Combination of anti-HER2 antibody-drug conjugate and HER2 dimerization inhibitor

Abstract

A pharmaceutical composition characterized in that a combination of an (anti-HER2 antibody)-drug conjugate and a HER dimerization inhibitor is administered, in which the (anti-HER2 antibody)-drug conjugate comprises a drug linker represented by the formula shown below (wherein A represents a binding position to an anti-HER2 antibody) and an anti-HER2 antibody bonded to each other through a thioether bond; and / or a treatment method characterized in that a combination of the (anti-HER2 antibody)-drug conjugate and the HER dimerization inhibitor is administered to an individual.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition characterized in that a specific anti-HER2 antibody-drug conjugate and a HER dimerization inhibitor are administered in combination, and / or a treatment method characterized in that a specific anti-HER2 antibody-drug conjugate and a HER dimerization inhibitor are administered to an individual in combination.

Background Art

[0002] Human epidermal growth factor receptor 2 (HER2) is a transmembrane receptor belonging to the epidermal growth factor receptor subfamily of receptor protein tyrosine kinases (Non-Patent Documents 1 to 6). HER2 is overexpressed in various cancer types such as breast cancer and gastric cancer (Non-Patent Documents 7 to 12), and it has been reported that HER2 is a negative prognostic factor in breast cancer (Non-Patent Documents 13, 14).

[0003] <00​​​​​​​​​​​​​​​​Antibody-drug conjugates (ADCs), which involve attaching a cytotoxic drug to an antibody that binds to an antigen expressed on the surface of cancer cells and can be internalized within the cell, are expected to selectively deliver the drug to cancer cells, thereby accumulating the drug within the cancer cells and ultimately killing them (Non-patent documents 17-21).

[0008] One known antibody-drug conjugate is one in which an anti-HER2 antibody and a derivative of exatecan, a topoisomerase I inhibitor, are components (Patent Documents 3-6, Non-Patent Documents 22-25). [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] U.S. Patent No. 5821337 [Patent Document 2] International Publication No. 01 / 00245 [Patent Document 3] International Publication No. 2015 / 115091 [Patent Document 4] International Publication No. 2015 / 155976 [Patent Document 5] International Publication No. 2018 / 066626 [Patent Document 6] International Publication No. 2019 / 230645 [Non-patent literature]

[0010] [Non-Patent Document 1] Coussens L, et al., Science. 1985; 230(4730): 1132-1139. [Non-Patent Document 2] Graus-Porta G, et al., EMBO J. 1997;16:1647-1655. [Non-Patent Document 3] Karnagaran D, et al., EMBO J. 1996;15:254-264.

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[0011] Combination studies of anti-HER2 antibody-drug conjugates and HER2 dimerization inhibitors are being conducted with the expectation of antitumor effects similar to those of combination therapy with trastuzumab and pertuzumab (see Oncol Rep. 2013 Sep;30(3):1087-93 and Clin Cancer Res. 2014 Jan 15;20(2):456-68, etc.).

[0012] However, there are reports that the expected antitumor effect could not be confirmed with the combination of trastuzumab emtansine, an anti-HER2 antibody-drug conjugate, and pertuzumab (see Oncotarget. 2018 Aug 7; 9(61): 31915-31919, etc.).

[0013] Therefore, combination therapy with anti-HER2 antibody-drug conjugates and HER2 dimerization inhibitors has not been established.

[0014] The present invention aims to provide a pharmaceutical composition characterized by the administration of a combination of a specific anti-HER2 antibody-drug conjugate and a HER dimerization inhibitor, and / or a therapeutic method characterized by the administration of the combination of the anti-HER2 antibody-drug conjugate and the HER dimerization inhibitor to an individual. [Means for solving the problem]

[0015] The inventors of the present invention conducted intensive studies to solve the above problems and discovered that a combination of a specific anti-HER2 antibody-drug conjugate and a HER dimerization inhibitor, when administered together, exhibits excellent combined efficacy, thus completing the present invention.

[0016] In other words, the present invention provides the following [1] to

[0100] . [1] A pharmaceutical composition characterized by the administration of an anti-HER2 antibody-drug conjugate and a HER2 dimerization inhibitor in combination, The anti-HER2 antibody-drug conjugate is formulated as follows:

[0017] [ka]

[0018] (In the formula, A indicates the binding site with the anti-HER2 antibody.) A pharmaceutical composition comprising an anti-HER2 antibody-drug conjugate in which a drug linker represented by [the symbol] and an anti-HER2 antibody are linked by a thioether bond. [2] The pharmaceutical composition according to [1], wherein the anti-HER2 antibody comprises a heavy chain containing CDRH1 having the amino acid sequence described in SEQ ID NO: 3, CDRH2 having the amino acid sequence described in SEQ ID NO: 4, and CDRH3 having the amino acid sequence described in SEQ ID NO: 5, and a light chain containing CDRL1 having the amino acid sequence described in SEQ ID NO: 6, CDRL2 having the amino acid sequence described in SEQ ID NO: 7, and CDRL3 having the amino acid sequence described in SEQ ID NO: 8. [3] The pharmaceutical composition according to [1], wherein the anti-HER2 antibody comprises a heavy chain containing a heavy chain variable region consisting of the amino acid sequence described in SEQ ID NO: 9, and a light chain containing a light chain variable region consisting of the amino acid sequence described in SEQ ID NO: 10. [4] The pharmaceutical composition according to [1], wherein the anti-HER2 antibody comprises a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence described in SEQ ID NO: 2. [5] The pharmaceutical composition according to [1], wherein the anti-HER2 antibody comprises a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 11 and a light chain consisting of the amino acid sequence described in SEQ ID NO: 2. [6] The anti-HER2 antibody-drug conjugate is formulated as follows:

[0019] [ka]

[0020] (In the formula, the drug linker is bound to the anti-HER2 antibody by a thioether bond, where n represents the average number of drug linkers bound per antibody, and n is in the range of 7 to 8.) A pharmaceutical composition according to any one of [1] to [5], which is an anti-HER2 antibody-drug conjugate represented by [1]. [7] A pharmaceutical composition according to any one of [1] to [6], wherein the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan. [8] The pharmaceutical composition according to any one of [1] to [7], wherein the HER dimerization inhibitor is an antibody that binds to subdomain II of the extracellular domain of the HER2 protein. [9] The pharmaceutical composition according to any one of [1] to [7], wherein the HER dimerization inhibitor is pertuzumab.

[10] A pharmaceutical composition according to any one of claims [1] to [9], characterized in that an anti-HER2 antibody-drug conjugate and a HER2 dimerization inhibitor are each contained as active ingredients in separate formulations and administered simultaneously or at different times.

[11] A pharmaceutical composition according to any one of [1] to [9], characterized in that an anti-HER2 antibody-drug conjugate and a HER2 dimerization inhibitor are contained as active ingredients in a single formulation and administered.

[12] A pharmaceutical composition according to any one of items [1] to

[11] for the treatment of cancer.

[13] The pharmaceutical composition according to

[12] , wherein the cancer is 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, bladder cancer, prostate cancer, urothelial carcinoma, 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, sarcoma, osteosarcoma, and melanoma.

[14] The pharmaceutical composition according to

[12] , wherein the cancer is 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, bladder cancer, and prostate cancer.

[15] The pharmaceutical composition according to

[12] , wherein the cancer is breast cancer.

[16] The pharmaceutical composition according to any one of the claims

[12] to

[15] , wherein the cancer is a HER2-overexpressing cancer.

[17] The pharmaceutical composition according to

[16] , wherein the HER2-overexpressing cancer is determined to be a cancer in which HER2 expression is 3+ by immunohistochemistry.

[18] The pharmaceutical composition according to

[16] , wherein the HER2-overexpressing cancer is determined to have HER2 expression as 2+ by immunohistochemistry and to be positive for HER2 expression by in situ hybridization.

[19] The pharmaceutical composition according to any one of the claims

[12] to

[15] , wherein the cancer is a HER2-low expressing cancer.

[20] The pharmaceutical composition according to

[19] , wherein the HER2-low-expressing cancer is determined to have 2+ HER2 expression by immunohistochemistry and to be negative for HER2 expression by in situ hybridization. [twenty one] The pharmaceutical composition according to

[19] , wherein the HER2-low-expressing cancer is determined to be a cancer in which HER2 expression is 1+ by immunohistochemistry. [twenty two] The pharmaceutical composition according to

[19] , wherein the HER2-low-expressing cancer is determined to be a cancer in which HER2 expression is >0 and <1+ by immunohistochemistry. [twenty three] A pharmaceutical composition according to any one of

[12] to

[22] , characterized by exhibiting a significantly superior antitumor effect compared to administration of an anti-HER2 antibody-drug conjugate alone. [twenty four] A pharmaceutical composition according to any one of

[12] to

[23] for treating cancer that cannot be treated by monotherapy with an anti-HER2 antibody-drug conjugate. [twenty five] A pharmaceutical composition according to any one of

[12] to

[24] , characterized in that an anti-HER2 antibody-drug conjugate and a HER dimerization inhibitor exhibit a synergistic antitumor effect.

