Therapy for drug-resistant cancer by administration of Anti-her2 antibody / drug conjugate

Abstract

Use of an antibody-drug conjugate in the production of a medicine for treating HER2 expressing cancers, which are resistant to or are not easily cured by conventional anti-HER2 drugs is provided. The use involves an antibody / drug conjugate comprising a linker and a drug, which are represented by the formula -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX), and an anti-HER2 antibody bonded thereto.

Description

Treatment of drug-resistant cancer by administration of anti-HER2 antibody-drug conjugate The present invention relates to the treatment of drug-resistant cancer (hereinafter also simply referred to as "resistant cancer"), particularly cancer that has acquired resistance, with an antibody-drug conjugate in which an anti-HER2 antibody and exatecan are linked via a linker structure. An antibody-drug conjugate (Antibody-Drug Conjugate; ADC) in which a drug having cytotoxicity is bound to an antibody that binds to an antigen expressed on the surface of cancer cells and can be internalized into cells is expected to accumulate the drug in cancer cells and kill the cancer cells by selectively delivering the drug to cancer cells (Non-Patent Documents 1 to 3). As an ADC, for example, Mylotarg (registered trademark; INN: gemtuzumab ozogamicin), in which calicheamicin is bound to an anti-CD33 antibody, was approved as a therapeutic agent for acute myeloid leukemia. In addition, Adcetris (registered trademark; INN: brentuximab vedotin), in which auristatin E is bound to an anti-CD30 antibody, was approved as a therapeutic agent for Hodgkin lymphoma and anaplastic large cell lymphoma (Non-Patent Document 4). Furthermore, Kadcyla (registered trademark; T-DM1; INN: trastuzumab emtansine; Non-Patent Document 34), in which the antitumor drug maytansinoid (DM1) is bound to the anti-HER2 antibody trastuzumab via a linker structure, was also approved. The drugs contained in the ADCs approved so far target DNA or tubulin. Camptothecin derivatives, which are compounds that inhibit topoisomerase I and exhibit antitumor activity as antitumor low-molecular compounds, are known. Among them, the following formula: The antitumor compound shown by (exatecan, IUPAC name: (1S,9S)-1-amino-9-ethyl-5-fluoro-1,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione, which can also be represented as (chemical name: (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione)) is a water-soluble camptothecin derivative (Patent Documents 1 and 2). This compound, unlike irinotecan currently used clinically, does not require enzymatic activation for the manifestation of its antitumor effect. Also, stronger topoisomerase I inhibitory activity was observed than that of SN-38, which is the active moiety of irinotecan, and topotecan, also used clinically, and stronger cytotoxic activity against various cancer cells was recognized in vitro. In particular, an effect was recognized even against cancer cells that show resistance to SN-38, etc. due to the expression of P-glycoprotein. Also, a strong antitumor effect was recognized in a human tumor subcutaneous transplantation model in mice, but although clinical trials have been conducted, it has not reached the market (Non-Patent Documents 5 to 10). It was not clear whether exatecan would act effectively as a drug for ADC. DE-310 is a complex in which exatecan is conjugated to a biodegradable carboxymethyldextran polyalcohol polymer via a GGFG peptide spacer (Patent Document 3). By formulating exatecan as a polymeric prodrug, it retains high blood retention, and further enhances the permeability of tumor neovessels and tumor tissue retention to passively enhance its targeting to tumor sites. DE-310 continuously releases exatecan, which is the active entity, and exatecan with glycine bound to its amino group by cleavage of the peptide spacer by an enzyme, resulting in improved pharmacokinetics. In various tumor evaluation models in preclinical trials, DE-310 showed higher efficacy than when administered as a single agent, even though the total amount of exatecan contained therein was decreased compared to when administered as a single agent. Clinical trials have been conducted on DE-310 and positive cases have been confirmed, and there are reports that it has been confirmed that the active entity accumulates in tumors more than in normal tissues. On the other hand, there are also reports that the accumulation of DE-310 and the active entity in tumors is not much different from that in normal tissues, and no passive targeting was observed in humans (Non-Patent Documents 11 to 14). As a result, DE-310 has not been launched, and it was not clear whether exatecan functioned effectively as a drug targeting such targeting. As a related compound of DE-310, a complex is also known in which a structural moiety represented by -NH-(CH2)4-C(=O)- is inserted between the -GGFG- spacer and exatecan, and -GGFG-NH-(CH2)4-C(=O)- is used as the spacer structure (Patent Document 4), but nothing is known about the antitumor effect of this complex. HER2 is one of the representative growth factor receptor-type cancer gene products identified as the human epidermal growth factor receptor type 2-related cancer gene, and is a transmembrane receptor protein having a tyrosine kinase domain with a molecular weight of 185 kDa (Non-Patent Document 15). The DNA sequence and amino acid sequence of HER2 are publicly available on public databases and can be referenced by accession numbers such as M11730 (Genbank), NP_004439.2 (NCBI), etc. HER2 (neu, ErbB-2) is a member of the EGFR (epidermal growth factor receptor) family. It is known to play an important role in cell growth, differentiation, and survival in normal and cancer cells by autophosphorylating intracellular tyrosine residues and becoming activated through the formation of homodimers or heterodimers with other EGFR receptors, namely HER1 (EGFR, ErbB-1), HER3 (ErbB-3), and HER4 (ErbB-4) (Non-Patent Documents 16 to 18). HER2 is overexpressed in various cancer types such as breast cancer, gastric cancer, and ovarian cancer (Non-Patent Documents 21 to 26), and it has been reported to be a negative prognostic factor in breast cancer (Non-Patent Documents 27, 28). Trastuzumab is a humanized antibody (Patent Document 6) of the mouse anti-HER2 antibody 4D5 (Non-Patent Document 29, Patent Document 5), which is called a recombinant humanized anti-HER2 monoclonal antibody (huMAb4D5-8, rhuMAb HER2, Herceptin (registered trademark)). Trastuzumab specifically binds to the extracellular domain IV of HER2 and exerts an anti-cancer effect through antibody-dependent cell-mediated cytotoxicity (ADCC) induction and inhibition of signal transduction from HER2 (Non-Patent Documents 30, 31). Since trastuzumab shows a high effect against tumors overexpressing HER2 (Non-Patent Document 32), it was marketed in the United States in 1999 and in Japan in 2001 as a therapeutic agent for patients with metastatic breast cancer overexpressing HER2. While the therapeutic effect of trastuzumab in breast cancer has been well proven (Non-Patent Document 33), it is said that only about 15% of breast cancer patients overexpressing HER2 who have received a wide range of conventional anti-cancer treatments respond to trastuzumab, and about 85% of patients in this group either do not respond to trastuzumab treatment or have only a poor response. Therefore, there is a recognized need for therapeutic agents that target diseases associated with HER2 expression for patients suffering from tumors that overexpress HER2 and do not respond to or have poor responses to trastuzumab, or disorders associated with HER2 expression. Antibody-drug conjugates such as T-DM1, in which an anti-tumor drug is conjugated to trastuzumab via a linker structure, and pertuzumab (Perjeta®; Non-Patent Document 35, Patent Document 7), which targets extracellular domain II of HER2 and is designed to inhibit heterodimer formation, have been developed. However, the responsiveness, strength of activity, and scope of application are still not sufficient, and there are unmet needs for targeting HER2. As an antibody-drug conjugate, an antibody-drug conjugate comprising an anti-HER2 antibody and exatecan as components is known, and in particular, those having the following structure have been shown to have excellent properties (Patent Document 8). That is, it is an antibody-drug conjugate in which a linker and a drug represented by the following formula are bound to an anti-HER2 antibody. -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX) (In the formula, -(Succinimid-3-yl-N)- has the following formula: It is a structure represented by, which binds to an anti-HER2 antibody by a thioether bond at the 3-position and binds to a methylene group in the linker structure containing this on the nitrogen atom at the 1-position. -(NH-DX) has the following formula: It represents a group in which the nitrogen atom of the amino group at the 1-position is the binding site. The above anti-HER2 antibody-drug conjugate has a drug-linker structure represented by the following formula for one molecule of the anti-HER2 antibody: -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX) are conjugated. This drug-linker structure can be conjugated up to 8 via thioether bonds to the disulfide bond sites between the chains of the antibody (two heavy chain-heavy chain sites and two heavy chain-light chain sites). An anti-HER2 antibody-drug conjugate conjugated with almost 8 drug-linker structures, close to this maximum number, has been obtained. Antibody-drug conjugates with a large number of drug conjugations per antibody molecule have been shown to exhibit very excellent anti-cancer effects. For example, in preclinical studies using cancer-bearing mice, it has been confirmed that even when the expression of HER2 in cancer cells is low, it has cell-killing activity (Patent Document 8, Non-Patent Document 36). Thus, the above anti-HER2 antibody-drug conjugate is expected as an excellent anti-cancer drug, and clinical trials are underway. JP-A-5-59061 JP-A-8-337584 WO 1997 / 46260 WO 2000 / 25825 US Patent No. 5,677,171 Specification US Patent No. 5,821,337 Specification WO 01 / 00244 WO 2015 / 115091 Ducry, L., et al., Bioconjugate Chem. (2010) 21, 5-13. Alley, S. C., et al., Current Opinion in Chemical Biology (2010) 14, 529-537. Damle N. K. Expert Opin. Biol. Ther. (2004) 4, 1445-1452. Senter P. D., et al., Nature Biotechnology (2012) 30, 631-637. Kumazawa, E., Tohgo, A., Exp. Opin. Invest. Drugs (1998) 7, 625-632. Mitsui, I., et al., Jpn J. Cancer Res. (1995) 86, 776-786. Takiguchi, S., et al., Jpn J. Cancer Res. (1997) 88, 760-769. Joto, N. et al., Int J Cancer (1997) 72, 680-686. Kumazawa, E. et al., Cancer Chemother. Pharmacol. (1998) 42, 210-220. De Jager, R., et al., Ann N Y Acad Sci (2000) 922, 260-273. Inoue, K. et al., Polymer Drugs in the Clinical Stage, Edited by Maeda et al. (2003) 145-153. Kumazawa, E. et al., Cancer Sci (2004) 95, 168-175. Soepenberg, O. et al., Clinical Cancer Research, (2005) 11, 703-711. Wente M. N. et al., Investigational New Drugs (2005) 23, 339-347. Coussens L, et al., Science. 1985;230(4730):1132-1139. Graus-Porta G, et al., EMBO J. 1997;16:1647-1655.Karnagaran D, et al., EMBO J. 1996;15:254-264. Sliwkowski MX, et al., J Biom Chem. 1994;269:14661-14665. Di Fore PP, et al., Science. 1987; 237: 178-182. Hudziak RM, et al., Proc Natl Acad Sci U S A. 1987; 84: 7159-7163. Hardwick R, et al., Eur. J Surg Oncol. 1997 (23):30-35. Korkaya H, et al., Oncogene. 2008;27(47):6120-6130. Yano T, et al., Oncol Rep. 2006; 15(1): 65-71. Slamon DJ, et al., Science. 1987; 235: 177-182. Gravalos C, et al., Ann Oncol 19: 1523-1529, 2008. Fukushige S et al., Mol Cell Biol 6: 955-958, 1986. Slamon DJ, et al. Science. 1989; 244: 707-712. Kaptain S et al., Diagn Mol Pathol 10: 139-152, 2001. Fendly., et al., Cancer Research 1990(50):1550-1558. Sliwkowski MX, et al., Semin Oncol. 1999; 26(4,Suppl 12): 60-70. Hudis CA, et al., N Engl J Med. 357: 39-51, 2007. Vogel CL, et al., J Clin Oncol. 2002; 20(3): 719-726. Baselga et al., J. Clin. Oncol. 14: 737-744 (1996). Howard A. et al., J Clin Oncol 29: 398-405. Adams CW, et al., Cancer Immunol Immunother. 2006; 6: 717-727. Ogitani Y.et al., Clinical Cancer Research, 2016, Oct 15;22(20):5097-5108, Epub 2016 Mar 29. When an anticancer drug is continuously administered for treatment, even if an effect is once observed, the treatment effect is known to disappear due to acquired resistance of cancer cells (hereinafter also referred to as "secondary resistance" in the present invention). For example, in HER2-expressing cancer, it is known that as a result of treatment with trastuzumab emtansine, new cancer that has acquired resistance or intractability to trastuzumab emtansine occurs. Therefore, a drug that can provide a new treatment method effective against such resistant cancer (hereinafter also referred to as "secondary resistant cancer" in the present invention) is desired. The main object of the present invention is to provide a therapeutic agent and a treatment method that show a sufficient treatment effect even in HER2-expressing cancer that has acquired resistance or intractability by treatment with an existing anti-HER2 drug. In addition, there are cancers that express HER2 but do not show a treatment effect from the beginning with existing anti-HER2 drugs (in other words, HER2-expressing cancers that have inherent resistance or intractability to existing anti-HER2 drugs without treatment with existing anti-HER2 drugs). Examples of such HER2-expressing cancers include cancers with low HER2 expression and solid cancers other than breast cancer and gastric cancer (for example, colorectal cancer, non-small cell lung cancer, etc.). The present invention also has as a main object to provide a therapeutic agent and a treatment method that show a sufficient treatment effect even in such HER2-expressing cancers. The present inventors have found an antibody-drug conjugate in which a linker and a drug represented by the following formula are bound to an anti-HER2 antibody: -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX) It has been found in preclinical and clinical trials that it shows excellent antitumor effects against HER2-expressing cancers that are resistant or intractable to existing anti-HER2 drugs and is also excellent in safety. According to this antibody-drug conjugate, effective treatment can be expected even for secondary resistant cancer. That is, the present invention provides the following [1] to

[144] . [1] A therapeutic agent for HER2-expressing cancer resistant or refractory to existing anti-HER2 drugs, comprising an antibody-drug conjugate in which a linker and a drug represented by the following formula are bound to an anti-HER2 antibody: -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX). (In the formula, -(Succinimid-3-yl-N) is the following formula: It is a structure represented by, and binds to the anti-HER2 antibody by a thioether bond at the 3-position, and binds to the methylene group in the linker structure containing this on the nitrogen atom at the 1-position, -(NH-DX) is the following formula: It represents a group in which the nitrogen atom of the amino group at the 1-position is the binding site, -GGFG- represents a tetrapeptide residue of -Gly-Gly-Phe-Gly-.) [2] The therapeutic agent according to [1], wherein the resistance or refractoriness is resistance or refractoriness acquired by treatment with an existing anti-HER2 drug. [3] The therapeutic agent according to [1], wherein the resistance or refractoriness is inherent resistance or refractoriness without treatment with an existing anti-HER2 drug. [4] The therapeutic agent according to any one of [1] to [3], wherein the existing anti-HER2 drug is at least one selected from the group consisting of trastuzumab emtansine, trastuzumab, pertuzumab, and lapatinib. [5] The therapeutic agent according to any one of [1] to [3], wherein the existing anti-HER2 drug is trastuzumab emtansine. [6] The therapeutic agent according to any one of [1] to [3], wherein the existing anti-HER2 drug is trastuzumab. [7] The therapeutic agent according to any one of [1] to [6], for administration to a patient having a treatment history with an existing anticancer drug. [8] The therapeutic agent according to [7], wherein the existing anticancer drug comprises at least one selected from the group consisting of trastuzumab emtansine, trastuzumab, pertuzumab, lapatinib, irinotecan, cisplatin, carboplatin, oxaliplatin, fluorouracil, 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, and pemetrexed. [9] The therapeutic agent according to [7], wherein the existing anticancer drug comprises trastuzumab emtansine.

[10] The therapeutic agent according to [7], wherein the existing anticancer drug comprises trastuzumab.

[11] The therapeutic agent according to [7], wherein the existing anticancer drug comprises irinotecan.

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

[11] , wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate ranges from 7 to 8.

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

[11] , wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate ranges from 7.5 to 8.

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

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

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

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

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

[15] , wherein the dosage per administration of the antibody-drug conjugate ranges from 5.4 mg / kg to 8 mg / kg. The therapeutic agent according to any one of [1] to

[15] , wherein the dose per administration of the antibody-drug conjugate is 5.4 mg / kg. The therapeutic agent according to any one of [1] to

[15] , wherein the dose per administration of the antibody-drug conjugate is 6.4 mg / kg. The therapeutic agent according to any one of [1] to

[15] , wherein the dose per administration of the antibody-drug conjugate is 7.4 mg / kg. The therapeutic agent according to any one of [1] to

[15] , wherein the dose per administration of the antibody-drug conjugate is 8 mg / kg. The therapeutic agent according to any one of [1] to

[20] , wherein the antibody-drug conjugate is administered at intervals of once every three weeks. The therapeutic agent according to any one of [1] to

[21] for the treatment of at least one cancer selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, non-small cell lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, cholangiocarcinoma, Paget's disease, pancreatic cancer, ovarian cancer, and uterine carcinosarcoma. The therapeutic agent according to any one of [1] to

[21] for the treatment of breast cancer. The therapeutic agent according to any one of [1] to

[21] for the treatment of gastric cancer. The therapeutic agent according to any one of [1] to

[21] for the treatment of gastric cancer and gastroesophageal junction adenocarcinoma. The therapeutic agent according to any one of [1] to

[21] for the treatment of colorectal cancer. The therapeutic agent according to any one of [1] to

[21] for the treatment of non-small cell lung cancer. The therapeutic agent according to any one of [1] to

[21] for the treatment of salivary gland cancer. The therapeutic agent according to any one of [1] to

[28] , wherein the HER2-expressing cancer is a cancer with HER2 overexpression. The therapeutic agent according to

[29] , wherein the cancer with HER2 overexpression is a cancer in which the expression of HER2 is determined to be 3+ by immunohistochemistry.

[31] The therapeutic agent according to

[29] , wherein the cancer with overexpression of HER2 is a cancer in which the expression of HER2 is determined to be 2+ by immunohistochemistry and the expression of HER2 is determined to be positive by in situ hybridization method.

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

[28] , wherein the HER2-expressing cancer is a cancer with low expression of HER2.

[33] The therapeutic agent according to

[32] , wherein the cancer with low expression of HER2 is a cancer in which the expression of HER2 is determined to be 2+ by immunohistochemistry and the expression of HER2 is determined to be negative by in situ hybridization method.

[34] The therapeutic agent according to

[32] , wherein the cancer with low expression of HER2 is a cancer in which the expression of HER2 is determined to be 1+ by immunohistochemistry.

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

[34] for the treatment of inoperable or recurrent cancer.

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

[35] , which contains pharmaceutically acceptable formulation components.

[37] A method for treating HER2-expressing cancer resistant or refractory to existing anti-HER2 drugs, by administering an antibody-drug conjugate in which a linker and a drug represented by the following formula are bound to an anti-HER2 antibody to a patient in need of treatment for HER2-expressing cancer resistant or refractory to existing anti-HER2 drugs: -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX). (In the formula, -(Succinimid-3-yl-N)- has the structure represented by the following formula: It is a structure represented by, and binds to the anti-HER2 antibody by a thioether bond at the 3-position thereof, and binds to the methylene group in the linker structure containing this at the nitrogen atom at the 1-position, -(NH-DX) has the following formula: It represents a group in which the nitrogen atom of the amino group at the 1-position is the binding site, -GGFG- represents a tetrapeptide residue of -Gly-Gly-Phe-Gly-. )

[38] The method according to

[37] , wherein the resistance or refractoriness is resistance or refractoriness acquired by treatment with an existing anti-HER2 drug.

