQ ID NO: 8 An antibody comprising a light chain consisting of an acid sequence, as described in

[0215] , an antibody-drug conjugate. .

[0217] The anti-B7-H3 antibody lacks a lysine residue at the heavy chain carboxyl terminus,

[0216] Antibody-drug conjugate as described above.

[0218] The average number of drug linkers bound per antibody in antibody-drug conjugates is 3.5. The antibody-drug described in any one of the items

[0215] to

[0217] , which is in the range of 4.5 from

[0215] to

[0217] . Object conjugate.

[0219] In the antibody-drug conjugate, the antibody is an anti-GPR20 antibody, as described in

[0202] . The antibody-drug conjugates listed.

[0220] The anti-GPR20 antibody is the amino acid number 20 to 472 described in SEQ ID NO: 9. A heavy chain consisting of an acid sequence and the amino acids described in SEQ ID NO: 10, amino acid numbers 21 to 234. An antibody comprising a light chain consisting of an acid sequence, the antibody-drug conjugate described in

[0219] gate.

[0043]

[0221] The anti-GPR20 antibody lacks a lysine residue at the heavy chain carboxyl terminus,

[0220] Antibody-drug conjugate as described above.

[0222] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. Antibody-drug condyloma described in any one of the eight ranges from

[0219] to

[0221] Gate.

[0223] The antibody in the antibody-drug conjugate is an anti-CDH6 antibody, as described in

[0202] . Antibody-drug conjugates.

[0224] The anti-CDH6 antibody is the amino acid numbered 20 to 471 in SEQ ID NO: 11. A heavy chain consisting of an acid sequence and the amino acids described in SEQ ID NO: 12, amino acid numbers 21 to 233. An antibody comprising a light chain consisting of an acid sequence, the antibody-drug conjugate described in

[0223] gate.

[0225] The anti-CDH6 antibody lacks a lysine residue at the heavy chain carboxyl terminus,

[0224] The antibody-drug conjugate described.

[0226] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. Antibody-drug condyloma described in any one of the eight ranges from

[0223] to

[0225] Gate.

[0227] Tubulin inhibitors include paclitaxel, docetaxel, cabazitaxel, or The antibody-drug conjugate described in any one of the items

[0201] to

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

[0228] The tubulin inhibitor is paclitaxel, as described in

[0227] for antibody-drug condyloma. Gate.

[0229] The tubulin inhibitor is eribulin or a pharmacoacceptable salt thereof, or eribulin This is an antibody-drug conjugate in which an antibody and an antibody are linked via a linker, from

[0201] An antibody-drug conjugate as described in any one of the items in

[0226] .

[0230] The tubulin inhibitor is eribulin mesylate, as described in

[0229] . Conjugate.

[0044]

[0231] Antibody-drug conjugates and tubulin inhibitors are active ingredients in different formulations. It is characterized by being contained as and administered simultaneously or at different times, from

[0201] An antibody-drug conjugate as described in any one of the items in

[0230] .

[0232] Breast cancer, stomach cancer, colorectal cancer, lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, bile duct cancer Cancers of the pelvis, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, and uterine cancer For at least one treatment selected from the group consisting of tumors,

[0201] to

[0231] An antibody-drug conjugate as described in any one of the items.

[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 the expression of drug sensitivity factors caused by the administration of antibody-drug conjugates is controlled by tubes. A phosphorus inhibitor is characterized by suppression, as described in any one of items

[0201] to

[0236] . The antibody-drug conjugates listed.

[0238] The antibody-drug conjugate described in

[0237] has SLFN11 as the drug sensitivity factor. .

[0239] The increased expression of drug resistance factors caused by the administration of antibody-drug conjugates is addressed by tubulo. The characteristic is that the inhibitor suppresses it, as described in any one of items

[0201] to

[0236] . Antibody-drug conjugates.

[0240] The antibody-drug conjugate described in

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

[0241] When administered in combination with tubulin inhibitors, it is used to treat the disease. For the manufacture of pharmaceuticals formula

[0045] [ka]

[0046] (In the formula, A indicates the binding site with the antibody.) An antibody-drug linker, represented by the symbol, is linked to an antibody via a thioether bond. Use of Jugate.

[0242] In antibody-drug conjugates, the antibodies are anti-HER2 antibodies, anti-HER3 antibodies, and anti-TR antibodies. Use as described in

[0241] , which is OP2 antibody, anti-B7-H3 antibody, anti-GPR20 antibody, or anti-CDH6 antibody.

[0243] The antibody in the antibody-drug conjugate is an anti-HER2 antibody, as described in

[0242] . Use.

[0244] The anti-HER2 antibody has the amino acid combination described in SEQ ID NO: 1, from amino acid numbers 1 to 449. Heavy chain consisting of columns and amino acid sequences described in Sequence ID No. 2 for amino acid numbers 1 to 214 The antibody comprises a light chain consisting of the following, as described in

[0243] .

[0245] The anti-HER2 antibody consists of a heavy chain comprising the amino acid sequence described in SEQ ID NO: 1 and SEQ ID NO: 2 The antibody comprises a light chain consisting of the amino acid sequence described, as used in

[0243] .

[0246] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. Use as described in any one of the eight ranges, from

[0243] to

[0245] .

[0247] The antibody in the antibody-drug conjugate is an anti-HER3 antibody, as described in

[0242] . Use.

[0248] The anti-HER3 antibody consists of a heavy chain comprising the amino acid sequence described in SEQ ID NO: 3 and SEQ ID NO: 4. The antibody comprises a light chain consisting of the amino acid sequence described, as used in

[0247] .

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

[0248] Use as described.

[0250] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. Use as described in any one of the eight ranges,

[0247] to

[0249] .

[0047]

[0251] In the antibody-drug conjugate, the antibody is an anti-TROP2 antibody, as described in

[0242] . Use on a vehicle.

[0252] The anti-TROP2 antibody is the amino acid described in SEQ ID NO: 5, amino acid numbers 20 to 470. A heavy chain consisting of an acid sequence and amino acids listed as amino acid numbers 21 to 234 in SEQ ID NO: 6 The antibody comprises a light chain consisting of an acid sequence, as described in

[0251] .

[0253] The anti-TROP2 antibody lacks a lysine residue at the heavy chain carboxyl terminus,

[0252] Use as described above.

[0254] The average number of drug linkers bound per antibody in antibody-drug conjugates is 3.5. Uses described in any one of items

[0251] to

[0253] , within the range of 4.5.

[0255] In the antibody-drug conjugate, the antibody is an anti-B7-H3 antibody, as described in

[0242] . Use on a vehicle.

[0256] The anti-B7-H3 antibody is the amino acid described in SEQ ID NO: 7, amino acid numbers 20 to 471. A heavy chain consisting of an acid sequence and amino acids listed as amino acid numbers 21 to 233 in SEQ ID NO: 8 The antibody comprises a light chain consisting of an acid sequence, as described in

[0255] .

[0257] The anti-B7-H3 antibody lacks a lysine residue at the heavy chain carboxyl terminus,

[0256] Use as described above.

[0258] The average number of drug linkers bound per antibody in antibody-drug conjugates is 3.5. Uses described in any one of items

[0255] to

[0257] , within the range of 4.5.

[0259] The antibody in the antibody-drug conjugate is an anti-GPR20 antibody, as described in

[0242] . Use on a vehicle.

[0260] The anti-GPR20 antibody is the amino acid number 20 to 472 described in SEQ ID NO: 9. A heavy chain consisting of an acid sequence and the amino acids described in SEQ ID NO: 10, amino acid numbers 21 to 234. The antibody comprises a light chain consisting of an acid sequence, as described in

[0259] .

[0048]

[0261] The anti-GPR20 antibody lacks a lysine residue at the heavy chain carboxyl terminus,

[0260] Use as described above.

[0262] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. Use as described in any one of the eight ranges, from

[0259] to

[0261] .

[0263] The antibody in the antibody-drug conjugate is an anti-CDH6 antibody, as described in

[0242] . Use.

[0264] The anti-CDH6 antibody is the amino acid numbered 20 to 471 in SEQ ID NO: 11. A heavy chain consisting of an acid sequence and the amino acids described in SEQ ID NO: 12, amino acid numbers 21 to 233. The antibody comprises a light chain consisting of an acid sequence, as described in

[0263] .

[0265] The anti-CDH6 antibody lacks a lysine residue at the heavy chain carboxyl terminus,

[0264] Use as described.

[0266] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. Use as described in any one of the eight ranges, from

[0263] to

[0265] .

[0267] Tubulin inhibitors include paclitaxel, docetaxel, cabazitaxel, or The use of any one of the pharmacoposly acceptable salts thereof, or nab-paclitaxel, as described in any one of paragraphs

[0241] to

[0266] .

[0268] The use described in

[0267] , where the tubulin inhibitor is paclitaxel.

[0269] The tubulin inhibitor is eribulin or a pharmacoacceptable salt thereof, or eribulin This is an antibody-drug conjugate in which an antibody is linked to an antibody via a linker, from

[0241] Use as described in any one of the items in

[0266] .

[0270] The use described in

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

[0049]

[0271] Antibody-drug conjugates and tubulin inhibitors are active ingredients in different formulations. It is characterized by being contained as and administered simultaneously or at different times, from

[0241] Use as described in any one of the items in

[0270] .

[0272] Breast cancer, stomach cancer, colorectal cancer, lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, bile duct cancer Cancers of the pelvis, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, and uterine cancer For at least one treatment selected from the group consisting of tumors,

[0241] to

[0271] Use as described in any one of the items.

[0273] Use as described in

[0272] for the treatment of breast cancer.

[0274] Use as described in

[0272] for the treatment of gastric cancer.

[0275] Use as described in

[0272] for the treatment of lung cancer.

[0276] Use as described in

[0272] for the treatment of ovarian cancer.

[0277] The decrease in the expression of drug sensitivity factors caused by the administration of antibody-drug conjugates is controlled by tubes. A phosphorus inhibitor is characterized by suppression, as described in any one of items

[0241] to

[0276] . Use on a vehicle.

[0278] Use as described in

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

[0279] The increased expression of drug resistance factors caused by the administration of antibody-drug conjugates is addressed by tubulo. The characteristic is that the inhibitor suppresses it, as described in any one of items

[0241] to

[0276] . Use.

[0280] Use as described in

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

[0281] When administered in combination with tubulin inhibitors, it is used to treat the disease. For the manufacture of pharmaceuticals formula

[0050] [ka]

[0051] (In the formula, the drug linker is bound to the antibody by a thioether bond, and n is per antibody) (This shows the average number of linkers in each drug.) Use of antibody-drug conjugates as indicated.

[0282] In antibody-drug conjugates, the antibodies are anti-HER2 antibodies, anti-HER3 antibodies, and anti-TR antibodies. Use as described in

[0281] , which is OP2 antibody, anti-B7-H3 antibody, anti-GPR20 antibody, or anti-CDH6 antibody.

[0283] The antibody in the antibody-drug conjugate is an anti-HER2 antibody, as described in

[0282] . Use.

[0284] The anti-HER2 antibody has the amino acid combination described in SEQ ID NO: 1, from amino acid numbers 1 to 449. Heavy chain consisting of columns and amino acid sequences described in Sequence ID No. 2 for amino acid numbers 1 to 214 The antibody comprises a light chain consisting of the following, as described in

[0283] .

[0285] The anti-HER2 antibody consists of a heavy chain comprising the amino acid sequence described in SEQ ID NO: 1 and SEQ ID NO: 2 The antibody comprises a light chain consisting of the amino acid sequence described, as used in

[0283] .

[0286] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. Use as described in any one of the eight ranges, from

[0283] to

[0285] .

[0287] The antibody in the antibody-drug conjugate is an anti-HER3 antibody, as described in

[0282] . Use.

[0288] The anti-HER3 antibody consists of a heavy chain comprising the amino acid sequence described in SEQ ID NO: 3 and SEQ ID NO: 4. The antibody comprises a light chain consisting of the amino acid sequence described, as used in

[0287] .

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

[0288] Use as described.

[0290] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. Use as described in any one of the eight ranges,

[0287] to

[0289] .

[0052]

[0291] In the antibody-drug conjugate, the antibody is an anti-TROP2 antibody, as described in

[0282] . Use on a vehicle.

[0292] The anti-TROP2 antibody is the amino acid described in SEQ ID NO: 5, amino acid numbers 20 to 470. A heavy chain consisting of an acid sequence and amino acids listed as amino acid numbers 21 to 234 in SEQ ID NO: 6 The antibody comprises a light chain consisting of an acid sequence, as described in

[0291] .

[0293] The anti-TROP2 antibody lacks a lysine residue at the heavy chain carboxyl terminus,

[0292] Use as described above.