[26] A therapeutic method characterized in that an anti-HER2 antibody-drug conjugate and a HER2 dimerization inhibitor are administered in combination to an individual requiring treatment, The anti-HER2 antibody-drug conjugate is formulated as follows:

[0021] [ka]

[0022] (In the formula, A indicates the binding site with the anti-HER2 antibody.) A treatment method comprising an anti-HER2 antibody-drug conjugate in which a drug linker, indicated by [the symbol], and an anti-HER2 antibody are linked by a thioether bond.

[27] The therapeutic method according to

[26] , wherein the anti-HER2 antibody comprises a heavy chain containing CDRH1 having the amino acid sequence described in SEQ ID NO: 3, CDRH2 having the amino acid sequence described in SEQ ID NO: 4, and CDRH3 having the amino acid sequence described in SEQ ID NO: 5, and a light chain containing CDRL1 having the amino acid sequence described in SEQ ID NO: 6, CDRL2 having the amino acid sequence described in SEQ ID NO: 7, and CDRL3 having the amino acid sequence described in SEQ ID NO: 8.

[28] The therapeutic method according to

[26] , wherein the anti-HER2 antibody comprises a heavy chain containing a heavy chain variable region having the amino acid sequence described in SEQ ID NO: 9, and a light chain containing a light chain variable region having the amino acid sequence described in SEQ ID NO: 10.

[29] The therapeutic method according to

[26] , wherein the anti-HER2 antibody comprises a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence described in SEQ ID NO: 2.

[30] The therapeutic method according to

[26] , wherein the anti-HER2 antibody comprises a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 11 and a light chain consisting of the amino acid sequence described in SEQ ID NO: 2.

[31] The anti-HER2 antibody-drug conjugate is formulated as follows:

[0023] [ka]

[0024] (In the formula, the drug linker is bound to the anti-HER2 antibody by a thioether bond, where n represents the average number of drug linkers bound per antibody, and n is in the range of 7 to 8.) A therapeutic method according to any one of the items

[26] to

[30] , wherein the anti-HER2 antibody-drug conjugate is represented by

[26] .

[32] The treatment method described in any one of paragraphs

[26] to

[31] , wherein the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan.

[33] The therapeutic method according to any one of paragraphs

[26] to

[32] , wherein the HER dimerization inhibitor is an antibody that binds to subdomain II of the extracellular domain of the HER2 protein.

[34] The treatment method described in any one of the paragraphs

[26] to

[32] , wherein the HER dimerization inhibitor is pertuzumab.

[35] A therapeutic method according to any one of

[26] to

[34] , characterized in that an anti-HER2 antibody-drug conjugate and a HER2 dimerization inhibitor are each contained as active ingredients in separate formulations and administered simultaneously or at different times.

[36] A therapeutic method according to any one of

[26] to

[34] , characterized in that an anti-HER2 antibody-drug conjugate and a HER2 dimerization inhibitor are contained as active ingredients in a single formulation and administered.

[37] A treatment method for cancer as described in any one of paragraphs

[26] to

[36] .

[38] The treatment method described in

[37] , wherein the cancer is 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, bladder cancer, prostate cancer, urothelial carcinoma, 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, sarcoma, osteosarcoma, and melanoma.

[39] The treatment method according to

[37] , wherein the cancer is selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, bladder cancer, and prostate cancer.

[40] The cancer is breast cancer, and the treatment method is as described in

[37] .

[41] The cancer is a HER2-overexpressing cancer, and the treatment method is one of the items described in any one of

[37] to

[40] .

[42] The treatment method described in

[41] , wherein the cancer is characterized by HER2 overexpression and is determined to have HER2 expression of 3+ by immunohistochemistry.

[43] The treatment method described in

[41] , wherein the cancer is characterized by HER2 overexpression, in which HER2 expression is determined to be 2+ by immunohistochemistry and HER2 expression is determined to be positive by in situ hybridization.

[44] The cancer is a HER2-low expressing cancer, and the treatment method is one of the items described in any one of

[37] to

[40] .

[45] The treatment method described in

[44] , wherein the cancer is characterized by low HER2 expression, in which HER2 expression is determined to be 2+ by immunohistochemistry and HER2 expression is determined to be negative by in situ hybridization.

[46] The treatment method described in

[44] , wherein the cancer is characterized by low HER2 expression and is determined to have HER2 expression of 1+ by immunohistochemistry.

[47] The treatment method described in

[44] , wherein the HER2-low-expressing cancer is determined to have HER2 expression >0 and <1+ by immunohistochemistry.

[48] A treatment method according to any one of paragraphs

[37] to

[47] , characterized by showing a significantly superior antitumor effect compared to administration of an anti-HER2 antibody-drug conjugate alone.

[49] A treatment method described in any one of paragraphs

[37] to

[48] for treating cancer that cannot be treated with monotherapy of an anti-HER2 antibody-drug conjugate.

[50] A therapeutic method according to any one of

[37] to

[49] , characterized in that an anti-HER2 antibody-drug conjugate and a HER2 dimerization inhibitor exhibit a synergistic antitumor effect.

[51] When administered in combination with HER dimerization inhibitors, it is used to treat the disease. formula

[0025] [ka]

[0026] (In the formula, A indicates the binding site with the anti-HER2 antibody.) An anti-HER2 antibody-drug conjugate in which a drug linker, shown as indicated by the symbol, and an anti-HER2 antibody are linked by a thioether bond.

[52] The anti-HER2 antibody-drug conjugate according to

[51] , wherein the anti-HER2 antibody comprises a heavy chain containing CDRH1 having the amino acid sequence described in SEQ ID NO: 3, CDRH2 having the amino acid sequence described in SEQ ID NO: 4, and CDRH3 having the amino acid sequence described in SEQ ID NO: 5, and a light chain containing CDRL1 having the amino acid sequence described in SEQ ID NO: 6, CDRL2 having the amino acid sequence described in SEQ ID NO: 7, and CDRL3 having the amino acid sequence described in SEQ ID NO: 8.

[53] The anti-HER2 antibody-drug conjugate according to

[51] , wherein the anti-HER2 antibody comprises a heavy chain containing a heavy chain variable region consisting of the amino acid sequence described in SEQ ID NO: 9, and a light chain containing a light chain variable region consisting of the amino acid sequence described in SEQ ID NO: 10.

[54] The anti-HER2 antibody-drug conjugate according to

[51] , wherein the anti-HER2 antibody comprises a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence described in SEQ ID NO: 2.

[55] The anti-HER2 antibody-drug conjugate according to

[51] , wherein the anti-HER2 antibody comprises a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 11 and a light chain consisting of the amino acid sequence described in SEQ ID NO: 2.

[56] The anti-HER2 antibody-drug conjugate is formulated as follows:

[0027] [ka]

[0028] (In the formula, the drug linker is bound to the anti-HER2 antibody by a thioether bond, where n represents the average number of drug linkers bound per antibody, and n is in the range of 7 to 8.) An anti-HER2 antibody-drug conjugate as shown in any one of the items

[51] to

[55] .

[57] An anti-HER2 antibody-drug conjugate according to any one of the paragraphs

[51] to

[56] , wherein the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan.

[58] An anti-HER2 antibody-drug conjugate according to any one of

[51] to

[57] , wherein the HER dimerization inhibitor is an antibody that binds to subdomain II of the extracellular domain of the HER2 protein.

[59] An anti-HER2 antibody-drug conjugate as described in any one of paragraphs

[51] to

[57] , wherein the HER dimerization inhibitor is pertuzumab.

[60] An anti-HER2 antibody-drug conjugate according to any one of

[51] to

[59] , characterized in that an anti-HER2 antibody-drug conjugate and a HER2 dimerization inhibitor are each contained as active ingredients in separate formulations and administered simultaneously or at different times.

[61] An anti-HER2 antibody-drug conjugate according to any one of

[51] to

[59] , characterized in that an anti-HER2 antibody-drug conjugate and a HER2 dimerization inhibitor are contained as active ingredients in a single formulation and administered.

[62] An anti-HER2 antibody-drug conjugate as described in any one of paragraphs

[51] to

[61] for the treatment of cancer.

[63] The anti-HER2 antibody-drug conjugate described in

[62] is characterized by the cancer being at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, bladder cancer, prostate cancer, urothelial carcinoma, 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, sarcoma, osteosarcoma, and melanoma.

[64] The anti-HER2 antibody-drug conjugate described in

[62] , wherein the cancer is at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, bladder cancer, and prostate cancer.

[65] The cancer is breast cancer, as described in

[62] , an anti-HER2 antibody-drug conjugate.

[66] The cancer is a HER2-overexpressing cancer, and is an anti-HER2 antibody-drug conjugate as described in any one of paragraphs

[62] to

[65] .

[67] The anti-HER2 antibody-drug conjugate described in

[66] is a cancer in which HER2 overexpression is determined to be 3+ by immunohistochemistry.

[68] The anti-HER2 antibody-drug conjugate described in

[66] is a cancer in which HER2 overexpression is determined to be 2+ by immunohistochemistry and HER2 expression is determined to be positive by in situ hybridization.

[69] The cancer is a HER2-low expressing cancer, and is an anti-HER2 antibody-drug conjugate as described in any one of paragraphs

[62] to

[65] .