[39] The method according to

[37] , wherein the resistance or refractoriness is inherent resistance or refractoriness not due to treatment with an existing anti-HER2 drug.

[40] The method according to any one of

[37] to

[39] , wherein the existing anti-HER2 drug is at least one selected from the group consisting of trastuzumab emtansine, trastuzumab, pertuzumab, and lapatinib.

[41] The method according to any one of

[37] to

[39] , wherein the existing anti-HER2 drug is trastuzumab emtansine.

[42] The method according to any one of

[37] to

[39] , wherein the existing anti-HER2 drug is trastuzumab.

[43] The method according to any one of

[37] to

[42] , which is for use in a patient having a history of treatment with an existing anti-cancer drug.

[44] The method according to

[43] , wherein the existing anti-cancer drug comprises at least one selected from the group consisting of trastuzumab emtansine, trastuzumab, pertuzumab, lapatinib, irinotecan, cisplatin, carboplatin, oxaliplatin, fluorouracil, gemcitabine, capecitabine, paclitaxel, docetaxel, doxorubicin, epirubicin, cyclophosphamide, mitomycin C, tegafur / gimeracil / oteracil potassium, cetuximab, panitumumab, bevacizumab, ramucirumab, regorafenib, trifluridine / tipiracil, gefitinib, erlotinib, afatinib, methotrexate, and pemetrexed.

[45] The method according to

[43] , wherein the existing anti-cancer drug comprises trastuzumab emtansine.

[46] The method according to

[43] , wherein the existing anti-cancer drug comprises trastuzumab.

[47] The method according to

[43] , wherein the existing anti-cancer drug comprises irinotecan.

[48] The method according to any one of

[37] to

[47] , wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate is in the range of 7 to 8. The method according to any one of

[37] to

[47] , wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate ranges from 7.5 to 8. The method according to any one of

[37] to

[49] , wherein the anti-HER2 antibody in the antibody-drug conjugate is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO: 2. The method according to any one of

[37] to

[49] , wherein the anti-HER2 antibody in the antibody-drug conjugate is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2. The method according to any one of

[37] to

[51] , wherein the dosage per administration of the antibody-drug conjugate ranges from 5.4 mg / kg to 8 mg / kg. The method according to any one of

[37] to

[51] , wherein the dosage per administration of the antibody-drug conjugate is 5.4 mg / kg. The method according to any one of

[37] to

[51] , wherein the dosage per administration of the antibody-drug conjugate is 6.4 mg / kg. The method according to any one of

[37] to

[51] , wherein the dosage per administration of the antibody-drug conjugate is 7.4 mg / kg. The method according to any one of

[37] to

[51] , wherein the dosage per administration of the antibody-drug conjugate is 8 mg / kg. The method according to any one of

[37] to

[56] , wherein the antibody-drug conjugate is administered at intervals of once every three weeks. The method according to any one of

[37] to

[57] for the treatment of at least one cancer selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, non-small cell lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, cholangiocarcinoma, Paget's disease, pancreatic cancer, ovarian cancer, and uterine carcinosarcoma. The method according to any one of

[37] to

[57] for the treatment of breast cancer.

[60] A method according to any one of

[37] to

[57] for the treatment of gastric cancer.

[61] A method according to any one of

[37] to

[57] for the treatment of gastric cancer and gastroesophageal junction adenocarcinoma.

[62] A method according to any one of

[37] to

[57] for the treatment of colorectal cancer.

[63] A method according to any one of

[37] to

[57] for the treatment of non-small cell lung cancer.

[64] A method according to any one of

[37] to

[57] for the treatment of salivary gland cancer.

[65] A method according to any one of

[37] to

[64] , wherein the HER2-expressing cancer is a cancer with HER2 overexpression.

[66] The method according to

[65] , wherein the cancer with HER2 overexpression is a cancer in which the expression of HER2 is determined to be 3+ by immunohistochemistry.

[67] The method according to

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

[68] A method according to any one of

[37] to

[64] , wherein the HER2-expressing cancer is a cancer with low HER2 expression.

[69] The method according to

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

[70] The method according to

[68] , wherein the cancer with low HER2 expression is a cancer in which the expression of HER2 is determined to be 1+ by immunohistochemistry.

[71] A method according to any one of

[37] to

[70] for the treatment of inoperable or recurrent cancer.

[72] A method according to any one of

[37] to

[71] , wherein an antibody-drug conjugate is administered together with a pharmaceutically acceptable formulation component.

[73] An antibody-drug conjugate in which a linker and a drug represented by the following formula are bound to an anti-HER2 antibody, for use as a therapeutic agent for HER2-expressing cancer resistant or refractory to existing anti-HER2 drugs: -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX). (In the formula,[[]] -(Succinimid-3-yl-N)-has the following formula:[[]] It is a structure represented by the formula, which binds to the anti-HER2 antibody by a thioether bond at the 3-position and binds to the methylene group in the linker structure containing this at the nitrogen atom at the 1-position.[[]] -(NH-DX) has the following formula:[[]] It represents a group in which the nitrogen atom of the amino group at the 1-position is a binding site.[[]] -GGFG- represents a tetrapeptide residue of -Gly-Gly-Phe-Gly-.)[[]]

[74] The antibody-drug conjugate according to

[73] , wherein the resistance or refractoriness is resistance or refractoriness acquired by treatment with an existing anti-HER2 drug.[[]]

[75] The antibody-drug conjugate according to

[73] , wherein the resistance or refractoriness is inherent resistance or refractoriness not due to treatment with an existing anti-HER2 drug.[[]]

[76] The antibody-drug conjugate according to any one of

[73] to

[75] , wherein the existing anti-HER2 drug is at least one selected from the group consisting of trastuzumab emtansine, trastuzumab, pertuzumab, and lapatinib.[[]]

[77] The antibody-drug conjugate according to any one of

[73] to

[75] , wherein the existing anti-HER2 drug is trastuzumab emtansine.[[]]

[78] The antibody-drug conjugate according to any one of

[73] to

[75] , wherein the existing anti-HER2 drug is trastuzumab.[[]]

[79] The antibody-drug conjugate according to any one of

[73] to

[78] , for administration to a patient having a history of treatment with an existing anti-cancer drug.[[]]

[80] The antibody-drug conjugate according to

[79] , wherein the existing anticancer drug comprises at least one selected from the group consisting of trastuzumab emtansine, trastuzumab, pertuzumab, lapatinib, irinotecan, cisplatin, carboplatin, oxaliplatin, fluorouracil, 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, and pemetrexed.

[81] The antibody-drug conjugate according to

[79] , wherein the existing anticancer drug comprises trastuzumab emtansine.

[82] The antibody-drug conjugate according to

[79] , wherein the existing anticancer drug comprises trastuzumab.

[83] The antibody-drug conjugate according to

[79] , wherein the existing anticancer drug comprises irinotecan.

[84] The antibody-drug conjugate according to any one of

[73] to

[83] , wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate ranges from 7 to 8.

[85] The antibody-drug conjugate according to any one of

[73] to

[83] , wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate ranges from 7.5 to 8.

[86] The antibody-drug conjugate according to any one of

[73] to

[85] , wherein the anti-HER2 antibody in the antibody-drug conjugate is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO: 2.

[87] The antibody-drug conjugate according to any one of

[73] to

[85] , wherein the anti-HER2 antibody in the antibody-drug conjugate is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2. An antibody-drug conjugate as described in any of

[73] to

[87] , wherein the dosage per administration of the antibody-drug conjugate is in the range of 5.4 mg / kg to 8 mg / kg. An antibody-drug conjugate as described in any of

[73] to

[87] , wherein the dosage per administration of the antibody-drug conjugate is 5.4 mg / kg. An antibody-drug conjugate as described in any of

[73] to

[87] , wherein the dosage per administration of the antibody-drug conjugate is 6.4 mg / kg. An antibody-drug conjugate as described in any of

[73] to

[87] , wherein the dosage per administration of the antibody-drug conjugate is 7.4 mg / kg. An antibody-drug conjugate as described in any of

[73] to

[87] , wherein the dosage per administration of the antibody-drug conjugate is 8 mg / kg. An antibody-drug conjugate as described in any of

[73] to

[92] , wherein the antibody-drug conjugate is administered at intervals of once every three weeks. An antibody-drug conjugate as described in any of

[73] to

[93] for the treatment of at least one cancer selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, non-small cell lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, cholangiocarcinoma, Paget's disease, pancreatic cancer, ovarian cancer, and uterine carcinosarcoma. An antibody-drug conjugate as described in any of

[73] to

[93] for the treatment of breast cancer. An antibody-drug conjugate as described in any of

[73] to

[93] for the treatment of gastric cancer. An antibody-drug conjugate as described in any of

[73] to

[93] for the treatment of gastric cancer and gastroesophageal junction adenocarcinoma. An antibody-drug conjugate as described in any of

[73] to

[93] for the treatment of colorectal cancer. An antibody-drug conjugate as described in any of

[73] to

[93] for the treatment of non-small cell lung cancer.

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

[73] to

[93] for the treatment of salivary gland cancer.

[101] The antibody-drug conjugate according to any one of

[73] to

[100] , wherein the HER2-expressing cancer is a cancer with HER2 overexpression.

[102] The antibody-drug conjugate according to

[101] , wherein the cancer with HER2 overexpression is a cancer in which the expression of HER2 is determined to be 3+ by immunohistochemistry.

[103] The antibody-drug conjugate according to

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

[104] The antibody-drug conjugate according to any one of

[73] to

[100] , wherein the HER2-expressing cancer is a cancer with low HER2 expression.

[105] The antibody-drug conjugate according to

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

[106] The antibody-drug conjugate according to

[104] , wherein the cancer with low HER2 expression is a cancer in which the expression of HER2 is determined to be 1+ by immunohistochemistry.

[107] The antibody-drug conjugate according to any one of

[73] to

[106] for the treatment of inoperable or recurrent cancer.

[108] The antibody-drug conjugate according to any one of

[73] to

[107] , which is administered together with pharmaceutically acceptable formulation components.

[109] Use of an antibody-drug conjugate in which a linker and a drug represented by the following formula are bound to an anti-HER2 antibody for the manufacture of a medicament for treating a HER2-expressing cancer resistant or refractory to an existing anti-HER2 drug: -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX). (In the formula, -(Succinimid-3-yl-N)- has the following formula: It has a structure represented by the following formula, and binds to the anti-HER2 antibody by a thioether bond at the 3-position thereof, and binds to the methylene group in the linker structure containing this at the nitrogen atom at the 1-position. -(NH-DX) has the following formula: It represents a group in which the nitrogen atom of the amino group at the 1-position serves as the binding site, -GGFG- represents a tetrapeptide residue of -Gly-Gly-Phe-Gly-.)

[110] The use according to

[109] , wherein the resistance or refractoriness is resistance or refractoriness acquired by treatment with an existing anti-HER2 drug.

[111] The use according to

[109] , wherein the resistance or refractoriness is inherent resistance or refractoriness not caused by treatment with an existing anti-HER2 drug.

[112] The use according to any one of

[109] to

[111] , wherein the existing anti-HER2 drug is at least one selected from the group consisting of trastuzumab emtansine, trastuzumab, pertuzumab, and lapatinib.

[113] The use according to any one of

[109] to

[111] , wherein the existing anti-HER2 drug is trastuzumab emtansine.

[114] The use according to any one of

[109] to

[111] , wherein the existing anti-HER2 drug is trastuzumab.

[115] The use according to any one of

[109] to

[114] for the manufacture of a medicament for administration to a patient having a treatment history with an existing anti-cancer drug. The use according to

[115] , wherein the existing anticancer drug comprises at least one selected from the group consisting of trastuzumab emtansine, trastuzumab, pertuzumab, lapatinib, irinotecan, cisplatin, carboplatin, oxaliplatin, fluorouracil, gemcitabine, capecitabine, paclitaxel, docetaxel, doxorubicin, epirubicin, cyclophosphamide, mitomycin C, tegafur / gimeracil / oteracil potassium, cetuximab, panitumumab, bevacizumab, ramucirumab, regorafenib, trifluridine / tipiracil, gefitinib, erlotinib, afatinib, methotrexate, and pemetrexed. The use according to

[115] , wherein the existing anticancer drug comprises trastuzumab emtansine. The use according to

[115] , wherein the existing anticancer drug comprises trastuzumab. The use according to

[115] , wherein the existing anticancer drug comprises irinotecan. The use according to any one of

[109] to

[119] , wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate ranges from 7 to 8. The use according to any one of

[109] to

[119] , wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate ranges from 7.5 to 8. The use according to any one of

[109] to

[121] , wherein the anti-HER2 antibody in the antibody-drug conjugate is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO: 2. The use according to any one of

[109] to

[121] , wherein the anti-HER2 antibody in the antibody-drug conjugate is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2. The use according to any one of

[109] to

[123] , wherein the dose of the antibody-drug conjugate per administration is in the range of 5.4 mg / kg to 8 mg / kg. The use according to any one of

[109] to

[123] , wherein the dose of the antibody-drug conjugate per administration is 5.4 mg / kg. The use according to any one of

[109] to

[123] , wherein the dose of the antibody-drug conjugate per administration is 6.4 mg / kg. The use according to any one of

[109] to

[123] , wherein the dose of the antibody-drug conjugate per administration is 7.4 mg / kg. The use according to any one of

[109] to

[123] , wherein the dose of the antibody-drug conjugate per administration is 8 mg / kg. The use according to any one of

[109] to

[128] , wherein the antibody-drug conjugate is administered at intervals of once every three weeks. The use according to any one of

[109] to

[129] for the manufacture of a medicament for the treatment of at least one cancer selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, non-small cell lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, cholangiocarcinoma, Paget's disease, pancreatic cancer, ovarian cancer, and uterine carcinosarcoma. The use according to any one of

[109] to

[129] for the manufacture of a medicament for the treatment of breast cancer. The use according to any one of

[109] to

[129] for the manufacture of a medicament for the treatment of gastric cancer. The use according to any one of

[109] to

[129] for the manufacture of a medicament for the treatment of gastric cancer and gastroesophageal junction adenocarcinoma. The use according to any one of

[109] to

[129] for the manufacture of a medicament for the treatment of colorectal cancer. The use according to any one of

[109] to

[129] for the manufacture of a medicament for the treatment of non-small cell lung cancer. The use according to any one of

[109] to

[129] for the manufacture of a medicament for the treatment of salivary gland cancer. The use according to any one of

[109] to

[136] , wherein the HER2-expressing cancer is a cancer with HER2 overexpression. The use according to

[137] , wherein the cancer with HER2 overexpression is a cancer in which the expression of HER2 is determined to be 3+ by immunohistochemistry. The use according to

[137] , wherein the cancer with HER2 overexpression is a cancer in which the expression of HER2 is determined to be 2+ by immunohistochemistry and the expression of HER2 is determined to be positive by in situ hybridization. The use according to any one of

[109] to

[136] , wherein the HER2-expressing cancer is a cancer with low HER2 expression. The use according to

[140] , wherein the cancer with low HER2 expression is a cancer in which the expression of HER2 is determined to be 2+ by immunohistochemistry and the expression of HER2 is determined to be negative by in situ hybridization. The use according to

[140] , wherein the cancer with low HER2 expression is a cancer in which the expression of HER2 is determined to be 1+ by immunohistochemistry. The use according to any one of

[109] to

[142] for the manufacture of a medicament for the treatment of inoperable or recurrent cancer. The use according to any one of

[109] to

[143] , wherein the medicament contains pharmaceutically acceptable formulation components. (Regarding) Also, the present invention can be expressed as follows. [1] The use of an antibody-drug conjugate, a salt thereof, or a hydrate thereof, in which a linker represented by the following formula and a drug are bound to an anti-HER2 antibody, for the treatment of drug-resistant cancer. -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX) (In the formula, -(Succinimid-3-yl-N)- is the following formula: It has the structure shown by , and at the 3-position thereof, it binds to an anti-HER2 antibody through a thioether bond, and binds to a methylene group in a linker structure containing this on the nitrogen atom at the 1-position. -(NH-DX) is the following formula: It shows a group in which the nitrogen atom of the amino group at the 1-position serves as a binding site. ) 〔2〕 The use according to 〔1〕, wherein the resistant cancer is a secondary resistant cancer. 〔3〕 The use according to 〔2〕, wherein the secondary resistance is secondary resistance due to administration of an antibody-drug conjugate containing an anti-HER2 antibody. 〔4〕 The use according to 〔2〕 or 〔3〕, wherein the secondary resistance is secondary resistance acquired by administration of T-DM1, which is an anti-HER2 antibody-drug conjugate. 〔5〕 The use according to 〔2〕, wherein the secondary resistance is secondary resistance due to administration of an anti-HER2 antibody. 〔6〕 The use according to any one of 〔1〕 to 〔5〕, wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate is in the range of 2 to 8. 〔7〕 The use according to any one of 〔1〕 to 〔5〕, wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate is in the range of 3 to 8. 〔8〕 The use according to any one of 〔1〕 to 〔5〕, wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate is in the range of 7 to 8. 〔9〕 The use according to any one of 〔1〕 to 〔5〕, wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate is in the range of 7.5 to 8. 〔10〕 The use according to any one of 〔1〕 to 〔9〕, wherein the dosage of the antibody-drug conjugate is in the range of 0.8 mg / kg to 8 mg / kg. 〔11〕 The use according to any one of 〔1〕 to 〔10〕, wherein the antibody-drug conjugate is administered once every 3 weeks. 〔12〕Use according to any one of 〔1〕 to 〔11〕, wherein the resistant cancer is lung cancer, urothelial cancer, colorectal cancer, prostate cancer, ovarian cancer, pancreatic cancer, breast cancer, bladder cancer, gastric cancer, gastrointestinal stromal tumor, cervical cancer, esophageal cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, or sarcoma. 〔13〕A pharmaceutical composition for treating resistant cancer, comprising an antibody-drug conjugate in which a linker and a drug represented by the following formula are bound to an anti-HER2 antibody, a salt thereof, or a hydrate thereof as an active ingredient, and a pharmaceutically acceptable formulation ingredient. -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX) (In the formula, -(Succinimid-3-yl-N) has the structure represented by the following formula: which is bound to the anti-HER2 antibody by a thioether bond at the 3-position, and is bound to a methylene group in the linker structure containing this at the nitrogen atom at the 1-position, -(NH-DX) has the following formula: and represents a group in which the nitrogen atom of the amino group at the 1-position is the binding site.) 〔14〕The pharmaceutical composition for treatment according to 〔13〕, wherein the resistant cancer is secondary resistant cancer. 〔15〕The pharmaceutical composition for treatment according to 〔13〕, wherein the secondary resistance is secondary resistance due to administration of an antibody-drug conjugate containing an anti-HER2 antibody. 〔16〕The pharmaceutical composition for treatment according to 〔14〕 or 〔15〕, wherein the secondary resistance is secondary resistance acquired by administration of T-DM1, which is an anti-HER2 antibody-drug conjugate. 〔17〕The pharmaceutical composition for treatment according to 〔14〕, wherein the secondary resistance is secondary resistance due to administration of an anti-HER2 antibody. 〔18〕The pharmaceutical composition for treatment according to any one of 〔13〕 to 〔17〕, wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate is in the range of 2 to 8. A therapeutic pharmaceutical composition according to any one of