[0294] The average number of drug linkers bound per antibody in antibody-drug conjugates is 3.5. Uses described in any one of items

[0291] to

[0293] , within the range of 4.5.

[0295] In the antibody-drug conjugate, the antibody is an anti-B7-H3 antibody, as described in

[0282] . Use on a vehicle.

[0296] The anti-B7-H3 antibody is the amino acid described in SEQ ID NO: 7, amino acid numbers 20 to 471. A heavy chain consisting of an acid sequence and amino acids listed as amino acid numbers 21 to 233 in SEQ ID NO: 8 The antibody comprises a light chain consisting of an acid sequence, as described in

[0295] .

[0297] The anti-B7-H3 antibody lacks a lysine residue at the heavy chain carboxyl terminus,

[0296] Use as described above.

[0298] The average number of drug linkers bound per antibody in antibody-drug conjugates is 3.5. Uses described in any one of items

[0295] to

[0297] , within the range of 4.5.

[0299] The antibody in the antibody-drug conjugate is an anti-GPR20 antibody, as described in

[0282] . Use on a vehicle.

[0300] The anti-GPR20 antibody is the amino acid number 20 to 472 described in SEQ ID NO: 9. A heavy chain consisting of an acid sequence and the amino acids described in SEQ ID NO: 10, amino acid numbers 21 to 234. The antibody comprises a light chain consisting of an acid sequence, as described in

[0299] .

[0053]

[0301] The anti-GPR20 antibody lacks a lysine residue at the heavy chain carboxyl terminus,

[0300] Use as described above.

[0302] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. Use as described in any one of the eight ranges, from

[0299] to

[0301] .

[0303] The antibody in the antibody-drug conjugate is an anti-CDH6 antibody, as described in

[0282] . Use.

[0304] The anti-CDH6 antibody is the amino acid numbered 20 to 471 in SEQ ID NO: 11. A heavy chain consisting of an acid sequence and the amino acids described in SEQ ID NO: 12, amino acid numbers 21 to 233. The antibody comprises a light chain consisting of an acid sequence, as described in

[0303] .

[0305] The anti-CDH6 antibody lacks a lysine residue at the heavy chain carboxyl terminus,

[0304] Use as described.

[0306] The average number of drug linkers bound per antibody in antibody-drug conjugates is 7. Use as described in any one of the eight ranges, from

[0303] to

[0305] .

[0307] Tubulin inhibitors include paclitaxel, docetaxel, cabazitaxel, or The use of any one of the pharmacoposly acceptable salts thereof, or nab-paclitaxel, as described in any one of paragraphs

[0281] to

[0306] .

[0308] The use described in

[0307] , where the tubulin inhibitor is paclitaxel.

[0309] The tubulin inhibitor is eribulin or a pharmacoacceptable salt thereof, or eribulin This is an antibody-drug conjugate in which an antibody is linked to an antibody via a linker, from

[0281] Use as described in any one of the items in

[0306] .

[0310] The use described in

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

[0054]

[0311] Antibody-drug conjugates and tubulin inhibitors are active ingredients in different formulations. It is characterized by being contained as and administered simultaneously or at different times, from

[0281] Use as described in any one of the items in

[0310] .

[0312] Breast cancer, stomach cancer, colorectal cancer, lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, bile duct cancer Cancers of the pelvis, Paget's disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, and uterine cancer For at least one treatment selected from the group consisting of tumors,

[0281] to

[0311] Use as described in any one of the items.

[0313] Use as described in

[0312] for the treatment of breast cancer.

[0314] Use as described in

[0312] for the treatment of gastric cancer.

[0315] Use as described in

[0312] for the treatment of lung cancer.

[0316] Use as described in

[0312] for the treatment of ovarian cancer.

[0317] The decrease in the expression of drug sensitivity factors caused by the administration of antibody-drug conjugates is controlled by tubes. A phosphorus inhibitor is characterized by suppression, as described in any one of items

[0281] to

[0316] . Use on a vehicle.

[0318] Use as described in

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

[0319] The increased expression of drug resistance factors caused by the administration of antibody-drug conjugates is addressed by tubulo. The characteristic is that the inhibitor suppresses it, as described in any one of items

[0281] to

[0316] . Use.

[0320] Use as described in

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

[0055]

[0321] The combination of an antibody-drug conjugate and a tubulin inhibitor is administered. A pharmaceutical composition characterized by, 1) The decrease in the expression of drug sensitivity factors caused by the administration of the antibody-drug conjugate, The suppression by a bubrin inhibitor, and / or 2) The increased expression of drug resistance factors caused by the administration of the antibody-drug conjugate, - Suppression by brin inhibitors, A pharmaceutical composition characterized by the following.

[0322] The pharmaceutical composition described in

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

[0323] The pharmaceutical composition according to

[0321] or

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

[0324] A pharmaceutical composition according to any one of claims

[0321] to

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

[0325] Antibody-drug conjugates are,

[0056] [ka]

[0057] (In the formula, A indicates the binding site with the antibody.) An antibody-drug linker, represented by the symbol, is linked to an antibody via a thioether bond. A pharmaceutical composition that is a jugate, as described in any one of items

[0321] to

[0323] .

[0326] Antibody-drug conjugates are,

[0058] [ka]

[0059] (In the formula, the drug linker is bound to the antibody by a thioether bond, and n is per antibody) (This shows the average number of linkers in each drug.) The antibody-drug conjugate shown is one of the following items from

[0321] to

[0323] . The pharmaceutical composition described above.

[0327] Antibody-drug conjugates and tubulin inhibitors are used in combination to treat conditions requiring treatment. A treatment method characterized by being administered to an individual, 1) The decrease in the expression of drug sensitivity factors caused by the administration of the antibody-drug conjugate, The suppression by a bubrin inhibitor, and / or 2) The increased expression of drug resistance factors caused by the administration of the antibody-drug conjugate, - Suppression by brin inhibitors, A treatment method characterized by the following.

[0328] The treatment method described in

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

[0329] The treatment method described in

[0327] or

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

[0330] A therapeutic method according to any one of items

[0327] to

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

[0331] Antibody-drug conjugates are,

[0060] [ka]

[0061] (In the formula, A indicates the binding site with the antibody.) An antibody-drug linker, represented by the symbol, is linked to an antibody via a thioether bond. A treatment method described in any one of the items

[0327] to

[0329] , which is a jugate.

[0332] Antibody-drug conjugates are,

[0062] [ka]

[0063] (In the formula, the drug linker is bound to the antibody by a thioether bond, and n is per antibody) (This shows the average number of linkers in each drug.) The antibody-drug conjugate shown is one of the items from

[0327] to

[0329] . The treatment methods described.

[0333] When administered in combination with tubulin inhibitors, it is used to treat the disease. Antibody-drug conjugate, 1) The decrease in the expression of drug sensitivity factors caused by the administration of the antibody-drug conjugate, The suppression by a bubrin inhibitor, and / or 2) The increased expression of drug resistance factors caused by the administration of the antibody-drug conjugate, - Suppression by brin inhibitors, An antibody-drug conjugate characterized by the following:

[0334] The antibody-drug conjugate described in

[0333] has SLFN11 as the drug sensitivity factor. .

[0335] The antibody-drug compound described in

[0333] or

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

[0336] An antibody-drug conjugate according to any one of items

[0333] to

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

[0337] Antibody-drug conjugates are,

[0064] [ka]

[0065] (In the formula, A indicates the binding site with the antibody.) An antibody-drug linker, represented by the symbol, is linked to an antibody via a thioether bond. Jugate, an antibody-drug condyloma described in any one of items

[0333] to

[0335] . Gate.

[0338] Antibody-drug conjugates are,

[0066] [ka]

[0067] (In the formula, the drug linker is bound to the antibody by a thioether bond, and n is per antibody) (This shows the average number of linkers in each drug.) The antibody-drug conjugate shown is one of the following items from

[0333] to

[0335] . Antibody-drug conjugate as described above.

[0339] When administered in combination with tubulin inhibitors, it is used to treat the disease. The use of antibody-drug conjugates for the manufacture of pharmaceuticals, 1) The decrease in the expression of drug sensitivity factors caused by the administration of the antibody-drug conjugate, The suppression by a bubrin inhibitor, and / or 2) The increased expression of drug resistance factors caused by the administration of the antibody-drug conjugate, - Suppression by brin inhibitors, Features, usage.

[0340] Use as described in

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

[0341] Use as described in

[0339] or

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

[0342] The use described in any one of items

[0339] to

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

[0343] Antibody-drug conjugates are,

[0068] [ka]

[0069] (In the formula, A indicates the binding site with the antibody.) An antibody-drug linker, represented by the symbol, is linked to an antibody via a thioether bond. The use of a jugate as described in any one of items

[0339] to

[0341] .

[0344] Antibody-drug conjugates are,

[0070] [ka]

[0071] (In the formula, the drug linker is bound to the antibody by a thioether bond, and n is per antibody) (This shows the average number of linkers in each drug.) The antibody-drug conjugate shown is one of the following items from

[0339] to

[0341] . Use as described above. [Effects of the Invention]

[0072] The present invention provides a combination of a specific antibody-drug conjugate and a tubulin inhibitor. A pharmaceutical composition and / or a specific antibody-drug conjugate characterized by being administered via a specific method. A treatment method characterized by the administration of a combination of a gate and a tubulin inhibitor to the individual. We can provide the law. [Brief explanation of the drawing]

[0073] [Figure 1] This figure shows the amino acid sequence (SEQ ID NO: 1) of the anti-HER2 antibody heavy chain. [Figure 2] This figure shows the amino acid sequence (SEQ ID NO: 2) of the anti-HER2 antibody light chain. [Figure 3] This figure shows the amino acid sequence (SEQ ID NO: 3) of the anti-HER3 antibody heavy chain. [Figure 4] This figure shows the amino acid sequence of the anti-HER3 antibody light chain (SEQ ID NO: 4). [Figure 5] This figure shows the amino acid sequence (SEQ ID NO: 5) of the anti-TROP2 antibody heavy chain. [Figure 6] This figure shows the amino acid sequence (SEQ ID NO: 6) of the light chain of the anti-TROP2 antibody. [Figure 7] This figure shows the amino acid sequence (SEQ ID NO: 7) of the anti-B7-H3 antibody heavy chain. [Figure 8] This figure shows the amino acid sequence (SEQ ID NO: 8) of the light chain of the anti-B7-H3 antibody. [Figure 9] This figure shows the tumor growth inhibitory effects of antibody-drug conjugate (1), paclitaxel, and combination therapy (antibody-drug conjugate (1) and paclitaxel) in mice subcutaneously transplanted with KPL-4 cells. [Figure 10] This figure shows the tumor growth inhibitory effects of antibody-drug conjugate (1) and eribulin mesylate monotherapy, as well as the combined administration of antibody-drug conjugate (1) and eribulin mesylate, in mice subcutaneously transplanted with KPL-4 cells. [Figure 11] This figure shows the tumor growth inhibitory effects of antibody-drug conjugate (1), Paclitaxel, and combination therapy (antibody-drug conjugate (1) and Paclitaxel) in mice subcutaneously transplanted with JIMT-1 cells. [Figure 12]This figure shows the tumor growth inhibitory effects of antibody-drug conjugate (1) and eribulin mesylate monotherapy, as well as the combined administration of antibody-drug conjugate (1) and eribulin mesylate, in mice subcutaneously transplanted with JIMT-1 cells. [Figure 13] This figure shows the tumor growth inhibitory effects of antibody-drug conjugate (1), paclitaxel, and combination therapy of antibody-drug conjugate (1) and paclitaxel in mice subcutaneously transplanted with NCI-N87 cells. [Figure 14] This figure shows the tumor growth inhibitory effects of antibody-drug conjugate (1) and eribulin mesylate monotherapy, as well as the combined administration of antibody-drug conjugate (1) and eribulin mesylate, in mice subcutaneously transplanted with NCI-N87 cells. [Figure 15] This figure shows the tumor growth inhibitory effects of antibody-drug conjugate (1), paclitaxel, and combination therapy (antibody-drug conjugate (1) and paclitaxel) in mice subcutaneously transplanted with MDA-MB-453 cells. [Figure 16] This figure shows the tumor growth inhibitory effects of antibody-drug conjugate (1), paclitaxel, and combination therapy (antibody-drug conjugate (1) and paclitaxel) in mice subcutaneously transplanted with SNU-1 cells. [Figure 17] This figure shows the tumor growth inhibitory effects of antibody-drug conjugate (1), paclitaxel, and combination therapy (antibody-drug conjugate (1) and paclitaxel) in mice subcutaneously transplanted with NCI-H441 cells. [Figure 18] This figure shows the amino acid sequence (SEQ ID NO: 9) of the anti-GPR20 antibody heavy chain. [Figure 19] This figure shows the amino acid sequence of the anti-GPR20 antibody light chain (SEQ ID NO: 10). [Figure 20]This figure shows the amino acid sequence of the anti-CDH6 antibody heavy chain (SEQ ID NO: 11). [Figure 21] This figure 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 antibody-drug conjugate (2), Paclitaxel, and combination therapy (antibody-drug conjugate (2) and Paclitaxel) in mice subcutaneously transplanted with JIMT-1 cells. [Figure 23] This figure shows the tumor growth inhibitory effects of antibody-drug conjugate (3), paclitaxel, and combination therapy (antibody-drug conjugate (3) and paclitaxel) in mice subcutaneously transplanted with OV-90 cells. [Modes for carrying out the invention]

[0074] The following describes preferred embodiments for carrying out the present invention. The embodiment shown is an example of a typical embodiment of the present invention, and by this, the present invention The scope will not be interpreted narrowly.