[70] The anti-HER2 antibody-drug conjugate described in

[69] is a cancer with low HER2 expression in which HER2 expression is determined to be 2+ by immunohistochemistry and HER2 expression is determined to be negative by in situ hybridization.

[71] A cancer with low HER2 expression, determined to have HER2 expression of 1+ by immunohistochemistry, is an anti-HER2 antibody-drug conjugate as described in

[69] .

[72] The anti-HER2 antibody-drug conjugate described in

[69] is a cancer with low HER2 expression, in which HER2 expression is determined to be >0 and <1+ by immunohistochemistry.

[73] An anti-HER2 antibody-drug conjugate according to any one of

[62] to

[72] , characterized by exhibiting a significantly superior antitumor effect compared to administration of an anti-HER2 antibody-drug conjugate alone.

[74] An anti-HER2 antibody-drug conjugate as described in any one of paragraphs

[62] to

[73] , for treating cancers that cannot be treated by monotherapy with an anti-HER2 antibody-drug conjugate.

[75] An anti-HER2 antibody-drug conjugate according to any one of

[62] to

[74] , characterized in that the anti-HER2 antibody-drug conjugate and the HER dimerization inhibitor exhibit a synergistic antitumor effect.

[76] HER dimerization inhibitors, when administered in combination, for the manufacture of pharmaceuticals for treating diseases. formula

[0029] [ka]

[0030] (In the formula, A indicates the binding site with the anti-HER2 antibody.) Use of an anti-HER2 antibody-drug conjugate in which a drug linker, indicated by [the symbol], and an anti-HER2 antibody are linked by a thioether bond.

[77] The use described in

[76] , wherein the anti-HER2 antibody comprises a heavy chain containing CDRH1 having the amino acid sequence described in SEQ ID NO: 3, CDRH2 having the amino acid sequence described in SEQ ID NO: 4, and CDRH3 having the amino acid sequence described in SEQ ID NO: 5, and a light chain containing CDRL1 having the amino acid sequence described in SEQ ID NO: 6, CDRL2 having the amino acid sequence described in SEQ ID NO: 7, and CDRL3 having the amino acid sequence described in SEQ ID NO: 8.

[78] The use according to

[76] , wherein the anti-HER2 antibody comprises a heavy chain containing a heavy chain variable region consisting of the amino acid sequence described in SEQ ID NO: 9, and a light chain containing a light chain variable region consisting of the amino acid sequence described in SEQ ID NO: 10.

[79] The use according to

[76] , wherein the anti-HER2 antibody comprises a heavy chain having the amino acid sequence described in SEQ ID NO: 1 and a light chain having the amino acid sequence described in SEQ ID NO: 2.

[80] The use according to

[76] , wherein the anti-HER2 antibody comprises a heavy chain having the amino acid sequence described in SEQ ID NO: 11 and a light chain having the amino acid sequence described in SEQ ID NO: 2.

[81] The anti-HER2 antibody-drug conjugate is formulated as follows:

[0031] [ka]

[0032] (In the formula, the drug linker is bound to the anti-HER2 antibody by a thioether bond, where n represents the average number of drug linkers bound per antibody, and n is in the range of 7 to 8.) The use described in any one of the paragraphs

[76] to

[80] , which is an anti-HER2 antibody-drug conjugate as shown.

[82] The use described in any one of paragraphs

[76] to

[81] , wherein the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan.

[83] The use described in any one of paragraphs

[76] to

[82] , wherein the HER dimerization inhibitor is an antibody that binds to subdomain II of the extracellular domain of the HER2 protein.

[84] The use described in any one of paragraphs

[76] to

[82] , wherein the HER dimerization inhibitor is pertuzumab.

[85] The use according to any one of paragraphs

[76] to

[84] , characterized in that an anti-HER2 antibody-drug conjugate and a HER2 dimerization inhibitor are each contained as active ingredients in separate formulations and administered simultaneously or at different times.

[86] The use according to any one of

[76] to

[84] , characterized in that an anti-HER2 antibody-drug conjugate and a HER2 dimerization inhibitor are contained as active ingredients in a single formulation and administered.

[87] Uses described in any one of paragraphs

[76] to

[86] for the treatment of cancer.

[88] The use described in

[87] , wherein the cancer is 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, bladder cancer, prostate cancer, urothelial carcinoma, 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 pleomorphoni, sarcoma, osteosarcoma, and melanoma.

[89] The use described in

[87] , wherein the cancer is 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, bladder cancer, and prostate cancer.

[90] Use as described in

[87] , where the cancer is breast cancer.

[91] Use as described in any one of paragraphs

[87] to

[90] , wherein the cancer is a HER2-overexpressing cancer.

[92] The use described in

[91] refers to cancer with HER2 overexpression, which is determined to have HER2 expression of 3+ by immunohistochemistry.

[93] The use described in

[91] is for HER2-overexpressing cancer in which HER2 expression is determined to be 2+ by immunohistochemistry and HER2 expression is determined to be positive by in situ hybridization.

[94] Use as described in any one of paragraphs

[87] to

[90] , wherein the cancer is a HER2-low expressing cancer.

[95] The use described in

[94] is for cancers with low HER2 expression in which HER2 expression is determined to be 2+ by immunohistochemistry and HER2 expression is determined to be negative by in situ hybridization.

[96] The use described in

[94] is for cancers with low HER2 expression, in which HER2 expression is determined to be 1+ by immunohistochemistry.

[97] The use described in

[94] is for cancers with low HER2 expression, where HER2 expression is determined to be >0 and <1+ by immunohistochemistry.

[98] The use according to any one of paragraphs

[76] to

[97] , characterized by exhibiting a significantly superior antitumor effect compared to administration of an anti-HER2 antibody-drug conjugate alone.

[99] Uses described in any one of paragraphs

[76] to

[98] for the treatment of cancers that cannot be treated with monotherapy of an anti-HER2 antibody-drug conjugate.

[0100] The use according to any one of

[76] to

[99] , characterized in that an anti-HER2 antibody-drug conjugate and a HER dimerization inhibitor exhibit a synergistic antitumor effect. [Effects of the Invention]

[0033] The present invention provides a pharmaceutical composition characterized by the administration of a combination of a specific anti-HER2 antibody-drug conjugate and a HER dimerization inhibitor, and / or a therapeutic method characterized by the administration of a combination of a specific anti-HER2 antibody-drug conjugate and a HER dimerization inhibitor to an individual. [Brief explanation of the drawing]

[0034] [Figure 1] The amino acid sequence of the anti-HER2 antibody heavy chain (SEQ ID NO: 1) is shown. [Figure 2] The amino acid sequence of the anti-HER2 antibody light chain (SEQ ID NO: 2) is shown. [Figure 3] The amino acid sequence of the anti-HER2 antibody CDRH1 (SEQ ID NO: 3) is shown. [Figure 4] The amino acid sequence of the anti-HER2 antibody CDRH2 (SEQ ID NO: 4) is shown. [Figure 5] The amino acid sequence of the anti-HER2 antibody CDRH3 (SEQ ID NO: 5) is shown. [Figure 6] The amino acid sequence of the anti-HER2 antibody CDRL1 (SEQ ID NO: 6) is shown. [Figure 7] The amino acid sequence (SEQ ID NO: 7) of the anti-HER2 antibody CDRL2, including the amino acid sequence (SAS), is shown. [Figure 8] The amino acid sequence of CDRL3 in the anti-HER2 antibody (SEQ ID NO: 8) is shown. [Figure 9] The amino acid sequence of the heavy chain variable region of the anti-HER2 antibody (SEQ ID NO: 9) is shown. [Figure 10] The amino acid sequence of the light chain variable region of the anti-HER2 antibody (SEQ ID NO: 10) is shown. [Figure 11] The amino acid sequence of the anti-HER2 antibody heavy chain (SEQ ID NO: 11) is shown. [Figure 12] The amino acid sequence of the HER2 protein (SEQ ID NO: 12) is shown. [Figure 13]This figure shows the tumor growth inhibitory effects of HER2-ADC(1) and pertuzumab monotherapy, as well as the combination therapy of HER2-ADC(1) and pertuzumab, in mice subcutaneously transplanted with KPL4 cells. [Figure 14] This figure shows the tumor growth inhibitory effects of HER2-ADC(1) and pertuzumab monotherapy, as well as the combination therapy of HER2-ADC(1) and pertuzumab, in mice subcutaneously transplanted with MDA-MB-453 cells. [Modes for carrying out the invention]

[0035] The following describes preferred embodiments for carrying out the present invention. The embodiments described below are merely examples of typical embodiments of the present invention, and this should not be interpreted as narrowing the scope of the invention.

[0036] 1.Definition In this invention, "HER2" is synonymous with human epidermal growth factor receptor 2 (neu, sometimes called ErbB-2), and is a transmembrane receptor belonging to the epidermal growth factor receptor (EGFR) subfamily of receptor protein tyrosine kinases, along with HER1 (EGFR, ErbB-1), HER3 (ErbB-3), and HER4 (ErbB-4). HER2 is known to play an important role in cell proliferation, differentiation, and survival in normal and tumor cells by being activated through autophosphorylation of intracellular tyrosine residues via heterodimer formation with HER1, HER3, or HER4.