[13] to

[17] , wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate ranges from 3 to 8. A therapeutic pharmaceutical composition according to any one of

[13] to

[17] , wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate ranges from 7 to 8. A therapeutic pharmaceutical composition according to any one of

[13] to

[17] , wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate ranges from 7.5 to 8. A therapeutic pharmaceutical composition according to any one of

[13] to

[21] , wherein the dosage of the antibody-drug conjugate ranges from 0.8 mg / kg to 8 mg / kg. A therapeutic pharmaceutical composition according to any one of

[13] to

[21] , which is administered once every three weeks. A therapeutic pharmaceutical composition according to any one of

[13] to

[23] , wherein the resistant cancer is lung cancer, urothelial cancer, colorectal cancer, prostate cancer, ovarian cancer, pancreatic cancer, breast cancer, bladder cancer, gastric cancer, gastrointestinal stromal tumor, cervical cancer, esophageal cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, or sarcoma. A method for treating resistant cancer, comprising administering an antibody-drug conjugate in which a linker and a drug represented by the following formula are bound to an anti-HER2 antibody, a salt thereof, or a hydrate thereof. -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX) (In the formula, -(Succinimid-3-yl-N) has the structure represented by the following formula: It is a structure represented by, and binds to the anti-HER2 antibody by a thioether bond at the 3-position, and binds to the methylene group in the linker structure containing this on the nitrogen atom at the 1-position. -(NH-DX) has the following formula: It represents a group in which the nitrogen atom of the amino group at the 1-position serves as the binding site. 〔26〕The treatment method according to 〔25〕, wherein the resistant cancer is a secondary resistant cancer. 〔27〕The treatment method according to 〔26〕, wherein the secondary resistance is secondary resistance caused by administration of an antibody-drug conjugate containing an anti-HER2 antibody. 〔28〕The treatment method according to 〔26〕 or 〔27〕, wherein the secondary resistance is secondary resistance acquired by administration of T-DM1, which is an anti-HER2 antibody-drug conjugate. 〔29〕The treatment method according to 〔26〕, wherein the secondary resistance is secondary resistance caused by administration of an anti-HER2 antibody. 〔30〕The treatment method according to any one of 〔25〕 to 〔29〕, wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate ranges from 2 to 8. 〔31〕The treatment method according to any one of 〔25〕 to 〔29〕, wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate ranges from 3 to 8. 〔32〕The treatment method according to any one of 〔25〕 to 〔29〕, wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate ranges from 7 to 8. 〔33〕The treatment method according to any one of 〔25〕 to 〔29〕, wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate ranges from 7.5 to 8. 〔34〕The treatment method according to any one of 〔25〕 to 〔33〕, wherein the dosage of the antibody-drug conjugate ranges from 0.8 mg / kg to 8 mg / kg. 〔35〕The treatment method according to any one of 〔25〕 to 〔34〕, wherein the antibody-drug conjugate is administered once every three weeks. 〔36〕The treatment method according to any one of 〔25〕 to 〔35〕, wherein the resistant cancer is lung cancer, urothelial cancer, colorectal cancer, prostate cancer, ovarian cancer, pancreatic cancer, breast cancer, bladder cancer, gastric cancer, gastrointestinal stromal tumor, cervical cancer, esophageal cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, multiple myeloma, or sarcoma. A therapeutic pharmaceutical composition containing, as an active ingredient, an antibody-drug conjugate in which a linker and a drug represented by the following formula are bound to an anti-HER2 antibody, a salt thereof, or a hydrate thereof, and a pharmaceutically acceptable formulation ingredient, and is applied to cancer patients showing resistance to anticancer drugs. -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX) (In the formula, -(Succinimid-3-yl-N) has the structure represented by the following formula: It is a structure represented by, binds to the anti-HER2 antibody by a thioether bond at the 3-position thereof, and binds to the methylene group in the linker structure containing this at the nitrogen atom at the 1-position. -(NH-DX) has the following formula: It represents a group in which the nitrogen atom of the amino group at the 1-position is the binding site.) 〔38〕 The therapeutic pharmaceutical composition according to 〔37〕, which is applied to cancer patients having a treatment history with anticancer drugs. 〔39〕 The therapeutic pharmaceutical composition according to 〔37〕 or 〔38〕, which is used in place of other anticancer drugs or in combination with other anticancer drugs. 〔40〕 The therapeutic pharmaceutical composition according to any one of 〔37〕 to 〔39〕, wherein the resistance to the anticancer drug is secondary resistance. 〔41〕 The therapeutic pharmaceutical composition according to any one of 〔37〕 to 〔40〕, wherein the anticancer drug is an antibody-drug conjugate containing an anti-HER2 antibody. 〔42〕 The therapeutic pharmaceutical composition according to 〔41〕, wherein the anticancer drug is trastuzumab emtansine (T-DM1). 〔43〕 The therapeutic pharmaceutical composition according to any one of 〔37〕 to 〔40〕, wherein the anticancer drug is an anti-HER2 antibody. 〔44〕 The therapeutic pharmaceutical composition according to any one of 〔37〕 to 〔43〕, wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate is in the range of 2 to 8. A therapeutic pharmaceutical composition according to any one of

[37] to

[43] , wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate ranges from 3 to 8. 〔46〕Average number of drug-linker structures per antibody of the antibody-drug conjugate A therapeutic pharmaceutical composition according to any one of

[37] to

[43] , wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate ranges from 7 to 8. A therapeutic pharmaceutical composition according to any one of

[37] to

[43] , wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate ranges from 7.5 to 8. A therapeutic pharmaceutical composition according to any one of

[37] to

[47] , wherein the dosage of the antibody-drug conjugate ranges from 0.8 mg / kg to 8 mg / kg. A therapeutic pharmaceutical composition according to any one of

[37] to

[48] , which is administered once every three weeks. 〔50〕A therapeutic pharmaceutical composition according to any one of