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

[0076] [ka]

[0077] (In the formula, A indicates the binding site with the antibody.) The antibody-drug linker, shown as indicated, is linked to the antibody by a thioether bond. It is a denjugate.

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

[0079] The drug linker of the present invention is exatecan (IUPAC), a topoisomerase I inhibitor. Name: (1S,9S)-1-amino-9-ethyl-5-fluoro-1,2,3,9,12, 15-Hexahydro-9-hydroxy-4-methyl-10H,13H-benzo[de]p Lano[3',4':6,7]Indrizino[1,2-b]Quinoline-10,13-Zion (Chemical name: (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydr Ro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4': 6,7]Indrizino[1,2-b]Quinoline-10,13(9H,15H)-Zione It can also be expressed as ()) and has as its constituent elements. Exatecan is formula

[0080] [ka]

[0081] It is a camptothecin derivative having antitumor effects, as shown in [the formula].

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

[0083] [ka]

[0084] Here, the drug linker is bound to the antibody by a thioether bond. Also, n is The so-called average drug-to-antibody ratio (DAR) and These terms are synonymous and indicate the average number of drug linkers bound per antibody.

[0085] The antibody-drug conjugate used in this invention is transferred into cancer cells and then linked by a linker. The part was cut off, formula

[0086] [ka]

[0087] The compound represented by [formula] is released.

[0088] The above compound is the main component of the antitumor activity of the antibody-drug conjugate used in the present invention. It is thought that this is the case, and it has been confirmed that it has topoisomerase I inhibitory activity (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, thereby modifying the higher-order structure of DNA. It is an enzyme that transforms DNA and is involved in DNA synthesis. Therefore, topoisomerase I inhibitory activity The drug inhibits DNA synthesis, thereby affecting the S phase (DNA synthesis phase) of the cell cycle. By stopping cell division and inducing apoptosis (programmed cell death), cancer cells proliferate. It can be suppressed.

[0090] On the other hand, tubulin inhibitors affect microtubule dynamics, thereby influencing the circumcellular environment. Cell division is stopped during the G2 phase (preparatory phase) and / or M phase (mitotic phase), and apoptosis By inducing cell death through stimulants, the proliferation of cancer cells can be suppressed (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 used in the present invention (topoisomerase I inhibitory activity) Drugs that possess the properties of the antitumor agent are administered in combination with tubulin inhibitors. This allows for complex cell division during the S phase, G2 phase, and / or M phase of the cell cycle. Because it can stop the growth, it can exhibit excellent combined effects (antitumor effects).

[0092] Furthermore, the antibody-drug conjugate used in this invention has a bystander effect. It is also known that (Ogitani Y. et al., Cancer Science (2016) 107, 1039-1046).

[0093] This bystander effect occurs when the antibody-drug conjugate used in the present invention targets the target After being internalized in existing cancer cells, the above compound is released and targets nearby cancer cells that do not express the target. This effect is exerted by also exerting an antitumor effect on cysts.

[0094] This bystander effect is due to the antibody-drug conjugate according to the present invention being tubular Even when used in combination with antitumor inhibitors, it exhibits excellent antitumor effects. .

[0095] 2. Antibodies in antibody-drug conjugates The antibody in the antibody-drug conjugate used in this invention is derived from any species. Antibodies derived from humans, rats, mice, and rabbits are also acceptable, but preferably they are antibodies derived from humans, rats, mice, and rabbits. If the organism originates from a species other than human, it is preferable to use known techniques to create a chimera or human form. It is clear. The antibody of the present invention is a polyclonal antibody, or a monoclonal antibody. While other types are also acceptable, monoclonal antibodies are preferred.

[0096] The antibody in the antibody-drug conjugate used in the present invention preferably targets cancer cells. It possesses properties that allow it to target cancer cells, including the ability to recognize cancer cells and bind to them. Characteristics, characteristics of being taken up and internalized within cancer cells, and / or cytotoxic activity against cancer cells It is preferable that the product has properties such as [specific characteristics].

[0097] The binding ability of antibodies to cancer cells can be confirmed using flow cytometry. Antibody uptake is achieved by (1) using a secondary antibody (fluorescently labeled) that binds to the therapeutic antibody within the cell. An assay that visualizes antibodies incorporated into the body using a fluorescence microscope (Cell Death and Differential Analysis). (2008) 15, 751-761), (2) Using a secondary antibody (fluorescently labeled) that binds to the therapeutic antibody to further refine the treatment. Assay to measure the amount of fluorescence taken up into cells (Molecular Biology of the Cell Vol. 1) (5, 5268-5282, December 2004), or (3) using an immunotoxin that binds to the therapeutic antibody When taken into cells, Mab-ZA releases toxins that inhibit cell proliferation. This can be confirmed using a P assay (Bio Techniques 28:162-165, January 2000). The xin is a recombinant complex protein of the catalytic domain of diphtheria toxin and protein G. White matter can also be used.

[0098] The antitumor activity of an antibody can be measured in vitro by its inhibitory activity on cell proliferation. It can be confirmed. For example, by culturing cancer cell lines that overexpress antibody target proteins, the culture system Antibodies were added at various concentrations to induce focus formation, colony formation, and spheroid proliferation. The inhibitory activity can be measured. In vivo, for example, it can be used to increase the activity of target proteins. Nude mice transplanted with the cancer cell line in question were given antibodies, and changes in the cancer cells were measured. By doing so, antitumor activity can be confirmed.

[0099] While it is desirable for the antibody itself to have an antitumor effect, antibody-drug conjugates are not antitumor. Since the antibody has been conjugated with a compound that exerts an antitumor effect, the antitumor effect of the antibody itself is not essential. The purpose is to specifically and selectively exert the cytotoxic effects of antitumor compounds on cancer cells. It is important and desirable that the antibody has the property of being internalized and migrated into cancer cells.

[0100] The antibody in the antibody-drug conjugate used in the present invention is obtained by known means. It can be obtained. For example, using methods commonly practiced in this field, the antigenic polymer This can be obtained by immunizing animals with peptides, collecting the antibodies produced in the body, and purifying them. This is possible. The antigen is not limited to human origin, but can also be derived from non-human animals such as mice and rats. It is also possible to immunize animals with the antigen that was obtained. In this case, the antigen binds to the acquired heterologous antigen. By testing the cross-reactivity between antibodies and human antigens, antibodies applicable to human diseases can be selected. can.

[0101] Also, known methods (e.g., Kohler and Milstein, Nature (1975) 256, p.495-497; K ennet, R. ed., Monoclonal Antibodies, p.365-367, Plenum Press, NY (1980)). This involves fusing antibody-producing cells, which produce antibodies against an antigen, with myeloma cells. Therefore, hybridomas can be established and monoclonal antibodies can be obtained.

[0102] Furthermore, antigens are produced in host cells by genetically modifying the genes that code for the antigen protein. This can be obtained by creating a vector capable of expressing the antigen gene. Then, this can be introduced into host cells to express the gene, and the expressed antigen can be purified. The following genetically modified antigen-expressing cells, or cell lines expressing the antigen, are used to immunize animals. Antibodies can also be obtained by using certain methods.

[0103] The antibody in the antibody-drug conjugate used in this invention is a heterologous antigen against humans. Genetically modified recombinant antibodies intended to reduce sexual properties, for example, It is preferable that the antibody be a chimeric antibody or a humanized antibody. Alternatively, it is preferable that the antibody has only the gene sequence of a human-derived antibody, i.e., a human antibody. These antibodies can be produced using known methods.

[0104] Chimeric antibodies are antibodies in which the variable region and constant region are heterogeneous, for example, mau Examples include chimeric antibodies in which the variable region of a rat-derived antibody is conjugated to a human-derived constant region. This is possible (Proc. Natl. Acad. Sci. USA, 81, 6851-6855, (1984)).

[0105] Humanized antibodies include heterologous antibody complementarity-determining regions (CDRs). Antibodies incorporating only the ity determining region into human-derived antibodies (Nature (1986) 321, p.522-525), the sequence of the CDR of a heterologous antibody was obtained by CDR transplantation. In addition, some amino acid residues of the framework of heterologous antibodies were also transplanted into human antibodies. International Publication No. 90 / 07861), gene conversion mutagenesis (U.S. 5) Humanized antibodies using the ion mutagenesis strategy (No. 821337) can be cited.

[0106] Human antibodies are human antibodies that possess human chromosome fragments containing the genes for the heavy and light chains of human antibodies. Antibodies produced 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, pp. 722-727, etc. This can be cited as an example. Alternatively, phage displays selected from a human antibody library. Antibodies obtained by (I) (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 See halmology (2002) 109(3), pp. 427-431, etc. ) can also be cited.

[0107] The antibody in the antibody-drug conjugate used in this invention also includes modified antibodies. The modified product is an antibody according to the present invention that has been chemically or biologically modified. This means that. Chemically modified organisms include the attachment of a chemical moiety to the amino acid backbone, N-bonds, or O -Includes chemically modified compounds that have a chemical moiety attached to a linked carbohydrate chain. Biological modifications The body undergoes post-translational modifications (e.g., addition of N-linked or O-linked sugar chains, N-terminal or C-terminal modifications). (Processing, deamidation, isomerization of aspartic acid, oxidation of methionine, etc.) By expressing it using prokaryotic host cells, a methionine residue is added to the N-terminus. This includes things like that. Furthermore, in order to enable the detection or isolation of antibodies or antigens according to the present invention Labeled compounds, such as enzyme-labeled, fluorescently labeled, and affinity-labeled compounds, are also subject to such modifications. It is included in the meaning of body. Such modified antibodies according to the present invention have improved antibody stability and blood retention. It is useful for improving sexual properties, reducing antigenicity, and detecting or isolating antibodies or antigens.

[0108] Furthermore, the glycosylation and deglycosylation of the glycosylation chains attached to the antibody according to the present invention can be controlled. Antibody-dependent cell-mediated cytotoxicity can be enhanced by coagulation, etc. For techniques of regulating chain modification, see International Publication No. 99 / 54342 and International Publication No. 00 / 6173. Publication No. 9, International Publication No. 02 / 31140, International Publication No. 2007 / 133855, and International Publication No. 2013 / 120066 is known, but this is not an exhaustive list. The antibodies according to the present invention also include antibodies in which the glycosylation has been controlled.

[0109] Furthermore, in antibodies produced in mammalian cultured cells, the lysine residue at the carboxyl terminus of the heavy chain is It is known that the group is missing (Journal of Chromatography A, 705: 129-134 (1995)). ), also, the two amino acid residues glycine and lysine at the heavy chain carboxyl terminus are deleted, It is known that a proline residue located at the carboxyl terminus is newly amidated. Analytical Biochemistry, 360: 75-83 (2007). However, deletions of these heavy chain sequences and Modification affects the antigen-binding ability and effector function of antibodies (complement activation and antibody-dependent cell-mediated cytotoxicity). It does not affect (use, etc.). Therefore, the antibody according to the present invention has the modified antibody The body and functional fragments of the antibody also include one or two amino acids at the heavy chain carboxyl terminus. Deletion products lacking acid, and said deletion products that have been amidated (for example, the carboxyl terminal portion) This also includes heavy chains with amidated proline residues. However, antigen-binding ability and effectors are also included. - As long as the function is maintained, the deletion of the carboxyl terminus of the heavy chain of the antibody according to the present invention is as described above. It is not limited to the type. The two heavy chains constituting the antibody according to the present invention have full length and the above-mentioned defect. It may be any one of the heavy chains selected from the group consisting of atrophies, or any two of them combined. They may be combined. The ratio of each deletion is determined by the mammal culture medium that produces the antibody according to the present invention. Although it may be affected by the type of cell culture and culture conditions, the antibody according to the present invention preferably has two List the amino acids in which one amino acid residue is missing from the carboxyl terminal in both the heavy chains. It is possible.