[0037] In this invention, the term "HER2 protein" is used interchangeably with "HER2". HER2 protein expression can be detected using methods well known to those skilled in the art, such as immunohistochemistry (IHC).

[0038] The amino acid sequence of the HER2 protein is shown in Sequence ID No. 12 (Figure 12). In Sequence ID No. 12, the amino acid sequence described in amino acid numbers 1 to 652 is called the "extracellular domain of the HER2 protein," the amino acid sequence described in amino acid numbers 653 to 675 is called the "transmembrane domain of the HER2 protein," and the amino acid sequence described in amino acid numbers 676 to 1255 is called the "intracellular domain of the HER2 protein."

[0039] In the present invention, "subdomain II of the extracellular domain of the HER2 protein" refers to the amino acid sequence described in Sequence ID No. 12, specifically amino acid numbers 162 to 342.

[0040] In the present invention, "subdomain IV of the extracellular domain of the HER2 protein" refers to the amino acid sequence described in Sequence ID No. 12, specifically amino acid numbers 475 to 641.

[0041] In this invention, "HER2 gene" is synonymous with the human epidermal growth factor receptor type 2-related oncogene. The HER2 protein is one of the gene products of the HER2 gene.

[0042] The nucleotide sequence of the HER2 gene (cDNA) is shown in Sequence ID No. 13.

[0043] In the present invention, "anti-HER2 antibody" refers to an antibody that specifically binds to HER2 and, preferably, has the activity to internalize HER2-expressing cells by binding to HER2; in other words, an antibody that has the activity to move into HER2-expressing cells after binding to HER2.

[0044] In this invention, the terms "cancer" and "tumor" are used interchangeably.

[0045] 2. Anti-HER2 antibody-drug conjugate The anti-HER2 antibody-drug conjugate used in the present invention is,

[0046] [ka]

[0047] (In the formula, A indicates the binding site with the anti-HER2 antibody.) This is an anti-HER2 antibody-drug conjugate in which a drug linker, shown as indicated by the symbol, and an anti-HER2 antibody are linked by a thioether bond.

[0048] In this invention, the substructure of the anti-HER2 antibody-drug conjugate consisting of a linker and a drug is referred to as the "drug linker." This drug linker is bound to thiol groups (in other words, sulfur atoms of cysteine ​​residues) formed at disulfide bond sites between antibody chains (two heavy chain-to-heavy chain bonds and two heavy chain-to-light chain bonds).

[0049] The drug linker of the present invention is composed of exatecan (IUPAC name: (1S,9S)-1-amino-9-ethyl-5-fluoro-1,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione, (also expressed as chemical name: (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13(9H,15H)-dione), a topoisomerase I inhibitor.

[0050] [ka]

[0051] It is a camptothecin derivative that has antitumor effects, as shown by [the formula].

[0052] The anti-HER2 antibody-drug conjugate used in the present invention can also be represented by the following formula.

[0053] [ka]

[0054] Here, the drug linker is bound to the anti-HER2 antibody via a thioether linkage. Furthermore, n is synonymous with the so-called average drug-to-antibody ratio (DAR), representing the average number of drug linkers bound per antibody.

[0055] In the present invention, the average number of drug linkers bound per antibody in the anti-HER2 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 8, even more preferably 7 to 8, even more preferably 7.5 to 8, and even more preferably about 8.

[0056] The anti-HER2 antibody-drug conjugate used in this invention undergoes cleavage of the linker portion after entering tumor cells, and the formula

[0057] [ka]

[0058] The compound represented by [formula] is released.

[0059] The above compound is considered to be the main component of the antitumor activity of the anti-HER2 antibody-drug conjugate used in the present invention, and has been confirmed to have topoisomerase I inhibitory activity (Ogitani Y. et al., Clinical Cancer Research, 2016, Oct 15;22(20):5097-5108, Epub 2016 Mar 29).

[0060] Furthermore, the anti-HER2 antibody-drug conjugate used in the present invention is also known to have a bystander effect (Ogitani Y. et al., Cancer Science (2016) 107, 1039-1046). This bystander effect is exerted by the fact that, after the anti-HER2 antibody-drug conjugate used in the present invention is internalized in target-expressing cancer cells, the compound exerts an antitumor effect even on nearby cancer cells that do not express the target.

[0061] The anti-HER2 antibody-drug conjugate used in this invention can be manufactured by referring to the description in International Publication No. 2015 / 115091, etc.

[0062] The anti-HER2 antibody in the anti-HER2 antibody-drug conjugate used in the present invention is preferably an antibody comprising a heavy chain containing CDRH1 consisting of the amino acid sequence described in SEQ ID NO: 3 (amino acid sequence described in SEQ ID NO: 1, amino acid sequence described in SEQ ID NO: 4 (amino acid sequence described in SEQ ID NO: 1, amino5 (amino acid sequence described in SEQ ID NO: 1, amino acid sequence described in SEQ ID NO: 1, amino acid sequence described in SEQ ID NO: 1, amino acid sequence described in SEQ ID NO: 6 (amino acid sequence described in SEQ ID NO: 2, amino acid sequence described in SEQ ID NO: 2, amino acid sequence described in SEQ ID NO: 2, amino acid sequence described in SEQ ID NO: 7, amino acid sequence described in SEQ ID NO: 2, amino acid sequence described in SEQ ID NO: 8 (amino acid sequence described in SEQ ID NO: 2, amino acid sequence described in SEQ ID NO: 2, amino acid sequence described in SEQ ID NO: 8, and CDRL3 consisting of amino acid sequence described in SEQ ID NO: 2, amino acid sequence described in SEQ ID NO: 2, amino acid sequence described in SEQ ID NO: 2, amino acid sequence described in SEQ ID NO: 2, amino acid sequence described in SEQ ID NO: 8, More preferably, the antibody comprises a heavy chain including a heavy chain variable region consisting of the amino acid sequence described in SEQ ID NO: 9 (the amino acid sequence described in SEQ ID NO: 1, with amino acid numbers 1 to 120), and a light chain including a light chain variable region consisting of the amino acid sequence described in SEQ ID NO: 10 (the amino acid sequence described in SEQ ID NO: 2, with amino acid numbers 1 to 107). More preferably, the antibody comprises a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence described in SEQ ID NO: 2, or an antibody comprising a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 11 (the amino acid sequence described in SEQ ID NO: 1 to 449) and a light chain consisting of the amino acid sequence described in SEQ ID NO: 2.

[0063] The anti-HER2 antibody-drug conjugate used in the present invention is preferably trastuzumab deruxtecan.

[0064] 3. Manufacturing of anti-HER2 antibodies The HER2 protein used in this invention can be obtained by directly purifying it from HER2-expressing cells of humans or non-human mammals (rats, mice, etc.), or by preparing and using the cell membrane fraction of such cells. Furthermore, HER2 can be obtained by synthesizing it in vitro or by inducing its production in host cells through genetic manipulation. Specifically, in genetic manipulation, the protein can be obtained by incorporating HER2 cDNA into an expressionable vector and then synthesizing it in a solution containing enzymes, substrates, and energy substances necessary for transcription and translation, or by transforming other prokaryotes or eukaryotic host cells to express HER2. It is also possible to use HER2-expressing cells obtained through the aforementioned genetic manipulation, or cell lines expressing HER2, as the HER2 protein.

[0065] The DNA and amino acid sequences of HER2 are publicly available in official databases and can be accessed using accession numbers such as M11730 (Genbank) and NP_004439.2 (NCBI).

[0066] Furthermore, HER2 also includes proteins whose amino acid sequences consist of one or more amino acids substituted, deleted, and / or added to the HER2 protein, and which have equivalent biological activity to the HER2 protein.

[0067] The human HER2 protein consists of a signal sequence comprising 22 amino acid residues at the N-terminus, an extracellular domain comprising 630 amino acid residues, a transmembrane domain comprising 23 amino acid residues, and an intracellular domain comprising 580 amino acid residues.

[0068] The anti-HER2 antibodies used in this invention can be obtained by known means. For example, they can be obtained by immunizing animals with HER2 or any polypeptide selected from the amino acid sequence of HER2, using methods commonly practiced in this art, and then collecting and purifying the antibodies produced in vivo. The origin of the antigen is not limited to humans; animals can also be immunized with antigens derived from non-human animals such as mice and rats. In this case, anti-HER2 antibodies applicable to human diseases can be selected by testing the cross-reactivity between the obtained antibodies that bind to the heterologous antigen and the human antigen.

[0069] Furthermore, monoclonal antibodies can also be obtained by establishing hybridomas and fusing antibody-producing cells that produce antibodies against an antigen with myeloma cells, according to known methods (for example, Kohler and Milstein, Nature (1975) 256, p.495-497; Kennet, R. ed., Monoclonal Antibodies, p.365-367, Plenum Press, NY (1980)).

[0070] Antigens can be obtained by genetically modifying host cells to produce the gene encoding the antigen protein. Specifically, a vector capable of expressing the antigen gene is created, introduced into host cells to express the gene, and the expressed antigen is purified. Antibodies can also be obtained by immunizing animals with antigen-expressing cells or cell lines expressing the antigen, which have been genetically modified as described above.