[37] to

[49] , wherein the resistant cancer is lung cancer, urothelial cancer, colorectal cancer, prostate cancer, ovarian cancer, pancreatic cancer, breast cancer, bladder cancer, gastric cancer, gastrointestinal stromal tumor, cervical cancer, esophageal cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, multiple myeloma, or sarcoma. The therapeutic agent containing the antibody-drug conjugate used in the present invention exhibits excellent antitumor effects against HER2-expressing cancers that are resistant or refractory to existing anti-HER2 drugs, and also exhibits high antitumor effects even against secondary resistant cancers. In addition, since it is also excellent in safety, an effective treatment method can be provided. The amino acid sequence of the heavy chain of the humanized anti-HER2 monoclonal antibody (SEQ ID NO: 1) is shown. The amino acid sequence of the light chain of the humanized anti-HER2 monoclonal antibody (SEQ ID NO: 2) is shown. It is a figure showing the antitumor effect of antibody-drug conjugate (1) or T-DM1 against HER2-positive human breast cancer ST1616B / TDR tumor subcutaneous xenograft nude mice that have developed secondary resistance to T-DM1. In the figure, the horizontal axis represents the number of days from the first administration, and the vertical axis represents the tumor volume. It is a figure showing the antitumor effect of antibody-drug conjugate (1) or T-DM1 against HER2-positive human breast cancer ST1360B / TDR tumor subcutaneous xenograft nude mice that have developed secondary resistance to T-DM1. In the figure, the horizontal axis represents the number of days from the first administration, and the vertical axis represents the tumor volume. It is a figure showing the pharmacokinetics of antibody-drug conjugate (1) in a clinical trial. It is a figure showing the safety and tolerability of antibody-drug conjugate (1) in a clinical trial. It is a figure showing the ORR (objective response rate) and DCR (disease control rate) regarding the efficacy of antibody-drug conjugate (1) in a clinical trial. It is a figure showing the maximum tumor shrinkage rate (%) regarding the efficacy of antibody-drug conjugate (1) in a clinical trial. It is a figure showing the treatment period and effect regarding the efficacy of antibody-drug conjugate (1) in a clinical trial. It is a figure showing the maximum tumor shrinkage rate (%) regarding the efficacy of antibody-drug conjugate (1) in a clinical trial. It is a figure showing the time course of the tumor shrinkage rate (%) regarding the efficacy of antibody-drug conjugate (1) against breast cancer in a clinical trial. It is a figure showing the time course of the tumor shrinkage rate (%) regarding the efficacy of antibody-drug conjugate (1) against gastric cancer in a clinical trial. It is a figure showing the maximum tumor shrinkage rate (%) regarding the efficacy of antibody-drug conjugate (1) against HER2-expressing solid cancers (excluding breast cancer and gastric cancer) in a clinical trial. In the figure, "C" indicates the cohort of colorectal cancer, "L" indicates the cohort of non-small cell lung cancer, "S" indicates the cohort of salivary gland cancer, "P" indicates the cohort of Paget's disease, "Ch" indicates the cohort of cholangiocarcinoma, and "E" indicates the cohort of esophageal cancer. Also, in the figure, "※" indicates those under treatment. It is a figure showing the time course of the tumor shrinkage rate (%) regarding the efficacy of antibody-drug conjugate (1) against HER2-expressing solid cancers (excluding breast cancer and gastric cancer) in a clinical trial.In the figure, "Colorectal" indicates the cohort of colorectal cancer, "NSCLC" indicates the cohort of non-small cell lung cancer, "Salivary" indicates the cohort of salivary gland cancer, and "Other" indicates the cohort of other cancers. Hereinafter, preferred embodiments for carrying out the present invention will be described with reference to the drawings. It should be noted that the embodiments described below show an example of a typical embodiment of the present invention, and the scope of the present invention is not construed narrowly thereby. The antibody-drug conjugate used in the present invention is an anti-HER2 antibody-drug conjugate in which a linker and a drug represented by the following formula are bound to an anti-HER2 antibody. -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX) In the formula, -(Succinimid-3-yl-N)- has the following formula: It has a structure represented by the formula, binds to the anti-HER2 antibody by a thioether bond at the 3-position, and binds to the methylene group in the linker structure containing this at the nitrogen atom at the 1-position. -(NH-DX) has the following formula: It is a group in which the nitrogen atom of the amino group at the 1-position is the binding site, represented by the formula. Also, -GGFG- represents a tetrapeptide residue of -Gly-Gly-Phe-Gly-. In this specification, the partial structure consisting of the linker and the drug in the antibody-drug conjugate is referred to as a "drug-linker structure". This drug-linker structure binds to the thiol groups (in other words, the sulfur atoms of cysteine residues) generated at the disulfide bond sites (two heavy chain-heavy chain sites and two heavy chain-light chain sites) between the chains of the antibody. The anti-HER2 antibody-drug conjugate used in the present invention can also be represented by the following formula: It can also be represented by the structure shown by the formula. Here, the drug-linker structure is bound to the anti-HER2 antibody by a thioether bond. Also, n is synonymous with the so-called DAR (Drug-to-Antibody Ratio) and indicates the number of drug molecules bound to one molecule of the antibody. The DAR is a specific and expressed numerical value as an average value, that is, the average number of drug bindings. In the case of the antibody-drug conjugate of the present invention, n may be from 2 to 8, preferably from 3 to 8, more preferably from 7 to 8, still more preferably from 7.5 to 8, and those with n being about 8 can be preferably used. The antibody-drug conjugate used in the present invention will be described in detail below. [Antibody] The anti-HER2 antibody used in the anti-HER2 antibody-drug conjugate used in the present invention may be derived from any species, but preferably, examples include human, rat, mouse, and rabbit. When the antibody is derived from a species other than human, it is preferable to chimerize or humanize it using well-known techniques. The antibody of the present invention may be a polyclonal antibody or a monoclonal antibody, but a monoclonal antibody is preferable. The anti-HER2 antibody is an antibody that can target tumor cells, that is, it has the properties of recognizing tumor cells, binding to tumor cells, being taken up and internalized into tumor cells, and having cytotoxic activity against tumor cells, etc. A compound having antitumor activity can be bound via a linker to form an antibody-drug conjugate. The binding of an antibody to tumor cells can be confirmed using flow cytometry. The uptake of an antibody into tumor cells can be confirmed using the following assays: (1) an assay in which the antibody taken up into cells is visualized with a fluorescence microscope using a secondary antibody (fluorescently labeled) that binds to the therapeutic antibody (Cell Death and Differentiation (2008) 15, 751-761); (2) an assay in which the amount of fluorescence taken up into cells is measured using a secondary antibody (fluorescently labeled) that binds to the therapeutic antibody (Molecular Biology of the Cell Vol. 15, 5268-5282, December 2004); or (3) the Mab-ZAP assay in which an immunotoxin that binds to the therapeutic antibody is used, and when taken up into cells, the toxin is released and cell growth is inhibited (Bio Techniques 28:162-165, January 2000). As the immunotoxin, a recombinant complex protein of the catalytic region of diphtheria toxin and protein G can also be used. The antitumor activity of an antibody can be confirmed in vitro by measuring the inhibitory activity of cell growth. For example, a cancer cell line overexpressing the target protein of the antibody can be cultured, the antibody can be added to the culture system at various concentrations, and the inhibitory activities against focus formation, colony formation, and spheroid growth can be measured. In vivo, for example, the antitumor activity can be confirmed by administering the antibody to nude mice transplanted with a tumor cell line highly expressing the target protein and measuring the changes in cancer cells. Since an antibody-drug conjugate has a compound that exerts an antitumor effect bound thereto, it is preferable but not essential for the antibody itself to have an antitumor effect. For the purpose of specifically and selectively exerting the cytotoxicity of an antitumor compound in tumor cells, it is important and preferable for the antibody to have the property of being internalized and translocating into tumor cells. Anti-HER2 antibodies can be obtained by known means. For example, using methods commonly practiced in this field, an animal can be immunized with a polypeptide serving as an antigen, and the antibodies produced in vivo can be collected and purified to obtain them. The origin of the antigen is not limited to humans, and animals can also be immunized with antigens derived from non-human animals such as mice and rats. In this case, by testing the cross-reactivity between the obtained antibody that binds to the heterologous antigen and the human antigen, antibodies applicable to human diseases can be selected. Also, according to known methods (for example, Kohler and Milstein, Nature (1975) 256, p.495-497; Kennet, R. ed., Monoclonal Antibodies, p.365-367, Plenum Press, N.Y. (1980)), hybridomas can be established by fusing antibody-producing cells that produce antibodies against an antigen with myeloma cells, and monoclonal antibodies can also be obtained. In addition, the antigen can be obtained by causing a host cell to produce a gene encoding the antigen protein through genetic manipulation. Specifically, a vector capable of expressing the antigen gene can be prepared, introduced into the host cell to express the gene, and the expressed antigen can be purified. Antibodies can also be obtained by using the method of immunizing an animal with the above antigen-expressing cells obtained by genetic manipulation or a cell line expressing the antigen. The anti-HER2 antibodies that can be used in the present invention are not particularly limited, but for example, those having the following characteristics are desirable. (1) An anti-HER2 antibody characterized by having the following characteristics; (a) Specifically binds to HER2. (b) Has the activity of internalizing into HER2-expressing cells by binding to HER2. (2) The antibody according to (1) above that binds to the extracellular domain of HER2. (3) The antibody according to (1) or (2) above that is a monoclonal antibody. The antibody according to any one of (1) to (3) above, which has antibody-dependent cell-mediated cytotoxicity (ADCC) activity and / or complement-dependent cytotoxicity (CDC) activity. The antibody according to any one of (1) to (4) above, which is a mouse monoclonal antibody, a chimeric monoclonal antibody, or a humanized monoclonal antibody. The antibody according to any one of (1) to (5) above, which is a humanized monoclonal antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2. The antibody according to any one of (1) to (6) above, wherein the lysine residue at the carboxyl terminus of the heavy chain is deleted. The antibody according to (7) above, which comprises a heavy chain consisting of the amino acid sequence of amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence of amino acid numbers 1 to 214 in SEQ ID NO: 2. An antibody obtained by a method for producing the antibody, which comprises culturing a host cell transformed with an expression vector containing a polynucleotide encoding the antibody according to any one of (1) to (8) above and collecting the target antibody from the culture obtained in the step. Hereinafter, the anti-HER2 antibody used in the present invention will be described. In the present specification, "cancer" and "tumor" are used with the same meaning. In the present specification, the term "gene" includes not only DNA but also its mRNA, cDNA, and cRNA. In the present specification, the term "polynucleotide" is used with the same meaning as nucleic acid, and includes DNA, RNA, probe, oligonucleotide, and primer. In the present specification, "polypeptide", "protein", and "protein" are used without distinction. In the present specification, "cell" includes cells in an animal individual and cultured cells. In the present specification, the term "HER2" is used with the same meaning as HER2 protein. In this specification, the anti-HER2 antibody is not particularly limited, and examples thereof include pertuzumab (International Publication No. 01 / 00245), trastuzumab (U.S. Patent No. 5,821,337), etc., and trastuzumab is preferred. However, the present invention is not limited thereto as long as it specifically binds to HER2, and more preferably, it is an anti-HER2 antibody having an activity of internalizing into HER2-expressing cells by binding to HER2. In this specification, "trastuzumab" may also be referred to as HERCEPTIN (registered trademark), huMAb4D5-8, rhMAb4D5-8, and is a humanized antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1 (Figure 1) and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO: 2 (Figure 2). In this specification, the term "specifically binds" means a binding that is not non-specific adsorption. As a criterion for determining whether a binding is specific, for example, the dissociation constant (hereinafter, "Kd") can be mentioned. The Kd value of a suitable antibody for the HER2 protein is 1×10 －５ M or less, 5×10 －６ M or less, 2×10 －６ M or less, or 1×10 －６ M or less; more preferably 5×10 －７ M or less, 2×10 －７ M or less, or 1×10 －７ M or less; even more preferably 5×10 －８ M or less, 2×10 －８ M or less, or 1×10 －８ M or less; most preferably 5×10 －９ M or less, 2×10 －９ M or less, or 1×10 －９ M or less. The binding between the HER2 protein and the antibody can be measured using known methods such as the Surface Plasmon Resonance method, ELISA method, RIA method, etc. As used herein, "CDR" means Complementary Determining Region. It is known that there are three CDRs each in the heavy and light chains of an antibody molecule. CDRs, also called hypervariable domains, are regions within the variable regions of the heavy and light chains of an antibody where the primary structure has particularly high variability, and are separated into three locations each on the primary structure of the polypeptide chains of the heavy and light chains. In this specification, for the CDRs of an antibody, the CDRs of the heavy chain are denoted as CDRH1, CDRH2, and CDRH3 from the amino-terminal side of the heavy-chain amino acid sequence, and the CDRs of the light chain are denoted as CDRL1, CDRL2, and CDRL3 from the amino-terminal side of the light-chain amino acid sequence. These sites are close to each other in terms of three-dimensional structure and determine the specificity for the antigen to which they bind. In the present invention, "hybridizing under stringent conditions" means hybridizing at 68°C in a commercially available hybridization solution, ExpressHyb Hybridization Solution (manufactured by Clontech), or performing hybridization at 68°C in the presence of 0.7 - 1.0 M NaCl using a filter on which DNA is immobilized, and then washing at 68°C using an SSC solution at 0.1 - 2 times the concentration (1× concentration SSC consists of 150 mM NaCl and 15 mM sodium citrate), which can be identified by the conditions or conditions equivalent thereto for hybridizing. 1. HER2 HER2 is one of the representative growth factor receptor-type cancer gene products identified as a human epidermal growth factor receptor type 2-related cancer gene, and is a transmembrane receptor protein with a tyrosine kinase domain having a molecular weight of 185 kDa. It is one of the EGFR family consisting of HER1 (EGFR, ErbB-1), HER2 (neu, ErbB-2), HER3 (ErbB-3), and HER4 (ErbB-4). It is known to play an important role in cell growth, differentiation, and survival in normal cells and tumor cells by autophosphorylating and activating intracellular tyrosine residues through the formation of homodimers or heterodimers with other EGFRs such as HER1, HER3, or HER4. The HER2 protein used in the present invention can be directly purified from HER2-expressing cells of humans, non-human mammals (such as rats, mice, etc.) and used, or the cell membrane fraction of the cells can be prepared and used. Also, it can be obtained by synthesizing HER2 in vitro or producing it in host cells by genetic manipulation. In genetic manipulation, specifically, after integrating HER2 cDNA into an expressible vector, it is synthesized in a solution containing enzymes, substrates, and energy substances necessary for transcription and translation, or by transforming other prokaryotic or eukaryotic host cells to express HER2, the protein can be obtained. Also, it is possible to use the HER2-expressing cells obtained by the above genetic manipulation or cell lines expressing HER2 as the HER2 protein. The DNA sequence and amino acid sequence of HER2 are publicly available on public databases and can be referred to by accession numbers such as M11730 (Genbank), NP_004439.2 (NCBI), etc. Also, in the amino acid sequence of HER2 described above, proteins consisting of amino acid sequences in which one or several amino acids are substituted, deleted, and / or added and having biological activities equivalent to those of the protein are also included in HER2. The human HER2 protein is composed of a signal sequence consisting of 22 amino acid residues at the N-terminus, an extracellular domain consisting of 630 amino acid residues, a transmembrane domain consisting of 23 amino acid residues, and an intracellular domain consisting of 580 amino acid residues. 2. Production of anti-HER2 antibody The antibody against HER2 of the present invention can be obtained, for example, by immunizing an animal with HER2 or any polypeptide selected from the amino acid sequence of HER2 according to a method commonly practiced in this field, and collecting and purifying the antibody produced in vivo. The species of HER2 serving as the antigen is not limited to humans, and HER2 derived from non-human animals such as mice and rats, rat p185neu, etc. can also be used to immunize the animal. In this case, by testing the cross-reactivity between the antibody that binds to the obtained heterologous HER2 and human HER2, an antibody applicable to human diseases can be selected. In addition, according to a known method (for example, Kohler and Milstein, Nature (1975) 256, p. 495-497; Kennet, R. ed., Monoclonal Antibodies, p. 365-367, Plenum Press, N.Y. (1980)), hybridomas can be established by fusing antibody-producing cells that produce antibodies against HER2 with myeloma cells, and monoclonal antibodies can also be obtained. Note that HER2 serving as the antigen can be obtained by expressing the HER2 gene in a host cell by genetic engineering. Specifically, a vector capable of expressing the HER2 gene is prepared, introduced into a host cell to express the gene, and the expressed HER2 is purified. In addition, it is also possible to use the HER2-expressing cells obtained by the above genetic engineering or cell lines expressing HER2 as HER2 protein. The anti-HER2 antibody can be obtained by known means. Hereinafter, the method for obtaining an antibody against HER2 will be specifically described. (1) Preparation of antigen Examples of the antigen for preparing the anti-HER2 antibody include HER2 or a polypeptide consisting of at least 6 consecutive partial amino acid sequences thereof, or derivatives obtained by adding any amino acid sequence or carrier to these. HER2 can be directly purified and used from human tumor tissues or tumor cells, and can also be obtained by synthesizing HER2 in vitro or producing it in host cells by genetic engineering. In genetic engineering, specifically, after integrating the cDNA of HER2 into an expressible vector, it is synthesized in a solution containing enzymes, substrates, and energy substances necessary for transcription and translation, or antigens can be obtained by transforming other prokaryotic or eukaryotic host cells to express HER2. In addition, it is also possible to obtain an antigen as a secreted protein by expressing a fusion protein in which the extracellular region of HER2, which is a membrane protein, is linked to the constant region of an antibody in an appropriate host-vector system. The cDNA of HER2 can be obtained by, for example, the so-called PCR method, in which polymerase chain reaction (PCR; see Saiki, R. K., et al., Science (1988) 239, p. 487-489) is performed using primers that specifically amplify HER2 cDNA with a cDNA library expressing HER2 cDNA as a template. Examples of in vitro synthesis of polypeptides include, but are not limited to, the Rapid Translation System (RTS) manufactured by Roche Diagnostics. Examples of prokaryotic host cells include Escherichia coli and Bacillus subtilis. To transform the host cells with the target gene, the host cells are transformed with a plasmid vector containing a replicon, i.e., an origin of replication, derived from a species compatible with the host and regulatory sequences. In addition, as a vector, those having a sequence capable of conferring selectivity of a phenotype on the transformed cells are preferred. Host cells of eukaryotic cells include cells such as vertebrates, insects, and yeasts. Examples of vertebrate cells include COS cells, which are monkey cells (Gluzman, Y. Cell (1981) 23, p. 175-182, ATCC CRL-1650; ATCC: American Type Culture Collection), mouse fibroblasts NIH3T3 (ATCC No. CRL-1658), and dihydrofolate reductase-deficient strains of Chinese hamster ovary cells (CHO cells, ATCC CCL-61) (Urlaub, G. and Chasin, L. A. Proc. Natl. Acad. Sci. USA (1980) 77, p. 4126-4220), etc. These are often used, but are not limited thereto. The transformant obtained as described above can be cultured according to methods commonly practiced in this field, and the target polypeptide is produced intracellularly or extracellularly by the culture. As the medium used for the culture, various commonly used ones can be appropriately selected according to the host cell employed. For example, in the case of Escherichia coli, for example, antibiotics such as ampicillin and IPTG can be added to the LB medium as necessary and used. The recombinant protein produced intracellularly or extracellularly by the transformant by the above culture can be separated and purified by various known separation operation methods using the physical and chemical properties of the protein, etc. Specific examples of the method include, for example, treatment with a normal protein precipitant, ultrafiltration, molecular sieve chromatography (gel filtration), adsorption chromatography, ion exchange chromatography, various liquid chromatographies such as affinity chromatography, dialysis, combinations thereof, etc. In addition, by connecting a histidine tag consisting of 6 residues to the recombinant protein to be expressed, it can be efficiently purified using a nickel affinity column. Alternatively, by connecting the Fc region of IgG to the recombinant protein to be expressed, it can be efficiently purified using a protein A column. By combining the above methods, the target polypeptide can be easily produced in large quantities with high yield and high purity. It is also possible to use the above-described transformant itself as an antigen. It is also possible to use a cell line expressing HER2 as an antigen. Examples of such cell lines include human breast cancer cell lines SK-BR-3, BT-474, KPL-4, or JIMT-1, human gastric cancer cell line NCI-N87, and human ovarian cancer cell line SK-OV-3. However, as long as HER2 is expressed, it is not limited to these cell lines. (2) Production of anti-HER2 monoclonal antibody Examples of antibodies that specifically bind to HER2 include monoclonal antibodies that specifically bind to HER2. The method for obtaining them is as described below. In the production of monoclonal antibodies, generally the following working steps are necessary. That is, (a) Purification of the biopolymer used as an antigen, or preparation of antigen-expressing cells (b) After immunizing an animal by injecting the antigen, collecting blood, assaying the antibody titer to determine the timing of spleen removal, and then preparing antibody-producing cells (c) Preparation of myeloma cells (hereinafter referred to as "myeloma") (d) Cell fusion of antibody-producing cells and myeloma (e) Selection of a group of hybridomas that produce the target antibody (f) Splitting (cloning) into single cell clones (g) In some cases, culturing of hybridomas for mass production of monoclonal antibodies, or raising of animals transplanted with hybridomas (h) Examination of the biological activity of the monoclonal antibody thus produced, its binding specificity, or assay of its properties as a labeling reagent and so on. Hereinafter, the method for producing monoclonal antibodies will be described in detail according to the above steps. However, the method for producing the antibody is not limited thereto. For example, antibody-producing cells other than spleen cells and myeloma can also be used. (a) Purification of antigen As the antigen, HER2 prepared by the method as described above or a part thereof can be used. In addition, a membrane fraction prepared from HER2-expressing recombinant cells, or the HER2-expressing recombinant cells themselves, or a partial peptide of a protein related to the present invention chemically synthesized using methods well known to those skilled in the art can also be used as an antigen. Furthermore, an HER2-expressing cell line can also be used as an antigen. (b) Preparation of antibody-producing cells The antigen obtained in step (a) is mixed with Freund's complete or incomplete adjuvant, or an adjuvant such as aluminum hydroxide, and used to immunize experimental animals as an immunogen. In addition, there is also a method of immunizing experimental animals with antigen-expressing cells as an immunogen. As the experimental animals, animals used in known hybridoma production methods can be used without problems. Specifically, for example, mice, rats, goats, sheep, cows, horses, etc. can be used. However, from the viewpoint of the availability of myeloma cells to be fused with the isolated antibody-producing cells, etc., it is preferable to use mice or rats as the immunized animals. In addition, there are no particular restrictions on the strains of mice and rats actually used. In the case of mice, for example, each strain A, AKR, BALB / c, BDP, BA, CE, C3H, 57BL, C57BL, C57L, DBA, FL, HTH, HT1, LP, NZB, NZW, RF, R III, SJL, SWR, WB, 129, etc. can be used. In the case of rats, for example, Wistar, Low, Lewis, Sprague, Dawley, ACI, BN, Fischer, etc. can be used. These mice and rats can be obtained, for example, from experimental animal breeding and sales companies such as CLEA Japan, Inc. and Charles River Laboratories Japan, Inc. As the immunized animals, considering the fusibility with the myeloma cells described below, the BALB / c strain is particularly preferable for mice, and the Wistar and Low strains are particularly preferable for rats. In addition, considering the homology between humans and mice of the antigen, it is also preferable to use mice with a reduced biological mechanism for removing autoantibodies, that is, autoimmune disease mice. In