[0110] Examples of antibody isotypes according to the present invention include IgG (IgG1, IgG2, Ig Examples include G3, IgG4, etc., but preferably IgG1 or IgG2. It is possible.

[0111] The antibody used in the antibody-drug conjugate of the present invention is not particularly limited, but 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 include 4 antibodies, anti-GPR20 antibodies, and anti-CDH6 antibodies, preferably anti-HE R2 antibody, anti-HER3 antibody, anti-TROP2 antibody, anti-B7-H3 antibody, anti-GPR20 antibody, And anti-CDH6 antibodies can be cited as examples.

[0112] In this invention, "anti-HER2 antibody" refers to HER2 (Human Epidermal Reaction). l Growth Factor Receptor Type 2; ErbB-2) It specifically binds to HER2, and preferably binds to HER2, thereby introducing it into HER2-expressing cells. This shows an antibody that exhibits cellular activity.

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

[0114] In this invention, "anti-HER3 antibody" refers to HER3 (Human Epidermal Reactivity). l Growth Factor Receptor Type 3; ErbB-3) It specifically binds to HER3, and preferably binds to HER3, thereby introducing it into HER3-expressing cells. This shows an antibody that exhibits cellular activity.

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

[0116] In this invention, "anti-TROP2 antibody" refers to TROP2 (TACSTD2:Tumo r-associated calcium signal transducer 2 ; Specifically binds to EGP-1), and preferably binds to TROP2, thereby T This antibody exhibits activity that allows it to be internalized in ROP2-expressing cells.

[0117] Examples of anti-TROP2 antibodies include hTINA1-H1L1 (International Publication No. 2015 / (No. 098099) can be cited.

[0118] In this invention, "anti-B7-H3 antibody" refers to B7-H3 (B cell anti) en #7 homolog 3; PD-L3; CD276) specifically binds, and Furthermore, it has the activity to be internalized into B7-H3 expressing cells by binding to B7-H3. It shows antibodies that produce the antibody.

[0119] Examples of anti-B7-H3 antibodies include M30-H1-L4 (International Publication No. 2014 / 05). (No. 7687) can be cited.

[0120] In this invention, "anti-GPR20 antibody" refers to GPR20 (G Protein-Co Specifically binds to the upled receptor 20), preferably to GPR20. Combining these antibodies results in an antibody that exhibits activity to be internalized in GPR20-expressing cells.

[0121] Examples of anti-GPR20 antibodies include h046-H4e / L7 (International Publication No. 2018 / (No. 135501) can be cited.

[0122] In this invention, "anti-CDH6 antibody" refers to an antibody specific to CDH6 (Cadherin-6). It binds to CDH6, and preferably, by binding to CDH6, it is internalized in CDH6-expressing cells. It exhibits an antibody that has the activity to do so.

[0123] Examples of anti-CDH6 antibodies include H01L02 (International Publication No. 2018 / 212136) You can list the numbers.

[0124] 3. Manufacturing of antibody-drug conjugates The drug linker intermediate used in the production of antibody-drug conjugates according to the present invention is as follows: It is shown by the formula.

[0125] [ka]

[0126] The above drug linker intermediate is N-[6-(2,5-dioxo-2,5-dihydro-1 H-pyrrole-1-yl)hexanoyl]glycylglycyl-L-phenylalanyl-N -[(2-{[(1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl Lu-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12 H-benzo[de]pyrano[3',4':6,7]indridino[1,2-b]quinoline The chemical name is -1-yl]amino}-2-oxoethoxy)methyl]glycinamide. It can be expressed in International Publication No. 2014 / 057687, International Publication No. 2015 / 0980 Issue 99, International Publication No. 2015 / 115091, International Publication No. 2015 / 155998, It can also be manufactured by referring to the information in International Publication No. 2019 / 044947, etc.

[0127] The antibody-drug conjugate used in the present invention consists of the aforementioned drug linker intermediate and thio It is produced by reacting an antibody having a sulfhydryl group (also called a sulfhydryl group). It is possible.

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

[0129] Furthermore, 2 to 20 molar equivalents of drug linker per antibody containing a sulfhydryl group - Antibodies with 2 to 8 drugs conjugated per antibody using an intermediate - Drug conjugate It is possible to manufacture gates.

[0130] The calculation of the average number of drug conjugates per antibody molecule in the manufactured antibody-drug conjugate is as follows: For example, antibody-drug conjugates and their conjugates at two wavelengths, 280 nm and 370 nm. Methods that calculate by measuring the UV absorbance of the degation precursor (UV method), and Body-drug conjugates were treated with a reducing agent, and each resulting fragment was measured by HPLC. This can be done by a quantitative method (HPLC method).

[0131] Conjugation of antibodies and drug linker intermediates, and antibody-drug conjugates The calculation of the average number of drug bindings per molecule in the body is based on International Publication No. 2014 / 057687, International Publication No. 2015 / 098099, International Publication No. 2015 / 115091, International Publication No. 2 Publication No. 015 / 155998, International Publication No. 2018 / 135501, and International Publication No. 201 This can be implemented by referring to the information in issue 8 / 212136, etc.

[0132] In the present invention, "anti-HER2 antibody-drug conjugate" refers to the antibody- according to the present invention. This shows an antibody-drug conjugate in which the antibody in the drug conjugate is an anti-HER2 antibody. vinegar.

[0133] The anti-HER2 antibody preferably has amino acid numbers 1 to 449 in SEQ ID NO: 1. A heavy chain consisting of an amino acid sequence and the amino acid sequence described in SEQ ID NO: 2, amino acid numbers 1 to 214. An antibody comprising a light chain consisting of an amino acid sequence, or from the amino acid sequence described in Sequence ID No. 1. This antibody comprises a heavy chain and a light chain consisting of the amino acid sequence described in Sequence ID No. 2.

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

[0135] Anti-HER2 antibody-drug conjugates are described in International Publication No. 2015 / 115091, etc. It can be manufactured by referring to the specifications provided.

[0136] In the present invention, "anti-HER3 antibody-drug conjugate" refers to the antibody- This shows 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 the one described in SEQ ID NO: 3, specifically the one described in amino acid numbers 26 to 35. CDRH1, consisting of an amino acid sequence, is described in SEQ ID NO: 3, specifically amino acid numbers 50 to 65. CDRH2 consists of the amino acid sequence, and in SEQ ID NO: 3, amino acid numbers 98 to 10 A heavy chain containing CDRH3 consisting of the amino acid sequence described in 6, and in SEQ ID NO: 4 CDRL1 and SEQ ID NO: 4, which consist of the amino acid sequences described in amino acid numbers 24 to 39 CDRL2, consisting of the amino acid sequence described in amino acid numbers 56 to 62, and SEQ ID NO: 4 A light chain containing CDRL3 consisting of the amino acid sequence described for amino acid numbers 95 to 103. It is an antibody that contains, More preferably, the amino acid sequence described in SEQ ID NO: 3, with amino acid numbers 1 to 117 A heavy chain containing the following heavy chain variable regions, and the amino acid numbers 1 to 113 indicated in SEQ ID NO: 4 An antibody containing a light chain that includes a light chain variable region consisting of the amino acid sequence shown, More preferably, a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 3 and the sequence described in SEQ ID NO: 4 An antibody comprising a light chain consisting of the amino acid sequence shown, or the heavy chain carboxyl terminus of said antibody. This antibody is missing a lysine residue.

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

[0139] Anti-HER3 antibody-drug conjugates are described in International Publication No. 2015 / 155998, etc. It can be manufactured by referring to the specifications provided.

[0140] In the present invention, "anti-TROP2 antibody-drug conjugate" refers to the antibody according to the present invention. -An antibody-drug conjugate in which the antibody in the drug conjugate is an anti-TROP2 antibody. This indicates.

[0141] The anti-TROP2 antibody is preferably represented by amino acid numbers 50 to 54 in SEQ ID NO: 5. CDRH1 consists of the amino acid sequence, indicated in SEQ ID NO: 5, amino acid numbers 69 to 85. CDRH2, consisting of the amino acid sequence shown, and amino acid numbers 118 to in Sequence ID No. 5 A heavy chain containing CDRH3 consisting of the amino acid sequence described in 129, and the odor of SEQ ID NO: 6 CDRL1 and SEQ ID NO: 6 consist of the amino acid sequences described in amino acid numbers 44 to 54. CDRL2 and Sequence ID number consist of the amino acid sequence described in amino acid numbers 70 to 76. 6 contains CDRL3 consisting of the amino acid sequence described for amino acid numbers 109 to 117. It is an antibody that contains a light chain, More preferably, the amino acid sequence described for amino acid numbers 20 to 140 in Sequence ID No. 5. A heavy chain comprising a heavy chain variable region, and amino acids 21 to 129 in SEQ ID NO: 6 An antibody comprising a light chain containing a light chain variable region consisting of the amino acid sequence described above, More preferably, the amino acids described in SEQ ID NO: 5, specifically those with amino acid numbers 20 to 470. A heavy chain consisting of the sequence and amino acids listed as amino acid numbers 21 to 234 in SEQ ID NO: 6 An antibody comprising a light chain consisting of a sequence, or a lysine residue at the carboxyl terminus of the heavy chain of the antibody. This is an antibody that is missing a certain component.

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

[0143] Anti-TROP2 antibody-drug conjugates are described in International Publication No. 2015 / 098099, etc. It can be manufactured by referring to the description.

[0144] In the present invention, "anti-B7-H3 antibody-drug conjugate" refers to the antibody according to the present invention. -An antibody-drug conjugate in which the antibody is an anti-B7-H3 antibody. This indicates.

[0145] The anti-B7-H3 antibody is preferably described in amino acid numbers 50 to 54 in SEQ ID NO: 7. CDRH1 consists of the amino acid sequence indicated by amino acid numbers 69 to 85 in SEQ ID NO: 7. CDRH2 consisting of the amino acid sequence shown, and amino acid numbers 118 to in Sequence ID No. 7 A heavy chain containing CDRH3 consisting of the amino acid sequence described in 130, and the odor of SEQ ID NO: 8 CDRL1 and SEQ ID NO: 8 consist of amino acid sequences described in amino acid numbers 44 to 53. CDRL2 and Sequence IDs, consisting of the amino acid sequences described in amino acid numbers 69 to 75. 8 contains CDRL3 consisting of the amino acid sequence described for amino acid numbers 108 to 116. It is an antibody that contains a light chain, More preferably, the amino acid sequence described in SEQ ID NO: 7, with amino acid numbers 20 to 141. A heavy chain comprising a heavy chain variable region, and amino acids 21 to 128 in SEQ ID NO: 8 An antibody comprising a light chain containing a light chain variable region consisting of the amino acid sequence described above, More preferably, the amino acids described in SEQ ID NO: 7, specifically those with amino acid numbers 20 to 471. A heavy chain consisting of the sequence and amino acids listed as amino acid numbers 21 to 233 in Sequence ID No. 8 An antibody comprising a light chain consisting of a sequence, or a lysine residue at the carboxyl terminus of the heavy chain of the antibody. This is an antibody that is missing a certain component.

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

[0147] The anti-B7-H3 antibody-drug conjugate used in this invention is described in International Publication No. 20 It can be manufactured by referring to the description in issue 14 / 057687, etc.

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

[0149] The anti-GPR20 antibody is preferably represented by amino acid numbers 45 to 54 in SEQ ID NO: 9. CDRH1 consists of the amino acid sequence, as indicated by amino acid numbers 69 to 78 in SEQ ID NO: 9. CDRH2, consisting of the amino acid sequence shown, and amino acid numbers 118 to in Sequence ID No. 9 A heavy chain containing CDRH3 consisting of the amino acid sequence described in 131, and SEQ ID NO: 10 CDRL1 and SEQ ID NO: 10 consist of amino acid sequences described in amino acid numbers 44 to 54. CDRL2 consisting of the amino acid sequence described in amino acid numbers 70 to 76, and sequence CDRL consisting of the amino acid sequence described in amino acid numbers 109 to 117 in number 10. It is an antibody containing a light chain containing 3, More preferably, the amino acid sequence described in SEQ ID NO: 9, amino acid numbers 20 to 142 A heavy chain containing a heavy chain variable region, and amino acid numbers 21 to 12 in SEQ ID NO: 10 An antibody comprising a light chain containing a light chain variable region consisting of the amino acid sequence described in 9, More preferably, the amino acids listed as amino acid numbers 20 to 472 in Sequence ID No. 9 A heavy chain consisting of the sequence and amino acids listed as amino acid numbers 21 to 234 in SEQ ID NO: 10 An antibody comprising a light chain consisting of an acid sequence, or a lysine residue at the carboxyl terminus of the heavy chain of the antibody. This is an antibody that lacks a specific group.

