Treatment of HER2-mutated cancers by administration of anti-HER2 antibody-drug conjugates

Abstract

A therapeutic agent for treating cancers with HER2 mutations, which comprises an anti-HER2 antibody-drug conjugate as an active ingredient, wherein in the anti-HER2 antibody-drug conjugate, a drug-linker represented by the following formula (wherein A represents the position of linkage to the anti-HER2 antibody) is conjugated to the antibody via a thioether bond, and / or a method for treating cancers, which comprises administering the anti-HER2 antibody-drug conjugate to a subject determined to have a cancer with HER2 mutations.

Description

Technical Field

[0001] The present invention relates to a therapeutic agent for HER2-mutated cancer, which comprises a specific anti-HER2 antibody-drug conjugate, and / or a method for treating cancer, which comprises administering a specific anti-HER2 antibody-drug conjugate to a subject determined to have HER2-mutated cancer. 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 References 1 to 6).

[0003] HER2 is overexpressed in various cancer types such as breast cancer and gastric cancer (Non-Patent References 7 to 12), and has been reported as a negative prognostic factor in breast cancer (Non-Patent References 13 and 14). As anti-HER2 drugs effective against cancers overexpressing HER2, trastuzumab, trastuzumab emtansine, pertuzumab, lapatinib, etc. are known.

[0004] Meanwhile, HER2 has mutants, which are known as one of the cancer driver mutations. It has been reported that such HER2-mutated cancers are present, for example, in non-small cell lung cancer at a percentage of about 2% to 3% (Non-Patent References 15 to 20). Studies have been conducted to verify the effect of anti-HER2 drugs on HER2-mutated cancers (Non-Patent References 21 and 22).

[0005] Therefore, it is expected that an antibody-drug conjugate (ADC) causes the accumulation of a drug in cancer cells and kills the cancer cells, the ADC having a cytotoxic drug conjugated to an antibody, the antigen of the antibody being expressed on the surface of the cancer cells, and the antibody also binding to an antigen capable of being internalized by the cell, and thus being able to selectively deliver the drug to the cancer cells (Non-Patent References 23 to 27).

[0006] As such an antibody-drug conjugate, an antibody-drug conjugate containing an anti-HER2 antibody and a derivative of exatecan as its components is known, and exatecan is a topoisomerase I inhibitor (Patent References 1 to 3 and Non-Patent References 28 to 31).

[0007] Citation List

[0008] Patent Documents

[0009] Patent Reference 1

[0010] International Publication No. WO 2015 / 115091

[0011] Patent Reference 2

[0012] International Publication Number WO 2015 / 155976

[0013] Patent Reference 3

[0014] International Publication Number WO 2018 / 066626

[0015] Non-Patent Literature

[0016] Non-Patent Reference 1: Coussens L, et al., Science. 1985; 230(4730): 1132-1139.

[0017] Non-Patent Reference 2: Graus-Porta G, et al., EMBO J. 1997;16:1647-1655.

[0018] Non-Patent Reference 3: Karnagaran D, et al., EMBO J. 1996;15:254-264.

[0019] Non-Patent Reference 4: Sliwkowski MX, et al., J Biom Chem. 1994; 269:14661-14665.

[0020] Non-Patent Reference 5: Di Fore PP, et al., Science. 1987; 237: 178-182.

[0021] Non-Patent Reference 6: Hudziak RM, et al., Proc Natl Acad Sci U S A. 1987;84: 7159-7163.

[0022] Non-Patent Reference 7: Hardwick R, et al., Eur. J Surg Oncol. 1997 (23):30-35.

[0023] Non-Patent Reference 8: Korkaya H, et al., Oncogene. 2008;27(47):6120-6130.

[0024] Non-Patent Reference 9: Yano T, et al., Oncol Rep. 2006; 15(1): 65-71.

[0025] Non - Patent Reference 10: Slamon DJ, et al., Science. 1987; 235: 177 - 182.

[0026] Non - Patent Reference 11: Gravalos C, et al., Ann Oncol 19: 1523 - 1529, 2008.

[0027] Non - Patent Reference 12: Fukushige S et al., Mol Cell Biol 6: 955 - 958, 1986.

[0028] Non - Patent Reference 13: Slamon DJ, et al., Science. 1989; 244: 707 - 712.

[0029] Non - Patent Reference 14: Kaptain S, et al., Diagn Mol Pathol 10: 139 - 152,2001.

[0030] Non - Patent Reference 15: Mazieres J, et al., J Clin Oncol 2013; 31: 1997 - 2003.

[0031] Non - Patent Reference 16: Arcila ME, et al., Clin Cancer Res 2012; 18: 4910 - 8.

[0032] Non - Patent Reference 17: Li C, et al., J Thorac Oncol 2012; 7: 85 - 9.

[0033] Non - Patent Reference 18: Tomizaka K, et al., Lung Cancer 2011; 74: 139 - 44.

[0034] Non - Patent Reference 19: Shigematsu H, et al., Cancer Res 2005; 65: 1642 - 6.

[0035] Non - Patent Reference 20: Yokoyama T, et al., Cancer Sci 2006; 97: 753 - 9.

[0036] Non - Patent Reference 21: Connell CM, et al., ESMO Open 2017; 2:e000279.

[0037] Non - Patent Reference 22: M.G.Kris, et al., Annals of Oncology 26: 1421 - 1427,2015.

[0038] Non - Patent Reference 23: Ducry, L., et al., Bioconjugate Chem. (2010) 21, 5 - 13.

[0039] Non - Patent Reference 24: Alley, S. C., et al., Current Opinion in ChemicalBiology (2010) 14, 529 - 537.

[0040] Non - Patent Reference 25: Damle N. K. Expert Opin. Biol. Ther. (2004) 4,1445 - 1452.

[0041] Non - Patent Reference 26: Senter P. D., et al., Nature Biotechnology (2012)30, 631 - 637.

[0042] Non - Patent Reference 27: Howard A. et al., J Clin Oncol 29: 398 - 405.

[0043] Non - Patent Reference 28: Ogitani Y. et al., Clinical Cancer Research (2016)22(20), 5097 - 5108.

[0044] Non - Patent Reference 29: Ogitani Y. et al., Cancer Science (2016) 107, 1039 - 1046.

[0045] Non - Patent Reference 30: Doi T, et al., Lancet Oncol 2017; 18: 1512 - 22.

[0046] Non - Patent Reference 31: Takegawa N, et al., Int. J. Cancer: 141, 1682 - 1689(2017). Summary of the Invention

[0048] Technical Problem

[0049] An anti-HER2 antibody-drug conjugate known to contain an anti-HER2 antibody and a derivative of irinotecan (which is a topoisomerase I inhibitor) as active ingredients exerts an anti-tumor effect on cancers determined to have HER2 overexpression. However, it has not been proven that the anti-HER2 antibody-drug conjugate can exert an anti-tumor effect on HER2-mutated cancers. The object of the present invention is to provide a therapeutic agent for HER2-mutated cancers, which contains a specific anti-HER2 antibody-drug conjugate, and / or a method for treating cancers, which includes administering a specific anti-HER2 antibody-drug conjugate to a subject determined to have a HER2-mutated cancer.

[0050] Solution to the Problem

[0051] As a result of intensive studies conducted to solve the above problems, the present inventors found that a specific anti-HER2 antibody-drug conjugate exhibits excellent anti-tumor effects on HER2-mutated cancers, thereby completing the present invention.

[0052] Accordingly, the present invention provides the following [1] to

[176] . [1]

[0054] A therapeutic agent for HER2-mutated cancers, which contains an anti-HER2 antibody-drug conjugate as an active ingredient, in which a drug-linker represented by the following formula is conjugated to an anti-HER antibody through a thioether bond:

[0055] [Formula 1]

[0056]

[0057] wherein A represents the position of connection to the anti-HER2 antibody. [2]

[0059] A therapeutic agent according to [1], wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L, Q711H, G727A, T733I, E744G, N745D, L755P, L755A, L755F, S760F, D769H, D769N, D769Y, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, A775G, G776delinsLC, G776C, G776delinsAVGC, G776delinsVV, G776_V777insL, G776L, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779P, S779_P780insVGS, P780_Y781insGSP, R784C, R784H, L785R, L786V, T791I, G804S, L807F, S819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, W906*, T917S, Q943*, S1007* and S1151L. [3]

[0061] A therapeutic agent according to [2], wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L and S310F. [4]

[0063] A therapeutic agent according to [1], wherein the HER2 mutation in the HER2-mutated cancer is an exon 20 insertion mutation. [5]

[0065] A therapeutic agent according to [4], wherein the exon 20 insertion mutation is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, G776delinsLC, G776delinsAVGC, G776delinsVV, G776_V777insL, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779_P780insVGS, and P780_Y781insGSP. [6]

[0067] A therapeutic agent according to [5], wherein the exon 20 insertion mutation is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, and G776delinsVC. [7]

[0069] A therapeutic agent according to [1], wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the transmembrane domain of the HER2 protein. [8]

[0071] A therapeutic agent according to [7], wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is at least one selected from the group consisting of: V659E, G660D, I654V, I655V, and I661V. [9]

[0073] A therapeutic agent according to [8], wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is G660D.

[10]

[0075] A therapeutic agent according to [1], wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the extracellular domain of the HER2 protein.

[11]

[0077] The therapeutic agent according to

[10] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is at least one selected from the group consisting of: S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, and R647G.

[12]

[0079] The therapeutic agent according to

[11] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is S310F.

[13]

[0081] The therapeutic agent according to any one of [1] to

[12] , wherein the cancer in the HER2-mutated cancer is at least one selected from the group consisting of: non-small cell lung cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, salivary gland cancer, adenocarcinoma of the gastroesophageal junction, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, and uterine carcinosarcoma.

[14]

[0083] The therapeutic agent according to any one of [1] to

[12] , wherein the cancer is non-small cell lung cancer.

[15]

[0085] The therapeutic agent according to

[14] , wherein the non-small cell lung cancer is unresectable and / or metastatic non-small cell lung cancer.

[16]

[0087] The therapeutic agent according to any one of [1] to

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

[17]

[0089] The therapeutic agent according to any one of [1] to

[15] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain composed of the amino acid sequence shown in SEQ ID NO: 1 and a light chain composed of the amino acid sequence shown in SEQ ID NO: 2.

[18]

[0091] A therapeutic agent according to any one of [1] to

[17] , wherein the average number of drug-linker units conjugated to each antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7 to 8.

[19]

[0093] A therapeutic agent according to any one of [1] to

[17] , wherein the average number of drug-linker units conjugated to each antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7.5 to 8.

[20]

[0095] A therapeutic agent according to any one of [1] to

[19] , wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is in the range of 5.4 mg / kg to 8 mg / kg.

[21]

[0097] A therapeutic agent according to any one of [1] to

[19] , wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is 6.4 mg / kg.

[22]

[0099] A therapeutic agent according to any one of [1] to

[21] , wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

[23]

[0101] A therapeutic agent for the treatment of HER2-mutated cancer, comprising an anti-HER2 antibody-drug conjugate represented by the following formula as an active ingredient:

[0102] [Formula 2]

[0103]

[0104] wherein the drug-linker is conjugated to the anti-HER2 antibody via a thioether bond, and n is the average number of drug-linker units conjugated to each antibody molecule.

[24]

[0106] Therapeutic agent according to

[23] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L, Q711H, G727A, T733I, E744G, N745D, L755P, L755A, L755F, S760F, D769H, D769N, D769Y, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, A775G, G776delinsLC, G776C, G776delinsAVGC, G776delinsVV, G776_V777insL, G776L, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779P, S779_P780insVGS, P780_Y781insGSP, R784C, R784H, L785R, L786V, T791I, G804S, L807F, S819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, W906*, T917S, Q943*, S1007* and S1151L.

[25]

[0108] Therapeutic agent according to

[24] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L and S310F.

[26]

[0110] Therapeutic agent according to

[23] , wherein the HER2 mutation in the HER2-mutated cancer is an exon 20 insertion mutation.

[27]

[0112] A therapeutic agent according to

[26] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, G776delinsLC, G776delinsAVGC, G776delinsVV, G776_V777insL, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779_P780insVGS, and P780_Y781insGSP.

[28]

[0114] A therapeutic agent according to

[27] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, and G776delinsVC.

[29]

[0116] A therapeutic agent according to

[23] , wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the transmembrane domain of the HER2 protein.

[30]

[0118] A therapeutic agent according to

[29] , wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is at least one selected from the group consisting of: V659E, G660D, I654V, I655V, and I661V.

[31]

[0120] A therapeutic agent according to

[30] , wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is G660D.

[32]

[0122] A therapeutic agent according to

[23] , wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the extracellular domain of the HER2 protein.

[33]

[0124] Therapeutic agent according to

[32] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is at least one selected from the group consisting of: S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, and R647G.

[34]

[0126] Therapeutic agent according to

[33] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is S310F.

[35]

[0128] Therapeutic agent according to any one of

[23] to

[34] , wherein the cancer in the HER2-mutated cancer is at least one selected from the group consisting of: non-small cell lung cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, and uterine carcinosarcoma.

[36]

[0130] Therapeutic agent according to any one of

[23] to

[34] , wherein the cancer is non-small cell lung cancer.

[37]

[0132] Therapeutic agent according to

[36] , wherein the non-small cell lung cancer is unresectable and / or metastatic non-small cell lung cancer.

[38]

[0134] Therapeutic agent according to any one of

[23] to

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

[39]

[0136] Therapeutic agent according to any one of

[23] to

[37] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2.

[40]

[0138] A therapeutic agent according to any one of

[23] to

[39] , wherein the average number of drug-linker units conjugated to each antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7 to 8.

[41]

[0140] A therapeutic agent according to any one of

[23] to

[39] , wherein the average number of drug-linker units conjugated to each antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7.5 to 8.

[42]

[0142] A therapeutic agent according to any one of

[23] to

[41] , wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is in the range of 5.4 mg / kg to 8 mg / kg.

[43]

[0144] A therapeutic agent according to any one of

[23] to

[41] , wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is 6.4 mg / kg.

[44]

[0146] A therapeutic agent according to any one of

[23] to

[43] , wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

[45]

[0148] A method for treating cancer, comprising administering an anti-HER2 antibody-drug conjugate to a subject determined to have a cancer with a HER2 mutation, wherein in the anti-HER2 antibody-drug conjugate, a drug-linker represented by the following formula is conjugated to the anti-HER2 antibody through a thioether bond:

[0149] [Formula 3]

[0150]

[0151] wherein A represents the position of attachment to the anti-HER2 antibody.