addition, the age of these mice or rats at the time of immunization is preferably 5 to 12 weeks old, more preferably 6 to 8 weeks old. To immunize an animal with HER2 or its recombinant, for example, known methods described in detail in Weir, D.M., Handbook of Experimental Immunology Vol. I. II. III., Blackwell Scientific Publications, Oxford (1987); Kabat, E.A. and Mayer, M.M., Experimental Immunochemistry, Charles C Thomas Publisher Springfield, Illinois (1964), etc. can be used. Among these immunization methods, specific examples of the methods suitable for the present invention are as follows. That is, first, the membrane protein fraction as the antigen or the cells expressing the antigen are administered intradermally or intraperitoneally to the animal. However, in order to enhance the immunization efficiency, it is preferable to use both in combination. If intradermal administration is performed in the first half and intraperitoneal administration is performed only in the second half or the final dose, the immunization efficiency can be particularly enhanced. The antigen administration schedule varies depending on the type of immunized animal, individual differences, etc. Generally, the number of antigen administrations is preferably 3 to 6 times, and the administration interval is preferably 2 to 6 weeks. More preferably, the number of administrations is 3 to 4 times, and the administration interval is 2 to 4 weeks. Also, the antigen dosage varies depending on the type of animal, individual differences, etc. Generally, it is about 0.05 to 5 mg, preferably about 0.1 to 0.5 mg. The booster immunization is performed 1 to 6 weeks, preferably 1 to 4 weeks, more preferably 1 to 3 weeks after the antigen administration as described above. When the immunogen is a cell, 1×10 ６ to 1×10 ７ cells are used. Note that the antigen dosage for booster immunization varies depending on the type and size of the animal, etc. Generally, for example, in the case of a mouse, it is 0.05 to 5 mg, preferably 0.1 to 0.5 mg, more preferably about 0.1 to 0.2 mg. When the immunogen is a cell, 1×10 ６ to 1×10 ７ cells are used. From 1 to 10 days, preferably 2 to 5 days, and more preferably 2 to 3 days after the above additional immunization, spleen cells or lymphocytes containing antibody-producing cells are aseptically removed from the immunized animal. If the antibody titer is measured at that time and animals with a sufficiently high antibody titer are used as the source of antibody-producing cells, the efficiency of subsequent operations can be increased. Examples of the method for measuring the antibody titer used here include, but are not limited to, the RIA method or the ELISA method. The measurement of the antibody titer in the present invention can be performed, for example, by the ELISA method, according to the procedures described below. First, the purified or partially purified antigen is adsorbed on the solid phase surface such as a 96-well plate for ELISA. Further, the solid phase surface where the antigen is not adsorbed is covered with a protein irrelevant to the antigen, such as bovine serum albumin (BSA). After washing the surface, it is contacted with a serially diluted sample (for example, mouse serum) as the primary antibody to bind the antibody in the sample to the above antigen. Furthermore, an antibody against the enzyme-labeled mouse antibody is added as the secondary antibody to bind to the mouse antibody. After washing, the substrate of the enzyme is added, and the antibody titer is calculated by measuring the change in absorbance due to color development based on substrate degradation. The separation of antibody-producing cells from the spleen cells or lymphocytes of the immunized animal can be carried out according to known methods (for example, Kohler et al., Nature (1975) 256, p. 495; Kohler et al., Eur. J. Immunol. (1977) 6, p. 511; Milstein et al., Nature (1977), 266, p. 550; Walsh, Nature, (1977) 266, p. 495). For example, in the case of spleen cells, a general method can be adopted in which the spleen is minced, the cells are filtered through a stainless steel mesh, and then suspended in Eagle's minimum essential medium (MEM) to separate the antibody-producing cells. (c) Preparation of myeloma cells (hereinafter referred to as "myeloma") There are no particular restrictions on the myeloma cells used for cell fusion, and they can be appropriately selected from known cell lines for use. However, considering the convenience in selecting hybridomas from the fused cells, it is preferable to use HGPRT (Hypoxanthine-guanine phosphoribosyl transferase) -deficient strains for which the selection procedure has been established. That is, X63-Ag8 (X63), NS1-ANS / 1 (NS1), P3X63-Ag8.U1 (P3U1), X63-Ag8.653 (X63.653), SP2 / 0-Ag14 (SP2 / 0), MPC11-45.6TG1.7 (45.6TG), FO, S149 / 5XXO, BU.1, etc. derived from mice, 210.RSY3.Ag.1.2.3 (Y3), etc. derived from rats, U266AR (SKO-007), GM1500·GTG-A12 (GM1500), UC729-6, LICR-LOW-HMy2 (HMy2), 8226AR / NIP4-1 (NP41), etc. derived from humans. These HGPRT-deficient strains can be obtained, for example, from ATCC or the like. These cell lines are subcultured in an appropriate medium, for example, 8-azaguanine medium (a medium obtained by adding 8-azaguanine to a medium prepared by adding glutamine, 2-mercaptoethanol, gentamicin, and fetal bovine serum (hereinafter referred to as "FBS") to RPMI-1640 medium), Iscove's Modified Dulbecco's Medium (hereinafter referred to as "IMDM"), or Dulbecco's Modified Eagle Medium (hereinafter referred to as "DMEM"). However, 3 to 4 days before cell fusion, they are subcultured in a normal medium (for example, ASF104 medium (manufactured by Ajinomoto Co., Inc.) containing 10% FCS), and on the day of fusion, a cell number of 2×10 ７ or more is ensured. (d) Cell fusion The fusion of antibody-producing cells and myeloma cells can be appropriately carried out under conditions that do not extremely reduce the cell viability according to known methods (Weir, D.M., Handbook of Experimental Immunology Vol. I. II. III., Blackwell Scientific Publications, Oxford (1987); Kabat, E.A. and Mayer, M.M., Experimental Immunochemistry, Charles C Thomas Publisher Springfield, Illinois (1964), etc.). As such a method, for example, a chemical method of mixing antibody-producing cells and myeloma cells in a high-concentration polymer solution such as polyethylene glycol, a physical method using electrical stimulation, etc. can be used. Among these, specific examples of the above chemical method are as follows. That is, when using polyethylene glycol as the high-concentration polymer solution, in a polyethylene glycol solution with a molecular weight of 1500 to 6000, preferably 2000 to 4000, the antibody-producing cells and myeloma cells are mixed at a temperature of 30 to 40°C, preferably 35 to 38°C, for 1 to 10 minutes, preferably 5 to 8 minutes. (e) Selection of hybridoma group The method for selecting hybridomas obtained by the above cell fusion is not particularly limited, but usually the HAT (hypoxanthine - aminopterin - thymidine) selection method (Kohler et al., Nature (1975) 256, p. 495; Milstein et al., Nature (1977) 266, p. 550) is used. This method is effective when obtaining hybridomas using HGPRT-deficient strains of myeloma cells that cannot survive with aminopterin. That is, by culturing unfused cells and hybridomas in HAT medium, only hybridomas with resistance to aminopterin can be selectively retained and proliferated. (f) Subdivision into single cell clones (cloning) As a method for cloning hybridomas, known methods such as the methylcellulose method, soft agarose method, limiting dilution method, etc. can be used (see, for example, Barbara, B.M. and Stanley, M.S.: Selected Methods in Cellular Immunology, W.H. Freeman and Company, San Francisco (1980)). Among these methods, in particular, the three-dimensional culture method such as the methylcellulose method is preferred. For example, a group of hybridomas formed by cell fusion is suspended in a methylcellulose medium such as ClonaCell-HY Selection Medium D (manufactured by StemCell Technologies #03804) and cultured, and monoclonal hybridomas can be obtained by collecting the formed hybridoma colonies. Each of the collected hybridoma colonies is cultured, and those with a stable antibody titer in the obtained hybridoma culture supernatant are selected as HER2 monoclonal antibody-producing hybridoma strains. (g) Preparation of monoclonal antibody by culturing hybridoma The hybridoma thus selected can efficiently obtain a monoclonal antibody by culturing it. However, prior to culturing, it is desirable to screen the hybridoma that produces the target monoclonal antibody. Known methods per se can be employed for this screening. The measurement of the antibody titer in the present invention can be performed, for example, by the ELISA method described in the above item (b). The hybridoma obtained by the above method can be stored in a frozen state in liquid nitrogen or in a freezer at -80°C or lower. The hybridoma that has completed cloning is cultured by changing the medium from HT medium to a normal medium. Large-scale culture is carried out by rotary culture using a large culture flask or spinner culture. From the supernatant in this large-scale culture, a monoclonal antibody that specifically binds to the protein of the present invention can be obtained by purification using methods well known to those skilled in the art such as gel filtration. Also, by injecting the hybridoma into the abdominal cavity of mice of the same strain (e.g., the above-mentioned BALB / c) or Nu / Nu mice and proliferating the hybridoma, ascites containing a large amount of the monoclonal antibody of the present invention can be obtained. When administered intraperitoneally, if a mineral oil such as 2,6,10,14-tetramethylpentadecane (2,6,10,14-tetramethylpentadecane; pristane) is administered beforehand (3 to 7 days before), a larger amount of ascites can be obtained. For example, an immunosuppressant is injected into the abdominal cavity of a mouse of the same strain as the hybridoma in advance to inactivate T cells, and then 10 ６ to 10 ７ clone cells of the hybridoma are suspended (0.5 ml) in a serum-free medium and administered intraperitoneally. Usually, the abdomen becomes distended, and when ascites has accumulated, the ascites is collected from the mouse. By this method, a monoclonal antibody with a concentration about 100 times or more higher than that in the culture solution can be obtained. The monoclonal antibody obtained by the above method can be purified by, for example, the method described in Weir, D.M.: Handbook of Experimental Immunology, Vol. I, II, III, Blackwell Scientific Publications, Oxford (1978). The monoclonal antibody thus obtained has high antigen specificity for HER2. Although there is no particular limitation on the monoclonal antibody of the present invention, mouse monoclonal antibody 4D5 (ATCC CRL 10463) can be mentioned. (h) Assay of monoclonal antibody The isotype and subclass of the monoclonal antibody thus obtained can be determined as follows. First, examples of the identification method include the Ouchterlony method, ELISA method, or RIA method. The Ouchterlony method is simple, but a concentration operation is required when the concentration of the monoclonal antibody is low. On the other hand, when using the ELISA method or the RIA method, the culture supernatant is reacted with the antigen-adsorbed solid phase as it is, and by using antibodies corresponding to various immunoglobulin isotypes and subclasses as the secondary antibody, it is possible to identify the isotype and subclass of the monoclonal antibody. Also, as a more convenient method, commercially available kits for identification (for example, mouse typer kit; manufactured by Bio-Rad) can be used. Furthermore, protein quantification can be performed by the Folin-Lowry method and a method calculated from the absorbance at 280 nm (1.4 (OD280) = 1 mg / ml of immunoglobulin). Furthermore, even when the steps (a) to (h) of (2) are performed again to separately and independently obtain a monoclonal antibody, it is possible to obtain an antibody having the same cytotoxic activity as the anti-HER2 antibody obtained in the step (g). As an example of such an antibody, an antibody that binds to the same epitope as the anti-HER2 antibody obtained in the step (g) can be mentioned. If the newly produced monoclonal antibody binds to the partial peptide or partial three-dimensional structure to which the anti-HER2 antibody binds, it can be determined that the monoclonal antibody binds to the same epitope. In addition, by confirming that the monoclonal antibody competes with the binding of the anti-HER2 antibody to HER2 (that is, the monoclonal antibody inhibits the binding of the anti-HER2 antibody and HER2), even if the sequence or structure of the specific epitope has not been determined, it can be determined that the monoclonal antibody binds to the same epitope as the anti-HER2 antibody. When it is confirmed that the epitopes are the same, it is strongly expected that the monoclonal antibody has the same antigen-binding ability or biological activity as the anti-HER2 antibody. (3) Other antibodies In addition to the monoclonal antibody against HER2, the antibodies of the present invention also include genetically engineered antibodies artificially modified for the purpose of reducing the heterologous antigenicity against humans, such as chimeric antibodies, humanized antibodies, human antibodies, etc. These antibodies can be produced using known methods. Examples of chimeric antibodies include antibodies in which the variable region and the constant region of the antibody are heterologous to each other, such as chimeric antibodies in which the variable region of a mouse- or rat-derived antibody is joined to the constant region of a human-derived antibody (see Proc. Natl. Acad. Sci. U.S.A., 81, 6851-6855, (1984)). The chimeric antibody of the present invention is not particularly limited, but a chimeric antibody 4D5 containing the heavy chain constant region of human IgG1 or IgG2 can be mentioned. Examples of humanized antibodies include antibodies in which only the complementarity determining regions (CDRs) of heterologous antibodies are incorporated into human-derived antibodies (see Nature (1986) 321, p. 522-525), antibodies in which, in addition to the CDR sequences of heterologous antibodies, some framework amino acid residues of heterologous antibodies are also transplanted into human antibodies by the CDR transplantation method (International Publication No. 90 / 07861), and antibodies humanized using the gene conversion mutagenesis strategy (U.S. Patent No. 5821337). In the present specification, "several" means 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 or 2. In addition, as the amino acid substitution in this specification, conservative amino acid substitution is preferred. Conservative amino acid substitution refers to a substitution that occurs within an amino acid group related to the amino acid side chain. Suitable amino acid groups are as follows: acidic group = aspartic acid, glutamic acid; basic group = lysine, arginine, histidine; non-polar group = alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan; and uncharged polar family = glycine, asparagine, glutamine, cysteine, serine, threonine, tyrosine. Other suitable amino acid groups are as follows: aliphatic hydroxy group = serine and threonine; amide-containing group = asparagine and glutamine; aliphatic group = alanine, valine, leucine and isoleucine; and aromatic group = phenylalanine, tryptophan and tyrosine. Such amino acid substitution is preferably carried out within a range that does not reduce the characteristics of the substance having the original amino acid sequence. By combining sequences that show high homology with the above heavy chain amino acid sequence and light chain amino acid sequence, it is possible to select an antibody having biological activity equivalent to each of the above antibodies. Such homology is generally homology of 80% or more, preferably homology of 90% or more, more preferably homology of 95% or more, and most preferably homology of 99% or more. In addition, by combining amino acid sequences in which one to several amino acid residues are substituted, deleted or added to the amino acid sequence of the heavy chain or light chain, it is also possible to select an antibody having biological activity equivalent to each of the above antibodies. Note that "homology" in this specification is used in the same meaning as "identity". The homology between two kinds of amino acid sequences can be determined by using the default parameters of the Blast algorithm version 2.2.2 (Altschul, Stephen F., Thomas L. Madden, Alejandro A. Schaeffer, Jinghui Zhang, Zheng Zhang, Webb Miller, and David J. Lipman (1997), "Gapped BLAST and PSI-BLAST: a new generation of protein database search programs", Nucleic Acids Res. 25: 3389-3402). The Blast algorithm can also be used by accessing www.ncbi.nlm.nih.gov / blast on the Internet. Examples of the antibody of the present invention further include human antibodies that bind to HER2. The anti-HER2 human antibody means an anti-HER2 antibody having only an amino acid sequence derived from a human. The anti-HER2 human antibody can be obtained by a method using a human antibody-producing mouse having a human chromosomal fragment containing the genes of the heavy and light chains of a human antibody (see Tomizuka, K. et al., Nature Genetics (1997) 16, p. 133-143; Kuroiwa, Y. et al., Nucleic 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.). Such a human antibody-producing mouse can be specifically created by disrupting the endogenous immunoglobulin heavy and light chain loci and introducing the human immunoglobulin heavy and light chain loci via a yeast artificial chromosome (YAC) vector or the like, and by producing knockout animals and transgenic animals and crossing these animals with each other. In addition, by transforming eukaryotic cells with cDNA encoding each of the heavy and light chains of such a human antibody, preferably a vector containing the cDNA, and culturing the transformed cells that produce recombinant human monoclonal antibodies, this antibody can also be obtained from the culture supernatant. Here, as the host, for example, eukaryotic cells, preferably mammalian cells such as CHO cells, lymphocytes, and myelomas can be used. Also known is a method for obtaining phage display-derived human antibodies selected from a human antibody library (see, for example, Wormstone, I. M. et al, Investigative Ophthalmology & Visual Science. (2002) 43(7), p. 2301-2308; Carman, 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.). For example, the phage display method (Nature Biotechnology (2005), 23, (9), p. 1105-1116) can be used, in which the variable region of a human antibody is expressed on the phage surface as a single-chain antibody (scFv) and phages that bind to the antigen are selected. By analyzing the gene of the phage selected by binding to the antigen, the DNA sequence encoding the variable region of the human antibody that binds to the antigen can be determined. Once the DNA sequence of the scFv that binds to the antigen is identified, a human antibody can be obtained by preparing an expression vector having the sequence, introducing it into a suitable host, and expressing it (WO 92 / 01047, WO 92 / 20791, WO 93 / 06213, WO 93 / 11236, WO 93 / 19172, WO 95 / 01438, WO 95 / 15388; Annu. Rev. Immunol (1994) 12, p. 433-455; Nature Biotechnology (2005) 23(9), p. 1105-1116). As an example of another index for comparing the properties of antibodies, the stability of the antibody can be mentioned. Differential scanning calorimetry (DSC) is an apparatus that can quickly and accurately measure the heat denaturation midpoint (Tm), which is a good index of the relative structural stability of proteins. By measuring the Tm value using DSC and comparing the values, the difference in thermal stability can be compared. The storage stability of an antibody is known to show a certain degree of correlation with the thermal stability of the antibody (Lori Burton, et al., Pharmaceutical Development and Technology (2007) 12, p. 265-273), and a suitable antibody can be selected using thermal stability as an index. Other indices for selecting an antibody include high yield in a suitable host cell and low aggregability in an aqueous solution. For example, since the antibody with the highest yield does not necessarily show the highest thermal stability, it is necessary to comprehensively judge based on the above-mentioned indices and select the antibody most suitable for administration to humans. The antibodies used in the present invention also include modified antibodies. The modified antibody means an antibody obtained by chemically or biologically modifying the antibody of the present invention. Chemical modifications include chemically modified products having a bond of a chemical moiety to the amino acid backbone, or a bond of a chemical moiety to an N-linked or O-linked carbohydrate chain. Biological modifications include post-translational modifications (e.g., addition of N-linked or O-linked sugar chains, processing of the N-terminus or C-terminus, deamidation, isomerization of aspartic acid, oxidation of methionine, etc.), those with a methionine residue added to the N-terminus by expression using a prokaryotic host cell, and the like. In addition, those labeled to enable detection or isolation of the antibody or antigen of the present invention, for example, enzyme-labeled products, fluorescent-labeled products, and affinity-labeled products are also included in the meaning of such modified products. Such modified antibodies of the present invention are useful for improving the stability and blood retention of antibodies, reducing antigenicity, and detecting or isolating antibodies or antigens. In addition, it is possible to enhance antibody-dependent cell cytotoxic activity by regulating the sugar chain modification bound to the antibody used in the present invention (such as glycosylation, defucosylation, etc.). As techniques for regulating the sugar chain modification of antibodies, International Publication Nos. 99 / 54342, 00 / 61739, 02 / 31140, etc. are known, but are not limited thereto. The antibodies of the present invention also include antibodies in which the sugar chain modification has been regulated. When an antibody gene is isolated and then introduced into an appropriate host to produce an antibody, an appropriate combination of a host and an expression vector can be used. Specific examples of antibody genes include those obtained by combining the gene encoding the heavy chain sequence of the antibody described in this specification and the gene encoding the light chain sequence. When transforming a host cell, the heavy chain sequence gene and the light chain sequence gene can be inserted into the same expression vector or into separate expression vectors. When using eukaryotic cells as hosts, animal cells, plant cells, and eukaryotic microorganisms can be used. In particular, as animal cells, mammalian cells, for example, COS cells which are monkey cells (Gluzman, Y. Cell (1981) 23, p. 175 - 182, ATCC CRL - 1650), mouse fibroblasts NIH3T3 (ATCC No. CRL - 1658), and dihydrofolate reductase - deficient strains of Chinese hamster ovary cells (CHO cells, ATCC CCL - 61) (Urlaub, G. and Chasin, L. A. Proc. Natl. Acad. Sci. U.S.A. (1980) 77, p. 4126 - 4220) can be mentioned. When using prokaryotic cells, for example, Escherichia coli and Bacillus subtilis can be mentioned. The target antibody gene is introduced into these cells by transformation, and the antibody is obtained by culturing the transformed cells in vitro. In this culture, the yield may vary depending on the antibody sequence, and it is possible to select, from among antibodies having equivalent binding activity, those that are easy to produce as pharmaceuticals using the yield as an index. Therefore, the antibody of the present invention also includes an antibody obtained by a method for producing the antibody, which is characterized by including the step of culturing the above - transformed host cells and the step of collecting the target antibody or a functional fragment of the antibody from the culture obtained in this step. In addition, in the case of antibodies produced by mammalian cultured cells, it is known that the lysine residue at the carboxyl terminus of the heavy chain is deleted (Journal of Chromatography A, 705: 129-134 (1995)). Also, it is known that two amino acid residues, glycine and lysine, at the carboxyl terminus of the heavy chain are deleted and the proline residue newly located at the carboxyl terminus is amidated (Analytical Biochemistry, 360: 75-83 (2007)). However, these deletions and modifications of the heavy chain sequence do not affect the antigen-binding ability and effector functions (such as complement activation and antibody-dependent cell cytotoxicity) of the antibody. Therefore, the antibodies according to the present invention include antibodies that have undergone such modifications and functional fragments of such antibodies, including deletion bodies in which one or two amino acids are deleted at the carboxyl terminus of the heavy chain, and amidated deletion bodies thereof (for example, heavy chains in which the proline residue at the carboxyl terminus is amidated). However, as long as the antigen-binding ability and effector functions are maintained, the deletion bodies at the carboxyl terminus of the heavy chain of the antibodies according to the present invention are not limited to the above types. The two heavy chains constituting the antibody according to the present invention may be any one of the heavy chains selected from the group consisting of the full length and the above deletion bodies, or a combination of any two of them. The quantitative ratio of each deletion body can be affected by the type of mammalian cultured cells producing the antibody according to the present invention and the culture conditions. However, the antibody according to the present invention preferably includes those in which one amino acid residue at the carboxyl terminus is deleted in both of the two heavy chains. Examples of the isotype of the antibody used in the present invention include IgG (IgG1, IgG2, IgG3, IgG4), etc., and preferably IgG1 or IgG2. As the biological activities of an antibody, generally, antigen-binding activity, the activity of internalizing into cells expressing the antigen by binding to the antigen, the activity of neutralizing the activity of the antigen, the activity of enhancing the activity of the antigen, antibody-dependent cell-mediated cytotoxicity (ADCC) activity, complement-dependent cytotoxicity (CDC) activity, and antibody-dependent cell-mediated phagocytosis (ADCP) can be mentioned. However, the biological activity of the antibody according to the present invention is the binding activity to HER2, preferably the activity of internalizing into HER2-expressing cells by binding to HER2. Further, in addition to the cell internalization activity, the antibody of the present invention may also have ADCC activity, CDC activity, and / or ADCP activity. The obtained antibody can be purified to homogeneity. For the separation and purification of the antibody, the separation and purification methods usually used for ordinary proteins may be used. For example, column chromatography, filter filtration, ultrafiltration, salting out, dialysis, preparative polyacrylamide gel electrophoresis, isoelectric focusing electrophoresis, etc. can be appropriately selected and combined to separate and purify the antibody (Strategies for Protein Purification and Characterization: A Laboratory Course Manual, Daniel R. Marshak et al. eds., Cold