[0150] The average number of drug linkers bound per antibody in an anti-GPR20 antibody-drug conjugate. Preferably 2 to 8, more preferably 3 to 8, and even more preferably 7 to 8. Yes, more preferably 7.5 to 8, and even more preferably about 8.

[0151] The anti-GPR20 antibody-drug conjugate is described in International Publication No. 2018 / 135501, etc. It can be manufactured by referring to the description.

[0152] In the present invention, "anti-CDH6 antibody-drug conjugate" refers to the antibody- according to the present invention. This shows an antibody-drug conjugate in which the antibody in the drug conjugate is an anti-CDH6 antibody. vinegar.

[0153] The anti-CDH6 antibody is preferably represented by amino acid numbers 45 to 54 in SEQ ID NO: 11. CDRH1 consists of the amino acid sequence, and in SEQ ID NO: 11, amino acids 69 to 78 CDRH2, consisting of the amino acid sequence described, and amino acid number 118 in SEQ ID NO: 11 A heavy chain containing CDRH3 consisting of the amino acid sequence described in to 130, and SEQ ID NO: 12 CDRL1, consisting of the amino acid sequence described in amino acid numbers 44 to 54, SEQ ID NO: CDRL2 consisting of the amino acid sequence described in 12, and CD consisting of the amino acid sequence described in SEQ ID NO: 12, amino acid numbers 109 to 116 It is an antibody containing a light chain that includes RL3, More preferably, the amino acid combination described in SEQ ID NO: 11, with amino acid numbers 20 to 141 A heavy chain containing a heavy chain variable region consisting of columns, and amino acid numbers 21 to 1 in SEQ ID NO: 12. An antibody comprising a light chain containing a light chain variable region consisting of the amino acid sequence described in 28, More preferably, the amino acids described in SEQ ID NO: 11, specifically those with amino acid numbers 20 to 471. A heavy chain consisting of an acid sequence and the amino acids described in SEQ ID NO: 12, amino acid numbers 21 to 233. An antibody comprising a light chain consisting of a no-acid sequence, or the lysine at the carboxyl terminus of the heavy chain of the antibody. This is an antibody in which residues are missing.

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

[0155] The anti-CDH6 antibody-drug conjugate is described in International Publication No. 2018 / 212136, etc. It can be manufactured by referring to the specifications provided.

[0156] 4. Tubulin inhibitors In this invention, "tubulin inhibitor" refers to a substance that affects microtubule dynamics. This causes cell division to stop during the G2 phase (preparation phase) and / or M phase (mitotic phase) of the cell cycle. Therefore, it is a drug that suppresses the proliferation of cancer cells by inducing apoptosis (programmed cell death). (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 work by promoting tubulin polymerization, thereby altering microtubule dynamics. A drug that affects the tubulin (referred to as a "tubulin polymerization promoter" in this invention), and A drug that affects microtubule dynamics by inhibiting the polymerization of brin (as described in this invention) There are drugs called "tubulin polymerization inhibitors."

[0158] Examples of tubulin polymerization promoters include taxanes (paclitaxel, docetaxel, and Examples of known tubulin polymerization inhibitors include cabazitaxel, etc. Phosphorus compounds (such as eribulin), vinca alkaloids (vincristine, vinblastine, vin) Norelbine, vindesine, etc.), dorastatins (MMAE and MMAF, etc.), and meita Sinoids (DM1 and DM4, etc.) are known. These drugs and their pharmacological properties The salts used can be used as tubulin inhibitors in this invention. A conjugate of any drug with albumin (for example, the conjugate of paclitaxel with albumin) The body contains nab-paclitaxel, etc., and links any of these drugs with an antibody. -Antibody-drug conjugates conjugated via (e.g., MMAE and anti-CD30 antibody) Brentuximab vedotin, an antibody-drug conjugate conjugated via a linker, This is an antibody-drug conjugate in which DM1 and an anti-HER2 antibody are linked via a linker. Trastuzumab emtansine, MMAE, and an anti-GPMNB antibody are linked via a linker. CDX-011 (International Publication No. 2006 / 071441) is an antibody-drug conjugate. (e.g., DM4 and anti-FOLR1 antibody linked via a linker) IMGN-853 (International Publication No. 2017 / 049149, etc.), which is a MMAE and antimicrobial agent. RG-7 is an antibody-drug conjugate in which CD79b antibody is linked via a linker. 596 (US Publication No. 2017 / 304438, etc.), linking DM4 and anti-CD19 antibody SAR-3419 (US Public Release No. 20) is an antibody-drug conjugate that is linked via - (e.g., No. 15 / 071949), an anti-PSMA antibody linked to MMAE via a linker. PSMA-ADC, a systemic drug conjugate (International Publication No. 2007 / 002222) (e.g.) an antibody-drug conjugate in which DM4 and an anti-CD138 antibody are linked via a linker. BT-062 (US Public Issue No. 2007 / 183971, etc.), DM4 and anti-meso BAY is an antibody-drug conjugate in which the lin antibody is linked via a linker. -94-9343 (International Publication No. 2010 / 124797, etc.), MMAF and anti-CD19 SGN-CD19A is an antibody-drug conjugate in which the body is linked via a linker. International Publication No. 2009 / 052431, etc., linking MMAF and anti-ENPP3 antibody Antibody-drug conjugates such as AGS-16C3F, which are bound via the present invention, are also included in the present invention. It can be used as a bubrin inhibitor.

[0159] Among the tubulin inhibitors preferred for use in the present invention, as a tubulin polymerization promoter This refers to taxanes or pharmaceutically acceptable salts thereof, or taxanes and albumin. Examples of conjugates include paclitaxel, docetaxel, and cabazitaxel. List cells, or pharmacoagulably acceptable salts thereof, or nab-paclitaxel. This can be done, and more preferably, paclitaxel, docetaxel trihydrate, or cabazita Examples include xelacetone hydrate or nab-paclitaxel, and more preferably More preferably, paclitaxel can be mentioned.

[0160] Among the tubulin inhibitors preferred for use in the present invention, as a tubulin polymerization inhibitor This refers to halichondrins or their pharmacoperdinally acceptable salts, or interactions with halichondrins. Examples include antibody-drug conjugates in which the body is linked via a linker, and more preferably Suitable options include eribulin or a pharmacoagulably acceptable salt thereof, or eribulin and an antibody linked together. Antibody-drug conjugates linked via (e.g., eribulin and anti-FOLR1 antibody) MORAb-202 (USA) is an antibody-drug conjugate in which two substances are linked via a linker. National Publication No. 2017 / 252458, etc.) can be cited, and more preferably, One example is eribulin mesylate.

[0161] Furthermore, in this invention, "pharmacokinetically acceptable salt" refers to either an acid addition salt or a base addition salt. It is also acceptable to use acid addition salts such as camphorate (camphor sulfonate), etc. Silates (methanesulfonates), trifluoromethanesulfonates, and ethanesulfonates Lower alkanesulfonates such as phosphates; tosylates (p-toluenesulfonate), and Aryl sulfonates such as benzenesulfonates; phosphates, nitrates, perchlorates, and Inorganic salts such as sulfates; hydrochlorides, hydrobroms, hydroiodides, and hydrofluorides, etc. Hydrohalides; acetates, malates, fumarates, succinates, citrates, tartrates Organic acid salts such as salts, oxalates, and maleates; as well as ornithines and glutamates. Examples include amino acid salts such as aspartates. Examples of base addition salts include For example, alkali metal salts such as sodium salts, potassium salts, lithium salts; calcium salts, magnesium salts Alkaline earth metal salts such as ammonium salts; inorganic salts such as ammonium salts; dibenzylamine salts, mo Glufoline salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methyl glycine Lucamin salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, disic Lohexylamine salt, N,N'-dibenzylethylenediamine salt, diethanolamine salt N-benzyl-N-(2-phenylethoxy)amine salt, piperazine salt, tetramethyl Organic amine salts such as ammonium salts and tris(hydroxymethyl)aminomethane salt; argy Examples include amino acid salts such as nin salts.

[0162] Furthermore, pharmacokinetically acceptable salts may also exist as solvates, and these solvates This is also included in the "pharmacokinetically acceptable salts" of the present invention. Examples of such solvates include, for example, , hydrates (e.g., 0.5 hydrate, 1 hydrate, 2 hydrate, 3 hydrate), ethanol hydrate, And acetone dihydrate can be mentioned.

[0163] 5. Pharmaceuticals The following describes how the antibody-drug conjugate and tubulin inhibitor according to the present invention are combined. This document describes a pharmaceutical composition characterized by being administered and a method of treatment.

[0164] The pharmaceutical composition and therapeutic method of the present invention comprises an antibody-drug conjugate and tubulin inhibition. The drugs are contained as active ingredients in different formulations and administered simultaneously or at different times. It may be characterized by an antibody-drug conjugate and tubulin The inhibitor is characterized by being contained as an active ingredient in a single formulation and administered accordingly. That's fine.

[0165] The pharmaceutical composition and therapeutic method of the present invention can be used for the treatment of cancer, and preferably These include breast cancer, stomach cancer (sometimes called gastric adenocarcinoma), and colorectal cancer (sometimes called colorectal cancer). This also includes colon cancer and rectal cancer, and lung cancer (including small cell lung cancer and non-small cell lung cancer). (mu), 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 Routhelic carcinoma, 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 Leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma pleomorphoni, osteosarcoma, and melanocytoma It can be used for at least one treatment selected from the group consisting of -ma, Preferably used for breast cancer, stomach cancer, colorectal 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 children To be used for the treatment of at least one cancer selected from the group consisting of miya carcinosarcoma. This can be done, and more preferably, selected from the group consisting of breast cancer, stomach cancer, lung cancer, and ovarian cancer. It can be used for the treatment of at least one type of cancer.

[0166] Among the antibody-drug conjugates used in the present invention, which antibody has any particular type of antibody? Whether a body-drug conjugate is suitable depends on the type of cancer and whether tumor markers are being tested. This can be determined by the following: For example, if HER2 expression is confirmed in cancer, HER2 antibody-drug conjugates can be suitably used, and HER3 expression in cancer can be suppressed. If this is confirmed, an anti-HER3 antibody-drug conjugate can be suitably used. If TROP2 expression is confirmed in cancer, an anti-TROP2 antibody-drug conjugate is used. It can be suitably used, and if B7-H3 expression is confirmed in cancer, anti-B7-H 3. Antibody-drug conjugates can be suitably used, and the expression of GPR20 in cancer can be confirmed. If approved, an anti-GPR20 antibody-drug conjugate can be suitably used. If CDH6 expression is confirmed in cancer, an anti-CDH6 antibody-drug conjugate is preferred. It can be used for this purpose.

[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 taking tumor tissue from a cancer patient and fixing it in formalin. Raffin-embedded specimens (FFPE) are subjected to immunohistochemistry (IHC) and flow cytometry. Testing at the gene product (protein) level using methods such as Western blot, This includes in situ hybridization (ISH) and quantitative PCR (q-PC). R) This can be confirmed by testing at the transcription level of genes using microarray analysis, etc. Alternatively, cell-free circulating tumor DNA (ctDNA) can be collected from cancer patients and used for next-generation This can also be confirmed by testing using methods such as sequencing (NGS).

[0168] The pharmaceutical composition and therapeutic method of the present invention can be suitably used on mammals. More preferably, it can be used on humans.

[0169] The antitumor effect of the pharmaceutical composition and therapeutic method of the present invention is, for example, achieved by transplanting cancer cells into a test animal. A model is created, and the reduction in tumor volume is achieved by applying the pharmaceutical composition and treatment method of the present invention. This can be confirmed by measuring the life-extending effect. Furthermore, the anti- Antitumor effects compared to monotherapy of body-drug conjugates and tubulin inhibitors. By comparing the antibody-drug conjugate and tubulin inhibitor used in the present invention, The combined effect of the drugs can be confirmed.

[0170] Furthermore, the antitumor effect of the pharmaceutical composition and therapeutic method of the present invention was demonstrated in clinical trials, Resp onse Evaluation Criteria in Solid Tumors (RECIST) assessment method, WHO assessment method, Macdonald assessment method, weight measurement, and This can be confirmed by other methods, and complete response CR), Partial response (PR), Progression (PR), Pathogenic disease (PD), objective response rate Rate (ORR), Duration of Response (DoR) ), Progression-Free Survival (PFS) The determination is made using indicators such as overall survival (OS). It is possible.