[46]

[0153] The treatment method according to

[45] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L, Q711H, G727A, T733I, E744G, N745D, L755P, L755A, L755F, S760F, D769H, D769N, D769Y, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, A775G, G776delinsLC, G776C, G776delinsAVGC, G776delinsVV, G776_V777insL, G776L, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779P, S779_P780insVGS, P780_Y781insGSP, R784C, R784H, L785R, L786V, T791I, G804S, L807F, S819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, W906*, T917S, Q943*, S1007* and S1151L.

[47]

[0155] The treatment method according to

[46] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L and S310F.

[48]

[0157] The treatment method according to

[45] , wherein the HER2 mutation in the HER2-mutated cancer is an exon 20 insertion mutation.

[49]

[0159] The treatment method according to

[48] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, G776delinsLC, G776delinsAVGC, G776delinsVV, G776_V777insL, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779_P780insVGS, and P780_Y781insGSP.

[50]

[0161] The treatment method according to

[49] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, and G776delinsVC.

[51]

[0163] The treatment method according to

[45] , wherein the HER2 mutation in the HER2-mutated cancer is a single-base pair substitution mutation in the transmembrane domain of the HER2 protein.

[52]

[0165] The treatment method according to

[51] , wherein the single-base pair substitution mutation in the transmembrane domain of the HER2 protein is at least one selected from the group consisting of: V659E, G660D, I654V, I655V, and I661V.

[53]

[0167] The treatment method according to

[52] , wherein the single-base pair substitution mutation in the transmembrane domain of the HER2 protein is G660D.

[54]

[0169] The treatment method according to

[45] , wherein the HER2 mutation in the HER2-mutated cancer is a single-base pair substitution mutation in the extracellular domain of the HER2 protein.

[55]

[0171] The treatment method according to

[54] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is at least one selected from the group consisting of: S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, and R647G.

[56]

[0173] The treatment method according to

[55] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is S310F.

[57]

[0175] The treatment method according to any one of

[45] to

[56] , wherein the cancer in the HER2-mutated cancer is at least one selected from the group consisting of: non-small cell lung cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, salivary gland cancer, adenocarcinoma of the gastroesophageal junction, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, and uterine carcinosarcoma.

[58]

[0177] The treatment method according to any one of

[45] to

[56] , wherein the cancer is non-small cell lung cancer.

[59]

[0179] The treatment method according to

[58] , wherein the non-small cell lung cancer is inoperable and / or metastatic non-small cell lung cancer.

[60]

[0181] The treatment method according to any one of

[45] to

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

[61]

[0183] The treatment method according to any one of

[45] to

[59] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain composed of the amino acid sequence shown in SEQ ID NO:1 and a light chain composed of the amino acid sequence shown in SEQ ID NO: 2.

[62]

[0185] A treatment method according to any one of

[45] to

[61] , wherein the average number of drug-linker units conjugated to each antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7 to 8.

[63]

[0187] A treatment method according to any one of

[45] to

[61] , wherein the average number of drug-linker units conjugated to each antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7.5 to 8.

[64]

[0189] A treatment method according to any one of

[45] to

[63] , wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is in the range of 5.4 mg / kg to 8 mg / kg.

[65]

[0191] A treatment method according to any one of

[45] to

[63] , wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is 6.4 mg / kg.

[66]

[0193] A treatment method according to any one of

[45] to

[65] , wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

[67]

[0195] A treatment method for cancer, comprising administering an anti-HER2 antibody-drug conjugate represented by the following formula to a subject determined to have HER2-mutated cancer:

[0196] [Formula 4]

[0197]

[0198] wherein the drug-linker is conjugated to the anti-HER2 antibody via a thioether bond, and n is the average number of drug-linker units conjugated to each antibody molecule.

[68]

[0200] The treatment method according to

[67] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L, Q711H, G727A, T733I, E744G, N745D, L755P, L755A, L755F, S760F, D769H, D769N, D769Y, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, A775G, G776delinsLC, G776C, G776delinsAVGC, G776delinsVV, G776_V777insL, G776L, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779P, S779_P780insVGS, P780_Y781insGSP, R784C, R784H, L785R, L786V, T791I, G804S, L807F, S819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, W906*, T917S, Q943*, S1007* and S1151L.

[69]

[0202] The treatment method according to

[68] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L and S310F.

[70]

[0204] The treatment method according to

[67] , wherein the HER2 mutation in the HER2-mutated cancer is an exon 20 insertion mutation.

[71]

[0206] The treatment method according to

[70] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, G776delinsLC, G776delinsAVGC, G776delinsVV, G776_V777insL, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779_P780insVGS, and P780_Y781insGSP.

[72]

[0208] The treatment method according to

[71] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, and G776delinsVC.

[73]

[0210] The treatment method according to

[67] , wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the transmembrane domain of the HER2 protein.

[74]

[0212] The treatment method according to

[73] , wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is at least one selected from the group consisting of: V659E, G660D, I654V, I655V, and I661V.

[75]

[0214] The treatment method according to

[74] , wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is G660D.

[76]

[0216] The treatment method according to

[67] , wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the extracellular domain of the HER2 protein.

[77]

[0218] The treatment method according to

[76] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is at least one selected from the group consisting of: S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, and R647G.

[78]

[0220] The treatment method according to

[77] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is S310F.

[79]

[0222] The treatment method according to any one of

[67] to

[78] , wherein the cancer in the HER2-mutated cancer is at least one selected from the group consisting of: non-small cell lung cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, salivary gland cancer, adenocarcinoma of the gastroesophageal junction, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, and uterine carcinosarcoma.

[80]

[0224] The treatment method according to any one of

[67] to

[78] , wherein the cancer is non-small cell lung cancer.

[81]

[0226] The treatment method according to

[80] , wherein the non-small cell lung cancer is inoperable and / or metastatic non-small cell lung cancer.

[82]

[0228] The treatment method according to any one of

[67] to

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

[83]

[0230] The treatment method according to any one of

[67] to

[81] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain composed of the amino acid sequence shown in SEQ ID NO:1 and a light chain composed of the amino acid sequence shown in SEQ ID NO: 2.

[84]

[0232] A treatment method according to any one of

[67] to

[83] , wherein the average number of drug-linker units conjugated to each antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7 to 8.

[85]

[0234] A treatment method according to any one of

[67] to

[83] , wherein the average number of drug-linker units conjugated to each antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7.5 to 8.

[86]

[0236] A treatment method according to any one of

[67] to

[85] , wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is in the range of 5.4 mg / kg to 8 mg / kg.

[87]

[0238] A treatment method according to any one of

[67] to

[85] , wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is 6.4 mg / kg.

[88]

[0240] A treatment method according to any one of

[67] to

[87] , wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

[89]

[0242] An anti-HER2 antibody-drug conjugate for treating HER2-mutated cancer, wherein the drug-linker represented by the following formula is conjugated to the anti-HER antibody through a thioether bond:

[0243] [Formula 5]

[0244]

[0245] Wherein A represents the position of connection to the anti-HER2 antibody.

[90]

[0247] An anti-HER2 antibody-drug conjugate according to

[89] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L, Q711H, G727A, T733I, E744G, N745D, L755P, L755A, L755F, S760F, D769H, D769N, D769Y, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, A775G, G776delinsLC, G776C, G776delinsAVGC, G776delinsVV, G776_V777insL, G776L, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779P, S779_P780insVGS, P780_Y781insGSP, R784C, R784H, L785R, L786V, T791I, G804S, L807F, S819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, W906*, T917S, Q943*, S1007* and S1151L.

[91]

[0249] An anti-HER2 antibody-drug conjugate according to

[90] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L and S310F.

[92]

[0251] An anti-HER2 antibody-drug conjugate according to

[89] , wherein the HER2 mutation in the HER2-mutated cancer is an exon 20 insertion mutation.

[93]

[0253] An anti-HER2 antibody-drug conjugate according to

[92] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, G776delinsLC, G776delinsAVGC, G776delinsVV, G776_V777insL, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779_P780insVGS, and P780_Y781insGSP.

[94]

[0255] An anti-HER2 antibody-drug conjugate according to

[93] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, and G776delinsVC.

[95]

[0257] An anti-HER2 antibody-drug conjugate according to

[89] , wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the transmembrane domain of the HER2 protein.

[96]

[0259] An anti-HER2 antibody-drug conjugate according to

[95] , wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is at least one selected from the group consisting of: V659E, G660D, I654V, I655V, and I661V.

[97]

[0261] An anti-HER2 antibody-drug conjugate according to

[96] , wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is G660D.

[98]

[0263] An anti-HER2 antibody-drug conjugate according to

[89] , wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the extracellular domain of the HER2 protein.

[99]

[0265] An anti-HER2 antibody-drug conjugate according to

[98] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is at least one selected from the group consisting of: S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, and R647G.

[100]

[0267] An anti-HER2 antibody-drug conjugate according to

[99] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is S310F.

[101]

[0269] An anti-HER2 antibody-drug conjugate according to any one of

[89] to

[100] , wherein the cancer in the HER2-mutated cancer is at least one selected from the group consisting of: non-small cell lung cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, and uterine carcinosarcoma.

[102]

[0271] An anti-HER2 antibody-drug conjugate according to any one of

[89] to

[100] , wherein the cancer is non-small cell lung cancer.

[103]

[0273] An anti-HER2 antibody-drug conjugate according to

[102] , wherein the non-small cell lung cancer is unresectable and / or metastatic non-small cell lung cancer.

[104]

[0275] An anti-HER2 antibody-drug conjugate according to any one of

[89] to

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

[105]

[0277] An anti-HER2 antibody-drug conjugate according to any one of

[89] to

[103] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2.

[106]

[0279] An anti-HER2 antibody-drug conjugate according to any one of

[89] to

[105] , wherein the average number of drug-linker units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7 to 8.

[107]

[0281] An anti-HER2 antibody-drug conjugate according to any one of

[89] to

[105] , wherein the average number of drug-linker units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7.5 to 8.

[108]

[0283] An anti-HER2 antibody-drug conjugate according to any one of

[89] to

[107] , wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is in the range of 5.4 mg / kg to 8 mg / kg.

[109]

[0285] An anti-HER2 antibody-drug conjugate according to any one of

[89] to

[107] , wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is 6.4 mg / kg.

[110]

[0287] An anti-HER2 antibody-drug conjugate according to any one of

[89] to

[109] , wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

[111]

[0289] An anti-HER2 antibody-drug conjugate for treating HER2-mutated cancer, which is represented by the following formula:

[0290] [Formula 6]

[0291]

[0292] wherein the drug-linker is conjugated to the anti-HER2 antibody through a thioether bond, and n is the average number of drug-linker units conjugated per antibody molecule.

[112]

[0294] An anti-HER2 antibody-drug conjugate according to

[111] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L, Q711H, G727A, T733I, E744G, N745D, L755P, L755A, L755F, S760F, D769H, D769N, D769Y, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, A775G, G776delinsLC, G776C, G776delinsAVGC, G776delinsVV, G776_V777insL, G776L, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779P, S779_P780insVGS, P780_Y781insGSP, R784C, R784H, L785R, L786V, T791I, G804S, L807F, S819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, W906*, T917S, Q943*, S1007* and S1151L.

[113]

[0296] An anti-HER2 antibody-drug conjugate according to

[112] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L and S310F.

[114]

[0298] An anti-HER2 antibody-drug conjugate according to

[111] , wherein the HER2 mutation in the HER2-mutated cancer is an exon 20 insertion mutation.

[115]

[0300] An anti-HER2 antibody-drug conjugate according to

[114] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, G776delinsLC, G776delinsAVGC, G776delinsVV, G776_V777insL, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779_P780insVGS, and P780_Y781insGSP.

[116]

[0302] An anti-HER2 antibody-drug conjugate according to

[115] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, and G776delinsVC.

[117]

[0304] An anti-HER2 antibody-drug conjugate according to

[111] , wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the transmembrane domain of the HER2 protein.

[118]

[0306] An anti-HER2 antibody-drug conjugate according to

[117] , wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is at least one selected from the group consisting of: V659E, G660D, I654V, I655V, and I661V.

[119]

[0308] An anti-HER2 antibody-drug conjugate according to

[118] , wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is G660D.

[120]

[0310] An anti-HER2 antibody-drug conjugate according to

[111] , wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the extracellular domain of the HER2 protein.

[121]

[0312] An anti-HER2 antibody-drug conjugate according to

[120] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is at least one selected from the group consisting of: S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, and R647G.

[122]

[0314] An anti-HER2 antibody-drug conjugate according to

[121] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is S310F.

[123]

[0316] An anti-HER2 antibody-drug conjugate according to any one of

[111] to

[122] , wherein the cancer in the HER2-mutated cancer is at least one selected from the group consisting of: non-small cell lung cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, and uterine carcinosarcoma.

[124]

[0318] An anti-HER2 antibody-drug conjugate according to any one of

[111] to

[122] , wherein the cancer is non-small cell lung cancer.

[125]

[0320] An anti-HER2 antibody-drug conjugate according to

[124] , wherein the non-small cell lung cancer is unresectable and / or metastatic non-small cell lung cancer.

[126]

[0322] An anti-HER2 antibody-drug conjugate according to any one of

[111] to

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

[127]

[0324] An anti-HER2 antibody-drug conjugate according to any one of

[111] to

[125] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain composed of the amino acid sequence shown in SEQ ID NO: 1 and a light chain composed of the amino acid sequence shown in SEQ ID NO: 2.

[128]

[0326] An anti-HER2 antibody-drug conjugate according to any one of

[111] to

[127] , wherein the average number of drug-linker units conjugated to each antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7 to 8.

[129]

[0328] An anti-HER2 antibody-drug conjugate according to any one of

[111] to

[127] , wherein the average number of drug-linker units conjugated to each antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7.5 to 8.

[130]

[0330] An anti-HER2 antibody-drug conjugate according to any one of

[111] to

[129] , wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is in the range of 5.4 mg / kg to 8 mg / kg.

[131]

[0332] An anti-HER2 antibody-drug conjugate according to any one of

[111] to

[129] , wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is 6.4 mg / kg.

[132]

[0334] An anti-HER2 antibody-drug conjugate according to any one of

[111] to

[131] , wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

[133]

[0336] Use of an anti-HER2 antibody-drug conjugate for the preparation of a medicament for the treatment of HER2-mutated cancer, wherein in the anti-HER2 antibody-drug conjugate, a drug-linker represented by the following formula is conjugated to the anti-HER antibody via a thioether bond:

[0337] [Formula 7]

[0338]

[0339] wherein A represents the position of attachment to the anti-HER2 antibody.

[134]

[0341] For use according to

[133] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L, Q711H, G727A, T733I, E744G, N745D, L755P, L755A, L755F, S760F, D769H, D769N, D769Y, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, A775G, G776delinsLC, G776C, G776delinsAVGC, G776delinsVV, G776_V777insL, G776L, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779P, S779_P780insVGS, P780_Y781insGSP, R784C, R784H, L785R, L786V, T791I, G804S, L807F, S819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, W906*, T917S, Q943*, S1007* and S1151L.