Spring Harbor Laboratory Press (1996); Antibodies: A Laboratory Manual. Ed Harlow and David Lane, Cold Spring Harbor Laboratory (1988)), but it is not limited thereto. Examples of chromatography include affinity chromatography, ion exchange chromatography, hydrophobic chromatography, gel filtration chromatography, reverse phase chromatography, adsorption chromatography, etc. These chromatographies can be carried out using liquid chromatography such as HPLC or FPLC. Examples of columns used in affinity chromatography include Protein A columns and Protein G columns. For example, columns using Protein A columns include Hyper D, POROS, Sepharose F.F. (Pharmacia Corporation), etc. It is also possible to purify an antibody by using a carrier immobilized with an antigen and utilizing the binding property to the antigen. [Antitumor compound] The antitumor compound bound to the anti-HER2 antibody-drug conjugate used in the present invention will be described. Such an antitumor compound is exatecan, which is a camptothecin derivative (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, which can also be represented as (chemical name: (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione)). Exatecan is a compound represented by the following formula: It is a compound represented by. Since exatecan has a camptothecin structure, it is known that in an acidic aqueous medium (for example, about pH 3), the equilibrium is biased towards a structure in which a lactone ring is formed (closed ring form), while in a basic aqueous medium (for example, about pH 10), the equilibrium is biased towards a structure in which the lactone ring is opened (open ring form). It goes without saying that antibody-drug conjugates into which exatecan residues corresponding to such closed ring and open ring structures are introduced are all included in the scope of the antibody-drug conjugates used in the present invention. [Linker structure] The linker structure for binding the antitumor compound to the anti-HER2 antibody in the anti-HER2 antibody-drug conjugate used in the present invention will be described. The linker has the following formula: -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)- (In the formula, -(Succinimid-3-yl-N) has the following formula: It has a structure represented by the formula, binds to an anti-HER2 antibody by a thioether bond at the 3-position thereof, and binds to a methylene group in a linker structure containing this at the nitrogen atom at the 1-position. -GGFG- represents a tetrapeptide residue of -Gly-Gly-Phe-Gly-.) It can be represented by [Compound released in tumor cells] In the anti-HER2 antibody-drug conjugate used in the present invention, after moving into tumor cells, the linker portion is cleaved, and a drug derivative having a structure represented by the formula: NH2-CH2-O-CH2-C(=O)-(NH-DX) may be released. Since the aminals structure within the same molecule of the above drug derivative is unstable, it further self-decomposes to release a compound represented by the formula: HO-CH2-C(=O)-(NH-DX) It has been confirmed that the compound is released. The above compound can be represented by the following formula: (Hereinafter, in the present invention, it may also be referred to as "Compound 1".) Compound 1 is considered to be the main body of the antitumor activity of the antibody-drug conjugate used in the present invention, and it has been confirmed that it has a topoisomerase I inhibitory effect (Ogitani Y. et al., Clinical Cancer Research, 2016, Oct 15;22(20):5097-5108, Epub 2016 Mar 29). Incidentally, the antibody-drug conjugate used in the present invention is also known to have a bystander effect (Ogitani Y. et al., Cancer Science (2016) 107, 1039-1046). This bystander effect is exerted when the antibody-drug conjugate used in the present invention internalizes into HER2-expressing cancer cells and the released Compound 1 exerts an antitumor effect on neighboring cancer cells that do not express HER2. [Production Method] The antibody-drug conjugate used in the present invention is prepared by reacting an anti-HER2 antibody having a thiol group (also referred to as a sulfhydryl group) with the following compound (hereinafter also referred to as "Compound 2" in the present invention): (maleimid-N-yl)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX) (In the formula, (maleimid-N-yl)- is a group in which the nitrogen atom is the bonding site, represented by the following formula: -(NH-DX) is a group in which the nitrogen atom of the amino group at the 1-position is the bonding site, represented by the following formula: -GGFG- represents a tetrapeptide residue of -Gly-Gly-Phe-Gly-.) It can be produced by reacting them. ​Compound 2 can be produced with reference to the production methods and the like described in Examples 26, 32, and 33 of International Publication No. 2015 / 115091. Compound 2 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]indolizino[1,2-b]quinolin-1-yl]amino}-2-oxoethoxy)methyl]glycinamide. An anti-HER2 antibody having a sulfhydryl 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, methods such as reacting a reducing agent such as tris(2-carboxyethyl)phosphine hydrochloride (TCEP) with an anti-HER2 antibody to reduce the disulfide bond in the hinge region of the antibody to generate a sulfhydryl group can be mentioned, but are not limited thereto. Specifically, by using TCEP as a reducing agent in an amount of 0.3 to 3 molar equivalents per disulfide bond in the hinge region of the antibody and reacting it with the anti-HER2 antibody in a buffer solution containing a chelating agent, an anti-HER2 antibody in which the disulfide bond in the hinge region of the antibody is partially or completely reduced can be obtained. Examples of the chelating agent include ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA). These may be used at a concentration of 1 mM to 20 mM. As the buffer solution, sodium phosphate, sodium borate, sodium acetate solution, etc. can be used. Specifically, an anti-HER2 antibody having a sulfhydryl group that is partially or completely reduced can be obtained by reacting the anti-HER2 antibody with TCEP at 4°C to 37°C for 1 to 4 hours. Here, by carrying out a reaction in which a sulfhydryl group is added to the drug-linker moiety, the drug-linker moiety can be bonded by a thioether bond. Using 2 to 20 molar equivalents of Compound 2 per anti-HER2 antibody having a sulfhydryl group, an antibody-drug conjugate (1) to which 2 to 8 drugs are bound per anti-HER2 antibody can be produced. Specifically, a solution in which Compound 2 is dissolved may be added to a buffer solution containing an anti-HER2 antibody having a sulfhydryl group and reacted. Here, as the buffer solution, a sodium acetate solution, sodium phosphate, sodium borate, or the like may be used. The pH during the reaction is 5 to 9, and more preferably, the reaction may be carried out at around pH 7. As the solvent for dissolving Compound 2, an organic solvent such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMA), N-methyl-2-pyridone (NMP), or the like can be used. An organic solvent solution in which Compound 2 is dissolved may be added to a buffer solution containing an anti-HER2 antibody having a sulfhydryl group at 1 to 20% v / v and reacted. The reaction temperature is 0 to 37°C, more preferably 10 to 25°C, and the reaction time is 0.5 to 2 hours. The reaction can be terminated by inactivating the reactivity of unreacted Compound 2 with a thiol-containing reagent. The thiol-containing reagent is, for example, cysteine or N-acetyl-L-cysteine (NAC). More specifically, the reaction can be terminated by adding 1 to 2 molar equivalents of NAC to the used Compound 2 and incubating at room temperature for 10 to 30 minutes. The produced antibody-drug conjugate can be identified by performing concentration, buffer exchange, purification, antibody concentration, and measurement of the average number of drug conjugations per antibody molecule by the following common operations. Common operation A: Concentration of an aqueous solution of an antibody or an antibody-drug conjugate An antibody or antibody-drug conjugate solution was placed in a container of Amicon Ultra (50,000 MWCO, Millipore Co.), and the antibody or antibody-drug conjugate solution was concentrated by centrifugation (centrifugation at 2000 G to 3800 G for 5 to 20 minutes) using a centrifuge (Allegra X-15R, Beckman Coulter, Inc.). Common operation B: Measurement of antibody concentration Using a UV measuring instrument (NanoDrop 1000, Thermo Fisher Scientific Inc.), the antibody concentration was measured according to the manufacturer's specified method. At that time, different 280 nm extinction coefficients (1.3 mL mg －１ cm －１ to 1.8 mL mg －１ cm －１ ) were used for each antibody. Common operation C-1: Buffer exchange of antibody A NAP-25 column (Cat. No. 17-0852-02, GE Healthcare Japan Corporation) using a Sephadex G-25 carrier was equilibrated with a phosphate buffer (10 mM, pH 6.0; referred to as PBS6.0 / EDTA in this specification) containing sodium chloride (137 mM) and ethylenediaminetetraacetic acid (EDTA, 5 mM) according to the manufacturer's specified method. For each NAP-25 column, 2.5 mL of an aqueous antibody solution was loaded, and then a fraction (3.5 mL) eluted with 3.5 mL of PBS6.0 / EDTA was collected. This fraction was concentrated by common operation A, the antibody concentration was measured using common operation B, and then the antibody concentration was adjusted to 10 mg / mL using PBS6.0 / EDTA. Common operation C-2: Buffer exchange of antibody An NAP-25 column (Cat. No. 17-0852-02, GE Healthcare Japan Corporation) using Sephadex G-25 carrier was equilibrated with a phosphate buffer (50 mM, pH 6.5; referred to as PBS6.5 / EDTA herein) containing sodium chloride (50 mM) and EDTA (2 mM) according to the method specified by the manufacturer. After placing 2.5 mL of the antibody aqueous solution on one such NAP-25 column, a fraction (3.5 mL) eluted with 3.5 mL of PBS6.5 / EDTA was collected. This fraction was concentrated by common operation A, the antibody concentration was measured using common operation B, and then the antibody concentration was adjusted to 20 mg / mL using PBS6.5 / EDTA. Common operation D: Purification of antibody-drug conjugate The NAP-25 column was equilibrated with any one of a commercially available phosphate buffer (PBS7.4, Cat. No. 10010-023, Invitrogen), a sodium phosphate buffer (10 mM, pH 6.0; referred to as PBS6.0 herein) containing sodium chloride (137 mM), or an acetate buffer (10 mM, pH 5.5; referred to as ABS herein) containing sorbitol (5%). An antibody-drug conjugate reaction aqueous solution (about 1.5 mL) was placed on this NAP-25 column, and an antibody fraction was collected by eluting with the amount of buffer specified by the manufacturer. The collected fraction was placed on the NAP-25 column again, and the gel filtration purification operation of eluting with the buffer was repeated 2 to 3 times in total to obtain an antibody-drug conjugate from which unbound drug linker and low molecular weight compounds (tris(2-carboxyethyl)phosphine hydrochloride (TCEP), N-acetyl-L-cysteine (NAC), dimethyl sulfoxide) were removed. Common operation E: Measurement of antibody concentration and average number of drug bindings per antibody molecule in antibody-drug conjugate (1) The bound drug concentration in the antibody-drug conjugate can be calculated by performing the following calculation after measuring the UV absorbance at two wavelengths of 280 nm and 370 nm of the antibody-drug conjugate aqueous solution. Since the total absorbance at a certain wavelength is equal to the sum of the absorbances of all absorbing chemical species present in the system (additivity of absorbance), assuming no change in the molar extinction coefficients of the antibody and the drug before and after conjugation of the antibody and the drug, the antibody concentration and the drug concentration in the antibody-drug conjugate are represented by the following relational expressions. A ２８０ = A Ｄ，２８０ + A Ａ，２８０ = ε Ｄ，２８０ C Ｄ + ε Ａ，２８０ C Ａ　　 Equation (I) A ３７０ = A Ｄ，３７０ + A Ａ，３７０ = ε Ｄ，３７０ C Ｄ + ε Ａ，３７０ C Ａ　　 Equation (II) Here, A ２８０ represents the absorbance of the antibody-drug conjugate aqueous solution at 280 nm 、 A ３７０ represents the absorbance of the antibody-drug conjugate aqueous solution at 370 nm, A Ａ，２８０ represents the absorbance of the antibody at 280 nm, A Ａ，３７０ represents the absorbance of the antibody at 370 nm, A Ｄ，２８０ represents the absorbance of the conjugate precursor at 280 nm, A Ｄ，３７０ represents the absorbance of the conjugate precursor at 370 nm, ε Ａ，２８０ represents the molar extinction coefficient of the antibody at 280 nm, ε Ａ，３７０ represents the molar extinction coefficient of the antibody at 370 nm, ε Ｄ，２８０ represents the molar extinction coefficient of the conjugate precursor at 280 nm, ε Ｄ，３７０ represents the molar extinction coefficient of the conjugate precursor at 370 nm, C Ａ represents the antibody concentration in the antibody-drug conjugate, C Ｄ represents the drug concentration in the antibody-drug conjugate. Here, ε Ａ，２８０ ε Ａ，３７０ ε Ｄ，２８０ ε Ｄ，３７０A pre-prepared value (a calculated estimated value or an actually measured value obtained from UV measurement of a compound) is used. For example, ε Ａ，２８０ can be estimated from the amino acid sequence of the antibody by a known calculation method (Protein Science, 1995, vol. 4, 2411-2423). ε Ａ，３７０ is usually zero. In the production example, the molar extinction coefficient of trastuzumab was ε Ａ，２８０ = 215400 (calculated estimated value) and ε Ａ，３７０ = 0 were used. ε Ｄ，２８０ and ε Ｄ，３７０ can be obtained by measuring the absorbance of a solution in which the conjugate precursor to be used is dissolved at a certain molar concentration, according to Lambert-Beer's law (absorbance = molar concentration × molar extinction coefficient × cell optical path length). Unless otherwise specified, the molar extinction coefficient of the drug linker in the production example was ε Ｄ，２８０ = 5000 (actually measured average value), ε Ｄ，３７０ = 19000 (actually measured average value) were used. Measure A ２８０ and A ３７０ of the antibody-drug conjugate aqueous solution, substitute these values into formulas (I) and (II) and solve the simultaneous equations to obtain C Ａ and C Ｄ . Furthermore, by dividing C Ｄ by C Ａ , the average number of drug conjugations per antibody can be obtained. Common operation F: Measurement of the average number of drug conjugations per antibody molecule in an antibody-drug conjugate (2) The average number of drug conjugations per antibody molecule in an antibody-drug conjugate can also be determined by high performance liquid chromatography (HPLC) analysis using the following method in addition to the aforementioned common operation E. [F-1. Preparation of HPLC analysis sample (reduction of antibody-drug conjugate)] Mix an antibody-drug conjugate solution (about 1 mg / mL, 60 μL) with an aqueous dithiothreitol (DTT) solution (100 mM, 15 μL). Incubate the mixture at 37 °C for 30 minutes to obtain a sample in which the disulfide bonds between the L and H chains of the antibody-drug conjugate are cleaved, and use it for HPLC analysis. [F-2. HPLC Analysis] Perform HPLC analysis under the following measurement conditions. HPLC system: Agilent 1290 HPLC system (Agilent Technologies) Detector: Ultraviolet absorbance meter (measurement wavelength: 280 nm) Column: PLRP-S (2.1 × 50 mm, 8 μm, 1000 Å; Agilent Technologies, P / N PL1912-1802) Column temperature: 80 °C Mobile phase A: Aqueous solution of 0.04% trifluoroacetic acid (TFA) Mobile phase B: Acetonitrile solution containing 0.04% TFA Gradient program: 29% - 36% (0 min - 12.5 min), 36% - 42% (12.5 - 15 min), 42% - 29% (15 min - 15.1 min), 29% - 29% (15.1 min - 25 min) Sample injection volume: 15 μL [F-3. Data Analysis] [F-3-1] For the L chain (L ０ ) and H chain (H ０ ) of the antibody not conjugated with the drug, and the L chain conjugated with the drug (L chain conjugated with one drug: L １ ) and H chain (H chain conjugated with one drug: H １ , H chain conjugated with two drugs: H ２ , H chain conjugated with three drugs: H ３ ), since the hydrophobicity increases and the retention time becomes longer in proportion to the number of conjugated drugs, they are eluted in the order of L ０ , L １ , H ０ , H １ , H ２ , H ３ . L ０ and H ０By comparing the retention time with that of [substance], the detected peak can be assigned to any one of L ０ , L １ , H ０ , H １ , H ２ , H ３ . [F-3-2] Since the drug linker has UV absorption, according to the number of bindings of the drug linker, the peak area value is corrected according to the following formula using the molar extinction coefficients of the L chain, H chain and drug linker. Here, the molar extinction coefficients (280 nm) of the L chain and H chain in each antibody can be the values estimated from the amino acid sequences of the L chain and H chain of each antibody by a known calculation method (ProteinScience, 1995, vol.4, 2411-2423). In the case of trastuzumab, according to its amino acid sequence, 26150 was used as the estimated value of the molar extinction coefficient of the L chain and 81290 was used as the estimated value of the molar extinction coefficient of the H chain. Also, the molar extinction coefficient (280 nm) of the drug linker was the measured molar extinction coefficient (280 nm) of the compound obtained by reacting each drug linker with mercaptoethanol or N-acetylcysteine to convert the maleimide group into a succinimide thioether. [F-3-3] Calculate the ratio (%) of the peak area of each chain to the total peak area correction value according to the following formula. [F-3-4] Calculate the average number of drug bindings per molecule of antibody in the antibody-drug conjugate according to the following formula. Average number of drug bindings = (L ０ Peak area ratio x0 + L ０ Peak area ratio x1 + H ０ Peak area ratio x0 + H １ Peak area ratio x1 + H ２ Peak area ratio x2 + H ３ Peak area ratio x3) / 100 x 2 The anti-HER2 antibody-drug conjugate used in the present invention may absorb moisture, or adsorbed water may adhere thereto, etc., to form a hydrate when left in the air, or by recrystallization or purification operations. Such compounds or salts containing water are also included in the anti-HER2 antibody-drug conjugate used in the present invention. In addition, the anti-HER2 antibody-drug conjugate used in the present invention includes compounds labeled with various radioactive or non-radioactive isotopes. One or more of the atoms constituting the antibody-drug conjugate of the present invention may contain atomic isotopes at non-natural ratios. Examples of atomic isotopes include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C), etc. Further, the compounds of the present invention can be radio-labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). Radio-labeled compounds are useful as therapeutic or prophylactic agents, research reagents, for example, assay reagents, and diagnostic agents, for example, in vivo imaging diagnostic agents. All isotope variants of the antibody-drug conjugate used in the present invention are included in the scope of the present invention regardless of whether they are radioactive or not. [Medicine] The therapeutic agent of the present invention is characterized by containing the antibody-drug conjugate used in the present invention. Further, the treatment method of the present invention is characterized by administering the antibody-drug conjugate used in the present invention to a patient. These can be used as therapeutic agents and treatment methods for HER2-expressing cancers that are resistant or refractory to existing anti-HER2 drugs. In the present invention, "resistance" or "refractoriness" refers to the property of being non-responsive to treatment with an anticancer drug, and can also be expressed as "non-responsiveness" or "non-responsivity". Further, since the growth of a tumor cannot be prevented due to non-responsiveness, it can also be expressed as "intolerance". The "resistant or refractory" of the present invention may be "resistance or refractoriness acquired by treatment with existing anti-HER2 drugs", or may be "intrinsic resistance or refractoriness without treatment with existing anti-HER2 drugs". In the present invention, "HER2-expressing cancer" refers to cancer and / or tumor including cancer cells expressing HER2 protein on the cell surface. In the present invention, "existing anti-HER2 drugs" refers to drugs targeting HER2 that are used clinically, excluding the antibody-drug conjugate of the present invention, and preferably refers to anti-HER2 drugs used in standard treatment. "Existing anti-HER2 drugs" are not particularly limited as long as they meet the above requirements, but preferably at least one selected from the group consisting of Trastuzumab emtansine (T-DM1), Trastuzumab, Pertuzumab, and Lapatinib, more preferably Trastuzumab emtansine or Trastuzumab, and even more preferably Trastuzumab emtansine. The therapeutic agent and treatment method of the present invention can be preferably used for administration to patients with a treatment history with existing anticancer drugs. In the present invention, the "existing anticancer drug" refers to an anticancer drug that is clinically used, excluding the antibody-drug conjugate used in the present invention. The "existing anticancer drug" is not particularly limited as long as it satisfies the above requirements, but preferably includes at least one selected from the group consisting of trastuzumab emtansine, trastuzumab, pertuzumab, lapatinib, irinotecan (Irinotecan, CPT-11), cisplatin (Cisplatin), carboplatin (Carboplatin), oxaliplatin (Oxaliplatin), fluorouracil (Fluorouracil, 5-FU), gemcitabine (Gemcitabine), capecitabine (Capecitabine), paclitaxel (Paclitaxel), docetaxel (Docetaxel), doxorubicin (Doxorubicin), epirubicin (Epirubicin), cyclophosphamide (Cyclophosphamide), mitomycin C (Mitomycin C), tegafur (Tegafur)・gimeracil (Gimeracil)・oteracil (Oteracil) formulation, cetuximab (Cetuximab), panitumumab (Panitumumab), bevacizumab (Bevacizumab), ramucirumab (Ramucirumab), regorafenib (Regorafenib), trifluridine (Trifluridine)・tipiracil (Tipiracil) formulation, gefitinib (Gefitinib), erlotinib (Erlotinib), afatinib (Afatinib), methotrexate (Methotrexate), and pemetrexed (Pemetrexed). In the case of treating breast cancer, the "existing anticancer drug" preferably includes at least one selected from the group consisting of trastuzumab emtansine, trastuzumab, pertuzumab, lapatinib, fluorouracil, paclitaxel, docetaxel, doxorubicin, epirubicin, cyclophosphamide, and methotrexate, more preferably includes trastuzumab emtansine or trastuzumab, and even more preferably includes trastuzumab emtansine. In the case of treating gastric cancer, the "existing anticancer drug" preferably comprises at least one selected from the group consisting of trastuzumab, irinotecan, cisplatin, fluorouracil, paclitaxel, docetaxel, doxorubicin, epirubicin, and mitomycin C, more preferably comprises trastuzumab and / or irinotecan, and even more preferably comprises trastuzumab. In the case of treating colorectal cancer, the "existing anticancer drug" preferably comprises at least one selected from the group consisting of irinotecan, oxaliplatin, fluorouracil, cetuximab, panitumumab, bevacizumab, ramucirumab, regorafenib, and trifluridine / tipiracil combination, and more preferably comprises irinotecan. In the case of treating non-small cell lung cancer, the "existing anticancer drug" preferably comprises at least one selected from the group consisting of irinotecan, cisplatin, carboplatin, gemcitabine, gefitinib, erlotinib, afatinib, and pemetrexed. The therapeutic agent and treatment method of the present invention are preferably characterized in that the dosage of the antibody-drug conjugate used in the present invention per administration is in the range of 5.4 mg / kg (indicating that the dosage per 1 kg of body weight is 5.4 mg. The same applies hereinafter) to 8 mg / kg, more preferably 5.4 mg / kg, 6.4 mg / kg, 7.4 mg / kg, or 8 mg / kg, and even more preferably 5.4 mg / kg or 6.4 mg / kg. The therapeutic agent and treatment method of the present invention are preferably characterized in that the antibody-drug conjugate used in the present invention is administered at intervals of once every three weeks. The therapeutic agent and treatment method of the present invention can preferably be used for the treatment of at least one cancer selected from the group consisting of breast cancer, gastric cancer (also called gastric adenocarcinoma), colorectal cancer (also called colorectal cancer, including colon cancer and rectal cancer), non-small cell lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, cholangiocarcinoma, Paget's disease, pancreatic cancer, ovarian cancer, and uterine carcinosarcoma. More preferably, it can be used for the treatment of at least one cancer selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, non-small cell lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, cholangiocarcinoma, and Paget's disease. Even more preferably, it can be used for the treatment of breast cancer, gastric cancer, colorectal cancer, or non-small cell lung cancer. For breast cancer, treatment with the existing anti-HER2 drugs trastuzumab emtansine and trastuzumab is recognized. Also, for gastric cancer and gastroesophageal junction adenocarcinoma, treatment with the existing anti-HER2 drug trastuzumab is recognized. Therefore, when the therapeutic agent of the present invention is used for the treatment of at least one cancer selected from the group consisting of breast cancer, gastric cancer, and gastroesophageal junction adenocarcinoma, "resistance or refractoriness" is preferably "resistance or refractoriness acquired by treatment with existing anti-HER2 drugs". On the other hand, for colorectal cancer, non-small cell lung cancer, esophageal cancer, salivary gland cancer, cholangiocarcinoma, Paget's disease, pancreatic cancer, ovarian cancer, and uterine carcinosarcoma, no effective treatment method with existing anti-HER2 drugs has been established. Therefore, when the therapeutic agent and treatment method of the present invention are used for the treatment of at least one cancer selected from the group consisting of colorectal cancer, non-small cell lung cancer, esophageal cancer, salivary gland cancer, cholangiocarcinoma, Paget's disease, pancreatic cancer, ovarian cancer, and uterine carcinosarcoma, "resistance or refractoriness" is preferably "intrinsic resistance or refractoriness not caused by treatment with existing anti-HER2 drugs". The therapeutic agent and treatment method of the present invention can be used for HER2-expressing cancers, whether they are HER2-overexpressing cancers or HER2-low-expressing cancers. In the present invention, the "cancer with HER2 overexpression" is not particularly limited as long as it is recognized as a cancer with HER2 overexpression by those skilled in the art. Preferably, it includes cancers in which the expression of HER2 is determined to be 3+ by immunohistochemistry (IHC), or cancers in which the expression of HER2 is determined to be 2+ by immunohistochemistry and the expression of HER2 is determined to be positive by in situ hybridization (ISH). In addition, the in situ hybridization method of the present invention includes fluorescence in situ hybridization (FISH) and Dual Color in situ hybridization (DISH). In the present invention, the "cancer with low HER2 expression" is not particularly limited as long as it is recognized as a cancer with low HER2 expression by those skilled in the art. Preferably, it includes cancers in which the expression of HER2 is determined to be 2+ by immunohistochemistry and the expression of HER2 is determined to be negative by in situ hybridization, or cancers in