[0171] Furthermore, the combined effect of the pharmaceutical composition and therapeutic method of the present invention is that of drug sensitivity factors and / or drugs It can also be determined from changes in the expression levels of physical resistance factors. For example, if the subject is given the same material used in this invention... When antibody-drug conjugates and tubulin inhibitors were administered individually, Drug sensitivity factors and / or compare the expression levels of drug resistance factors. And the antibody-drug condyl used in the present invention Tubulin inhibitors suppress the decrease in the expression of drug sensitivity factors caused by the administration of tubulin. If this can be confirmed, then the combined effect of antibody-drug conjugates and tubulin inhibitors will be demonstrated. It can be determined that... Examples of such drug sensitivity factors include SLFN11... It can be said that SLFN11 is 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, a drug produced by the administration of the antibody-drug conjugate used in the present invention. If it can be confirmed that tubulin inhibitors suppress the increased expression of physical resistance factors, then antibody-drug It can be determined that there is a combined effect of the substance conjugate and the tubulin inhibitor. One example of a drug resistance factor is ABCG2. ABCG2 is, Drug resistance factors (transporters) released from antibody-drug conjugates according to the present invention It is known that... (Nagai Y. et al., Xenobiotica. 2019;49(9):1086-96) Furthermore, drug sensitivity factors and / or drug resistance factors are expressed at the gene (RNA, etc.) level. It is possible to compare quantities, and also to compare expression levels at the protein level.

[0172] By the method described above, the antitumor effect of the pharmaceutical composition and therapeutic method of the present invention is compared with existing methods. The superiority of the therapeutic pharmaceutical composition and treatment method can be confirmed.

[0173] The pharmaceutical composition and therapeutic method of the present invention slow down the growth of cancer cells, suppress their proliferation, and further... It can destroy cancer cells. Through these effects, in cancer patients, This can lead to relief from symptoms, improved quality of life, and the preservation of cancer patients' lives while achieving therapeutic effects. Even if it does not lead to the destruction of cancer cells, it can suppress or control the proliferation of cancer cells. This method helps cancer patients achieve a higher quality of life while also achieving longer-term survival. It is possible.

[0174] The pharmaceutical composition of the present invention is applied to patients as a systemic therapy, as well as locally to cancer tissue. It can be applied to [specific area] and is expected to have a therapeutic effect.

[0175] The pharmaceutical composition of the present invention contains one or more pharmaceutically compatible components and can be administered. The compatible components are the antibody-drug conjugate and tubulin inhibitor used in the present invention. Depending on the dosage and concentration of the agent, the pharmaceutical additives and other substances commonly used in this field may be used. They can be appropriately selected and applied. For example, the antibody-drug conjugate used in the present invention The gate contains buffering agents such as histidine buffering agents, excipients such as sucrose or trehalose, and It may be administered as a pharmaceutical composition containing a surfactant such as polysorbate 80 or 20. The pharmaceutical composition containing the antibody-drug conjugate used in the invention is preferably an injectable preparation. It can be used as an aqueous injection or a lyophilized injection. It can be used as a lyophilized injectable preparation, and more preferably as a lyophilized injectable preparation.

[0176] When the pharmaceutical composition containing the antibody-drug conjugate used in the present invention is an aqueous injectable preparation In combination, preferably, it can be administered intravenously by drip infusion after being diluted with an appropriate diluent. Examples include glucose solution and physiological saline solution, and preferably glucose solution A liquid can be given, and more preferably a 5% glucose solution.

[0177] The pharmaceutical composition containing the antibody-drug conjugate used in the present invention is a lyophilized injectable preparation. In such cases, preferably, dissolve with sterile water for injection, then dilute the required amount with an appropriate diluent, and then... It can be administered intravenously. Diluents include glucose solution, physiological saline solution, etc. Examples include, preferably, a glucose solution, and more preferably, a 5% glucose solution. One example is a sugar solution.

[0178] A possible route of introduction for administering the pharmaceutical composition of the present invention is, for example, intravenous. These include intradermal, subcutaneous, intramuscular, and intraperitoneal pathways, preferably intravenous pathways. One could list these:

[0179] The antibody-drug conjugate used in this invention is administered to humans over a period of 1 to 180 days. It can be administered at intervals of one dose, preferably once every 1, 2, 3, or 4 weeks. It can be administered, and more preferably, at intervals of once every three weeks. Furthermore, the antibody-drug conjugate used in this invention is approximately 0.001 to 10 per dose. It can be administered at a dose of 0 mg / kg, preferably 0.8 to 12.4 mg per dose. It can be administered in doses of g / kg. Antibody-drug conjugate used in this invention If the drug is an anti-ER2 antibody-drug conjugate, preferably 0.8 mg per dose. / kg, 1.6mg / kg, 3.2mg / kg, 5.4mg / kg, 6.4mg / kg, A dose of 7.4 mg / kg or 8 mg / kg can be administered at intervals of once every three weeks. The antibody-drug conjugate used in this invention is an anti-HER3 antibody-drug conjugate. In the case of [a specific type of drug], preferably, 1.6 mg / kg, 3.2 mg / kg, and 4.8 mg / kg per dose. g / kg, 5.6mg / kg, 6.4mg / kg, 8.0mg / kg, 9.6mg / kg Alternatively, a dose of 12.8 mg / kg can be administered at intervals of 3 weeks. The antibody-drug conjugate used is an anti-TROP2 antibody-drug conjugate. In this case, preferably, 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 The dosage can be administered at intervals of once every three weeks.

[0180] The tubulin inhibitor according to the present invention is administered to humans at intervals of once every 1 to 180 days. It can be administered, preferably at intervals of once every 1, 2, 3, or 4 weeks. This is possible. Furthermore, the tubulin inhibitor according to the present invention contains approximately 0.001 to 100 per dose. It can be administered at a dose of mg / kg. The tubulin inhibitor according to the present invention is pachy In the case of ritaxel, preferably 100, 125, 135, 175, or 2 per dose. 60 mg / m² 2 The dose (based on body surface area) is administered intravenously at intervals of once every one or three weeks (points). (Administered by intravenous drip) (If administered at intervals of once a week, it should be administered for three consecutive weeks.) (The drug will be discontinued for the fourth week.) The tubulin inhibitor according to the present invention is eribulin mesylate In some cases, preferably 1.4 mg / m² per dose. 2 (Body surface area) dosage once a week It can be administered intravenously at intervals of [number] weeks (after administering for two consecutive weeks, the drug is taken off for the third week).

[0181] The pharmaceutical composition and therapeutic method of the present invention are the antibody-drug conjugate and tubular drug conjugate according to the present invention. The present invention may further contain cancer treatment agents other than globulin inhibitors. Pharmaceutical composition and treatment of the present invention The method can also be administered in combination with other cancer treatments, thereby enhancing the antitumor effect. It can be made possible. Other cancer treatment agents used for such purposes are the pharmaceutical compositions of the present invention. At the same time, they may be administered to individuals separately or consecutively, and the intervals between each administration may be changed. It may be administered in this manner. Such cancer treatment agents are limited to drugs that have antitumor activity. It is not definitively established, but for example, irinotecan (CPT-11) Cisplatin, Carboplatin, Oxaliplatin, Fluoroura cil, 5-FU), gemcitabine, capecitabine ecitabine, doxorubicin, epirubicin (E pirubicin), cyclophosphamide, Mitomycin C, Tegafur Gimera Gimeracil / Oteracil combination drug, cetuximab ( Cetuximab, Panitumumab, Bevacizumab vacizumab, ramucirumab, regorafenib (R egorafenib, trifluridine, tipiracil Tipiracil combination drug, gefitinib, erlotinib (E (Afatinib), Afatinib, Methotrexate (Ta) otrexate, pemetrexed, tamoxifen moxifen, toremifene, fulvestrant vestrant, leuprorelin, goserelin serelin, letrozole, anastrozole trozole), progesterone preparations (Progesterone formula) A small number of drugs selected from the group consisting of ion, trastuzumab, pertuzumab, and lapatinib. At the very least, one example can be given.

[0182] The pharmaceutical composition and therapeutic method of the present invention can also be used in combination with radiotherapy. For example, cancer patients may, before and / or after receiving treatment with the pharmaceutical composition of the present invention, They also receive radiation therapy.

[0183] The pharmaceutical composition and therapeutic method of the present invention are used as adjuvant chemotherapy in combination with surgical procedures. It is also possible to reduce the size of a tumor before surgery using the pharmaceutical composition of the present invention. It may be administered (referred to as neoadjuvant chemotherapy or neoadjuvant therapy) and surgically It may be administered postoperatively to prevent tumor recurrence (as adjuvant chemotherapy or adjuvant therapy). (This is called pharmacotherapy.) [Examples]

[0184] The present invention will be specifically described by the following examples, but the present invention is not limited to these. No. Furthermore, these should not be interpreted restrictively in any sense.

[0185] Example 1: Production of antibody-drug conjugates Humanized anti-HER2 Body (heavy chain consisting of amino acid sequences described in SEQ ID NO: 1 to 449 and Furthermore, the light chain contains the amino acid sequence described in SEQ ID NO: 2, which consists of amino acid numbers 1 to 214. Using the antibody that is formed by the formula

[0186] [ka]

[0187] (In the formula, A indicates the binding site with the antibody.) The drug linker shown and the anti-HER2 antibody are linked by a thioether bond. - Manufacture a 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 Co., Ltd. Japan) It was used in an experiment.

[0189] Measurement and calculation formula: In all studies, the longest and shortest diameters of the tumor were measured using electronic digital calipers. The tumor volume was measured twice a week using (CD-15CX, Mitutoyo Corp.). mm 3 The calculation was performed. The formula is as follows: Tumor volume (mm 3 ) = 1 / 2 × major axis (mm) × minor axis (mm) 2 Antibody-drug conjugate (1) is ABS buffer (10mM acetate buffer ( Dilute with pH 5.5) and 5% sorbitol, and administer 10 mL / kg of the solution intravenously. Paclitaxel was dissolved in cremophor and ethanol (1:1) and physiological saline solution. After dilution with water, a volume of 10 or 20 mL / kg was administered intravenously via tail vein. Eribul In mesylate is diluted with physiological saline and administered intravenously at a volume of 10 mL / kg. Ta.

[0190] Dr. Junichi Kurebayashi, Kawasaki Medical University (British Journal of Cancer, (1999) 79(5 / 6).707-717) Human breast cancer cell line KPL-4 cells obtained from [source] were suspended in physiological saline, and 1.5 × 10⁶ cells were used. 7 Cells were subcutaneously transplanted into the right side of the body of female nude mice, and 17 days after transplantation, the mice were randomly divided into groups. The procedure was performed (Day 0). Antibody-drug conjugate (1) (DAR: 7.8) was performed on Day 0. Paclitaxel was administered intravenously at a dose of 7.5 mg / kg. Paclitaxel was administered on Day 0 and Day 1. Administer 15 mg / kg via tail vein on day 7, and Eribulin mesylate is D The drugs were administered via tail vein at a dose of 0.8 mg / kg on day 0 and day 4. They were also administered as monotherapy and in combination. A solvent-administered group was established as both a nourishment group and a control group.

[0191] Figure 9 shows the results of combining an antibody-drug conjugate (1) with Paclitaxel. Tumor growth suppression rate on the final day of the Paclitaxel monotherapy trial (Tumor Gr The risk inhibition (TGI) rate was 48%. Antibody-drug conjugate The TGI rate with monotherapy of (1) was 87%. On the other hand, antibody-drug conjugate ( 1) In combination therapy with Paclitaxel, compared to Paclitaxel monotherapy, A significantly superior tumor growth inhibitory effect was observed (P<0.01 (Dunnett's tes)). Calculated by t. The same applies below. )), and also compared to monotherapy of antibody-drug conjugate (1) A significantly superior tumor growth inhibitory effect was observed (P<0.05), and the combined effect was observed in all cases. The lesions were completely eliminated, indicating a very strong outcome (TGI, 100%). (Note: In the figure, the horizontal axis...) The vertical axis shows the number of days after cell transplantation, and the vertical axis shows the tumor volume. In addition, in all monotherapy and combination therapy groups... No particularly significant findings such as weight loss were observed. Furthermore, regarding the following antitumor trials... In the evaluation examples, unless otherwise specified, the tests were conducted using the method used in this evaluation example. ru.