[135]

[0343] For use according to

[134] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L and S310F.

[136]

[0345] For use according to

[133] , wherein the HER2 mutation in the HER2-mutated cancer is an exon 20 insertion mutation.

[137]

[0347] For the use according to

[136] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, G776delinsLC, G776delinsAVGC, G776delinsVV, G776_V777insL, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779_P780insVGS, and P780_Y781insGSP.

[138]

[0349] For the use according to

[137] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, and G776delinsVC.

[139]

[0351] For the use according to

[133] , wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the transmembrane domain of the HER2 protein.

[140]

[0353] For the use according to

[139] , wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is at least one selected from the group consisting of: V659E, G660D, I654V, I655V, and I661V.

[141]

[0355] For the use according to

[140] , wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is G660D.

[142]

[0357] For the use according to

[133] , wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the extracellular domain of the HER2 protein.

[143]

[0359] Use according to

[142] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is at least one selected from the group consisting of: S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, and R647G.

[144]

[0361] Use according to

[143] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is S310F.

[145]

[0363] Use according to any one of

[133] to

[144] , wherein the cancer in the HER2-mutated cancer is at least one selected from the group consisting of: non-small cell lung cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, and uterine carcinosarcoma.

[146]

[0365] Use according to any one of

[133] to

[144] , wherein the cancer is non-small cell lung cancer.

[147]

[0367] Use according to

[146] , wherein the non-small cell lung cancer is unresectable and / or metastatic non-small cell lung cancer.

[148]

[0369] Use according to any one of

[133] to

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

[149]

[0371] Use according to any one of

[133] to

[147] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2.

[150]

[0373] Use according to any one of

[133] to

[149] , wherein the average number of drug-linker units conjugated to each antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7 to 8.

[151]

[0375] Use according to any one of

[133] to

[149] , wherein the average number of drug-linker units conjugated to each antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7.5 to 8.

[152]

[0377] Use according to any one of

[133] to

[151] , wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is in the range of 5.4 mg / kg to 8 mg / kg.

[153]

[0379] Use according to any one of

[133] to

[151] , wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is 6.4 mg / kg.

[154]

[0381] Use according to any one of

[133] to

[153] , wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

[155]

[0383] Use of an anti-HER2 antibody-drug conjugate for the preparation of a medicament for the treatment of HER2-mutated cancer, wherein the anti-HER2 antibody-drug conjugate is represented by the following formula:

[0384] [Formula 8]

[0385]

[0386] wherein the drug-linker is conjugated to the anti-HER2 antibody via a thioether bond, and n is the average number of drug-linker units conjugated to each antibody molecule.

[156]

[0388] For the use according to

[155] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L, Q711H, G727A, T733I, E744G, N745D, L755P, L755A, L755F, S760F, D769H, D769N, D769Y, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, A775G, G776delinsLC, G776C, G776delinsAVGC, G776delinsVV, G776_V777insL, G776L, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779P, S779_P780insVGS, P780_Y781insGSP, R784C, R784H, L785R, L786V, T791I, G804S, L807F, S819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, W906*, T917S, Q943*, S1007* and S1151L.

[157]

[0390] For the use according to

[156] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L and S310F.

[158]

[0392] For the use according to

[155] , wherein the HER2 mutation in the HER2-mutated cancer is an exon 20 insertion mutation.

[159]

[0394] For the use according to

[158] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, G776delinsLC, G776delinsAVGC, G776delinsVV, G776_V777insL, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779_P780insVGS, and P780_Y781insGSP.

[160]

[0396] For the use according to

[159] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, and G776delinsVC.

[161]

[0398] For the use according to

[155] , wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the transmembrane domain of the HER2 protein.

[162]

[0400] For the use according to

[161] , wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is at least one selected from the group consisting of: V659E, G660D, I654V, I655V, and I661V.

[163]

[0402] For the use according to

[162] , wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is G660D.

[164]

[0404] For the use according to

[155] , wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the extracellular domain of the HER2 protein.

[165]

[0406] Use according to

[164] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is at least one selected from the group consisting of: S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, and R647G.

[166]

[0408] Use according to

[165] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is S310F.

[167]

[0410] Use according to any one of

[155] to

[166] , wherein the cancer in the HER2-mutated cancer is at least one selected from the group consisting of: non-small cell lung cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, and uterine carcinosarcoma.

[168]

[0412] Use according to any one of

[155] to

[166] , wherein the cancer is non-small cell lung cancer.

[169]

[0414] Use according to

[168] , wherein the non-small cell lung cancer is unresectable and / or metastatic non-small cell lung cancer.

[170]

[0416] Use according to any one of

[155] to

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

[171]

[0418] Use according to any one of

[155] to

[169] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2.

[172]

[0420] Use according to any one of

[155] to

[171] , wherein the average number of drug-linker units conjugated to each antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7 to 8.

[173]

[0422] Use according to any one of

[155] to

[171] , wherein the average number of drug-linker units conjugated to each antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7.5 to 8.

[174]

[0424] Use according to any one of

[155] to

[173] , wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is in the range of 5.4 mg / kg to 8 mg / kg.

[175]

[0426] Use according to any one of

[155] to

[173] , wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is 6.4 mg / kg.

[176]

[0428] Use according to any one of

[155] to

[175] , wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

[0429] Furthermore, the present invention can also be expressed as follows: [1]

[0431] A therapeutic agent for the treatment of cancer with HER2 gene mutation, which comprises an anti-HER2 antibody-drug conjugate as an active ingredient, in the anti-HER2 antibody-drug conjugate, a drug-linker represented by the following formula is conjugated to the anti-HER antibody through a thioether bond:

[0432] [Formula 9]

[0433]

[0434] wherein A represents the linking position with the anti-HER2 antibody. [2]

[0436] The therapeutic agent according to [1], wherein the cancer is at least one selected from the group consisting of non-small cell lung cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, and uterine carcinosarcoma. [3]

[0438] The therapeutic agent according to [1], wherein the cancer is non-small cell lung cancer. [4]

[0440] A therapeutic agent according to any one of [1] to [3], wherein the anti-HER2 antibody is an antibody comprising a heavy chain and a light chain, the heavy chain consisting of an amino acid sequence composed of amino acid residues 1 to 449 of SEQ ID NO: 1, and the light chain consisting of an amino acid sequence composed of amino acid residues 1 to 214 of SEQ ID NO: 2. [5]

[0442] A therapeutic agent according to any one of [1] to [3], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2. [6]

[0444] A therapeutic agent according to any one of [1] to [5], wherein the average number of drug-linker units conjugated to each antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7 to 8. [7]

[0446] A therapeutic agent according to any one of [1] to [5], wherein the average number of drug-linker units conjugated to each antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7.5 to 8. [8]

[0448] A therapeutic agent according to any one of [1] to [7], wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is in the range of 5.4 mg / kg to 8 mg / kg. [9]

[0450] A therapeutic agent according to any one of [1] to [7], wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is 6.4 mg / kg.

[10]

[0452] A therapeutic agent according to any one of [1] to [9], wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

[11]

[0454] A method for treating cancer, comprising administering an anti-HER2 antibody-drug conjugate to a subject determined to have cancer with a HER2 gene mutation, wherein in the anti-HER2 antibody-drug conjugate, a drug-linker represented by the following formula is conjugated to the anti-HER2 antibody through a thioether bond:

[0455] [Formula 10]

[0456]

[0457] Wherein A represents the linking position to the anti-HER2 antibody.

[12]

[0459] A treatment method according to

[11] , wherein the cancer is at least one selected from the group consisting of: non-small cell lung cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, salivary gland cancer, adenocarcinoma of the gastroesophageal junction, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, and uterine carcinosarcoma.

[13]

[0461] A treatment method according to

[11] , wherein the cancer is non-small cell lung cancer.

[14]

[0463] A treatment method according to any one of

[11] to

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

[15]

[0465] A treatment method according to any one of

[11] to

[13] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain composed of the amino acid sequence shown in SEQ ID NO: 1 and a light chain composed of the amino acid sequence shown in SEQ ID NO: 2.

[16]

[0467] A treatment method according to any one of

[11] to

[15] , wherein the average number of drug-linker units conjugated to each antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7 to 8.

[17]

[0469] A treatment method according to any one of

[11] to

[15] , wherein the average number of drug-linker units conjugated to each antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7.5 to 8.

[18]

[0471] A treatment method according to any one of

[11] to

[17] , wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is in the range of 5.4 mg / kg to 8 mg / kg.

[19]

[0473] A treatment method according to any one of

[11] to

[17] , wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is 6.4 mg / kg.

[20]

[0475] A treatment method according to any one of

[11] to

[19] , wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

[21]

[0477] An anti-HER2 antibody-drug conjugate for treating cancer with HER2 gene mutations, wherein the drug-linker represented by the following formula is conjugated to the anti-HER antibody through a thioether bond:

[0478] [Formula 11]

[0479]

[0480] Wherein A represents the position of connection to the anti-HER2 antibody.

[22]

[0482] The anti-HER2 antibody-drug conjugate according to

[21] , wherein the cancer is at least one selected from the group consisting of: non-small cell lung cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, and uterine carcinosarcoma.

[23]

[0484] The anti-HER2 antibody-drug conjugate according to

[21] , wherein the cancer is non-small cell lung cancer.

[24]

[0486] The anti-HER2 antibody-drug conjugate according to any one of

[21] to

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

[25]

[0488] The anti-HER2 antibody-drug conjugate according to any one of

[21] to

[23] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain composed of the amino acid sequence shown in SEQ ID NO: 1 and a light chain composed of the amino acid sequence shown in SEQ ID NO: 2.

[26]

[0490] The anti-HER2 antibody-drug conjugate according to any one of

[21] to

[25] , wherein the average number of drug-linker units conjugated to each antibody molecule is in the range of 7 to 8.

[27]

[0492] An anti-HER2 antibody-drug conjugate according to any one of

[21] to

[25] , wherein the average number of drug-linker units conjugated to each antibody molecule is in the range of 7.5 to 8.

[28]

[0494] An anti-HER2 antibody-drug conjugate according to any one of

[21] to

[27] , wherein the dose per administration is in the range of 5.4 mg / kg to 8 mg / kg.

[29]

[0496] An anti-HER2 antibody-drug conjugate according to any one of

[21] to

[27] , wherein the dose per administration is 6.4 mg / kg.

[30]

[0498] An anti-HER2 antibody-drug conjugate according to any one of

[21] to

[29] , which is administered once every three weeks.

[31]

[0500] Use of an anti-HER2 antibody-drug conjugate for the preparation of a medicament for the treatment of cancer with HER2 gene mutation, in the anti-HER2 antibody-drug conjugate, the drug-linker represented by the following formula is conjugated to the anti-HER antibody through a thioether bond:

[0501] [Formula 7]

[0502]

[0503] Wherein A represents the position of connection to the anti-HER2 antibody.

[32]

[0505] The use according to

[31] , wherein the cancer is at least one selected from the group consisting of: non-small cell lung cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, and uterine carcinosarcoma.

[33]

[0507] The use according to

[31] , wherein the cancer is non-small cell lung cancer.

[34]

[0509] The use according to any one of

[31] to

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

[35]

[0511] Use according to any one of

[31] to

[33] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2.

[36]

[0513] Use according to any one of

[31] to

[35] , wherein the average number of drug-linker units conjugated to each antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7 to 8.

[37]

[0515] Use according to any one of

[31] to

[35] , wherein the average number of drug-linker units conjugated to each antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7.5 to 8.

[38]

[0517] Use according to any one of

[31] to

[37] , wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is in the range of 5.4 mg / kg to 8 mg / kg.

[39]

[0519] Use according to any one of

[31] to

[37] , wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is 6.4 mg / kg.

[40]