[0071] The anti-HER2 antibody used in the present invention is preferably a genetically modified recombinant antibody, such as a chimeric antibody or a humanized antibody, which is artificially modified for purposes such as reducing heterologous antigenicity against humans, or preferably an antibody having only the gene sequence of a human-derived antibody, i.e., a human antibody. These antibodies can be manufactured using known methods.

[0072] Chimeric antibodies are antibodies in which the variable region and constant region are heterogeneous, for example, chimeric antibodies in which the variable region of a mouse or rat-derived antibody is conjugated to the constant region of a human-derived antibody (Proc. Natl. Acad. Sci. USA, 81, 6851-6855, (1984)).

[0073] Examples of humanized antibodies include antibodies in which only the complementarity determining region (CDR) of a heterologous antibody is incorporated into a human-derived antibody (Nature (1986) 321, pp. 522-525), antibodies in which, in addition to the CDR sequence of a heterologous antibody, amino acid residues of a portion of the framework of the heterologous antibody are also transplanted into a human antibody using the CDR transplantation method (International Publication No. 90 / 07861), and antibodies humanized using a gene conversion mutagenesis strategy (U.S. Patent No. 5821337).

[0074] Examples of human antibodies include antibodies produced using human antibody-producing mice that possess human chromosome fragments containing the genes for the heavy and light chains of human antibodies (see Tomizuka, K. et al., Nature Genetics (1997) 16, p.133-143; Kuroiwa, Y. et. al., Nucl. Acids Res. (1998) 26, p.3447-3448; Yoshida, H. et. al., Animal Cell Technology: Basic and Applied Aspects vol.10, p.69-73 (Kitagawa, Y., Matsuda, T. and Iijima, S. eds.), Kluwer Academic Publishers, 1999; Tomizuka, K. et. al., Proc. Natl. Acad. Sci. USA (2000) 97, p.722-727, etc.). Alternatively, antibodies obtained by phage display selected from a human antibody library can also be cited (see Wormstone, IM et. al, Investigative Ophthalmology & Visual Science. (2002) 43 (7), p.2301-2308; Carmen, S. et. al., Briefings in Functional Genomics and Proteomics (2002), 1(2), p.189-203; Siriwardena, D. et. al., Ophthalmology (2002) 109(3), p.427-431, etc.).

[0075] The anti-HER2 antibodies used in the present invention also include modified antibodies. Such modified antibodies are those that have undergone chemical or biological modification. Chemically modified antibodies include those having chemical moieties attached to an amino acid backbone, or chemical moieties attached to N- or O-linked carbohydrate chains. Biologically modified antibodies include those that have undergone post-translational modification (e.g., addition of N- or O-linked glycans, N-terminus or C-terminus processing, deamidation, aspartic acid isomerization, methionine oxidation, etc.), or those that have a methionine residue added to the N-terminus by expression using prokaryotic host cells. Furthermore, modified antibodies that have been labeled to enable detection or isolation of the anti-HER2 antibody or antigen used in the present invention, such as enzyme-labeled antibodies, fluorescently labeled antibodies, and affinity-labeled antibodies, are also included in the definition of such modified antibodies. Such modified anti-HER2 antibodies used in the present invention are useful for improving antibody stability and blood retention, reducing antigenicity, and for detection or isolation of antibodies or antigens.

[0076] Furthermore, antibody-dependent cytotoxic activity can be enhanced by modifying the glycosylation (glycosylation, defucoselation, etc.) of the anti-HER2 antibody used in the present invention. Known techniques for modifying antibody glycosylation include, but are not limited to, International Publication No. 99 / 54342, International Publication No. 00 / 61739, and International Publication No. 02 / 31140. Anti-HER2 antibodies used in the present invention also include antibodies in which such glycosylation has been modified.

[0077] It is known that antibodies produced in mammalian cultured cells have a deletion of the lysine residue at the carboxyl terminus of their heavy chain (Journal of Chromatography A, 705: 129-134 (1995)), and also that two amino acid residues, glycine and lysine, at the carboxyl terminus of the heavy chain are deleted, and a proline residue located at the carboxyl terminus is newly amidated (Analytical Biochemistry, 360: 75-83 (2007)). However, these deletions and modifications of the heavy chain sequence do not affect the antigen-binding ability or effector function (such as complement activation or antibody-dependent cell-mediated cytotoxicity) of the antibody. Therefore, the anti-HER2 antibodies used in the present invention include antibodies that have undergone such modifications and functional fragments of such antibodies, as well as deletions in which one or two amino acids are deleted at the carboxyl terminus of the heavy chain, and amidated deletions (for example, heavy chains in which the proline residue at the carboxyl terminus is amidated). However, as long as antigen-binding ability and effector function are maintained, the carboxyl-terminal deletions of the heavy chains of the anti-HER2 antibody used in the present invention are not limited to the above types. The two heavy chains constituting the anti-HER2 antibody used in the present invention may be one of the full-length heavy chains and heavy chains selected from the group consisting of the above-mentioned deletions, or a combination of either two. The quantity ratio of each deletion may be affected by the type of mammalian cultured cells and culture conditions used to produce the anti-HER2 antibody used in the present invention, but the anti-HER2 antibody used in the present invention preferably has a deletion of one amino acid residue at the carboxyl terminal of both heavy chains.

[0078] Examples of isotypes of the anti-HER2 antibody used in the present invention include IgG (IgG1, IgG2, IgG3, IgG4), but IgG1 or IgG2 are preferred. Modified versions of these can also be used as anti-HER2 antibodies according to the present invention.

[0079] 4. Manufacturing of anti-HER2 antibody-drug conjugates The drug linker intermediate used in the production of the anti-HER2 antibody-drug conjugate according to the present invention is represented by the following formula.

[0080] [ka]

[0081] The above drug linker intermediate can be represented by the chemical name N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)hexanoyl]glycylglycyl-L-phenylalanyl-N-[(2-{[(1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-1-yl]amino}-2-oxoethoxy)methyl]glycinamide, and can be manufactured with reference to the description in International Publication No. 2015 / 115091.

[0082] The anti-HER2 antibody-drug conjugate used in the present invention can be produced by reacting the aforementioned drug linker intermediate with an anti-HER2 antibody having a thiol group (also known as a sulfhydryl group).

[0083] Anti-HER2 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, by using a reducing agent such as tris(2-carboxyethyl)phosphine hydrochloride (TCEP) in an amount of 0.3 to 3 molar equivalents per interchain disulfide of the antibody, and reacting it with an anti-HER2 antibody in a buffer containing a chelating agent such as ethylenediaminetetraacetic acid (EDTA), an anti-HER2 antibody containing sulfhydryl groups can be obtained in which the interchain disulfides of the antibody are partially or completely reduced.

[0084] Furthermore, by using 2 to 20 molar equivalents of a drug linker intermediate per anti-HER2 antibody having a sulfhydryl group, an anti-HER2 antibody-drug conjugate can be produced in which 2 to 8 drugs are conjugated per antibody.

[0085] The average number of drug-bound molecules per antibody molecule in the manufactured anti-HER2 antibody-drug conjugate can be calculated, for example, by measuring the UV absorbance of the anti-HER2 antibody-drug conjugate and its conjugation precursor at two wavelengths, 280 nm and 370 nm (UV method), or by treating the antibody-drug conjugate with a reducing agent and quantifying each resulting fragment by HPLC measurement (HPLC method).

[0086] The conjugation of anti-HER2 antibodies and drug linker intermediates, and the calculation of the average number of drug conjugates per antibody in anti-HER2 antibody-drug conjugates, can be performed by referring to the information in International Publication No. 2015 / 115091, etc.

[0087] 5. HER dimerization inhibitors In the present invention, "HER dimerization inhibitor" means a drug that inhibits heterodimer formation between HER2 and HER1, HER3, or HER4 by binding to the HER2 protein. The HER dimerization inhibitor in the present invention is not limited to drugs having the above function, but preferably, an antibody that binds to subdomain II of the extracellular domain of the HER2 protein can be mentioned, and more preferably, pertuzumab can be mentioned.

[0088] 6. Pharmaceuticals The following describes a pharmaceutical composition and therapeutic method characterized by the administration of a combination of an anti-HER2 antibody-drug conjugate and an HER2 dimerization inhibitor according to the present invention.

[0089] The pharmaceutical composition and therapeutic method of the present invention may be characterized in that an anti-HER2 antibody-drug conjugate and a HER dimerization inhibitor are each contained as active ingredients in separate formulations and administered simultaneously or at different times, or it may be characterized in that an anti-HER2 antibody-drug conjugate and a HER dimerization inhibitor are each contained as active ingredients in a single formulation and administered.