[0192] Results of combining antibody-drug conjugate (1) with eribulin mesylate Figure 10 shows the TGI with eribulin mesylate monotherapy. The TGI with monotherapy of the antibody-drug conjugate (1) was 87%. On the other hand, combination therapy with antibody-drug conjugate (1) and eribulin mesylate In this case, it showed significantly better tumor growth suppression than eribulin mesylate monotherapy. A control effect was observed (P<0.05), and monotherapy with an antibody-drug conjugate (1) was also effective. A significantly superior tumor growth inhibitory effect was observed (P<0.05), and the combined effect was observed in all cases. The tumor disappeared very completely (TGI, 100%). The horizontal axis represents the number of days after cell transplantation, and the vertical axis represents the tumor volume. Furthermore, for all monotherapy and combination therapy groups... No particularly noticeable findings, such as weight loss, were observed.

[0193] Example 3: Antitumor test (2) DSMZ(Deutsche Sammlung von Mikroorganism) JIMT-, a human breast cancer strain purchased from en und Zellkulturen GmbH. Suspend 1 cell in physiological saline and measure 5 × 10 6 cells subcutaneously on the right side of the female nude mouse Transplantation was performed, and random group assignment was carried out 13 days after transplantation (Day 0). Antibody-drug conjugate (1) (DAR: 7.7) was administered intravenously at a dose of 10 mg / kg on Day 0. Paclitaxel is administered at a dose of 15 mg / kg on Day 0, Day 7, and Day 14. It was administered via tail vein. Eribulin mesylate was given at 0.8mg on Day 0 and Day 3. The drug was administered via tail vein at a dose of g / kg. The treatment groups were compared with monotherapy, combination therapy, and a control group. Then, a solvent administration group was established.

[0194] Figure 11 shows the results of combining an antibody-drug conjugate (1) with Paclitaxel. The transgestogenic gland index (TGI) with paclitaxel monotherapy was 30%. Antibody-drug conjugate The TGI rate with monotherapy of gate (1) was 73%. On the other hand, antibody-drug conjugate In combination therapy with (1) and Paclitaxel, Paclitaxel monotherapy is more effective than Paclitaxel monotherapy. A significantly superior tumor growth inhibitory effect was observed (P<0.001), and antibody-drug combination therapy was also found to be effective. A significantly superior tumor growth inhibitory effect was observed compared to monotherapy with denjugate (1) (P<0 0.001), the TGI was 97%. In addition, in all monotherapy and combination therapy groups, No particularly significant findings, such as a severe decrease, were observed.

[0195] Results of combining antibody-drug conjugate (1) with eribulin mesylate Figure 12 shows the TGI with eribulin mesylate monotherapy. The TGI with monotherapy of the antibody-drug conjugate (1) was 73%. On the other hand, combination therapy with antibody-drug conjugate (1) and eribulin mesylate In this case, it showed significantly better tumor growth suppression than eribulin mesylate monotherapy. A control effect was observed (P<0.05), and monotherapy with an antibody-drug conjugate (1) was also effective. A significantly superior tumor growth inhibitory effect was observed (P<0.001), and TGI was 97%. Yes, there were. Also, in all monotherapy and combination therapy groups, there were no particularly noticeable findings such as weight loss. It was not approved.

[0196] Example 4: Antitumor test (3) ATCC (American Type Culture Collection)? The purchased human gastric cancer cell line NCI-N87 was suspended in physiological saline and prepared in a 1 × 10⁶ solution. 7 cell The s molecule was subcutaneously transplanted into the right side of the body of female nude mice, and the mice were randomly divided into groups 6 days after transplantation. Day 0). Antibody-drug conjugate (1) (DAR: 7.8) 1 mg / Paclitaxel was administered intravenously at a dose of kg. Paclitaxel was 15 mg on Day 0 and Day 7. Administer via tail vein at a dose of / kg, and eribulin mesylate on Day 0 and Day 2. 4. The drug was administered via tail vein at a dose of 0.4 mg / kg. Each drug was administered as a monotherapy, in combination with other drugs, and in combination with other drugs. The solvent administration group was designated as the torol group.

[0197] Figure 13 shows the results of combining an antibody-drug conjugate (1) with Paclitaxel. The transdrug growth rate (TGI) with paclitaxel monotherapy was 50%. Antibody-drug conjugate The TGI rate with monotherapy of gate (1) was 45%. On the other hand, antibody-drug conjugate In combination therapy with (1) and Paclitaxel, Paclitaxel monotherapy is more effective than Paclitaxel monotherapy. A significantly superior tumor growth inhibitory effect was observed (P<0.001), and antibody-drug combination therapy was also found to be effective. A significantly superior tumor growth inhibitory effect was observed compared to monotherapy with denjugate (1) (P<0 0.001), the TGI was 82%. In addition, in all monotherapy and combination therapy groups, No particularly significant findings, such as a severe decrease, were observed.

[0198] Results of combining antibody-drug conjugate (1) with eribulin mesylate is shown in Figure 14. The TGI by single-agent administration of eribulin mesylate was 64% It was. The TGI by single-agent administration of the antibody-drug conjugate (1) was 45%. On the other hand, in the combined administration of the antibody-drug conjugate (1) and eribulin mesylate a significantly superior tumor growth inhibitory effect was observed compared to the single-agent administration of eribulin mesylate (P<0.01), and a significantly superior tumor growth inhibitory effect was also observed compared to the single-agent administration of the antibody-drug conjugate (1) (P<0.001), and the TGI was 77% It was. Also, in any of the single-agent and combined administration groups, no particularly remarkable findings such as weight loss were observed. Moreover, in any of the single-agent and combined administration groups, no particularly remarkable findings such as weight loss were observed.

[0199] Example 5: Antitumor test (4) Human breast cancer cell line MDA-MB-453 cells purchased from ATCC were suspended in Matrigel basement membrane matrix rix (Matrigel) and 1×10 7 cells were subcutaneously transplanted into the right side of female nude mice and randomly grouped 7 days after transplantation (Day0). The antibody-drug conjugate (1) (DAR: 7.8) was intravenously administered via the tail at a dose of 0.5 mg / kg on Day0 Paclitaxel was intravenously administered via the tail at a dose of 15 mg / kg on Day0 and Day7 A solvent administration group was set as each single-agent and combined administration group, and a control group.

[0200] The combined results of the antibody-drug conjugate (1) and paclitaxel are shown in Figure 15 The TGI by single-agent administration of paclitaxel was 96%. The TGI by single-agent administration of the antibody-drug conjugate (1) was 75%. On the other hand, in the combined administration of the antibody-drug conjugate (1) and paclitaxel, in the antibody-drug conjugate (1) A significantly superior tumor growth inhibitory effect was observed compared to monotherapy (P<0.01), and TGI was 1 The figure was 00%. In addition, in all monotherapy and combination therapy groups, particularly noticeable symptoms such as weight loss were observed. No such findings were observed.

[0201] Example 6: Antitumor test (5) Human gastric cancer cell line SNU-1 cells purchased from ATCC were suspended in Matrigel and prepared in a 1 × 10⁶ solution. 7 The cells were subcutaneously transplanted into the right side of the body of female nude mice, and 28 days after transplantation, the mice were randomly divided into groups. The procedure was performed (Day 0). Antibody-drug conjugate (1) (DAR: 7.8) was performed on Day 0. Paclitaxel was administered intravenously at a dose of 10 mg / kg on Day 0 and Day 1. 7. The drug was administered via tail vein at a dose of 15 mg / kg. Each drug was administered as a monotherapy, in combination with other drugs, and in control groups. A solvent administration group was designated as the roll group.

[0202] Figure 16 shows the results of combining an antibody-drug conjugate (1) with Paclitaxel. The transgestogenic dose grading (TGI) with paclitaxel monotherapy was 58%. Antibody-drug conjugate The TGI rate with monotherapy of gate (1) was 79%. On the other hand, antibody-drug conjugate In combination therapy with (1) and Paclitaxel, Paclitaxel monotherapy is more effective than Paclitaxel monotherapy. A significantly superior tumor growth inhibitory effect was observed (P<0.01), and the TGI was 87%. Furthermore, no particularly significant findings such as weight loss were observed in any of the monotherapy or combination therapy groups. I couldn't do it.

[0203] Example 7: Antitumor test (6) Human lung cancer cell line NCI-H441 cells purchased from ATCC were suspended in Matrigel and subjected to 5× 10 6 Cells were subcutaneously transplanted into the right side of the body of female nude mice, and 7 days after transplantation, the mice were randomly divided into groups. The procedure was performed (Day 0). The antibody-drug conjugate (1) (DAR: 7.8) was Da Paclitaxel was administered intravenously at a dose of 10 mg / kg on day 0. ay7 was administered via tail vein at a dose of 15 mg / kg. The groups receiving each agent as a monotherapy and in combination therapy, and the co-administration group, were also compared. A solvent administration group was designated as the control group.

[0204] Figure 17 shows the results of combining an antibody-drug conjugate (1) with Paclitaxel. The TGI rate with paclitaxel monotherapy was 55%. Antibody-drug conjugate The TGI rate with monotherapy of gate (1) was 92%. On the other hand, antibody-drug conjugate In combination therapy with (1) and Paclitaxel, Paclitaxel monotherapy is more effective than Paclitaxel monotherapy. A significantly superior tumor growth inhibitory effect was observed (P<0.001), and antibody-drug combination therapy was also found to be effective. A significantly superior tumor growth inhibitory effect was observed compared to monotherapy with denjugate (1) (P<0 0.01), the TGI was 99%. In all monotherapy and combination therapy groups, weight loss etc. No particularly noteworthy findings were observed.

[0205] Example 8: Production of antibody-drug conjugates (2) According to the manufacturing method described in International Publication No. 2015 / 155998, an anti-HER3 antibody (distributed A heavy chain consisting of the amino acid sequence described in column number 3 and the amino acid sequence described in sequence number 4 Using an antibody (containing a light chain),

[0206] [ka]

[0207] (In the formula, A indicates the binding site with the antibody.) The drug linker shown and the anti-HER3 antibody are linked by a thioether bond. - Manufacture a drug conjugate (hereinafter referred to as "antibody-drug conjugate (2)") The DAR of the antibody-drug conjugate (2) is 7.6.

[0208] Example 9: Production of antibody-drug conjugates (3) According to the manufacturing method described in International Publication No. 2018 / 212136, an anti-CDH6 antibody (distributed In column number 11, the heavy chain consists of the amino acid sequence described in amino acid numbers 20 to 471 and In Sequence ID No. 12, the light chain consisting of the amino acid sequence described for amino acid numbers 21 to 233 Using the antibody containing the formula

[0209] [ka]

[0210] (In the formula, A indicates the binding site with the antibody.) The drug linker shown and the anti-CDH6 antibody are linked by a thioether bond. - Manufacture 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 physiological saline in 5 × 10⁻¹⁴⁻¹ 6 Cells were subcutaneously transplanted into the right side of the body of female nude mice, and 10 days after transplantation, the mice were randomly divided into groups. The procedure was performed (Day 0). The antibody-drug conjugate (2) (DAR: 7.6) was performed on Day 0. Pacli was administered intravenously at a dose of 10 mg / kg on Day 0, Day 7, and Day 14. Taxel was administered via tail vein at a dose of 15 mg / kg on Day 0 and Day 7. We established groups for monotherapy, combination therapy, and a control group administered with a solvent.

[0212] Figure 22 shows the results of combining an antibody-drug conjugate (2) with Paclitaxel. The transgestogenic gland index (TGI) with paclitaxel monotherapy was 36%. Antibody-drug conjugate The TGI rate with monotherapy of gate (2) was 69%. On the other hand, antibody-drug conjugate In combination therapy with (2) and Paclitaxel, Paclitaxel monotherapy is more effective than Paclitaxel monotherapy. A significantly superior tumor growth inhibitory effect was observed (P<0.001), and antibody-drug combination therapy was also found to be effective. A significantly superior tumor growth inhibitory effect was observed compared to monotherapy with djugate (2) (P<0 Weight loss occurred in all monotherapy and combination therapy groups. No other particularly noteworthy findings were observed.

[0213] Example 11: Antitumor test (8) Human ovarian cancer cell line OV-90, purchased from ATCC, was suspended in Matrigel and 2.5 ×10 6 Cells were subcutaneously transplanted into the right side of the body of female nude mice, and 15 days after transplantation, they were randomly selected. Grouping was performed (Day 0). Antibody-drug conjugate (3) (DAR: 7.8) Paclitaxel was administered intravenously at a dose of 10 mg / kg on Day 0. Each drug was administered via tail vein at a dose of 15 mg / kg on Day 7 and Day 14. A group receiving the drug in combination with another drug, and a control group receiving the drug as a solvent, were established.