[0521] Use according to any one of

[31] to

[39] , wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

[0522] Advantages of the invention

[0523] The present invention can provide a therapeutic agent for treating HER2-mutated cancer, which comprises a specific anti-HER2 antibody-drug conjugate, and / or a method for treating HER2-mutated cancer, which comprises administering a specific anti-HER2 antibody-drug conjugate to a subject determined to have HER2-mutated cancer. Sequence Listing <110> Daiichi Sankyo Company, Limited <120> Treatment of HER2-Mutated Cancer by Administering an Anti-HER2 Antibody-Drug Conjugate <130> FP1907 <150> JP2018-101211 <151> 2018-05-28 <150> JP2018-177132 <151> 2018-09-21 <160> 4 <170> PatentIn version 3.5 <210> 1 <211> 450 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain of humanized anti-HER2 antibody <400> 1 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys 450 <210> 2 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Light chain of humanized anti-HER2 antibody <400> 2 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 3 <211> 1255 <212> PRT <213> Homo sapiens <400> 3 Met Glu Leu Ala Ala Leu Cys Arg Trp Gly Leu Leu Leu Ala Leu Leu 1 5 10 15 Pro Pro Gly Ala Ala Ser Thr Gln Val Cys Thr Gly Thr Asp Met Lys 20 25 30 Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu Arg His 35 40 45 Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu Thr Tyr 50 55 60 Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln Glu Val 65 70 75 80 Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val Pro Leu 85 90 95 Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr 100 105 110 Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Asn Asn Thr Thr Pro 115 120 125 Val Thr Gly Ala Ser Pro Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser 130 135 140 Leu Thr Glu Ile Leu Lys Gly Gly Val Leu Ile Gln Arg Asn Pro Gln 145 150 155 160 Leu Cys Tyr Gln Asp Thr Ile Leu Trp Lys Asp Ile Phe His Lys Asn 165 170 175 Asn Gln Leu Ala Leu Thr Leu Ile Asp Thr Asn Arg Ser Arg Ala Cys 180 185 190 His Pro Cys Ser Pro Met Cys Lys Gly Ser Arg Cys Trp Gly Glu Ser 195 200 205 Ser Glu Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly Gly Cys 210 215 220 Ala Arg Cys Lys Gly Pro Leu Pro Thr Asp Cys Cys His Glu Gln Cys 225 230 235 240 Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala Cys Leu 245 250 255 His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala Leu Val 260 265 270 Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu Gly Arg 275 280 285 Tyr Thr Phe Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn Tyr Leu 290 295 300 Ser Thr Asp Val Gly Ser Cys Thr Leu Val Cys Pro Leu His Asn Gln 305 310 315 320 Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys Ser Lys 325 330 335 Pro Cys Ala Arg Val Cys Tyr Gly Leu Gly Met Glu His Leu Arg Glu 340 345 350 Val Arg Ala Val Thr Ser Ala Asn Ile Gln Glu Phe Ala Gly Cys Lys 355 360 365 Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe Asp Gly Asp 370 375 380 Pro Ala Ser Asn Thr Ala Pro Leu Gln Pro Glu Gln Leu Gln Val Phe 385 390 395 400 Glu Thr Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala Trp Pro 405 410 415 Asp Ser Leu Pro Asp Leu Ser Val Phe Gln Asn Leu Gln Val Ile Arg 420 425 430 Gly Arg Ile Leu His Asn Gly Ala Tyr Ser Leu Thr Leu Gln Gly Leu 435 440 445 Gly Ile Ser Trp Leu Gly Leu Arg Ser Leu Arg Glu Leu Gly Ser Gly 450 455 460 Leu Ala Leu Ile His His Asn Thr His Leu Cys Phe Val His Thr Val 465 470 475 480 Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu His Thr 485 490 495 Ala Asn Arg Pro Glu Asp Glu Cys Val Gly Glu Gly Leu Ala Cys His 500 505 510 Gln Leu Cys Ala Arg Gly His Cys Trp Gly Pro Gly Pro Thr Gln Cys 515 520 525 Val Asn Cys Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu Glu Cys 530 535 540 Arg Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg His Cys 545 550 555 560 Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val Thr Cys 565 570 575 Phe Gly Pro Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr Lys Asp 580 585 590 Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro Asp Leu 595 600 605 Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala Cys Gln 610 615 620 Pro Cys Pro Ile Asn Cys Thr His Ser Cys Val Asp Leu Asp Asp Lys 625 630 635 640 Gly Cys Pro Ala Glu Gln Arg Ala Ser Pro Leu Thr Ser Ile Ile Ser 645 650 655 Ala Val Val Gly Ile Leu Leu Val Val Val Leu Gly Val Val Phe Gly 660 665 670 Ile Leu Ile Lys Arg Arg Gln Gln Lys Ile Arg Lys Tyr Thr Met Arg 675 680 685 Arg Leu Leu Gln Glu Thr Glu Leu Val Glu Pro Leu Thr Pro Ser Gly 690 695 700 Ala Met Pro Asn Gln Ala Gln Met Arg Ile Leu Lys Glu Thr Glu Leu 705 710 715 720 Arg Lys Val Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys 725 730 735 Gly Ile Trp Ile Pro Asp Gly Glu Asn Val Lys Ile Pro Val Ala Ile 740 745 750 Lys Val Leu Arg Glu Asn Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu 755 760 765 Asp Glu Ala Tyr Val Met Ala Gly Val Gly Ser Pro Tyr Val Ser Arg 770 775 780 Leu Leu Gly Ile Cys Leu Thr Ser Thr Val Gln Leu Val Thr Gln Leu 785 790 795 800 Met Pro Tyr Gly Cys Leu Leu Asp His Val Arg Glu Asn Arg Gly Arg 805 810 815 Leu Gly Ser Gln Asp Leu Leu Asn Trp Cys Met Gln Ile Ala Lys Gly 820 825 830 Met Ser Tyr Leu Glu Asp Val Arg Leu Val His Arg Asp Leu Ala Ala 835 840 845 Arg Asn Val Leu Val Lys Ser Pro Asn His Val Lys Ile Thr Asp Phe 850 855 860 Gly Leu Ala Arg Leu Leu Asp Ile Asp Glu Thr Glu Tyr His Ala Asp 865 870 875 880 Gly Gly Lys Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile Leu Arg 885 890 895 Arg Arg Phe Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val 900 905 910 Trp Glu Leu Met Thr Phe Gly Ala Lys Pro Tyr Asp Gly Ile Pro Ala 915 920 925 Arg Glu Ile Pro Asp Leu Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro 930 935 940 Pro Ile Cys Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys Trp Met 945 950 955 960 Ile Asp Ser Glu Cys Arg Pro Arg Phe Arg Glu Leu Val Ser Glu Phe 965 970 975 Ser Arg Met Ala Arg Asp Pro Gln Arg Phe Val Val Ile Gln Asn Glu 980 985 990 Asp Leu Gly Pro Ala Ser Pro Leu Asp Ser Thr Phe Tyr Arg Ser Leu 995 1000 1005 Leu Glu Asp Asp Asp Met Gly Asp Leu Val Asp Ala Glu Glu Tyr 1010 1015 1020 Leu Val Pro Gln Gln Gly Phe Phe Cys Pro Asp Pro Ala Pro Gly 1025 1030 1035 Ala Gly Gly Met Val His His Arg His Arg Ser Ser Ser Thr Arg 1040 1045 1050 Ser Gly Gly Gly Asp Leu Thr Leu Gly Leu Glu Pro Ser Glu Glu 1055 1060 1065 Glu Ala Pro Arg Ser Pro Leu Ala Pro Ser Glu Gly Ala Gly Ser 1070 1075 1080 Asp Val Phe Asp Gly Asp Leu Gly Met Gly Ala Ala Lys Gly Leu 1085 1090 1095 Gln Ser Leu Pro Thr His Asp Pro Ser Pro Leu Gln Arg Tyr Ser 1100 1105 1110 Glu Asp Pro Thr Val Pro Leu Pro Ser Glu Thr Asp Gly Tyr Val 1115 1120 1125 Ala Pro Leu Thr Cys Ser Pro Gln Pro Glu Tyr Val Asn Gln Pro 1130 1135 1140 Asp Val Arg Pro Gln Pro Pro Ser Pro Arg Glu Gly Pro Leu Pro 1145 1150 1155 Ala Ala Arg Pro Ala Gly Ala Thr Leu Glu Arg Pro Lys Thr Leu 1160 1165 1170 Ser Pro Gly Lys Asn Gly Val Val Lys Asp Val Phe Ala Phe Gly 1175 1180 1185 Gly Ala Val Glu Asn Pro Glu Tyr Leu Thr Pro Gln Gly Gly Ala 1190 1195 1200 Ala Pro Gln Pro His Pro Pro Pro Ala Phe Ser Pro Ala Phe Asp 1205 1210 1215 Asn Leu Tyr Tyr Trp Asp Gln Asp Pro Pro Glu Arg Gly Ala Pro 1220 1225 1230 Pro Ser Thr Phe Lys Gly Thr Pro Thr Ala Glu Asn Pro Glu Tyr 1235 1240 1245 Leu Gly Leu Asp Val Pro Val 1250 1255 <210> 4 <211> 3768 <212> DNA <213> Human <400> 4 atggagctgg cggccttgtg ccgctggggg ctcctcctcg ccctcttgcc ccccggagcc 60 gcgagcaccc aagtgtgcac cggcacagac atgaagctgc ggctccctgc cagtcccgag 120 acccacctgg acatgctccg ccacctctac cagggctgcc aggtggtgca gggaaacctg 180 gaactcacct acctgcccac caatgccagc ctgtccttcc tgcaggatat ccaggaggtg 240 cagggctacg tgctcatcgc tcacaaccaa gtgaggcagg tcccactgca gaggctgcgg 300 attgtgcgag gcacccagct ctttgaggac aactatgccc tggccgtgct agacaatgga 360 gacccgctga acaataccac ccctgtcaca ggggcctccc caggaggcct gcgggagctg 420 cagcttcgaa gcctcacaga gatcttgaaa ggaggggtct tgatccagcg gaacccccag 480 ctctgctacc aggacacgat tttgtggaag gacatcttcc acaagaacaa ccagctggct 540 ctcacactga tagacaccaa ccgctctcgg gcctgccacc cctgttctcc gatgtgtaag 600 ggctcccgct gctggggaga gagttctgag gattgtcaga gcctgacgcg cactgtctgt 660 gccggtggct gtgcccgctg caaggggcca ctgcccactg actgctgcca tgagcagtgt 720 gctgccggct gcacgggccc caagcactct gactgcctgg cctgcctcca cttcaaccac 780 agtggcatct gtgagctgca ctgcccagcc ctggtcacct acaacacaga cacgtttgag 840 tccatgccca atcccgaggg ccggtataca ttcggcgcca gctgtgtgac tgcctgtccc 900 tacaactacc tttctacgga cgtgggatcc tgcaccctcg tctgccccct gcacaaccaa 960 gaggtgacag cagaggatgg aacacagcgg tgtgagaagt gcagcaagcc ctgtgcccga 1020 gtgtgctatg gtctgggcat ggagcacttg cgagaggtga gggcagttac cagtgccaat 1080 atccaggagt ttgctggctg caagaagatc tttgggagcc tggcatttct gccggagagc 1140 tttgatgggg acccagcctc caacactgcc ccgctccagc cagagcagct ccaagtgttt 1200 gagactctgg aagagatcac aggttaccta tacatctcag catggccgga cagcctgcct 1260 gacctcagcg tcttccagaa cctgcaagta atccggggac gaattctgca caatggcgcc 1320 tactcgctga ccctgcaagg gctgggcatc agctggctgg ggctgcgctc actgagggaa 1380 ctgggcagtg gactggccct catccaccat aacacccacc tctgcttcgt gcacacggtg 1440 ccctgggacc agctctttcg gaacccgcac caagctctgc tccacactgc caaccggcca 1500 gaggacgagt gtgtgggcga gggcctggcc tgccaccagc tgtgcgcccg agggcactgc 1560 tggggtccag ggcccaccca gtgtgtcaac tgcagccagt tccttcgggg ccaggagtgc 1620 gtggaggaat gccgagtact gcaggggctc cccagggagt atgtgaatgc caggcactgt 1680 ttgccgtgcc accctgagtg tcagccccag aatggctcag tgacctgttt tggaccggag 1740 gctgaccagt gtgtggcctg tgcccactat aaggaccctc ccttctgcgt ggcccgctgc 1800 cccagcggtg tgaaacctga cctctcctac atgcccatct ggaagtttcc agatgaggag 1860 ggcgcatgcc agccttgccc catcaactgc acccactcct gtgtggacct ggatgacaag 1920 ggctgccccg ccgagcagag agccagccct ctgacgtcca tcatctctgc ggtggttggc 1980 attctgctgg tcgtggtctt gggggtggtc tttgggatcc tcatcaagcg acggcagcag 2040 aagatccgga agtacacgat gcggagactg ctgcaggaaa cggagctggt ggagccgctg 2100 acacctagcg gagcgatgcc caaccaggcg cagatgcgga tcctgaaaga gacggagctg 2160 aggaaggtga aggtgcttgg atctggcgct tttggcacag tctacaaggg catctggatc 2220 cctgatgggg agaatgtgaa aattccagtg gccatcaaag tgttgaggga aaacacatcc 2280 cccaaagcca acaaagaaat cttagacgaa gcatacgtga tggctggtgt gggctcccca 2340 tatgtctccc gccttctggg catctgcctg acatccacgg tgcagctggt gacacagctt 2400 atgccctatg gctgcctctt agaccatgtc cgggaaaacc gcggacgcct gggctcccag 2460 gacctgctga actggtgtat gcagattgcc aaggggatga gctacctgga ggatgtgcgg 2520 ctcgtacaca gggacttggc cgctcggaac gtgctggtca agagtcccaa ccatgtcaaa 2580 attacagact tcgggctggc tcggctgctg gacattgacg agacagagta ccatgcagat 2640 gggggcaagg tgcccatcaa gtggatggcg ctggagtcca ttctccgccg gcggttcacc 2700 caccagagtg atgtgtggag ttatggtgtg actgtgtggg agctgatgac ttttggggcc 2760 aaaccttacg atgggatccc agcccgggag atccctgacc tgctggaaaa gggggagcgg 2820 ctgccccagc cccccatctg caccattgat gtctacatga tcatggtcaa atgttggatg 2880 attgactctg aatgtcggcc aagattccgg gagttggtgt ctgaattctc ccgcatggcc 2940 agggaccccc agcgctttgt ggtcatccag aatgaggact tgggcccagc cagtcccttg 3000 gacagcacct tctaccgctc actgctggag gacgatgaca tgggggacct ggtggatgct 3060 gaggagtatc tggtacccca gcagggcttc ttctgtccag accctgcccc gggcgctggg 3120 ggcatggtcc accacaggca ccgcagctca tctaccagga gtggcggtgg ggacctgaca 3180 ctagggctgg agccctctga agaggaggcc cccaggtctc cactggcacc ctccgaaggg 3240 gctggctccg atgtatttga tggtgacctg ggaatggggg cagccaaggg gctgcaaagc 3300 ctccccacac atgaccccag ccctctacag cggtacagtg aggaccccac agtacccctg 3360 ccctctgaga ctgatggcta cgttgccccc ctgacctgca gcccccagcc tgaatatgtg 3420 aaccagccag atgttcggcc ccagccccct tcgccccgag agggccctct gcctgctgcc 3480 cgacctgctg gtgccactct ggaaaggccc aagactctct ccccagggaa gaatggggtc 3540 gtcaaagacg tttttgcctt tgggggtgcc gtggagaacc ccgagtactt gacaccccag 3600 ggaggagctg cccctcagcc ccaccctcct cctgccttca gcccagcctt cgacaacctc 3660 tattactggg accaggaccc accagagcgg ggggctccac ccagcacctt caaagggaca 3720 cctacggcag agaacccaga gtacctgggt ctggacgtgc cagtgtga 3768 Brief description of the drawings

[0525] Figure 1 Figure 1 Displays the amino acid sequence of the heavy chain of the humanized anti-HER2 antibody (SEQ ID No: 1).

[0526] Figure 2 Figure 2 Displays the amino acid sequence of the light chain of the humanized anti-HER2 antibody (SEQ ID No: 2).

[0527] Figure 3 Figure 3 Displays the maximum tumor shrinkage as the efficacy of HER2-ADC (1) in subjects with non-small cell lung cancer, the non-small cell lung cancer being determined to have HER2 expression or HER2 mutation. In the figure, "NE" represents subjects with unmeasured or unmeasurable HER2 mutations, "E20" represents subjects determined to have an exon 20 insertion mutation in the HER2 protein, "TM" represents subjects determined to have a single base pair substitution mutation in the transmembrane domain of the HER2 protein, and "EC" represents subjects determined to have a single base pair substitution mutation in the extracellular domain of the HER2 protein.

[0528] Figure 4 Figure 4 Displays the time course of tumor shrinkage as the efficacy of HER2-ADC (1) in subjects with non-small cell lung cancer, the non-small cell lung cancer being determined to have HER2 expression or HER2 mutation.

[0529] Figure 5 Figure 5 Displays the amino acid sequence of the HER2 protein (SEQ ID No: 3).

[0530] Description of the embodiments

[0531] ​​​​​​​​​​In the following, preferred ways for implementing the present invention are described. The embodiments given in the following description are only examples for illustrating typical embodiments of the present invention, and are not intended to limit the scope of the present invention.