[0090] The pharmaceutical composition and therapeutic method of the present invention are characterized by exhibiting significantly superior antitumor effects compared to the administration of an anti-HER2 antibody-drug conjugate alone. This makes it possible to treat cancers that cannot be treated with the administration of an anti-HER2 antibody-drug conjugate alone. Furthermore, the pharmaceutical composition and therapeutic method of the present invention are characterized by exhibiting significantly superior antitumor effects compared to the administration of a HER dimerization inhibitor alone. This makes it possible to treat cancers that cannot be treated with the administration of a HER dimerization inhibitor alone. Moreover, the pharmaceutical composition and therapeutic method of the present invention are characterized by the fact that the anti-HER2 antibody-drug conjugate and the HER dimerization inhibitor exhibit synergistic antitumor effects.

[0091] The pharmaceutical compositions and therapeutic methods of the present invention can be used for the treatment of cancer, preferably breast cancer (including triple-negative breast cancer and luminal breast cancer), gastric cancer (sometimes called gastric adenocarcinoma), colorectal cancer (sometimes called colorectal cancer, including colon cancer and rectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), esophageal cancer, head and neck cancer (including salivary gland cancer and pharyngeal cancer), gastroesophageal junction adenocarcinoma, biliary tract cancer (including bile duct cancer), Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, bladder cancer, prostate cancer, urothelial carcinoma, gastrointestinal stromal tumor, and cervical cancer. It can be used for the treatment of at least one selected from the group consisting of 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, sarcoma, osteosarcoma, and melanoma, and more preferably for the treatment of at least one cancer selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, bladder cancer, and prostate cancer.

[0092] The pharmaceutical composition and therapeutic method of the present invention can preferably be used for the treatment of HER2-overexpressing cancer. The presence or absence of HER2 expression can be confirmed, for example, by collecting tumor tissue from a cancer patient and examining the formalin-fixed, paraffin-embedded specimen (FFPE) at the gene product (protein) level using immunohistochemistry (IHC), flow cytometry, or Western blot, or by examining the gene transcription level using in situ hybridization (ISH), quantitative PCR (q-PCR), or microarray analysis. Alternatively, it can be confirmed by collecting cell-free circulating tumor DNA (ctDNA) from a cancer patient and examining it using methods such as next-generation sequencing (NGS).

[0093] Furthermore, the pharmaceutical composition and therapeutic method of the present invention can be suitably used not only for HER2 overexpression cancers, but also for HER2 low expression cancers and HER2 mutation cancers.

[0094] In the present invention, "HER2-overexpressing cancer" is not particularly limited as long as it is recognized as such by those skilled in the art, but preferably includes cancer in which HER2 expression is determined to be 3+ by immunohistochemistry, or cancer in which HER2 expression is determined to be 2+ by immunohistochemistry and HER2 expression is determined to be positive by in situ hybridization. The in situ hybridization method of the present invention includes fluorescence in situ hybridization (FISH) and dual color in situ hybridization (DISH).

[0095] In the present invention, "HER2 low-expression cancer" is not particularly limited as long as it is recognized as HER2 low-expression cancer by those skilled in the art. Preferably, it refers to cancer in which HER2 expression is determined to be 2+ by immunohistochemistry and HER2 expression is determined to be negative by in situ hybridization, cancer in which HER2 expression is determined to be 1+ by immunohistochemistry, or cancer in which HER2 expression is determined to be 0> and <1+ by immunohistochemistry.

[0096] There are no particular restrictions on the method for determining HER2 expression levels by immunohistochemistry or the method for determining HER2 expression positivity or negativity by in situ hybridization, as long as it is recognized by those skilled in the art. For example, the HER2 Testing Guide, Breast Cancer Edition, Fourth Edition (created by the Breast Cancer HER2 Testing Pathology Committee) can be cited.

[0097] The HER2-low-expressing cancers that can be used with the pharmaceutical composition and therapeutic method of the present invention are preferably HER2-low-expressing breast cancer, HER2-low-expressing gastric cancer, HER2-low-expressing colorectal cancer, or HER2-low-expressing non-small cell lung cancer, and more preferably HER2-low-expressing breast cancer.

[0098] In this invention, "HER2-mutated cancer" means cancer having a mutation in the amino acid sequence of the HER2 protein, or cancer having a mutation in the HER2 gene. Furthermore, even if the entire tumor tissue does not have a HER2 mutation, any cancer that contains cancer cells with a HER2 mutation is included in HER2-mutated cancer (see International Publication No. 2019 / 230645, etc.).

[0099] The HER2-mutated cancers that can be used with the pharmaceutical composition and treatment method of the present invention are preferably HER2-mutated non-small cell lung cancer, HER2-mutated gastric cancer, HER2-mutated breast cancer, or HER2-mutated colorectal cancer, and more preferably HER2-mutated non-small cell lung cancer or HER2-mutated gastric cancer.

[0100] The pharmaceutical composition and therapeutic method of the present invention can be suitably used in mammals, and more preferably in humans.

[0101] The antitumor effect of the pharmaceutical composition and treatment method of the present invention can be confirmed, for example, by creating a model in which cancer cells are transplanted into test animals and measuring the reduction in tumor volume and the effect of extending life after administering the pharmaceutical composition and treatment method of the present invention. Furthermore, the combined effect of the anti-HER2 antibody-drug conjugate and HER dimerizing inhibitor used in the present invention can be confirmed by comparing the antitumor effect with that of administering each of them alone.

[0102] Furthermore, the antitumor effect of the pharmaceutical composition and treatment method of the present invention can be confirmed in clinical trials by the Response Evaluation Criteria in Solid Tumors (RECIST) evaluation method, the WHO evaluation method, the Macdonald evaluation method, body weight measurement, and other methods, and can be determined by indicators such as complete response (CR), partial response (PR), progression (Progressive disease; PD), objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS).

[0103] By the method described above, the superiority of the pharmaceutical composition and treatment method of the present invention over existing cancer treatment pharmaceutical compositions and treatment methods in terms of their antitumor effect can be confirmed.

[0104] The pharmaceutical composition and therapeutic method of the present invention can slow the growth of cancer cells, suppress their proliferation, and even destroy them. Through these actions, cancer patients can achieve relief from cancer-related symptoms and an improvement in their quality of life (QOL), thus achieving therapeutic effects while preserving the patient's life. Even if the destruction of cancer cells is not achieved, the suppression and control of cancer cell proliferation can lead to a higher QOL and longer survival for cancer patients.

[0105] The pharmaceutical composition of the present invention can be applied to patients as a systemic therapy, and can also be applied locally to cancerous tissue to expect therapeutic effects.

[0106] The pharmaceutical composition of the present invention may be administered containing one or more pharmaceutically compatible components. The pharmaceutically compatible components can be appropriately selected from pharmaceutical additives and other substances commonly used in this field, depending on the dosage and concentration of the anti-HER2 antibody-drug conjugate and HER2 dimerization inhibitor used in the present invention. For example, the anti-HER2 antibody-drug conjugate used in the present invention may be administered as a pharmaceutical composition containing a buffer such as a histidine buffer, an excipient such as sucrose, and a surfactant such as polysorbate 80. The pharmaceutical composition containing the anti-HER2 antibody-drug conjugate used in the present invention can preferably be used as an injectable preparation, more preferably as an aqueous injectable preparation or a lyophilized injectable preparation, and even more preferably as a lyophilized injectable preparation.

[0107] When the pharmaceutical composition containing the anti-HER2 antibody-drug conjugate used in the present invention is an aqueous injection, it can preferably be diluted with an appropriate diluent and then administered intravenously by drip infusion. Examples of diluents include glucose solution and physiological saline solution, with glucose solution being preferred, and a 5% glucose solution being more preferred.

[0108] When the pharmaceutical composition containing the anti-HER2 antibody-drug conjugate used in the present invention is a lyophilized injectable preparation, it can preferably be dissolved in sterile water for injection, then diluted in an appropriate diluent for the required amount, and administered by intravenous drip infusion. Examples of diluents include glucose solution and physiological saline solution, with glucose solution being preferred, and a 5% glucose solution being more preferred.

[0109] Examples of routes of introduction that can be used to administer the pharmaceutical composition of the present invention include intravenous, intradermal, subcutaneous, intramuscular, and intraperitoneal routes, with intravenous routes being preferred.

[0110] The anti-HER2 antibody-drug conjugate used in the present invention can be administered to humans at intervals of 1 to 180 days, preferably at intervals of 1, 2, 3, or 4 weeks, and more preferably at intervals of 3 weeks. Furthermore, the anti-HER2 antibody-drug conjugate used in the present invention can be administered in doses of approximately 0.001 to 100 mg / kg per dose, preferably at doses of 0.8 to 12.4 mg / kg per dose. The anti-HER2 antibody-drug conjugate used in the present invention can be administered in doses of 0.8 mg / kg, 1.6 mg / kg, 3.2 mg / kg, 5.4 mg / kg, 6.4 mg / kg, 7.4 mg / kg, or 8 mg / kg at intervals of three weeks, and more preferably, in doses of 5.4 mg / kg or 6.4 mg / kg at intervals of three weeks.

[0111] The HER dimerization inhibitor used in the present invention (preferably pertuzumab) can be administered to humans, preferably in an initial dose of 840 mg, followed by a dose of 420 mg every three weeks thereafter.