which the expression of HER2 is determined to be 1+ by immunohistochemistry. The method for determining the degree of HER2 expression by immunohistochemistry and the method for determining the positivity or negativity of HER2 expression by in situ hybridization are not particularly limited as long as they are recognized by those skilled in the art. For example, HER2 Test Guide Breast Cancer Edition 4 (prepared by the Breast Cancer HER2 Test Pathology Subcommittee) can be mentioned. The therapeutic agent and treatment method of the present invention can preferably be used for the treatment of inoperable or recurrent cancers. The therapeutic agent and treatment method of the present invention can be used by containing pharmaceutically acceptable formulation components. In other words, the therapeutic agent of the present invention can also be used as a pharmaceutical composition for the treatment of resistant cancers, which contains the antibody-drug conjugate, its salt, or their hydrates used in the present invention as an active ingredient and pharmaceutically acceptable formulation components. The therapeutic pharmaceutical composition of the present invention exhibits excellent antitumor activity against cancers that are resistant to existing anticancer drugs (i.e., resistant cancers), particularly cancers that have acquired resistance to existing anticancer drugs (i.e., secondary resistant cancers). Therefore, the therapeutic pharmaceutical composition of the present invention is applied to the group of patients among cancer patients who are resistant to existing anticancer drugs (patients with a treatment history with existing anticancer drugs) and exhibits a remarkable antitumor effect. The definition of "existing anticancer drugs" is as described above. Preferably, it includes antibody-drug conjugates containing anti-HER2 antibodies such as trastuzumab emtansine (T-DM1), or anti-HER2 antibodies themselves such as trastuzumab or pertuzumab. The therapeutic pharmaceutical composition of the present invention, when administered to cancer patients in place of these existing anticancer drugs or in combination with these existing anticancer drugs, exhibits a high therapeutic effect against cancers that have acquired resistance to these existing anticancer drugs. The therapeutic pharmaceutical composition of the present invention is preferably characterized in that the dosage per administration of the antibody-drug conjugate used in the present invention is in the range of 0.8 mg / kg to 8 mg / kg, more preferably characterized in that it is 5.4 mg / kg, 6.4 mg / kg, 7.4 mg / kg, or 8 mg / kg, and even more preferably characterized in that it is 5.4 mg / kg or 6.4 mg / kg. The administration interval of the therapeutic pharmaceutical composition of the present invention may be once a week (q1w), once every two weeks (q2w), once every three weeks (q3w), or once every four weeks (q4w), but preferably it is once every three weeks. The therapeutic pharmaceutical composition of the present invention can preferably be used when the resistant cancer is lung cancer, urothelial cancer, colorectal cancer, prostate cancer, ovarian cancer, pancreatic cancer, breast cancer, bladder cancer, gastric cancer, gastrointestinal stromal tumor, cervical cancer, esophageal cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, multiple myeloma, or sarcoma. More preferably, it can be used when the resistant cancer is breast cancer, gastric cancer, colorectal cancer, or non-small cell lung cancer. Even more preferably, it can be used when the resistant cancer is breast cancer or gastric cancer. The therapeutic agent and therapeutic pharmaceutical composition of the present invention can slow down the growth of cancer cells, suppress their proliferation, and even destroy cancer cells. Through these actions, in cancer patients, liberation from cancer-related symptoms and improvement of QOL can be achieved, and the therapeutic effect can be achieved while maintaining the lives of cancer patients. Even if cancer cells are not destroyed, higher QOL can be achieved in cancer patients while achieving longer survival through suppression and control of cancer cell proliferation. In addition to being used alone as a drug in such drug therapies, it can also be used as a drug combined with other therapies in adjuvant therapy and can be combined with surgery, radiotherapy, hormone therapy, etc. Furthermore, it can also be used as a drug for drug therapy in neoadjuvant therapy. In addition to the above-described therapeutic uses, preventive effects such as suppressing and even destroying the growth of minute metastatic cancer cells can also be expected. In particular, when HER2 expression is confirmed in primary cancer cells, suppression and preventive effects of cancer metastasis can be expected by administering the anti-HER2 antibody-drug conjugate used in the present invention. For example, effects such as suppressing and destroying cancer cells in body fluids during the metastasis process and suppressing and destroying minute cancer cells immediately after implantation in any tissue can be expected. Therefore, in particular, suppression and preventive effects of cancer metastasis can be expected after surgical removal of cancer. The anti-HER2 antibody-drug conjugate used in the present invention can be applied to patients as a systemic therapy, and can also be locally applied to cancer tissues to expect a therapeutic effect. The therapeutic agent and therapeutic pharmaceutical composition of the present invention can be preferably administered to mammals, and more preferably can be administered to humans. The therapeutic agent and pharmaceutical composition for treatment of the present invention can be administered, including one or more pharmaceutically acceptable formulation components. The pharmaceutically acceptable formulation components can be appropriately selected and applied from commonly used formulation additives and others in this field according to the dosage and administration concentration of the antibody-drug conjugate used in the present invention. The pharmaceutically acceptable formulation components typically include one or more pharmaceutical carriers (for example, sterilized liquids). Here, the liquids include, for example, water and oils (petroleum, animal origin, plant origin, or synthetic origin oils). The oils can be, for example, peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is a more typical carrier when the therapeutic agent and pharmaceutical composition for treatment of the present invention are administered intravenously. Aqueous saline solutions, as well as aqueous dextrose solutions and aqueous glycerol solutions, can also be used as liquid carriers, particularly for injection solutions. Appropriate pharmaceutical excipients can be appropriately selected from those known in this field. The pharmaceutically acceptable formulation components can also include, if desired, trace amounts of wetting agents or emulsifiers, or pH buffering agents. Appropriate examples of the pharmaceutically acceptable formulation components are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. The formulation corresponds to the mode of administration. Various delivery systems are known and can be used to administer the therapeutic agent and pharmaceutical composition for treatment of the present invention. Examples of the introduction methods include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, and subcutaneous routes. Administration can be, for example, by infusion or bolus injection. In certain preferred embodiments, the administration of the therapeutic agent and pharmaceutical composition for treatment of the present invention is by infusion. Parenteral administration is the preferred route of administration. In a representative embodiment, the therapeutic agent and the pharmaceutical composition for treatment of the present invention are formulated according to conventional procedures as a composition suitable for intravenous administration to humans. Typically, the composition for intravenous administration is a solution in a sterile, isotonic, aqueous buffer. If necessary, the therapeutic agent and the pharmaceutical composition for treatment of the present invention may also contain a solubilizing agent and a local anesthetic (e.g., lidocaine) for alleviating pain at the injection site. Generally, the above components are supplied either separately or mixed together in unit dosage forms as dry lyophilized powders or anhydrous concentrates in sealed containers, such as ampoules or sachets indicating the amount of the active agent. In the case where the therapeutic agent and the pharmaceutical composition for treatment of the present invention are administered by infusion, it can be dosed with an infusion bottle containing, for example, sterile pharmaceutical grade water or saline. When the therapeutic agent and the pharmaceutical composition for treatment of the present invention are administered by injection, an ampoule of sterile water for injection or saline may be provided, for example, so that the above components can be mixed before administration. The therapeutic agent and the pharmaceutical composition for treatment of the present invention may be a pharmaceutical composition containing only the anti-HER2 antibody-drug conjugate used in the present invention, or may be a composition containing the anti-HER2 antibody-drug conjugate used in the present invention and at least one other anti-cancer agent. The anti-HER2 antibody-drug conjugate used in the present invention can also be administered together with an existing anti-cancer drug, thereby enhancing the anti-cancer effect. The existing anti-cancer drug used for such a purpose may be administered to an individual simultaneously with, separately from, or sequentially to the antibody-drug conjugate of the present invention, and the dosing intervals for each may be varied. The definition of "existing anti-cancer drug" is as described above. The therapeutic agent and the pharmaceutical composition for treatment of the present invention can be formulated as a lyophilized formulation or a liquid formulation as a formulation having a selected composition and the required purity. When formulating as a lyophilized formulation, it may be a formulation containing appropriate formulation additives used in this field. Similarly, in the case of a liquid formulation, it can be formulated as a liquid formulation containing various formulation additives used in this field. The present invention will be specifically described by the examples shown below, but the present invention is not limited thereto. Also, these are not to be construed as limiting in any sense. [Production Example: Preparation of Antibody-Drug Conjugate] According to the production method described in Patent Document 8 (International Publication No. 2015 / 115091), an antibody-drug conjugate represented by the following formula (hereinafter referred to as "antibody-drug conjugate (1)" or "ADC(1)") was produced. Here, the drug-linker structure is bound to the antibody by a thioether bond, and n is in the range of 7 to 8. [Evaluation Example 1: Antitumor Test] Mouse: 6- to 12-week-old female immunodeficient Crl:Nu(Ncr)-Foxn1 Nu Mice (Charles River) were used in the experiment. Measurement / calculation formula: The major axis and minor axis of the tumor were measured twice a week with an electronic digital caliper, and the tumor volume (mm 3 ) was calculated. The calculation formula is shown below. Tumor volume (mm 3 ) = 0.52 × major axis (mm) × [minor axis (mm)] 2 Antibody-drug conjugate (1) with DAR = 7.6 was used. The antibody-drug conjugate (1) was diluted with a solvent (10 mM Histidine, 10% Trehalose, 0.02% Polysorbate 20, pH 5.5). Trastuzumab emtansine (T-DM1) was diluted with physiological saline. The diluted solution of the antibody-drug conjugate (1) or the diluted solution of T-DM1 was administered into the tail vein of the mice at 10 mL / kg. Tumors excised from HER2-positive breast cancer patients who developed resistance after T-DM1 treatment were serially passaged and maintained multiple times by transplanting them into female immunodeficient mice. Subsequently, tumors with high resistance to T-DM1, namely ST1616B / TDR and ST1360B / TDR, were obtained by continuously administering T-DM1 to the mice. ST1616B / TDR is a tumor derived from a patient who received continuous T-DM1 administration for 13 months, and ST1360B / TDR is a tumor derived from a patient who received continuous T-DM1 administration for 3 months. All of these tumors showed overexpression of HER2 (judged as 3+ by immunohistochemical staining (IHC)). Tumor fragments of solid tumors were subcutaneously transplanted into the flank of female immunodeficient mice, and random grouping was performed when the tumor volume reached approximately 200 mm 3 ³. The day of grouping was designated as Day 0, and the antibody-drug conjugate (1) was intravenously administered into the tail vein at a dose of 3 mg / kg or 10 mg / kg on Day 0. T-DM1 was intravenously administered into the tail vein at a dose of 10 mg / kg on Days 0, 7, 14, and 21. As a control group, a group that received only the solvent used for diluting the antibody-drug conjugate (1) was set up. The results are shown in Figure 3 or Figure 4. Administration of T-DM1 did not suppress the growth of ST1616B / TDR tumors and ST1360B / TDR tumors. On the other hand, the antibody-drug conjugate (1) significantly suppressed tumor growth at both doses of 3 mg / kg and 10 mg / kg. No weight loss of the mice was observed in all drug administration groups. From the above, it was revealed that the antibody-drug conjugate (1) has significant antitumor activity against tumors that have acquired resistance to T-DM1 (i.e., secondary resistant cancer). It was also clarified that it is excellent in safety. [Evaluation Example 2: Clinical Trial] Antibody-drug conjugates are promising pharmaceuticals with the effect of efficient and specific drug delivery to cancer gene-expressing tumor cells. The antibody-drug conjugate (1) is an HER2-targeted antibody-drug conjugate having a novel topoisomerase I inhibitor (Table 1). The DAR of the antibody-drug conjugate (1) used in clinical trials was in the range of 7-8 and was close to 8. Preclinical data have demonstrated that HER2 targeting is highly specific. In preclinical models, the antibody-drug conjugate (1) showed a much broader antitumor spectrum than trastuzumab emtansine (T-DM1) and effects against T-DM1-resistant and HER2-low-expressing tumors. The dose escalation part (Part 1) study and the expanded dose part (Part 2) study are in progress in Phase 1 for HER2-positive breast cancer, gastric cancer, and even different HER2-expressing solid cancers as follows. Study Plan: Open-label, Phase 1 dose escalation study. Determine the maximum tolerated dose (MTD) by the mCRM method according to the EWOC principle. The antibody-drug conjugate (1) is administered intravenously once every 3 weeks until unacceptable toxicity or disease aversion is observed. Dose-limiting toxicity (DLT) is determined in Cycle 1 (Day 1-21). Part 1 Study: Dose Escalation Study (conducted in Japan) Breast cancer or gastric adenocarcinoma / gastroesophageal junction adenocarcinoma The number of subjects is at least 18, and it is assumed that 16% of the subjects (i.e., 1 / 6 of the subjects) have HER2 expression (IHC 2+, 3+). Part 2 Study: Dose Expansion Study (conducted in Japan and the United States) Part 2a; 40 subjects, HER2 overexpression, breast cancer with a history of T-DM1 treatment. Part 2b; 40 subjects, HER2 overexpression, gastric adenocarcinoma / gastroesophageal junction adenocarcinoma with a history of trastuzumab treatment. Part 2c; 20 subjects, HER2 low expression, breast cancer. Part 2d; HER2-expressing solid cancers excluding breast cancer or gastric adenocarcinoma, with 20 subjects. Primary objective: To evaluate the safety and tolerability of antibody-drug conjugate (1). To determine the maximum tolerated dose (MTD) of antibody-drug conjugate (1) and the recommended dose for the Phase II trial. Secondary and exploratory objectives: To evaluate the pharmacokinetics of antibody-drug conjugate (1). To evaluate the efficacy of antibody-drug conjugate (1). Objective response rate (ORR; complete response (CR) + partial response (PR)). Disease control rate (DCR; CR + PR + stable disease (SD)). Duration of response, duration of SD, response time, progression-free survival. To evaluate human anti-humanized antibodies against antibody-drug conjugate (1). Test results Part 1 test: Dose escalation study (conducted in Japan) (1) Analysis of subjects The status of the subjects is as shown in Table 2. (2) Pharmacokinetics Antibody-drug conjugate (1) was administered once every 3 weeks (q3w) at a dose of either 0.8 mg / kg, 1.6 mg / kg, 3.2 mg / kg, 5.4 mg / kg, 6.4 mg / kg, or 8 mg / kg. The pharmacokinetics of antibody-drug conjugate (1) measured from these administrations are shown in Figure 5. The exposure of antibody-drug conjugate (1) was higher than the dose ratio at doses of 3.2 mg / kg and above, and T 1 / 2 was prolonged at doses of 3.2 mg / kg and above. The T of the compound described as "Compound 1" in the figure 1 / 2 was similar to that of antibody-drug conjugate (1) due to the flip-flop phenomenon (data not shown). Compound 1 has the following structure. In Cycle 1, the median Cmin (10,700 ng / mL) at a dose of 6.4 mg / kg of the antibody-drug conjugate (1) exceeded the target exposure (4,260 ng / ml) based on the overall preclinical active ingredient concentration and was almost the same as that of the marketed dose of 3.6 mg / kg of T-DM1. The target dose of the antibody-drug conjugate (1) was 5.0 mg / kg. (3) Safety and tolerability The results of safety and tolerability are shown in Figure 6. The 0.8 mg to 8 mg / kg cohorts did not reach the MTD. At any dose level, there was no dose-limiting toxicity or grade 4 cardiotoxicity. The most commonly observed adverse events (AEs) were low to moderate gastrointestinal and hematological events. Seven grade 3 adverse events (hypokalemia (1), anemia (1), neutropenia (1), lymphopenia (2), increased alkaline phosphatase (1), cholangitis (1)) occurred in 4 out of 22 subjects (18%). After Cycle 2, the doses of 6 subjects in the 6.4 mg / kg (n = 4 / 6) and 8.0 mg / kg (n = 2 / 3) cohorts were reduced due to adverse events, but no treatment discontinuation occurred. (4) Efficacy The efficacy is shown in Figures 7, 8, and 9. In 20 evaluable subjects including 12 previously treated cases with T-DM1 and 5 subjects with low HER2 expression, an ORR of 35% (7 PRs) and a DCR of 90% were achieved (Figures 8 and 9). The antibody-drug conjugate (1) achieved an ORR of 42% and a DCR of 92% in breast cancer patients who were refractory or intolerant to standard treatments including T-DM1 (Figure 7). The treatment effect of T-DM1 in the previous treatment was an ORR of 18% and a DCR of 64%, and the antibody-drug conjugate (1) showed a higher response rate than treatment with T-DM1. One of the cases that achieved a PR (Partial Response) was IHC1+ at registration (Figure 8). Most of the cases that achieved PR were at a dose of 5.4 mg / kg or more (Figs. 8 and 9). Part 2 Study: Dose Escalation Study (conducted in Japan and the US) (1) Analysis of Subjects The number of subjects in each cohort of the Part 2 study and the dose of antibody-drug conjugate (1) were as shown in Table 3. In each cohort, antibody-drug conjugate (1) was administered at intervals of once every three weeks. (2) Efficacy (2-1) Regarding the efficacy in the entire Part 2 study, Fig. 10 shows the maximum tumor shrinkage rate (%). In the figure, "Breast cancer HER2 Positive" indicates the cohort of breast cancer with HER2 overexpression, "Breast cancer HER2 Low" indicates the cohort of breast cancer with low HER2 expression, "Gastric cancer HER2 Positive" indicates the cohort of gastric cancer with HER2 overexpression, "Gastric cancer HER2 Low" indicates the cohort of gastric cancer with low HER2 expression, and "Others" indicates solid cancers with HER2 expression excluding breast cancer and gastric cancer. Antibody-drug conjugate (1) was found to show excellent tumor shrinkage effects in all cancer types, regardless of whether HER2 was overexpressed or underexpressed. (2-2) Regarding the efficacy of the antibody-drug conjugate (1) against breast cancer, the time course of the tumor shrinkage rate (%) is shown in FIG. 11. In the figure, "Breast cancer HER2 Positive" indicates a cohort of breast cancer with overexpression of HER2, and "Breast cancer HER2 Low" indicates a cohort of breast cancer with low expression of HER2. Regarding the efficacy of the antibody-drug conjugate (1) against gastric cancer, the time course of the tumor shrinkage rate (%) is shown in FIG. 12. In the figure, "Gastric cancer HER2 Positive" indicates a cohort of gastric cancer with overexpression of HER2, and "Gastric cancer HER2 Low" indicates a cohort of gastric cancer with low expression of HER2. The antibody-drug conjugate (1) was found to exhibit an excellent tumor shrinkage maintenance effect in any cancer type, whether HER2 is overexpressed or underexpressed. (2-3) Regarding the efficacy in the Part 2 trial, the ORR (objective response rate) and DCR (disease control rate) are shown in Table 4. The antibody-drug conjugate (1) showed high ORR and DCR in all cohorts. In particular, it showed high ORR and DCR in breast cancer patients with a treatment history of trastuzumab emtansine (T-DM1), breast cancer patients with a treatment history of combination of trastuzumab emtansine and pertuzumab, and gastric cancer patients with a treatment history of irinotecan (CPT-11). (2-4) The subjects in the Part 2d trial (HER2-expressing solid cancers excluding breast cancer and gastric cancer) included patients with colorectal cancer (11), non-small cell lung cancer (5), salivary gland cancer (4), Paget's disease (2), esophageal cancer (1), and cholangiocarcinoma (1). Among 12 evaluable patients, an ORR of 33% and a DCR of 91% were achieved. In colorectal cancer, 2 out of 5 achieved PR. In salivary gland cancer, 2 out of 4 achieved PR. (2-5) The results of the Part 2d trial are shown in Table 5. Antibody-drug conjugate (1) achieved an ORR of 31.8% and a DCR of 81.8% in the overall Part 2d trial in 22 evaluable patients. Among these, in the cohort of colorectal cancer, an ORR of 20.0% and a DCR of 80.0% were achieved; in the cohort of non-small cell lung cancer, an ORR of 20.0% and a DCR of 60.0% were achieved; in the cohort of salivary gland cancer, an ORR of 75.0% and a DCR of 100.0% were achieved; and in the cohort of other cancers (Paget's disease, esophageal cancer, and cholangiocarcinoma), an ORR of 33.3% and a DCR of 100.0% were achieved. Also, regarding the efficacy of antibody-drug conjugate (1) in the Part 2d trial, the maximum tumor shrinkage rate (%) is shown in Fig. 13 (in the figure, "C" indicates the cohort of colorectal cancer, "L" indicates the cohort of non-small cell lung cancer, "S" indicates the cohort of salivary gland cancer, "P" indicates the cohort of Paget's disease, "Ch" indicates the cohort of cholangiocarcinoma, "E" indicates the cohort of esophageal cancer. In the figure, "※" indicates those under treatment.). Furthermore, the time course of the tumor shrinkage rate (%) is shown in Fig. 14 (in the figure, "Colorectal" indicates the cohort of colorectal cancer, "NSCLC" indicates the cohort of non-small cell lung cancer, "Salivary" indicates the cohort of salivary gland cancer, "Other" indicates the cohort of other cancers). Antibody-drug conjugate (1) was found to show excellent tumor shrinkage effects in all cancer types, regardless of whether HER2 was overexpressed or underexpressed. (3) Safety and tolerability The results of safety and tolerability are shown in Table 6. The most commonly observed adverse events (AEs) were gastrointestinal toxicities such as nausea, decreased appetite, and vomiting. However, it was found that there were few grade 3 or higher adverse events. Also, myelosuppression such as thrombocytopenia and neutropenia was observed, but it was also found that there were few grade 3 or higher adverse events for these. Summary Antibody-drug conjugate (1) did not reach the MTD in the Part 1 trial (dose escalation trial) and showed high tolerability. Among 20 evaluable subjects, antibody-drug conjugate (1) achieved an ORR of 35% and a DCR of 90%. Antibody-drug conjugate (1) showed a higher efficacy rate than pre-treatment T-DM1 in breast cancer patients previously treated with T-DM1. In the Part 2 study (dose escalation study), antibody-drug conjugate (1) was administered at doses of 5.4 mg / kg and 6.4 mg / kg at 3-week intervals. Antibody-drug conjugate (1) was found to exhibit excellent antitumor effects in all cancer types, regardless of whether HER2 was overexpressed or underexpressed. In addition, it was confirmed that there were few grade 3 or higher adverse events, indicating excellent safety. From the above, it was shown that antibody-drug conjugate (1) has excellent antitumor effects even against cancers that have acquired resistance through pre-treatment with anticancer drugs. Examples of such pre-treatment include anti-HER2 therapy (treatment with existing anti-HER2 drugs, or treatment with a combination of existing anti-HER2 drugs and other anticancer drugs). Examples of anti-HER2 therapy include administration of antibodies such as trastuzumab and pertuzumab, or administration of T-DM1, an anti-HER2 antibody-drug conjugate. It is essential that it has been confirmed by pre-treatment tests that the cancer to be treated is HER2-positive (i.e., HER2 overexpressed). Therefore, administration is carried out expecting an effect on the cancer type based on the mechanism of action of recognizing HER2 and achieving efficacy. However, after continuous administration of these anti-HER2 drugs, it has been observed that, even if an antitumor effect has once been confirmed as expected, the disease state may reach a condition where the antitumor effect is no longer confirmed by some mechanism. In such a situation, antibody-drug conjugate (1) used in the present invention was confirmed to have excellent antitumor effects even in cancers in which the effect of pre-treatment anti-HER2 drug administration was no longer recognized. That is, it was confirmed that antibody-drug conjugate (1) exhibits excellent antitumor effects even in cancers (secondary resistant cancers) that have acquired resistance through administration of existing anti-HER2 drugs as pre-treatment. In addition, it has been demonstrated in clinical trials that the antibody-drug conjugate (1) also exhibits excellent therapeutic effects against HER2-low-expressing cancers and solid cancers other than breast cancer and gastric cancer (e.g., colorectal cancer, non-small cell lung cancer, salivary gland cancer, Paget's disease, esophageal cancer, and cholangiocarcinoma, etc.). These cancers are cancers that, despite expressing HER2, do not initially show a therapeutic effect with existing anti-HER2 drugs (in other words, HER2-expressing cancers that have inherent resistance or intractability to existing anti-HER2 drugs regardless of treatment with existing anti-HER2 drugs). As described above, it has been shown that the therapeutic agent and therapeutic pharmaceutical composition containing the antibody-drug conjugate used in the present invention, and the treatment method characterized by administering the antibody-drug conjugate of the present invention are excellent in the treatment of HER2-expressing cancers resistant or refractory to existing anti-HER2 drugs. SEQ ID NO: 1: Amino acid sequence of the heavy chain of a humanized anti-HER2 monoclonal antibody SEQ ID NO: 2: Amino acid sequence of the light chain of a humanized anti-HER2 monoclonal antibody