[0532] [Definitions]

[0533] In the present invention, "HER2" is synonymous with human epidermal growth factor receptor 2 (which may also be referred to as neu or ErbB-2), and is a transmembrane receptor belonging to the epidermal growth factor receptor (EGFR) subfamily of receptor protein tyrosine kinases together with HER1 (EGFR or ErbB-1), HER3 (ErbB-3), and HER4 (ErbB-4). It is known that HER2 plays an important role in cell proliferation, differentiation, and survival in normal cells and tumor cells by forming heterodimers with HER1, HER3, or HER4 and being activated by autophosphorylation of intracellular tyrosine residues.

[0534] In the present invention, the term "HER2 protein" is used with the same meaning as HER2. The expression of HER2 protein can be detected by methods well-known to those skilled in the art, such as immunohistochemistry (IHC).

[0535] SEQ ID No: 3 ( Figure 5 ) shows the amino acid sequence of HER2 protein. In SEQ ID No: 3, the amino acid sequence consisting of amino acid residues 1 to 652 is referred to as the "extracellular domain of HER2 protein", the amino acid sequence consisting of amino acid residues 653 to 675 is referred to as the "transmembrane domain of HER2 protein", and the amino acid sequence consisting of amino acid residues 676 to 1255 is referred to as the "intracellular domain of HER2 protein".

[0536] In the present invention, "HER2 gene" is synonymous with the human epidermal growth factor receptor type 2-related oncogene. HER2 protein is one of the gene products of the HER2 gene.

[0537] SEQ ID No: 4 shows the nucleotide sequence of the HER2 gene (cDNA).

[0538] In the present invention, "HER2 mutation" means having a mutation in the amino acid sequence of HER2 protein.

[0539] In the present invention, "HER2-mutated cancer" means a cancer having a mutation in the amino acid sequence of HER2 protein. In addition, a cancer containing cancer cells having a HER2 mutation, even if not all tumor tissues have a HER2 mutation, is included in the term HER2-mutated cancer.

[0540] In the present invention, "HER2 gene mutation" means having a mutation in the HER2 gene.

[0541] In the present invention, "cancer with HER2 gene mutation" means a cancer having a mutation in the HER2 gene. In addition, a cancer containing cancer cells with HER2 gene mutation is included in the term "cancer with HER2 gene mutation" even if not all tumor tissues have HER2 gene mutation.

[0542] The HER2 gene mutation causes a mutation in the amino acid sequence of the HER2 protein as a gene product, thereby causing HER2 mutation.

[0543] Specific examples of HER2 mutations may include mutations that duplicate the amino acid sequence YVMA (tyrosine, valine, methionine, and alanine) at positions 772 to 775 of the HER2 protein (which may also be referred to as "Y772_A775dup" or "A775_G776insYVMA") (see, for example, Nature. 2004 Sep 30;431(7008):525-6, Cancer Res. 2005 Mar 1;65(5):1642-6, Cancer Res. 2005 Sep 1;65(17):7591-5, Int J Cancer. 2006 Dec 1;119(11):2586-91, Mol Cancer Res. 2008 Nov;6(11):1678-90, Nat Med. 2017 Jun;23(6):703-713, and Nature. 2018 Feb 8;554(7691):189-194), mutations that duplicate the amino acid sequence GSP (glycine, serine, and proline) at positions 778 to 780 of the HER2 protein (which may also be referred to as "G778_P780dup" or "P780_Y781insGSP") (see, for example, Cancer Res. 2005 Mar 1;65(5):1642-6, Pathobiology. 2008;75(1):2-8, Nature. 2012 May 16;486(7403):400-4, Clin Cancer Res. 2013 May 15;19(10):2668-76, Nature. 2016 Jun 2;534(7605):47-54, Cancer. 2016 Sep 1;122(17):2654-62, PLoS Med. 2016 Dec 27;13(12):e1002201, and Nat Med. 2017 Jun;23(6):703-713), mutations that replace G (glycine) at amino acid position 776 of the HER2 protein with VC (valine and cysteine) (which may also be referred to as "G776delinsVC" or "G776>VC") (see, for example, Cancer Res. 2005 Mar 1;65(5):1642-6, Cancer Sci. 2006 Aug;97(8):753-9, Cancer Genet Cytogenet. 2007 Mar;173(2):107-13, Clin Cancer Res.Sep 15, 2012; 18(18):4910 - 8, and Nature. Feb 8, 2018; 554(7691):189 - 194), a mutation that replaces L (leucine) at amino acid position 775 of the HER2 protein with S (serine) (which can also be referred to as "L755S") (see, for example, ClinCancer Res. Jan 1, 2006; 12(1):57 - 61, Hum Mutat. Mar 2008; 29(3):441 - 50, Nature. Apr 4, 2012; 486(7403):395 - 9, Breast Cancer Res Treat. Jul 2012; 134(2):561 - 7, Clin Cancer Res. Sep 15, 2012; 18(18):4910 - 8, and Cancer Lett. Mar 1, 2013; 330(1):33 - 40), a mutation that replaces V (valine) at amino acid position 777 of the HER2 protein with L (leucine) (which can also be referred to as "V777L") (see, for example, Clin Cancer Res. Jan 1, 2006; 12(1):57 - 61, Int J Cancer. Dec 1, 2006; 119(11):2586 - 91, Nature. Aug 12, 2010; 466(7308):869 - 73, Nature. Jun 10, 2012; 486(7403):353 - 60, Cancer Cell. Feb 8, 2016; 29(2):229 - 40, and Cancer. Sep 1, 2016; 122(17):2654 - 62), a mutation that replaces V (valine) at amino acid position 659 of the HER2 protein with E (glutamic acid) (which can also be referred to as "V659E") (see, for example, Cancer Discov. Nov 2013; 3(11):1238 - 44, J Natl Cancer Inst. Jan 2014; 106(1):djt338, Nat Med. Jun 2017; 23(6):703 - 713, and Nature. Feb 8, 2018; 554(7691):189 - 194), a mutation that replaces G (glycine) at amino acid position 660 of the HER2 protein with D (aspartic acid) (which can also be referred to as "G660D"), (see, for example, Nat Genet. Dec 2014; 46(12):1264 - 6, Cancer Cell.Feb 8, 2016; 29(2):229-40, and Cell Rep. Apr 26, 2016;15(4):857-865), and the mutation that replaces S (serine) at amino acid position 310 of the HER2 protein with F (phenylalanine) (which may also be referred to as "S310F") (see, for example, Nature. Oct 23, 2008;455(7216):1069-75, Nature. Jun 29, 2011;474(7353):609-15, Nat Genet. Oct 30, 2011;43(12):1219-23, Nature. Apr 4, 2012;486(7403):395-9, Genome Res. Nov 2012;22(11):2109-19, and Clin Cancer Res. May 15, 2013;19(10):2668-76).

[0544] Furthermore, other specific examples of HER2 mutations may also include a mutation that replaces A (alanine) at amino acid position 20 of the HER2 protein with T (threonine) (which may also be referred to as "A20T") (see, for example, Nature 2010;466(7308):869-73), a mutation that replaces A (alanine) at amino acid position 21 of the HER2 protein with S (serine) (which may also be referred to as "A21S") (see, for example, Nature medicine 2017;23(6):703-713), a mutation that replaces R (arginine) at amino acid position 143 of the HER2 protein with Q (glutamine) (which may also be referred to as "R143Q") (see, for example, Nature communications 2015;6:10131, and Cancer biology & therapy 2014;15(9):1239-47), a mutation that replaces K (lysine) at amino acid position 200 of the HER2 protein with N (asparagine) (which may also be referred to as "K200N") (see, for example, Nature medicine 2017;23(6):703-713), a mutation that replaces A (alanine) at amino acid position 242 of the HER2 protein with V (valine) (which may also be referred to as "A242V")(see, for example, Nature medicine 2017;23(6):703-713), a mutation that replaces D (aspartic acid) at amino acid position 277 of the HER2 protein with Y (tyrosine) (which may also be referred to as "D277Y") (see, for example, Naturemedicine 2017;23(6):703-713, and Nature genetics 2013;45(12):1459-63), a mutation that replaces A (alanine) at amino acid position 293 of the HER2 protein with P (proline) (which may also be referred to as "A293P")(see, for example, Nature medicine 2017;23(6):703-713), a mutation that replaces N (asparagine) at amino acid position 302 of the HER2 protein with K (lysine) (which may also be referred to as "N302K") (see, for example, Naturemedicine 2017;23(6):703-713), a mutation that replaces V (valine) at amino acid position 308 of the HER2 protein with M (methionine) (which may also be referred to as "V308M") (see, for example, Cell Rep. 2016 Apr 26;15(4):857 - 865), the mutation that replaces S (serine) at amino acid position 310 of the HER2 protein with Y (tyrosine) (which can also be referred to as "S310Y") (see, for example, Nature genetics 2014;46(8):872 - 6, Nature 2016;534(7605):47 - 54, and Nature medicine 2017;23(6):703 - 713), the mutation that replaces N (asparagine) at amino acid position 319 of the HER2 protein with Y (tyrosine) (which can also be referred to as "N319Y") (see, for example, Cell.2018 May 3;173(4):864 - 878. e29), the mutation that replaces S (serine) at amino acid position 335 of the HER2 protein with C (cysteine) (which can also be referred to as "S335C") (see, for example, Nature medicine 2017;23(6):703 - 713), the mutation that replaces R (arginine) at amino acid position 340 of the HER2 protein with P (proline) (which can also be referred to as "R340P") (see, for example, Nature medicine 2017;23(6):703 - 713), the mutation that replaces S (serine) at amino acid position 418 of the HER2 protein with T (threonine) (which can also be referred to as "S418T")(see, for example, Cell 2012;150(6):1107 - 20), the mutation that replaces W (tryptophan) at amino acid position 452 of the HER2 protein with C (cysteine) (which can also be referred to as "W452C") (see, for example, Cell. 2018 May 3;173(4):864 - 878. e29), the mutation that replaces V (valine) at amino acid position 541 of the HER2 protein with M (methionine) (which can also be referred to as "V541M") (see, for example, Cell. 2018 May 3;173(4):864 - 878. e29), the mutation that replaces I (isoleucine) at amino acid position 613 of the HER2 protein with V (valine) (which can also be referred to as "I613V") (see, for example, Scientific reports 2016;6:31628), the mutation that replaces P (proline) at amino acid position 627 of the HER2 protein with H (histidine) (which can also be referred to as "P627H") (see, for example, PloS one2016;11(4): e0154133), a mutation that replaces A (alanine) at amino acid position 644 of the HER2 protein with V (valine) (which can also be referred to as "A644V") (see, for example, Nat Genet. 2012 Oct;44(10):1104-10, and Nature 2015;524(7563):47-53), a mutation that replaces R (arginine) at amino acid position 647 of the HER2 protein with G (glycine) (which can also be referred to as "R647G") (see, for example, Cell. 2018 May 3;173(4):864-878.e29), a mutation that replaces I (isoleucine) at amino acid position 654 of the HER2 protein with V (valine) (which can also be referred to as "I654V") (see, for example, Br J Cancer. 2017 Jun 27;117(1):136-143, and Cell. 2018 May 3;173(4):864-878.e29), a mutation that replaces I (isoleucine) at amino acid position 655 of the HER2 protein with V (valine) (which can also be referred to as "I655V") (see, for example, Oncotarget 2017;8(40):68026-68037, Nature communications 2015;6:10131, and Nature genetics 2014;46(6):595-600), a mutation that replaces I (isoleucine) at amino acid position 661 of the HER2 protein with V (valine) (which can also be referred to as "I661V") (see, for example, Nature medicine 2017;23(6):703-713), a mutation that replaces R (arginine) at amino acid position 678 of the HER2 protein with Q (glutamine) (which can also be referred to as "R678Q") (see, for example, Nature 2018;554(7691):189-194), a mutation that replaces Q (glutamine) at amino acid position 680 of the HER2 protein with H (histidine) (which can also be referred to as "Q680H") (see, for example, Nature medicine 2017;23(6):703-713), a mutation that replaces V (valine) at amino acid position 697 of the HER2 protein with L (leucine) (which can also be referred to as "V697L") (see, for example, Nature 2018;554(7691):189-194, Nature medicine 2017;23(6):703-713, and PLoS medicine 2016;13(12):e1002162), a mutation that replaces G (glycine) at amino acid position 704 of the HER2 protein with R (arginine) (which can also be referred to as "G704R") (see, for example, Lung 2016;194(1):125-35), a mutation that replaces Q (glutamine) at amino acid position 709 of the HER2 protein with L (leucine) (which can also be referred to as "Q709L") (see, for example, Nature medicine 2017;23(6):703-713), a mutation that replaces Q (glutamine) at amino acid position 711 of the HER2 protein with H (histidine) (which can also be referred to as "Q711H") (see, for example, Nature medicine 2017;23(6):703-713), a mutation that replaces G (glycine) at amino acid position 727 of the HER2 protein with A (alanine) (which can also be referred to as "G727A") (see, for example, Nature medicine 2017;23(6):703-713), a mutation that replaces T (threonine) at amino acid position 733 of the HER2 protein with I (isoleucine) (which can also be referred to as "T733I") (see, for example, Nature 2018;554(7691):189-194), a mutation that replaces E (glutamic acid) at amino acid position 744 of the HER2 protein with G (glycine) (which can also be referred to as "E744G") (see, for example, Cancer research 2007;67(12):5667-72), a mutation that replaces N (asparagine) at amino acid position 745 of the HER2 protein with D (aspartic acid) (which can also be referred to as "N745D") (see, for example, Cancer research 2007;67(12):5667-72), a mutation that replaces L (leucine) at amino acid position 755 of the HER2 protein with P (proline) (which can also be referred to as "L755P") (see, for example, Oncotarget 2016;7(28):44322-44329, Nature 2004;431(7008):525-6, and Naturemedicine 2017;23(6):703-713), a mutation that replaces L (leucine) at amino acid position 755 of the HER2 protein with A (alanine) (which can also be referred to as "L755A") (see, for example, Nature 2018;554(7691):189-194, and Nature medicine 2017;a mutation that replaces the L (leucine) at amino acid position 755 of the HER2 protein with F (phenylalanine) (which may also be referred to as "L755F") (see, e.g., Clin Cancer Res. 2015 Aug 15;21(16):3631-9), a mutation that replaces the S (serine) at amino acid position 760 of the HER2 protein with F (phenylalanine) (which may also be referred to as "S760F") (see, e.g., Clin Cancer Res. 2006 Apr 15;12(8):2538-44), a mutation that replaces the D (aspartic acid) at amino acid position 769 of the HER2 protein with H (histidine) (which may also be referred to as "D769H") (see, e.g., Cancer 2016; 122(17):2654-62, Nature medicine 2017;23(6):703-713, and Nature 2018;554(7691):189-194), a mutation that replaces the D (aspartic acid) at amino acid position 769 of the HER2 protein with N (asparagine) (which may also be referred to as "D769N") (see, e.g., Nature 2018;554(7691):189-194), and a mutation that replaces the D (aspartic acid) at amino acid position 769 of the HER2 protein with Y (tyrosine) (which may also be referred to as "D769Y") (see, e.g., Nature 2018;554(7691):189-194).;