[0112] The pharmaceutical composition and therapeutic method of the present invention may further contain cancer therapeutic agents other than the anti-HER2 antibody-drug conjugate and HER2 dimerization inhibitor used in the present invention. The pharmaceutical composition and therapeutic method of the present invention can also be administered in combination with other cancer therapeutic agents, thereby enhancing the antitumor effect. Other cancer therapeutic agents used for such purposes may be administered to the individual simultaneously with, separately from, or consecutively with the pharmaceutical composition of the present invention, or with varying administration intervals.Such cancer treatments are not limited to drugs with antitumor activity, but examples include irinotecan (CPT-11), cisplatin, carboplatin, oxaliplatin, fluorouracil (5-FU), gemcitabine, capecitabine, paclitaxel, docetaxel, doxorubicin, epirubicin, cyclophosphamide, and mitomycin C. C) Tegafur / Gimeracil / Oteracil combination, Cetuximab, Panitumumab, Bevacizumab, Ramucirumab, Regorafenib, Trifluridine / Tipiracil combination, Gefitinib, Erlotinib At least one selected from the group consisting of nib, afatinib, methotrexate, pemetrexed, tamoxifen, toremifene, fulvestrant, leuprorelin, goserelin, letrozole, anastrozole, progesterone formulations, and lapatinib can be mentioned.

[0113] The pharmaceutical composition and therapeutic method of the present invention can also be used in combination with radiotherapy. For example, a cancer patient may receive radiotherapy before and / or after or simultaneously with treatment with the pharmaceutical composition of the present invention.

[0114] The pharmaceutical composition and therapeutic method of the present invention can also be used as adjuvant chemotherapy in combination with surgery. The pharmaceutical composition of the present invention may be administered before surgery to reduce the size of the tumor (referred to as neoadjuvant chemotherapy or neoadjuvant therapy), or after surgery to prevent tumor recurrence (referred to as adjuvant chemotherapy or adjuvant therapy). [Examples]

[0115] The present invention will be specifically illustrated by the following examples, but the present invention is not limited to these examples. Furthermore, these examples are not intended to be interpreted restrictively in any way.

[0116] Example 1: Production of anti-HER2 antibody-drug conjugate Using a humanized anti-HER2 antibody (an antibody comprising a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 11 (the amino acid sequence described in SEQ ID NO: 1 to 449) and a light chain consisting of the amino acid sequence described in SEQ ID NO: 2) according to the manufacturing method described in International Publication No. 2015 / 115091,

[0117] [ka]

[0118] (In the formula, A indicates the binding site with the anti-HER2 antibody.) An anti-HER2 antibody-drug conjugate (referred to as "HER2-ADC(1)" in this invention) was prepared by linking a drug linker, shown in the diagram, with an anti-HER2 antibody via a thioether bond. The DAR of HER2-ADC(1) is 7.8.

[0119] Example 2: Antitumor test (1) Mice: Female BALB / c nude mice (Charles River Co., Ltd., Japan) aged 5-6 weeks were used in the experiment.

[0120] Measurement and calculation formula: In all studies, the longest and shortest diameters of the tumor were measured twice a week using an electronic digital caliper, and the tumor volume (mm³) was calculated. 3 The calculation was performed. The formula is as follows: Tumor volume (mm 3 ) = 1 / 2 × major axis (mm) × minor axis (mm) 2 HER2-ADC(1) was diluted with ABS buffer (10 mM acetate buffer (pH 5.5), 5% sorbitol) and administered intravenously at a volume of 10 mL / kg. Pertuzumab was diluted with physiological saline and administered intravenously at a volume of 10 mL / kg.

[0121] KPL-4 cells, a human breast cancer cell line obtained from Dr. Junichi Kurebayashi of Kawasaki Medical University (British Journal of Cancer, (1999) 79(5 / 6).707-717), were suspended in physiological saline and 1.5 × 10⁶ cells were used. 7 Cells were subcutaneously transplanted into the right lateral region of female nude mice, and randomization was performed 17 days after transplantation (Day 0). HER2-ADC(1) was administered intravenously at a dose of 7.5 mg / kg on Day 0. Pertuzumab was administered intravenously at a dose of 30 mg / kg on Day 0 and 15 mg / kg on Day 7. Groups were established for monotherapy, combination therapy, and a control group administered via solvent.

[0122] Figure 13 shows the results of combination therapy with HER2-ADC(1) and Pertuzumab. The tumor growth inhibition rate (TGI) on the evaluation day for the efficacy of Pertuzumab monotherapy was 66%, and no tumor disappearance was observed in any of the 6 patients. The TGI with HER2-ADC(1) monotherapy was 83%, and tumor disappearance was observed in 1 out of 6 patients. On the other hand, combination therapy with HER2-ADC(1) and Pertuzumab showed a significantly better tumor growth inhibition effect than Pertuzumab monotherapy (P<0.001 (calculated by Dunnett's test; the same applies below)), with a TGI of 100%, and tumor disappearance was observed in 4 out of 6 patients. In the figure, the horizontal axis represents the number of days after the first administration, and the vertical axis represents the tumor volume. Furthermore, no particularly notable findings such as weight loss were observed in any of the monotherapy or combination therapy groups. In the following evaluation examples of antitumor trials, unless otherwise specified, the trials were conducted using the same methods as those used in this evaluation example.

[0123] Example 3: Antitumor test (2) Human breast cancer cell line MDA-MB-453 (see Breast Cancer Res. 2011 Aug 12;13(4):215 and J Mol Diagn. 2017 Mar; 19(2): 244-254, etc.), purchased from ATCC (American Type Culture Collection), was suspended in a Matrigel matrix and divided into 1.0 × 10⁶ cells. 7 Cells were subcutaneously transplanted into the right lateral region of female nude mice, and randomization was performed 7 days after transplantation (Day 0). HER2-ADC(1) was administered intravenously at a dose of 0.5 mg / kg on Day 0. Pertuzumab was administered intravenously at a dose of 30 mg / kg on Day 0, and 15 mg / kg on Days 7 and 14. Groups receiving each agent as a monotherapy, a group receiving the agent in combination, and a control group receiving the agent in a solvent were established.

[0124] Figure 14 shows the results of combination therapy with HER2-ADC(1) and Pertuzumab. The TGI on the evaluation day for Pertuzumab monotherapy was 95%, with tumor disappearance observed in 3 out of 6 patients. The TGI for HER2-ADC(1) monotherapy was 74%, with no tumor disappearance observed in any of the 6 patients. On the other hand, combination therapy with HER2-ADC(1) and Pertuzumab showed significantly better tumor growth inhibition than HER2-ADC(1) monotherapy (P<0.001), with a TGI of 99%, and tumor disappearance observed in 5 out of 6 patients. Furthermore, no particularly significant findings such as weight loss were observed in either the monotherapy or combination therapy groups. [Sequence Listing Free Text]

[0125] 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 anti-HER2 antibody CDRH1 Sequence ID 4: Amino acid sequence of the anti-HER2 antibody CDRH2 SEQ ID NO: 5: Amino acid sequence of the anti-HER2 antibody CDRH3 Sequence ID 6: Amino acid sequence of CDRL1 in the anti-HER2 antibody Sequence ID 7: Amino acid sequence (SAS) of CDRL2 of the anti-HER2 antibody Sequence ID 8: Amino acid sequence of CDRL3 in the anti-HER2 antibody SEQ ID NO: 9: Amino acid sequence of the heavy chain variable region of the anti-HER2 antibody Sequence ID 10: Amino acid sequence of the light chain variable region of an anti-HER2 antibody SEQ ID NO: 11: Amino acid sequence of the heavy chain of the anti-HER2 antibody Sequence ID 12: Amino acid sequence of the HER2 protein Sequence ID 13: Nucleotide sequence of the HER2 gene (cDNA)

Claims

1. This is a combination drug containing an anti-HER2 antibody-drug conjugate and a HER2 dimerization inhibitor. The anti-HER2 antibody-drug conjugate and the HER2 dimerization inhibitor are administered in combination. The anti-HER2 antibody-drug conjugate is formulated as follows: 【Chemistry 1】 (In the formula, A indicates the binding site with the anti-HER2 antibody.) This is an anti-HER2 antibody-drug conjugate in which a drug linker and an anti-HER2 antibody are linked by a thioether bond. The aforementioned HER dimerization inhibitor is a combination drug, which is an antibody that binds to subdomain II of the extracellular domain of the HER2 protein.

2. The combination pharmaceutical according to claim 1, wherein the anti-HER2 antibody comprises a heavy chain containing CDRH1 having the amino acid sequence described in SEQ ID NO: 3, CDRH2 having the amino acid sequence described in SEQ ID NO: 4, and CDRH3 having the amino acid sequence described in SEQ ID NO: 5, and a light chain containing CDRL1 having the amino acid sequence described in SEQ ID NO: 6, CDRL2 having the amino acid sequence described in SEQ ID NO: 7, and CDRL3 having the amino acid sequence described in SEQ ID NO:

8.

3. The combination pharmaceutical according to claim 1, wherein the anti-HER2 antibody comprises a heavy chain including a heavy chain variable region consisting of the amino acid sequence described in SEQ ID NO: 9, and a light chain including a light chain variable region consisting of the amino acid sequence described in SEQ ID NO:

10.