[0214] Figure 23 shows the results of combining an antibody-drug conjugate (3) with Paclitaxel. On Day 17, the TGI rate with paclitaxel monotherapy was 80%, compared to antibody-drug therapy. The TGI rate with monotherapy of drug conjugates (3) was 97%, while with antibody-drug conjugates ( 3) The TGI rate with concomitant administration of paclitaxel was 99%. Also, antibody- In combination therapy with drug conjugate (3) and Paclitaxel, on Day 27, A significantly superior tumor growth inhibitory effect was observed compared to paclitaxel monotherapy. P<0.001). Furthermore, at Day 38, the antibody-drug conjugate (3) monotherapy A significantly superior tumor growth inhibitory effect was observed compared to administration (P<0.01(Student Calculated using 's t-test. )) Also, in all monotherapy and combination therapy groups, No particularly significant findings, such as a severe decrease, were observed.

[0215] Example 12: RNA expression analysis Human breast cancer cell line JIMT-1 was transplanted into nude mice, and antibody-drug conjugates were used. 1) Paclitaxel, or Eribulin mesylate Monotherapy group, antibody-drug conjugate (1) and Paclitaxel, or antibody- The group receiving combination therapy with a drug conjugate (1) and eribulin mesylate, A control group will be established. Tumors will be collected before and after drug administration, and RNA expression will be analyzed. Used for analysis. Tumors are subjected to RNAlater RNA stabilization after weight measurement. Incubate overnight in n Reagent, then remove RNAlater and return to -80°C. Store in [location]. RNA is processed using the RNeasy Mini Kit (QIAGEN) for QIA analysis. Extracted using Cube, the obtained RNA was analyzed using NEBNext poly(A)mRNA. Magnetic Module and NEBNext Ultra RNA Libra Create a library using the ry Prep Kit for Illumina. Ibrali is Illmina NextSeq500 / 550 High Output Using Kit v2.5, you can use Illmina NextSeq500 or 550 sequencers. Analyze with SAR and output a base call file. The obtained base call file is b Convert to fastq file using cl2fastq ver.2.20.0.422 The fastq file read is based on the human reference genome GRCh37 assembly. For the reference sequence of the transcript, STAR ver.2.5.3a15 was used for analysis. The read count for each gene was estimated using RSEM ver.1.3.016. Gene expression levels were measured between samples using EBSeq ver.1.22.0. Normalized Transcripts Per Ki using Median Ratio Normalization Method The value is shown as base million (TPM).

[0216] Compared to the average TPM of the SLFN11 gene in tumors in the control group, antibody-drug The average TPM of the SLFN11 gene after monotherapy with a substance conjugate (1) is Confirm that it shows a low value. Also, antibody-drug conjugate (1) and Paclita After concomitant administration of xel or antibody-drug conjugate (1) and Eribulin me The average TPM of the SLFN11 gene after concomitant administration of sylate was higher than that of antibodies. Drug conjugate (1) The TPM of the SLFN11 gene after monotherapy is Confirm that it shows a high value.

[0217] Furthermore, compared to the average TPM of the ABCG2 gene in tumors in the control group, Mean TPM of ABCG2 gene after monotherapy with a body-drug conjugate (1) Confirm that the latter shows a higher value. Also, antibody-drug conjugate (1) and Pacl After concomitant administration of itaxel or antibody-drug conjugate (1) and Eribulin The average TPM of the ABCG2 gene after concomitant administration of mesylate was higher than that of anti- The mean TPM of the ABCG2 gene after monotherapy with a body-drug conjugate (1) Confirm that it shows an even lower value.

[0218] Example 13: Protein expression analysis Human breast cancer cell line JIMT-1 was transplanted into nude mice, and antibody-drug conjugates were used. 1) Paclitaxel, or Eribulin mesylate Monotherapy group, antibody-drug conjugate (1) and Paclitaxel, or antibody- The group receiving combination therapy with a drug conjugate (1) and eribulin mesylate, A control group will be established. Tumors will be collected before and after drug administration, and protein analysis will be performed. This will be used for the current analysis. Tumors excised from mice are lysed and dissolved in RIPA buffer. The supernatant after centrifugation is collected as tumor lysate. SL is obtained from the tumor lysate. FN11 protein expression and β-Actin expression are controlled using a simple Western blotting system (W). Detected using es or Peggy Sue, Compass for SW v Calculate the peak area value using er.4.0.0. SLFN11 for each tumor lysate. The protein expression level ratio is calculated using the following formula.

[0219] SLFN11 protein expression level ratio = (peak expression level of SLFN11 protein at each time point) (Rear value / Peak area value of β-Actin at each time point) / (SLFN11 tamper on Day 0) (Peak area value of β-Actin / Peak area value of β-Actin on Day 0) SLFN11 protein expression levels in monotherapy groups with antibody-drug conjugates (1) The group receiving combination therapy with an antibody-drug conjugate (1) and Paclitaxel was more advanced than Bell. Or, combination therapy with antibody-drug conjugate (1) and eribulin mesylate Confirm that the SLFN11 protein expression levels are higher in the treatment group. . [Sequence Listing Free Text]

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

Claims

1. A pharmaceutical composition comprising an antibody-drug conjugate for use in combination with a tubulin inhibitor, The antibody-drug conjugate is, 【Chemistry 1】 (In the formula, A indicates the binding site with the anti-CDH6 antibody.) This is an anti-CDH6 antibody-drug conjugate in which a drug linker and an anti-CDH6 antibody are linked by a thioether bond. The anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 11 (amino acid numbers 20 to 471) and a light chain consisting of the amino acid sequence described in SEQ ID NO: 12 (amino acid numbers 21 to 233), or an antibody comprising a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 11 (amino acid numbers 20 to 470) and a light chain consisting of the amino acid sequence described in SEQ ID NO: 12 (amino acid numbers 21 to 233). The tubulin inhibitor is paclitaxel, docetaxel, cabazitaxel, or pharmacologically acceptable salts thereof, nab-paclitaxel, eribulin, or pharmacologically acceptable salts thereof, or an antibody-drug conjugate in which eribulin and an antibody are linked via a linker, or an antibody-drug conjugate in which DM4 and an antibody are linked via a linker. Pharmaceutical composition.

2. A pharmaceutical composition comprising a tubulin inhibitor for use in combination with an antibody-drug conjugate, The antibody-drug conjugate is, 【Chemistry 2】 (In the formula, A indicates the binding site with the anti-CDH6 antibody.) This is an anti-CDH6 antibody-drug conjugate in which a drug linker and an anti-CDH6 antibody are linked by a thioether bond. The anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 11 (amino acid numbers 20 to 471) and a light chain consisting of the amino acid sequence described in SEQ ID NO: 12 (amino acid numbers 21 to 233), or an antibody comprising a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 11 (amino acid numbers 20 to 470) and a light chain consisting of the amino acid sequence described in SEQ ID NO: 12 (amino acid numbers 21 to 233). The tubulin inhibitor is paclitaxel, docetaxel, cabazitaxel, or pharmacologically acceptable salts thereof, nab-paclitaxel, eribulin, or pharmacologically acceptable salts thereof, or an antibody-drug conjugate in which eribulin and an antibody are linked via a linker, or an antibody-drug conjugate in which DM4 and an antibody are linked via a linker. Pharmaceutical composition.

3. A pharmaceutical composition comprising an antibody-drug conjugate, An antibody-drug conjugate and a tubulin inhibitor are administered in combination. The antibody-drug conjugate is, 【Transformation 3】 (In the formula, A indicates the binding site with the anti-CDH6 antibody.) This is an anti-CDH6 antibody-drug conjugate in which a drug linker and an anti-CDH6 antibody are linked by a thioether bond. The anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 11 (amino acid numbers 20 to 471) and a light chain consisting of the amino acid sequence described in SEQ ID NO: 12 (amino acid numbers 21 to 233), or an antibody comprising a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 11 (amino acid numbers 20 to 470) and a light chain consisting of the amino acid sequence described in SEQ ID NO: 12 (amino acid numbers 21 to 233). The tubulin inhibitor is paclitaxel, docetaxel, cabazitaxel, or pharmacologically acceptable salts thereof, nab-paclitaxel, eribulin, or pharmacologically acceptable salts thereof, or an antibody-drug conjugate in which eribulin and an antibody are linked via a linker, or an antibody-drug conjugate in which DM4 and an antibody are linked via a linker. Pharmaceutical composition.

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

5. A pharmaceutical composition according to any one of claims 1 to 3, wherein an anti-CDH6 antibody-drug conjugate and a 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 is, 【Chemistry 4】 (In the formula, A indicates the binding site with the anti-CDH6 antibody.) This is an anti-CDH6 antibody-drug conjugate in which a drug linker and an anti-CDH6 antibody are linked by a thioether bond. The anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 11 (amino acid numbers 20 to 471) and a light chain consisting of the amino acid sequence described in SEQ ID NO: 12 (amino acid numbers 21 to 233), or an antibody comprising a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 11 (amino acid numbers 20 to 470) and a light chain consisting of the amino acid sequence described in SEQ ID NO: 12 (amino acid numbers 21 to 233). The tubulin inhibitor is paclitaxel, docetaxel, cabazitaxel, or pharmacologically acceptable salts thereof, nab-paclitaxel, eribulin, or pharmacologically acceptable salts thereof, or an antibody-drug conjugate in which eribulin and an antibody are linked via a linker, or an antibody-drug conjugate in which DM4 and an antibody are linked via a linker. Pharmaceutical composition.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the anti-CDH6 antibody comprises a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 11 (amino acid numbers 20 to 471) and a light chain consisting of the amino acid sequence described in SEQ ID NO: 12 (amino acid numbers 21 to 233).

8. The pharmaceutical composition according to any one of claims 1 to 6, wherein the anti-CDH6 antibody comprises a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 11 (amino acid numbers 20 to 470) and a light chain consisting of the amino acid sequence described in SEQ ID NO: 12 (amino acid numbers 21 to 233).

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 is formulated as follows: 【Transformation 5】 (In the formula, the antibody is an anti-CDH6 antibody, the drug linker is bound to the antibody by a thioether bond, and n represents the average number of drug linkers bound per antibody.) A pharmaceutical composition according to any one of claims 1 to 8, as shown in [the provided text].

11. The anti-CDH6 antibody-drug conjugate is formulated as follows: 【Transformation 6】 (In the formula, the antibody is an anti-CDH6 antibody, the drug linker is bound to the antibody by a thioether bond, and n represents the drug-antibody ratio.) A pharmaceutical composition according to any one of claims 1 to 8, as shown in [the provided text].

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 pharmaceutically acceptable salt thereof, or nab-paclitaxel.

14. The pharmaceutical composition according to 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 pharmaceutically acceptable salt thereof, or an antibody-drug conjugate in which eribulin and an antibody are linked via a linker.

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

21. A 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, stomach 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 carcinoma, prostate cancer, bladder cancer, gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, endometrial cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma pleomorphic, osteosarcoma, and melanoma.

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

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

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

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

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

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

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

29. 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 combination drug 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 is, 【Transformation 7】 (In the formula, A indicates the binding site with the anti-CDH6 antibody.) This is an anti-CDH6 antibody-drug conjugate in which a drug linker and an anti-CDH6 antibody are linked by a thioether bond. The anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 11 (amino acid numbers 20 to 471) and a light chain consisting of the amino acid sequence described in SEQ ID NO: 12 (amino acid numbers 21 to 233), or an antibody comprising a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 11 (amino acid numbers 20 to 470) and a light chain consisting of the amino acid sequence described in SEQ ID NO: 12 (amino acid numbers 21 to 233). The tubulin inhibitor is paclitaxel, docetaxel, cabazitaxel, or pharmacologically acceptable salts thereof, nab-paclitaxel, eribulin, or pharmacologically acceptable salts thereof, or an antibody-drug conjugate in which eribulin and an antibody are linked via a linker, or an antibody-drug conjugate in which DM4 and an antibody are linked via a linker. Combination medicine.

32. The combination pharmaceutical according to claim 31, wherein the anti-CDH6 antibody comprises a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 11 (amino acid numbers 20 to 471) and a light chain consisting of the amino acid sequence described in SEQ ID NO: 12 (amino acid numbers 21 to 233).

33. The combination pharmaceutical according to claim 31, wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 11 (amino acid numbers 20 to 470) and a light chain consisting of the amino acid sequence described in SEQ ID NO: 12 (amino acid numbers 21 to 233).

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

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

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

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

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

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

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

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

42. A combination pharmaceutical according to any one of claims 31 to 40, for the treatment of at least one selected from the group consisting of breast cancer, stomach 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 carcinoma, prostate cancer, bladder cancer, gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, endometrial cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma pleomorphic, osteosarcoma, and melanoma.

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

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

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