[0545] Further, other specific examples of HER2 mutations may also include mutations in which AYVM (alanine, tyrosine, valine, and methionine) is inserted between E (glutamic acid) at amino acid position 770 and A (alanine) at amino acid position 771 of the HER2 protein (which may also be referred to as "E770_A771insAYVM") (see, for example, Nature medicine 2017;23(6):703-713, and Nature 2018;554(7691):189-194), mutations in which YVMA (tyrosine, valine, methionine, and alanine) is inserted between A (alanine) at amino acid position 771 and Y (tyrosine) at amino acid position 772 of the HER2 protein (which may also be referred to as "A771_Y772insYVMA") (see, for example, Nature 2018;554(7691):189-194), mutations in which AYVM (alanine, tyrosine, valine, and methionine) is inserted between M (methionine) at amino acid position 774 and A (alanine) at amino acid position 775 of the HER2 protein (which may also be referred to as "M774_A775insAYVM") (see, for example, J Thorac Oncol. 2013 Feb;8(2):e19-20, and The American journal of surgical pathology 2006;30(10):1309-15), mutations in which YVMA (tyrosine, valine, methionine, and alanine) is inserted between A (alanine) at amino acid position 775 and G (glycine) at amino acid position 776 of the HER2 protein (which may also be referred to as "A775_G776insYVMA") (see, for example, Clin Cancer Res.(Cancer 2016;122(17):2654-62, and European urology 2016;70(2):348-57), a mutation that replaces A (alanine) at amino acid position 775 of the HER2 protein with G (glycine) (which can also be referred to as "A775G") (see, for example, Anticancer research 2013;33(11):5127-33), a mutation that replaces G (glycine) at amino acid position 776 of the HER2 protein with LC (leucine and cysteine) (which can also be referred to as "G776delinsLC" or "G776>LC") (see, for example, Cancer research 2005;65(5):1642-6), a mutation that replaces G (glycine) at amino acid position 776 of the HER2 protein with C (cysteine) (which can also be referred to as "G776C") (see, for example, Clin Cancer Res. 2012 Sep 15;18(18):4910-8), a mutation that replaces G (glycine) at amino acid position 776 of the HER2 protein with AVGC (alanine, valine, glycine, and cysteine) (which can also be referred to as "G776delinsAVGC" or "G776>AVGC") (see, for example, Nature 2018;554(7691):189-194, and Nature medicine 2017;23(6):703-713), a mutation that replaces G (glycine) at amino acid position 776 of the HER2 protein with VV (valine and valine) (which can also be referred to as "G776delinsVV" or "G776>VV") (see, for example, Nature medicine 2017;23(6):703-713), a mutation that inserts L (leucine) between G (glycine) at amino acid position 776 and V (valine) at amino acid position 777 of the HER2 protein (which can also be referred to as "G776_V777insL") (see, for example, Oncotarget 2016;7(20):29761-9), a mutation that replaces G (glycine) at amino acid position 776 of the HER2 protein with L (leucine) (which can also be referred to as "G776L") (see, for example, Lung Cancer.In April 2012; 76(1):123 - 7), a mutation inserting VC (valine and cysteine) between G (glycine) at amino acid position 776 and V (valine) at amino acid position 777 of the HER2 protein (which can also be referred to as "G776_V777insVC") (for example, see J Clin Oncol. 2013 Jun 1;31(16):1997 - 2003), a mutation inserting VGC (valine, glycine, and cysteine) between G (glycine) at amino acid position 776 and V (valine) at amino acid position 777 of the HER2 protein (which can also be referred to as "G776_V777insVGC") (for example, see Nature 2018;554(7691):189 - 194), a mutation inserting CG (cysteine and glycine) between V (valine) at amino acid position 777 and G (glycine) at amino acid position 778 of the HER2 protein (which can also be referred to as "V777_G778insCG") (for example, see Clin Cancer Res. 2012 Sep 15;18(18):4910 - 8), a mutation inserting G (glycine) between V (valine) at amino acid position 777 and G (glycine) at amino acid position 778 of the HER2 protein (which can also be referred to as "V777_G778insG") (for example, see Nature 2018;554(7691):189 - 194), a mutation inserting G (glycine) between G (glycine) at amino acid position 778 and S (serine) at amino acid position 779 of the HER2 protein (which can also be referred to as "G778_S779insG") (for example, see Nature 2018;554(7691):189 - 194), a mutation substituting S (serine) at amino acid position 779 of the HER2 protein with P (proline) (which can also be referred to as "S779P") (for example, see Virchows Arch. 2016 Jun;468(6):651 - 62), a mutation inserting VGS (valine, glycine, and serine) between S (serine) at amino acid position 779 and P (proline) at amino acid position 780 of the HER2 protein (which can also be referred to as "S779_P780insVGS") (for example, see Nature 2004;431(7008):525 - 6, and J Thorac Oncol.(Glycine, serine, and proline), inserting the mutation of GSP between P (proline) at amino acid position 780 and Y (tyrosine) at amino acid position 781 of the HER2 protein (which can also be called "P780_Y781insGSP") (for example, see Nature medicine 2017;23(6):703-713), the mutation of replacing R (arginine) at amino acid position 784 of the HER2 protein with C (cysteine) (which can also be called "R784C") (for example, see Gynecol Oncol. 2018 Feb;148(2):311-316, Nature genetics 2014;46(12):1264-6, and Cell Rep. 2016 Apr 26;15(4):857-865), the mutation of replacing R (arginine) at amino acid position 784 of the HER2 protein with H (histidine) (which can also be called "R784H") (for example, see Cell Rep. 2016 Apr 26;15(4):857-865, Virchows Arch. 2016 Jun;468(6):651-62, and Eur J Cancer. 2014 Jul;50(10):1740-1746), the mutation of replacing L (leucine) at amino acid position 785 of the HER2 protein with R (arginine) (which can also be called "L785R") (for example, see Br J Cancer. 2015 Dec 22;113(12):1704-11), the mutation of replacing L (leucine) at amino acid position 786 of the HER2 protein with V (valine) (which can also be called "L786V") (for example, see Nature 2018;554(7691):189-194), the mutation of replacing T (threonine) at amino acid position 791 of the HER2 protein with I (isoleucine) (which can also be called "T791I") (for example, see Cancerresearch 2007;67(12):5667-72), the mutation of replacing G (glycine) at amino acid position 804 of the HER2 protein with S (serine) (which can also be called "G804S") (for example, see Clin Cancer Res. 2006 Apr 15;12(8):2538-44), the mutation of replacing L (leucine) at amino acid position 807 of the HER2 protein with F (phenylalanine) (which can also be called "L807F") (for example, see Eur J Cancer.In September 2015;51(13):1803 - 11), a mutation that replaces S (serine) at amino acid position 819 of the HER2 protein with F (phenylalanine) (which can also be referred to as "S819F") (see, for example, PLoS medicine 2016;13(12):e1002162, and Cancer cell 2015;27(3):327 - 41), a mutation that replaces I (isoleucine) at amino acid position 829 of the HER2 protein with T (threonine) (which can also be referred to as "I829T") (see, for example, Clin Cancer Res. 2006 Apr 15;12(8):2538 - 44), a mutation that replaces V (valine) at amino acid position 842 of the HER2 protein with I (isoleucine) (which can also be referred to as "V842I") (see, for example, Nature 2018;554(7691):189 - 194), a mutation that replaces L (leucine) at amino acid position 846 of the HER2 protein with F (phenylalanine) (which can also be referred to as "L846F") (see, for example, Oncotarget. 2016 Sep 20;7(38):61755 - 61763), a mutation that replaces T (threonine) at amino acid position 862 of the HER2 protein with I (isoleucine) (which can also be referred to as "T862I") (see, for example, Nature 2018;554(7691):189 - 194), a mutation that replaces R (arginine) at amino acid position 868 of the HER2 protein with W (tryptophan) (which can also be referred to as "R868W") (see, for example, Nature 2012;487(7407):330 - 7, and Br J Cancer.2015 Dec 22;113(12):1704 - 11), a mutation that replaces L (leucine) at amino acid position 869 of the HER2 protein with R (arginine) (which can also be referred to as "L869R") (see, for example, Nature medicine 2017;23(6):703 - 713, Nature 2018;554(7691):189 - 194, and PLoS medicine 2016;13(12):e1002201), a mutation that replaces T (threonine) at amino acid position 875 of the HER2 protein with I (isoleucine) (which can also be referred to as "T875I") (see, for example, Br J Cancer.On December 22, 2015;113(12):1704-11), removing the mutation of W (tryptophan) at amino acid position 906 of the HER2 protein (which can also be referred to as "W906*") (see, for example, Nature 2008;455(7216):1069-75), replacing the mutation of T (threonine) at amino acid position 917 of the HER2 protein with S (serine) (which can also be referred to as "T917S") (see, for example, Carcinogenesis. 2012 Jul;33(7):1270-6), removing the mutation of Q (glutamine) at amino acid position 943 of the HER2 protein (which can also be referred to as "Q943*") (see, for example, Cell 2012;150(6):1107-20), removing the mutation of S (serine) at amino acid position 1007 of the HER2 protein (which can also be referred to as "S1007*") (see, for example, Cell. 2018 May 3;173(4):864-878. e29), and replacing the mutation of S (serine) at amino acid position 1151 of the HER2 protein with L (leucine) (which can also be referred to as "S1151L")(see, for example, Nature medicine 2017;23(6):703-713).

[0546] The HER2 mutations in the present invention are not particularly limited as long as the amino acid sequence of the HER2 protein has a mutation, but specific examples thereof may include at least one selected from the above HER2 mutations, and preferably, at least one selected from Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, and S310F.

[0547] In the present invention, "exon 20 insertion mutation" refers to a HER2 mutation caused by the insertion of base pairs into exon 20 of the HER2 gene. Exon 20 of the HER2 gene is shown by the nucleotide sequence of nucleotides 2308 to 2493 of SEQ ID No: 4, and the HER2 protein encoded thereby is shown by the amino acid sequence consisting of amino acid residues 770 to 831 of SEQ ID No: 3.

[0548] The exon 20 insertion mutation in the present invention is not particularly limited as long as it is a HER2 mutation caused by the insertion of base pairs into exon 20 of the HER2 gene. However, examples thereof may include at least one selected from Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, G776delinsLC, G776delinsAVGC, G776delinsVV, G776_V777insL, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779_P780insVGS, and P780_Y781insGSP, and preferably, at least one selected from Y772_A775dup, G778_P780dup, and G776delinsVC.

[0549] In the present invention, the "single base pair substitution mutation" refers to a HER2 mutation caused by the substitution of one base pair of the HER2 gene with another base pair.

[0550] The single base pair substitution mutation in the present invention is not particularly limited as long as it is a HER2 mutation caused by substitution of one base pair of the HER2 gene with another base pair. However, examples thereof may include at least one selected from L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L, Q711H, G727A, T733I, E744G, N745D, L755P, L755A, L755F, S760F, D769H, D769N, D769Y, G776C, G776L, S779P, R784C, R784H, L785R, L786V, T791I, G804S, L807F, S819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, W906*, T917S, Q943*, S1007* and S1151L, and preferably at least one selected from L755S, V777L, V659E, G660D and S310F.

[0551] In the present invention, "single base pair substitution mutation in the transmembrane domain of the HER2 protein" refers to a HER2 mutation caused in the transmembrane domain of the HER2 protein by substituting one base pair of the HER2 gene with another base pair.

[0552] The single base pair substitution mutation in the transmembrane domain of the HER2 protein in the present invention is not particularly limited as long as it is a HER2 mutation caused in the transmembrane domain of the HER2 protein by substituting one base pair of the HER2 gene with another base pair. However, examples thereof may include at least one selected from V659E, G660D, I654V, I655V and I661V, and preferably G660D.

[0553] In the present invention, "single base pair substitution mutation in the extracellular domain of the HER2 protein" refers to a HER2 mutation caused in the extracellular domain of the HER2 protein by substituting one base pair of the HER2 gene with another base pair.

[0554] The single base pair substitution mutation in the extracellular domain of the HER2 protein in the present invention is not particularly limited as long as it is a HER2 mutation caused by substituting one base pair of the HER2 gene with another base pair in the extracellular domain of the HER2 protein. However, examples thereof may include at least one selected from S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, and R647G, and preferably S310F.

[0555] The therapeutic agent and / or treatment method of the present invention can preferably be used to determine a cancer with a HER2 mutation having at least one of the above mutations, but there is no limitation to these mutations as long as the cancer has a mutation in HER2.

[0556] For example, by collecting tumor tissue from a subject with cancer and performing real-time quantitative PCR (qRT-PCR) or microarray analysis on a formalin-fixed paraffin-embedded specimen (FFPE), the presence or absence of a HER2 mutation can be determined.

[0557] In addition, the presence or absence of a HER2 mutation can also be determined by collecting cell-free circulating tumor DNA (ctDNA) from a subject with cancer and performing next-generation sequencing (NGS) thereon (see, for example, J Clin Oncol 2013;31:1997-2003, Clin Cancer Res 2012;18:4910-8, J Thorac Oncol 2012;7:85-9, Lung Cancer 2011;74:139-44, Cancer Res 2005;65:1642-6, Cancer Sci 2006;97:753-9, ESMO Open 2017;2:e000279, and Annals of Oncology 26:1421-1427, 2015).

[0558] In the present invention, the term "HER2 mutation" is used in the same meaning as a HER2 gene mutation.

[0559] In the present invention, an "anti-HER2 antibody" refers to an antibody that specifically binds to HER2, preferably has the activity of binding to HER2, and is thereby internalized into cells expressing HER2, in other words, has the activity of binding to HER2 and then moves into cells expressing HER2.

[0560] [Anti-HER2 antibody-drug conjugate]

[0561] The anti-HER2 antibody-drug conjugate used in the present invention is an anti-HER2 antibody-drug conjugate in which the drug-linker represented by the following formula is conjugated to the antibody via a thioether bond:

[0562] [Formula 13]

[0563]

[0564] where A represents the position of attachment to the antibody.

[0565] In the present invention, the partial structure composed of the linker and the drug of the anti-HER2 antibody-drug conjugate is referred to as "drug-linker". The drug-linker is linked to the thiol groups (in other words, the sulfur atoms of cysteine residues) formed at the interchain disulfide bond sites of the antibody (two sites between the heavy chains and two sites between the heavy chain and the light chain).