4. The combination pharmaceutical according to claim 1, wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence described in SEQ ID NO:

2.

5. The combination pharmaceutical according to claim 1, wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence described in SEQ ID NO: 11 and a light chain consisting of the amino acid sequence described in SEQ ID NO:

2.

6. The anti-HER2 antibody-drug conjugate is formulated as follows: 【Chemistry 2】 The combination pharmaceutical according to any one of claims 1 to 5, which is an anti-HER2 antibody-drug conjugate represented by the formula (wherein the formula the drug linker is bound to the anti-HER2 antibody by a thioether bond, n represents the average number of drug linkers bound per antibody, where n is in the range of 7 to 8).

7. The combination pharmaceutical according to any one of claims 1 to 6, wherein the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan.

8. The combination pharmaceutical according to any one of claims 1 to 7, wherein the HER dimerization inhibitor is pertuzumab.

9. The combination pharmaceutical according to claim 1, wherein the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan and the HER2 dimerization inhibitor is pertuzumab.

10. A combination pharmaceutical according to any one of claims 1 to 9, characterized in that an anti-HER2 antibody-drug conjugate and a HER2 dimerization inhibitor are each contained as active ingredients in separate formulations and administered simultaneously or at different times.

11. A combination pharmaceutical according to any one of claims 1 to 9, characterized in that an anti-HER2 antibody-drug conjugate and a HER2 dimerization inhibitor are contained as active ingredients in a single formulation and administered.

12. A combination pharmaceutical for the treatment of cancer, according to any one of claims 1 to 11.

13. The combination pharmaceutical according to claim 12, wherein the cancer is 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, bladder cancer, prostate cancer, urothelial carcinoma, 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, sarcoma, osteosarcoma, and melanoma.

14. The combination pharmaceutical according to claim 12 for the treatment of at least one cancer 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, bladder cancer, and prostate cancer.

15. The combination drug according to claim 12, wherein the cancer is breast cancer.

16. The combination pharmaceutical according to any one of claims 12 to 15, wherein the cancer is a cancer characterized by HER2 overexpression.

17. The combination drug according to claim 16, wherein the cancer with HER2 overexpression is a cancer in which HER2 expression is determined to be 3+ by immunohistochemistry.

18. The combination drug according to claim 16, wherein the HER2-overexpressing cancer is a cancer in which HER2 expression is determined to be 2+ by immunohistochemistry and HER2 expression is determined to be positive by in situ hybridization.

19. The combination pharmaceutical according to any one of claims 12 to 15, wherein the cancer is a cancer with low HER2 expression.

20. The combination drug according to claim 19, wherein the cancer with low HER2 expression is determined to have HER2 expression as 2+ by immunohistochemistry and to have negative HER2 expression by in situ hybridization.

21. The combination drug according to claim 19, wherein the cancer with low HER2 expression is a cancer in which HER2 expression is determined to be 1+ by immunohistochemistry.

22. The combination drug according to claim 19, wherein the cancer with low HER2 expression is a cancer in which HER2 expression is determined to be >0 and <1+ by immunohistochemistry.

23. The combination pharmaceutical according to any one of claims 12 to 22, characterized in that the anti-HER2 antibody-drug conjugate and the HER dimerization inhibitor exhibit significantly superior antitumor effects compared to the administration of the anti-HER2 antibody-drug conjugate alone.

24. The combination pharmaceutical according to any one of claims 12 to 23, wherein an anti-HER2 antibody-drug conjugate and a HER2 dimerization inhibitor are used to treat cancer that cannot be treated by administration of the anti-HER2 antibody-drug conjugate alone.

25. A combination pharmaceutical according to any one of claims 12 to 24, characterized in that an anti-HER2 antibody-drug conjugate and a HER dimerization inhibitor exhibit a synergistic antitumor effect.

26. A pharmaceutical composition comprising an anti-HER2 antibody-drug conjugate for use in combination with a HER dimerization inhibitor, The anti-HER2 antibody-drug conjugate is formulated as follows: 【Transformation 3】 (In the formula, A indicates the binding site with the anti-HER2 antibody.) This is an anti-HER2 antibody-drug conjugate in which a drug linker and an anti-HER2 antibody are linked by a thioether bond. The HER dimerization inhibitor is a pharmaceutical composition in which an antibody binds to subdomain II of the extracellular domain of the HER2 protein.

27. The pharmaceutical composition according to claim 26, wherein the anti-HER2 antibody comprises a heavy chain containing CDRH1 having the amino acid sequence described in SEQ ID NO: 3, CDRH2 having the amino acid sequence described in SEQ ID NO: 4, and CDRH3 having the amino acid sequence described in SEQ ID NO: 5, and a light chain containing CDRL1 having the amino acid sequence described in SEQ ID NO: 6, CDRL2 having the amino acid sequence described in SEQ ID NO: 7, and CDRL3 having the amino acid sequence described in SEQ ID NO:

8.

28. The pharmaceutical composition according to claim 26, wherein the anti-HER2 antibody comprises a heavy chain including a heavy chain variable region consisting of the amino acid sequence described in SEQ ID NO: 9, and a light chain including a light chain variable region consisting of the amino acid sequence described in SEQ ID NO:

10.

29. The pharmaceutical composition according to claim 26, wherein the anti-HER2 antibody is an antibody comprising a heavy chain having the amino acid sequence described in SEQ ID NO: 1 and a light chain having the amino acid sequence described in SEQ ID NO:

2.

30. The pharmaceutical composition according to claim 26, wherein the anti-HER2 antibody is an antibody comprising a heavy chain having the amino acid sequence described in SEQ ID NO: 11 and a light chain having the amino acid sequence described in SEQ ID NO:

2.

31. The anti-HER2 antibody-drug conjugate is formulated as follows: 【Chemistry 4】 A pharmaceutical composition according to any one of claims 26 to 30, which is an anti-HER2 antibody-drug conjugate represented by the formula (wherein the drug linker is linked to the anti-HER2 antibody by a thioether bond, n is the average number of drug linkers linked per antibody, where n is in the range of 7 to 8).

32. The pharmaceutical composition according to any one of claims 26 to 31, wherein the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan.

33. The pharmaceutical composition according to any one of claims 26 to 32, wherein the HER dimerization inhibitor is pertuzumab.

34. The pharmaceutical composition according to claim 26, wherein the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan and the HER2 dimerization inhibitor is pertuzumab.

35. A pharmaceutical composition according to any one of claims 26 to 34, characterized in that an anti-HER2 antibody-drug conjugate and a HER2 dimerization inhibitor are each contained as active ingredients in different formulations and administered simultaneously or at different times.

36. A pharmaceutical composition according to any one of claims 26 to 34, characterized in that an anti-HER2 antibody-drug conjugate and a HER2 dimerization inhibitor are contained as active ingredients in a single formulation and administered.

37. A pharmaceutical composition according to any one of claims 26 to 36 for the treatment of cancer.

38. The pharmaceutical composition according to claim 37, wherein the cancer is 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, bladder cancer, prostate cancer, urothelial carcinoma, 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, sarcoma, osteosarcoma, and melanoma.

39. The pharmaceutical composition according to claim 37, wherein the cancer is 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, bladder cancer, and prostate cancer.

40. The pharmaceutical composition according to claim 37, wherein the cancer is breast cancer.

41. The pharmaceutical composition according to any one of claims 37 to 40, wherein the cancer is a cancer characterized by HER2 overexpression.

42. The pharmaceutical composition according to claim 41, wherein the cancer with HER2 overexpression is a cancer in which HER2 expression is determined to be 3+ by immunohistochemistry.

43. The pharmaceutical composition according to claim 41, wherein the HER2-overexpressing cancer is a cancer in which HER2 expression is determined to be 2+ by immunohistochemistry and HER2 expression is determined to be positive by in situ hybridization.

44. The pharmaceutical composition according to any one of claims 37 to 40, wherein the cancer is a cancer with low HER2 expression.

45. The pharmaceutical composition according to claim 44, wherein the cancer with low HER2 expression is determined to have HER2 expression as 2+ by immunohistochemistry and to have negative HER2 expression by in situ hybridization.

46. The pharmaceutical composition according to claim 44, wherein the cancer with low HER2 expression is a cancer in which HER2 expression is determined to be 1+ by immunohistochemistry.

47. The pharmaceutical composition according to claim 44, wherein the cancer with low HER2 expression is a cancer in which HER2 expression is determined to be >0 and <1+ by immunohistochemistry.

48. The pharmaceutical composition according to any one of claims 37 to 47, characterized in that the anti-HER2 antibody-drug conjugate and the HER dimerization inhibitor exhibit significantly superior antitumor effects compared to the administration of the anti-HER2 antibody-drug conjugate alone.

49. A pharmaceutical composition according to any one of claims 37 to 48, wherein an anti-HER2 antibody-drug conjugate and a HER2 dimerization inhibitor are used to treat cancer that cannot be treated by administration of the anti-HER2 antibody-drug conjugate alone.

50. A pharmaceutical composition according to any one of claims 37 to 49, characterized in that an anti-HER2 antibody-drug conjugate and a HER dimerization inhibitor exhibit a synergistic antitumor effect.

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