Claims

1. A therapeutic agent for HER2-expressing cancer resistant or refractory to existing anti-HER2 drugs, comprising an antibody-drug conjugate in which a linker and a drug represented by the following formula are bound to an anti-HER2 antibody: -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX). (In the formula, -(Succinimid-3-yl-N)- represents the following formula: and represents a group in which the nitrogen atom of the amino group at the 1-position is the binding site, and -GGFG- represents a tetrapeptide residue of -Gly-Gly-Phe-Gly.) 2. The therapeutic agent according to claim 1, wherein the resistance or refractoriness is resistance or refractoriness acquired by treatment with an existing anti-HER2 drug.

3. The therapeutic agent according to claim 1, wherein the resistance or refractoriness is inherent resistance or refractoriness without treatment with an existing anti-HER2 drug.

4. The therapeutic agent according to any one of claims 1 to 3, wherein the existing anti-HER2 drug is at least one selected from the group consisting of trastuzumab emtansine, trastuzumab, pertuzumab, and lapatinib.

5. The therapeutic agent according to any one of claims 1 to 3, wherein the existing anti-HER2 drug is trastuzumab emtansine.

6. The therapeutic agent according to any one of claims 1 to 3, wherein the existing anti-HER2 drug is trastuzumab.

7. The therapeutic agent according to any one of claims 1 to 6, for administration to a patient having a treatment history with an existing anticancer drug.

8. The therapeutic agent according to claim 7, wherein the existing anticancer drug comprises at least one selected from the group consisting of trastuzumab emtansine, trastuzumab, pertuzumab, lapatinib, irinotecan, cisplatin, carboplatin, oxaliplatin, fluorouracil, 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, and pemetrexed.

9. The therapeutic agent according to claim 7, wherein the existing anticancer drug comprises trastuzumab emtansine.

10. The therapeutic agent according to claim 7, wherein the existing anticancer drug comprises trastuzumab.

11. The therapeutic agent according to claim 7, wherein the existing anticancer drug comprises irinotecan.

12. The therapeutic agent according to any one of claims 1 to 11, wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate ranges from 7 to 8.

13. The therapeutic agent according to any one of claims 1 to 11, wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate ranges from 7.5 to 8.

14. The therapeutic agent according to any one of claims 1 to 13, wherein the anti-HER2 antibody in the antibody-drug conjugate is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO:

2.

15. The therapeutic agent according to any one of claims 1 to 13, wherein the anti-HER2 antibody in the antibody-drug conjugate is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO:

2.

16. The therapeutic agent according to any one of claims 1 to 15, wherein the dosage per administration of the antibody-drug conjugate ranges from 5.4 mg / kg to 8 mg / kg.

17. The therapeutic agent according to any one of claims 1 to 15, wherein the dose per administration of the antibody-drug conjugate is 5.4 mg / kg.

18. The therapeutic agent according to any one of claims 1 to 15, wherein the dose per administration of the antibody-drug conjugate is 6.4 mg / kg.

19. The therapeutic agent according to any one of claims 1 to 15, wherein the dose per administration of the antibody-drug conjugate is 7.4 mg / kg.

20. The therapeutic agent according to any one of claims 1 to 15, wherein the dose per administration of the antibody-drug conjugate is 8 mg / kg.

21. The therapeutic agent according to any one of claims 1 to 20, wherein the antibody-drug conjugate is administered at intervals of once every three weeks.

22. The therapeutic agent according to any one of claims 1 to 21, for the treatment of at least one cancer selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, non-small cell lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, cholangiocarcinoma, Paget's disease, pancreatic cancer, ovarian cancer, and uterine carcinosarcoma.

23. The therapeutic agent according to any one of claims 1 to 21, for the treatment of breast cancer.

24. The therapeutic agent according to any one of claims 1 to 21, for the treatment of gastric cancer.

25. The therapeutic agent according to any one of claims 1 to 21, for the treatment of gastric cancer and gastroesophageal junction adenocarcinoma.

26. The therapeutic agent according to any one of claims 1 to 21, for the treatment of colorectal cancer.

27. The therapeutic agent according to any one of claims 1 to 21, for the treatment of non-small cell lung cancer.

28. The therapeutic agent according to any one of claims 1 to 21, for the treatment of salivary gland cancer.

29. The therapeutic agent according to any one of claims 1 to 28, wherein the HER2-expressing cancer is a cancer with HER2 overexpression.

30. The therapeutic agent according to claim 29, wherein the cancer with HER2 overexpression is a cancer in which the expression of HER2 is determined to be 3+ by immunohistochemistry.

31. The therapeutic agent according to claim 29, wherein the cancer with overexpression of HER2 is a cancer in which the expression of HER2 is determined to be 2+ by immunohistochemistry and the expression of HER2 is determined to be positive by in situ hybridization.

32. The therapeutic agent according to any one of claims 1 to 28, wherein the HER2-expressing cancer is a cancer with low expression of HER2.

33. The therapeutic agent according to claim 32, wherein the cancer with low expression of HER2 is a cancer in which the expression of HER2 is determined to be 2+ by immunohistochemistry and the expression of HER2 is determined to be negative by in situ hybridization.

34. The therapeutic agent according to claim 32, wherein the cancer with low expression of HER2 is a cancer in which the expression of HER2 is determined to be 1+ by immunohistochemistry.

35. The therapeutic agent according to any one of claims 1 to 34, for the treatment of inoperable or recurrent cancer.

36. The therapeutic agent according to any one of claims 1 to 35, containing pharmaceutically acceptable formulation components.

37. A method for treating HER2-expressing cancer resistant or refractory to existing anti-HER2 drugs, by administering to a patient in need of treatment for HER2-expressing cancer resistant or refractory to existing anti-HER2 drugs an antibody-drug conjugate in which a linker and a drug represented by the following formula are bound to an anti-HER2 antibody: -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX). (In the formula, -(Succinimid-3-yl-N)- represents a group in which the nitrogen atom of the amino group at the 1-position is the binding site, represented by the following formula: and -GGFG- represents a tetrapeptide residue of -Gly-Gly-Phe-Gly-.) 38. The method according to claim 37, wherein the resistance or refractoriness is resistance or refractoriness acquired by treatment with an existing anti-HER2 drug.

39. The method according to claim 37, wherein the resistance or refractoriness is inherent resistance or refractoriness without treatment with an existing anti-HER2 drug.

40. The method according to any one of claims 37 to 39, wherein the existing anti-HER2 drug is at least one selected from the group consisting of trastuzumab emtansine, trastuzumab, pertuzumab, and lapatinib.

41. The method according to any one of claims 37 to 39, wherein the existing anti-HER2 drug is trastuzumab emtansine.

42. The method according to any one of claims 37 to 39, wherein the existing anti-HER2 drug is trastuzumab.

43. The method according to any one of claims 37 to 42, which is for use in a patient having a treatment history with an existing anti-cancer drug.

44. The method according to claim 43, wherein the existing anti-cancer drug comprises at least one selected from the group consisting of trastuzumab emtansine, trastuzumab, pertuzumab, lapatinib, irinotecan, cisplatin, carboplatin, oxaliplatin, fluorouracil, gemcitabine, capecitabine, paclitaxel, docetaxel, doxorubicin, epirubicin, cyclophosphamide, mitomycin C, tegafur / gimeracil / oteracil potassium, cetuximab, panitumumab, bevacizumab, ramucirumab, regorafenib, trifluridine / tipiracil, gefitinib, erlotinib, afatinib, methotrexate, and pemetrexed.

45. The method according to claim 43, wherein the existing anti-cancer drug comprises trastuzumab emtansine.

46. The method according to claim 43, wherein the existing anti-cancer drug comprises trastuzumab.

47. The method according to claim 43, wherein the existing anti-cancer drug comprises irinotecan.

48. The method according to any one of claims 37 to 47, wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate ranges from 7 to 8.

49. The method according to any one of claims 37 to 47, wherein the average number of drug-linker structures per antibody of the antibody-drug conjugate ranges from 7.5 to 8.

50. The method according to any one of claims 37 to 49, wherein the anti-HER2 antibody in the antibody-drug conjugate is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO:

2.

51. The method according to any one of claims 37 to 49, wherein the anti-HER2 antibody in the antibody-drug conjugate is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO:

2.

52. The method according to any one of claims 37 to 51, wherein the dosage per administration of the antibody-drug conjugate is in the range of 5.4 mg / kg to 8 mg / kg.

53. The method according to any one of claims 37 to 51, wherein the dosage per administration of the antibody-drug conjugate is 5.4 mg / kg.

54. The method according to any one of claims 37 to 51, wherein the dosage per administration of the antibody-drug conjugate is 6.4 mg / kg.

55. The method according to any one of claims 37 to 51, wherein the dosage per administration of the antibody-drug conjugate is 7.4 mg / kg.

56. The method according to any one of claims 37 to 51, wherein the dosage per administration of the antibody-drug conjugate is 8 mg / kg.

57. The method according to any one of claims 37 to 56, wherein the antibody-drug conjugate is administered at intervals of once every three weeks.

58. The method according to any one of claims 37 to 57, for the treatment of at least one cancer selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, non-small cell lung cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, cholangiocarcinoma, Paget's disease, pancreatic cancer, ovarian cancer, and uterine carcinosarcoma.

59. The method according to any one of claims 37 to 57, for the treatment of breast cancer.

60. The method according to any one of claims 37 to 57, for the treatment of gastric cancer.

61. The method according to any one of claims 37 to 57, for the treatment of gastric cancer and gastroesophageal junction adenocarcinoma.

62. The method according to any one of claims 37 to 57 for the treatment of colorectal cancer.

63. The method according to any one of claims 37 to 57 for the treatment of non-small cell lung cancer.

64. The method according to any one of claims 37 to 57 for the treatment of salivary gland cancer.

65. The method according to any one of claims 37 to 64, wherein the HER2-expressing cancer is a cancer with HER2 overexpression.

66. The method according to claim 65, wherein the cancer with HER2 overexpression is a cancer in which the expression of HER2 is determined to be 3+ by immunohistochemistry.

67. The method according to claim 65, wherein the cancer with HER2 overexpression is a cancer in which the expression of HER2 is determined to be 2+ by immunohistochemistry and the expression of HER2 is determined to be positive by in situ hybridization.

68. The method according to any one of claims 37 to 64, wherein the HER2-expressing cancer is a cancer with low HER2 expression.

69. The method according to claim 68, wherein the cancer with low HER2 expression is a cancer in which the expression of HER2 is determined to be 2+ by immunohistochemistry and the expression of HER2 is determined to be negative by in situ hybridization.

70. The method according to claim 68, wherein the cancer with low HER2 expression is a cancer in which the expression of HER2 is determined to be 1+ by immunohistochemistry.

71. The method according to any one of claims 37 to 70 for the treatment of inoperable or recurrent cancer.

72. The method according to any one of claims 37 to 71, wherein an antibody-drug conjugate is administered together with a pharmaceutically acceptable formulation ingredient.

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