[0566] The drug-linker of the present invention includes irinotecan (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]indolizino[1-2,b]quinoline-10,13-dione (also expressed as the chemical name: (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione)), which is a topoisomerase I inhibitor, as a component. Irinotecan is a camptothecin derivative represented by the following formula and has antitumor effects:

[0567] [Formula 14]

[0568] .

[0569] The anti-HER2 antibody-drug conjugate used in the present invention can also be represented by the following formula:

[0570] [Formula 15]

[0571]

[0572] wherein the drug-linker is conjugated to the anti-HER2 antibody via a thioether bond. The meaning of n is the same as the meaning of the average number of conjugated drug molecules (DAR; drug-to-antibody ratio) and represents the average number of drug-linker units conjugated to each antibody molecule.

[0573] The average number of drug linker units conjugated to each antibody molecule in the anti-HER2 antibody-drug conjugate for the present invention is preferably from 2 to 8, more preferably from 3 to 8, even more preferably from 7 to 8, even more preferably from 7.5 to 8, and even more preferably about 8.

[0574] After migrating into cancer cells, the anti-HER2 antibody-drug conjugate for the present invention is cleaved at the linker moiety, and a compound represented by the following formula is released:

[0575] [Formula 16]

[0576] .

[0577] It is inferred that the above compound is the original source of the antitumor activity of the anti-HER2 antibody-drug conjugate for the present invention, and it 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).

[0578] It is also known that the anti-HER2 antibody-drug conjugate for the present invention has a bystander effect (Ogitani Y. et al., Cancer Science (2016)107,1039-1046). The bystander effect is exerted through a process in which the anti-HER2 antibody-drug conjugate for the present invention is internalized into cancer cells expressing the target, and the above compound then also exerts an antitumor effect on cancer cells present in the vicinity thereof and not expressing the target.

[0579] The anti-HER2 antibody-drug conjugate for the present invention can be produced with reference to the descriptions in International Publication No. WO 2015 / 115091 and the like.

[0580] [Production of anti-HER2 antibody]

[0581] The HER2 protein for the present invention can be directly purified from cells expressing HER2 of humans or non-human mammals (such as rats and mice), or prepared using the cell membrane fraction of such cells, or can be obtained by in vitro synthesis of HER2 or by production of HER2 in host cells by genetic engineering. In genetic engineering, HER2 can be specifically obtained by incorporating HER2 cDNA into an expressible vector and then synthesizing HER2 in a solution containing enzymes, substrates, and energy substances required for transcription and translation, or by transforming other prokaryotic or eukaryotic host cells to express HER2. Further, cells expressing HER2 or cell lines expressing HER2 as HER2 protein can also be used by genetic engineering.

[0582] The HER2 protein used in the present invention can be directly purified from cells expressing human HER2, can be prepared using the cell membrane fraction of such cells as the HER2 protein (when used as an antigen), or can be obtained by in vitro synthesis of HER2 or by producing HER2 in a host cell through genetic engineering. In genetic engineering, HER2 can be specifically synthesized by incorporating HER2 cDNA into an expressible vector and then incubating the vector in a solution containing the enzymes, substrates, and energy substances required for transcription and translation. Alternatively, the protein can be obtained by transforming other prokaryotic or eukaryotic host cells with the vector to express HER2. Further, cells expressing HER2 or cell lines expressing HER2 as the HER2 protein antigen can also be used through genetic engineering.

[0583] The DNA sequence and amino acid sequence of HER2 are publicly available in public databases and can be accessed, for example, by accession numbers such as M11730 (Genbank) and NP_004439.2 (NCBI).

[0584] Further, HER2 also includes proteins composed of amino acid sequences having one or several substitutions, deletions, and / or additions of amino acids in the amino acid sequence of HER2 and having biological activity equivalent to that of the protein.

[0585] The human HER2 protein consists of: a signal sequence composed of 22 amino acid residues at the N-terminus, an extracellular domain composed of 630 amino acid residues, a cell transmembrane domain composed of 23 amino acid residues, and an intracellular domain composed of 580 amino acid residues.

[0586] The anti-HER2 antibody used in the present invention can be obtained by known methods. For example, an antibody can be obtained using methods routinely performed in the art, which involve immunizing an animal with any polypeptide selected from HER2 or the amino acid sequence of HER2 used as an antigen, collecting the antibodies produced in vivo, and purifying the antibodies. The source of the antigen is not limited to humans, and animals can be immunized with antigens derived from non-human animals such as mice, rats, etc. In this case, the cross-reactivity of the antibodies binding to the obtained heterologous antigen with the human antigen can be tested to screen anti-HER2 antibodies applicable to human diseases.

[0587] Alternatively, cells that produce antibodies that are directed against an antigen are fused with myeloma cells according to methods known in the art (e.g., Kohler and Milstein, Nature (1975) 256, p. 495-497; Kennet, R. ed., Monoclonal Antibodies, p. 365-367, Plenum Press, N.Y. (1980)) to establish hybridomas from which monoclonal antibodies can then be obtained.

[0588] An antigen can be obtained by genetically engineering a host cell to produce a gene encoding an antigenic protein. Specifically, a vector that permits expression of the antigen gene is prepared and transferred into the host cell to express the gene. The antigen thus expressed can be purified. Antibodies can also be obtained by immunizing an animal with the above-described genetically engineered cells that express the antigen or cell lines that express the antigen.

[0589] The anti-HER2 antibodies used in the present invention are preferably recombinant antibodies obtained by artificial modification for the purpose of reducing the heterologous antigenicity to humans, such as chimeric antibodies or humanized antibodies, or preferably antibodies having only the gene sequences of antibodies derived from humans, i.e., human antibodies. These antibodies can be produced using known methods.

[0590] As chimeric antibodies, examples include antibodies in which the antibody variable region and constant region are derived from different species, for example, chimeric antibodies in which the antibody variable region derived from a mouse or rat is linked to the antibody constant region derived from a human (Proc. Natl. Acad. Sci. USA, 81, 6851-6855, (1984)).

[0591] As humanized antibodies, examples include antibodies obtained by integrating only the complementarity-determining regions (CDRs) of a heterologous antibody into an antibody derived from a human (Nature (1986) 321, pp. 522-525), and antibodies obtained by transplanting a part of the amino acid residues of the heterologous antibody framework and the CDR sequences of the heterologous antibody into a human antibody by the CDR transplantation method (WO90 / 07861), and antibodies humanized using a gene conversion mutagenesis strategy (U.S. Patent No. 5821337).

[0592] Examples of human antibodies include antibodies produced by mice for producing human antibodies having human chromosomal fragments, said human chromosomal fragments including 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, examples include antibodies obtained by phage display, said antibodies selected from a human antibody library (see Wormstone, I. M. et. al, Investigative Ophthalmology & Visual Science. (2002) 43 (7), p.2301-2308; Carmen, S. et. al., Briefings in Functional Genomics and Proteomics (2002), 1 (2), p.189-203; Siriwardena, D. et. al., Ophthalmology (2002) 109 (3), p.427-431, etc.).

[0593] In the present invention, there are also provided modified variants of the anti-HER2 antibody of the present invention. The modified variants refer to variants obtained by chemically or biologically modifying the antibody according to the present invention. Examples of chemically modified variants include: variants comprising a linkage of a chemical moiety to the amino acid backbone; variants comprising a linkage of a chemical moiety to an N-linked or O-linked carbohydrate chain, etc. Examples of biologically modified variants include variants obtained by post-translational modifications (such as N-linked or O-linked glycosylation, N- or C-terminal processing, deamidation, isomerization of aspartic acid or oxidation of methionine), and variants in which a methionine residue has been added to the N-terminus by expression in a prokaryotic host cell. Further, antibodies labeled so as to enable detection or isolation of the anti-HER2 antibody or antigen of the present invention, for example, enzyme-labeled antibodies, fluorescent-labeled antibodies, and affinity-labeled antibodies, are also included in the meaning of the modified variants. Such modified variants of the anti-HER2 antibody for the present invention can be used to improve the stability and blood retention of the antibody, reduce its antigenicity, detect or isolate the antibody or antigen, etc.

[0594] Furthermore, by modulating the modification of the glycan linked to the anti-HER2 antibody of the present invention (such as glycosylation, defucosylation, etc.), the antibody-dependent cell cytotoxic activity can be enhanced. As techniques for modulating the modification of the glycan of the antibody, WO 99 / 54342, WO 00 / 61739, WO 02 / 31140, etc. are known. However, the technique is not limited thereto. In the anti-HER2 antibody for the present invention, there are also included antibodies in which the modification of the glycan is modulated.

[0595] It is known that the lysine residue at the carboxyl terminus of the heavy chain of an antibody produced in cultured mammalian cells is deleted (Journal of Chromatography A, 705: 129-134 (1995)), and it is also known that two amino acid residues (glycine and lysine) at the carboxyl terminus of the heavy chain of an antibody produced in cultured mammalian cells are deleted, and the newly located proline residue at the carboxyl terminus is amidated (Analytical Biochemistry, 360: 75-83 (2007)). However, such deletions and modifications of the heavy chain sequence do not affect the antigen-binding affinity and effector functions (activation of complement, antibody-dependent cellular cytotoxicity, etc.) of the antibody. Therefore, in the anti-HER2 antibody used in the present invention, there are also included antibodies that have undergone such modifications and functional fragments of the antibody, and also deletion variants in which 1 or 2 amino acids are deleted at the carboxyl terminus of the heavy chain, variants obtained by amidation of the deletion variants (for example, a heavy chain in which the carboxyl-terminal proline residue has been amidated), etc. The type of deletion variant having a deletion at the carboxyl terminus of the heavy chain of the anti-HER2 antibody used in the present invention is not limited to the above variants, as long as the antigen-binding affinity and effector functions are retained. The two heavy chains constituting the anti-HER2 antibody used in the present invention can be of one type selected from the full-length heavy chain and the above deletion variants, or can be of two types selected from a combination thereof. The proportion of the amount of each deletion variant can be affected by the type of cultured mammalian cells and the culture conditions for producing the anti-HER2 antibody used in the present invention. However, preferably, an example of such an antibody is one in which one amino acid residue at the carboxyl terminus has been deleted in both of the two heavy chains of the anti-HER2 antibody used in the present invention.

[0596] As an isotype of the anti-HER2 antibody used in the present invention, for example, IgG (IgG1, IgG2, IgG3, IgG4) can be exemplified, and preferably IgG1 or IgG2 can be exemplified.

[0597] Examples of the anti-HER2 antibody used in the present invention include trastuzumab (U.S. Patent No. 5,821,337) and pertuzumab (International Publication No. WO 01 / 00245), and preferably trastuzumab can be exemplified.

[0598] In the present invention, "trastuzumab" is a humanized anti-HER2 antibody that comprises a heavy chain and a light chain, the heavy chain consisting of an amino acid sequence composed of amino acid residues 1 to 449 of SEQ ID NO: 1 ( Figure 1 ), and the light chain consisting of an amino acid sequence composed of amino acid residues 1 to 214 of SEQ ID NO: 2 ( Figure 2 ).

[0599] Preferred anti-HER2 antibodies for the production of the anti-HER2 antibody-drug conjugate according to the present invention are:

[0600] (1) An antibody comprising a heavy chain and a light chain, the heavy chain consisting of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1, and the light chain consisting of an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2; or

[0601] (2) An antibody comprising a heavy chain and a light chain, the heavy chain consisting of the amino acid sequence shown in SEQ ID No: 1, and the light chain consisting of the amino acid sequence shown in SEQ ID No: 2.

[0602] [Production of anti-HER2 antibody-drug conjugate]

[0603] The drug-linker intermediate for the production of the anti-HER2 antibody-drug conjugate according to the present invention is represented by the following formula.

[0604] [Formula 17]

[0605] 。

[0606] The drug-linker intermediate can be represented by the chemical name N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-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]indazino[1,2-b]quinolin-1-yl]amino}-2-oxoethoxy)methyl]glycine amide, and can be produced with reference to the description in International Publication No. WO2015 / 115091.

[0607] The anti-HER2 antibody-drug conjugate for the present invention can be produced by reacting the above drug-linker intermediate with an anti-HER2 antibody having a thiol group (alternatively referred to as a mercapto group).

[0608] Anti-HER2 antibodies having a thiol group 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 0.3 to 3 molar equivalents of a reducing agent, such as tris(2-carboxyethyl)phosphine hydrochloride (TCEP), for each interchain disulfide in the antibody, and reacting with the anti-HER2 antibody in a buffer solution containing a chelating agent such as ethylenediaminetetraacetic acid (EDTA), anti-HER2 antibodies having a thiol group can be obtained, which have partially or fully reduced interchain disulfides in the antibody.

[0609] Furthermore, by using 2 to 20 molar equivalents of a drug-linker intermediate for each anti-HER2 antibody having a thiol group, an anti-HER2 antibody-drug conjugate in which each antibody molecule is conjugated with 2 to 8 drug molecules can be produced.

[0610] The average number of drug molecules conjugated to each antibody molecule of the produced anti-HER2 antibody-drug conjugate can be determined, for example, by a calculation method based on the measurement of the UV absorbance of the anti-HER2 antibody-drug conjugate and its conjugating precursor at two wavelengths of 280 nm and 370 nm (UV method), or by a calculation method based on the quantification by HPLC measurement of the fragments obtained by treating the antibody-drug conjugate with a reducing agent (HPLC method).

[0611] The conjugation of the anti-HER2 antibody with the drug-linker intermediate, and the calculation of the average number of drug molecules conjugated to each antibody molecule of the anti-HER2 antibody-drug conjugate, can be carried out with reference to the descriptions in International Publication No. WO 59 2015 / 115091 and the like.

[0612] [Therapeutic agent and / or therapeutic method]

[0613] The therapeutic agent and / or therapeutic method of the present invention includes administering a specific anti-HER2 antibody-drug conjugate, and can be used for treating HER2-mutated cancer.

[0614] The HER2-mutated cancers that can use the therapeutic agent and / or treatment method of the present invention are preferably at least one selected from the group consisting of: lung cancer (including non-small cell lung cancer), breast cancer, gastric cancer (also known as gastric adenocarcinoma), colorectal cancer (also known as colon and rectal cancer, and including colon cancer and rectal cancer), esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer (including cholangiocarcinoma), Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, endometrial cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, head and neck cancer, pharyngeal cancer, glioblastoma multiforme, and melanoma, more preferably at least one selected from the following: non-small cell lung cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, and uterine carcinosarcoma, even more preferably non-small cell lung cancer, and even more preferably unresectable and / or metastatic non-small cell lung cancer.

[0615] In the therapeutic agent and treatment method of the present invention, the dose of the anti-HER2 antibody-drug conjugate used in each administration is preferably in the range of 5.4 mg / kg (indicating that the dose per kg body weight is 5.4 mg, which is applicable to the following description) to 8 mg / kg, more preferably 5.4 mg / kg, 6.4 mg / kg, 7.4 mg / kg, or 8 mg / kg, even more preferably 5.4 mg / kg or 6.4 mg / kg, and even more preferably 6.4 mg / kg.

[0616] The therapeutic agent and treatment method of the present invention preferably include administering the anti-HER2 antibody-drug conjugate used in the present invention once every 3 weeks.

[0617] In addition to the anti-HER2 antibody-drug conjugate for use in the present invention, the therapeutic agents and treatment methods of the present invention may comprise one or more drugs (e.g., a second drug). Accordingly, the therapeutic agent of the present invention or the anti-HER2 antibody-drug conjugate for use in the present invention may be administered in combination with another drug, and the anti-cancer effect may thereby be enhanced. Another drug for such purpose may be administered to a subject simultaneously with, separately from, or sequentially to the anti-HER2 antibody-drug conjugate for use in the present invention, or may be administered at different dosing intervals. The other drug or second drug is preferably an anti-cancer therapeutic agent. Such anti-cancer therapeutic agents are not limited as long as they are drugs having anti-tumor activity, but examples thereof may include at least one selected from the group consisting of irinotecan (CPT-11), cisplatin, carboplatin, oxaliplatin, fluorouracil (5-FU), gemcitabine, capecitabine, paclitaxel, docetaxel, doxorubicin, epirubicin, cyclophosphamide, mitomycin C, tegafur-gimeracil-oteracil combination, cetuximab, panitumumab, bevacizumab, ramucirumab, regorafenib, trifluridine-tipiracil combination, gefitinib, erlotinib, afatinib, methotrexate, pemetrexed, trastuzumab-emtansine, trastuzumab, pertuzumab, tamoxifen, toremifene, fulvestrant, leuprorelin, goserelin, letrozole, anastrozole, and progesterone preparations.

[0618] The therapeutic agents and treatment methods of the present invention may be selectively used as pharmaceutical therapeutic agents, which are the main method for treating cancer, and as a result, the development of cancer cells may be delayed, their growth may be inhibited, and the cancer cells may be further killed. These effects may allow cancer patients to be free from the symptoms caused by cancer, or may achieve an improvement in the quality of life of cancer patients, and the therapeutic effect may be achieved by maintaining the life of cancer patients. Even if the therapeutic agents and treatment methods of the present invention do not achieve the killing of cancer cells, they may achieve a higher quality of life for cancer patients by inhibiting or controlling the growth of cancer cells, while achieving longer-term survival.

[0619] In such pharmaceutical treatment, the therapeutic agents and treatment methods of the present invention may be used alone, and in addition, they may be used in combination with other treatments for adjuvant treatment, and may be combined with surgery, radiotherapy, hormone therapy, etc. In addition, they may also be used for pharmaceutical treatment in neoadjuvant treatment.

[0620] In addition to the therapeutic uses described above, for example, for the therapeutic agents and treatment methods of the present invention, preventive effects may also be expected, such as inhibiting the growth of small metastatic cancer cells and further killing them. For example, effects of inhibiting and killing cancer cells in body fluids during the metastasis process may be expected, or for example, effects of inhibiting and killing small cancer cells immediately after implantation into any tissue may be expected. Accordingly, inhibitory effects on cancer metastasis or preventive effects may be expected, particularly after surgical resection of cancer.

[0621] It is expected that the therapeutic agent and treatment method of the present invention exert a therapeutic effect by being applied as a systemic treatment to a patient and, additionally, by being locally applied to cancer tissue.

[0622] The therapeutic agent and treatment method of the present invention can be preferably used for mammals and can be more preferably used for humans.

[0623] The therapeutic agent of the present invention can be administered as a pharmaceutical composition containing at least one pharmaceutically suitable ingredient. Based on the dose, administration concentration, etc. of the anti-HER2 antibody-drug conjugate used in the present invention, pharmaceutically suitable ingredients can be appropriately selected and applied from formulation additives commonly used in the art. For example, the therapeutic agent of the present invention can be administered as a pharmaceutical composition (hereinafter referred to as "the pharmaceutical composition for the present invention") containing a buffering agent, such as a histidine buffering agent, an excipient, such as sucrose, and a surfactant, such as polysorbate 80. The pharmaceutical composition for the present invention can be preferably used as an injection, can be more preferably used as an aqueous injection or a freeze-dried injection, and can even be more preferably used as a freeze-dried injection.

[0624] In the case where the pharmaceutical composition for the present invention is an aqueous injection, it can be preferably diluted with a suitable diluent and then administered in the form of an intravenous infusion. Examples of the diluent include a glucose solution, physiological saline, etc., a glucose solution can be preferably exemplified, and a 5% glucose solution can be more preferably exemplified.

[0625] In the case where the pharmaceutical composition for the present invention is a freeze-dried injection, it is preferred to dissolve the composition in water for injection, and then the required amount can be diluted with a suitable diluent and then administered in the form of an intravenous infusion. Examples of the diluent include a glucose solution, physiological saline, etc., a glucose solution can be preferably exemplified, and a 5% glucose solution can be more preferably exemplified.

[0626] Examples of the administration route that can be used to administer the pharmaceutical composition for the present invention include intravenous, intradermal, subcutaneous, intramuscular, and intraperitoneal routes, and the intravenous route is preferably included. Examples

[0627] The present invention will be specifically described according to the examples shown below. However, the present invention is not limited to these. Further, it is not to be construed in a limiting manner.

[0628] Example 1: Production of anti-HER2 antibody-drug conjugate

[0629] According to the production method described in International Publication No. WO 2015 / 115091, a humanized anti-HER2 antibody (an antibody comprising a heavy chain and a light chain, the heavy chain consisting of an amino acid sequence composed of amino acid residues 1 to 449 of SEQ ID NO: 1, and the light chain consisting of an amino acid sequence composed of amino acid residues 1 to 214 of SEQ ID NO: 2) was used to produce an anti-HER2 antibody-drug conjugate, in which a drug-linker represented by the following formula was conjugated to the anti-HER2 antibody via a thioether bond (referred to as "HER2-ADC (1)" in the present invention):

[0630] [Formula 18]

[0631]

[0632] wherein A represents the position of attachment to the antibody. The average number of drug units conjugated per antibody molecule in HER2-ADC (1) is in the range of 7 to 8.

[0633] Example 2: Clinical study (Phase I study)

[0634] A Phase I study of HER2-ADC (1) was conducted on subjects with HER2-positive breast cancer (previously treated with trastuzumab emtansine), subjects with HER2-positive gastric cancer (previously treated with trastuzumab), subjects with HER2-low-expressing breast cancer (with IHC 1+ or IHC 2+ and ISH-), and subjects with other solid cancers expressing HER2 (with IHC 1+ or higher) or HER2-mutated (determined by IHC, FISH, NGS, or other methods). Adverse events (AEs), response rate (ORR: CR (complete response) + PR (partial response)), and disease control rate (DCR: CR + PR + SD (stable disease)) were evaluated.

[0635] From September 2015 to April 2018, 12 subjects with HER2-expressing or HER2-mutated non-small cell lung cancer were administered HER2-ADC(1) (6.4 mg / kg). The median age of the subjects was 58.5 years, and the median number of prior treatments of the subjects was 3. At the data cutoff, 8 / 12 (66.7%) of the subjects were still receiving treatment. The median duration of treatment was 3.663 months. The ORR and DCR in the evaluable subjects were 62.5% (5 / 8) and 75.0% (6 / 8), respectively. Among them, 4 subjects were determined to have HER2 mutations, and the PR was 75.0% (3 / 4). The median duration of response was 11.5 months. Tumor shrinkage was observed in 8 / 10 (80.0%) of the subjects who had one or more post-baseline scans (100% of the subjects showed tumor shrinkage at the first post-baseline scan (about 6 weeks after administration)). The reasons for treatment discontinuation were PD (3 / 4, 75.0%) and AE (1 / 4, 25.0%). Grade 3 or higher AEs were observed in 3 / 12 (25.0%) of the subjects. As the main AEs, the proportion of alopecia observed was 41.7% (0.0% for grade 3 or higher), and the proportion of fatigue observed was 41.7% (0.0% for grade 3 or higher) (data as of April 18, 2018).

[0636] Example 3: Clinical Study (Phase I Study)

[0637] According to Example 2, a Phase I study of HER2-ADC(1) was conducted. To date, 18 subjects with HER2-expressing or HER2-mutated non-small cell lung cancer have been administered HER2-ADC(1) (6.4 mg / kg). The median age of the subjects was 58.0 years, and the median number of prior treatments of the subjects was 3. Among these 18 subjects, 11 subjects were determined to have HER2 mutations (61.1%).

[0638] As the anti-tumor effect of HER2-ADC(1), Table 1 shows the objective response rate (ORR), disease control rate (DCR), duration of response (DoR), time to response (TTR), and progression-free survival (PFS).

[0639] [Table 1]

[0640] Subjects with non-small cell lung cancer expressing HER2 or with HER2 mutations (n = 18) Subjects with non-small cell lung cancer with HER2 mutations (n = 11) Confirmed ORR 58.8% (10 / 17) 72.7% (8 / 11) Confirmed DCR 88.2% (15 / 17) 100% (11 / 11) DoR (median) 9.9 months 11.5 months TTR (median) 1.4 months 1.4 months PFS (median) 14.1 months 14.1 months

[0641] In a cohort of subjects (18 subjects) with non-small cell lung cancer expressing HER2 or with HER2 mutations, HER2-ADC (1) showed an ORR of 58.8% (10 / 17) and a DCR of 88.2% (15 / 17). The median DoR was 9.9 months, the median TTR was 1.4 months, and the median PFS was 14.1 months.

[0642] In a cohort of subjects (11 subjects) with non-small cell lung cancer with HER2 mutations, HER2-ADC (1) showed an ORR of 72.7% (8 / 11) and a DCR of 100% (11 / 11). The median DoR was 11.5 months, the median TTR was 1.4 months, and the median PFS was 14.1 months. Further, Figure 3 showed the maximum tumor shrinkage, and Figure 4 showed the time course of tumor shrinkage.

[0643] Table 2 shows the major adverse events (AEs) observed during treatment with HER2-ADC (1). All AEs were generally low grade.

[0644] [Table 2]

[0645]

[0646] In addition to the above, adverse events of particular concern were interstitial lung disease observed in one patient (5.6%) and pneumonia observed in one patient (5.6%) (data as of August 10, 2018).

[0647] Example 4: Clinical Study (Phase II Study)

[0648] A Phase II study of HER2-ADC (1) was conducted on subjects with inoperable and / or metastatic non-small cell lung cancer with overexpression of HER2 (with IHC 3+ or 2+) (approximately 40 subjects: cohort 1) and subjects with inoperable and / or metastatic non-small cell lung cancer with HER2 mutations (approximately 40 subjects: cohort 2). HER2-ADC (1) was administered at a dose of 6.4 mg / kg once every three weeks to evaluate the response rate (ORR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS).

[0649] Free text of the sequence listing

[0650] SEQ ID No: 1 - Amino acid sequence of the heavy chain of a humanized anti-HER2 antibody

[0651] SEQ ID No: 2 - Amino acid sequence of the light chain of the humanized anti-HER2 antibody

[0652] SEQ ID No: 3 - Amino acid sequence of the HER2 protein

[0653] SEQ ID No: 4 - Nucleotide sequence (cDNA) of the HER2 gene

Claims

1. Use of an anti-HER2 antibody-drug conjugate for the preparation of a medicament for treating HER2-mutated cancer, wherein the anti-HER2 antibody-drug conjugate has a drug-linker represented by the following formula: [Formula 1] wherein A represents the attachment position to the anti-HER2 antibody, and the drug-linker is conjugated to the anti-HER2 antibody via a thioether bond; wherein the average number of drug-linker units conjugated to each antibody in the anti-HER2 antibody-drug conjugate ranges from 7 to 8; wherein the anti-HER2 antibody is an antibody comprising a heavy chain and a light chain, the heavy chain consists of an amino acid sequence composed of amino acid residues 1 to 449 of SEQ ID NO:1, the light chain consists of an amino acid sequence composed of amino acid residues 1 to 214 of SEQ ID NO:2, or an antibody comprising a heavy chain composed of the amino acid sequence shown in SEQ ID NO:1 and a light chain composed of the amino acid sequence shown in SEQ ID NO:2; wherein the HER2 mutation in the HER2-mutated cancer is an exon 20 insertion mutation, a single base pair substitution mutation in the transmembrane domain of the HER2 protein, or a single base pair substitution mutation in the extracellular domain of the HER2 protein; and wherein the HER2-mutated cancer is non-small cell lung cancer.

2. The use according to claim 1, wherein the HER2 mutation in the HER2-mutated cancer is an exon 20 insertion mutation, and the exon 20 insertion mutation is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, G776delinsLC, G776delinsAVGC, G776delinsVV, G776_V777insL, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779_P780insVGS, and P780_Y781insGSP.

3. The use according to claim 2, wherein the exon 20 insertion mutation is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, and G776delinsVC.

4. The use according to claim 1, wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the transmembrane domain of the HER2 protein, and the single base pair substitution mutation in the transmembrane domain of the HER2 protein is at least one selected from the group consisting of: V659E, G660D, I654V, I655V, and I661V.

5. Use according to claim 4, wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is G660D.

6. Use according to claim 1, wherein the HER2 mutation in the cancer with HER2 mutation is a single base pair substitution mutation in the extracellular domain of the HER2 protein, and the single base pair substitution mutation in the extracellular domain of the HER2 protein is at least one selected from the group consisting of: S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, and R647G.

7. Use according to claim 6, wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is S310F.

8. Use according to any one of claims 1 to 7, wherein the non-small cell lung cancer is inoperable and / or metastatic non-small cell lung cancer.

9. Use according to any one of claims 1 to 7, wherein the average number of drug-linker units conjugated to each antibody in the anti-HER2 antibody-drug conjugate is in the range of 7.5 to 8.

10. Use according to any one of claims 1 to 7, wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is in the range of 5.4 mg / kg to 8 mg / kg.

11. Use according to any one of claims 1 to 7, wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is 5.4 mg / kg or 6.4 mg / kg.

12. Use according to any one of claims 1 to 7, wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is 5.4 mg / kg.

13. Use according to any one of claims 1 to 7, wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is 6.4 mg / kg.

14. Use according to any one of claims 1 to 7, wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

15. Use according to claim 9, wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is 5.4 mg / kg or 6.4 mg / kg.

16. Use according to claim 9, wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is 5.4 mg / kg.

17. Use according to claim 9, wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is 6.4 mg / kg.

18. Use according to claim 15, wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

19. Use according to claim 16, wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

20. Use according to claim 17, wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

Images