Combination of Anti-her2 antibody-drug conjugate with other agents

Abstract

[Problem] To provide a novel drug combination treatment for diseases, particularly cancer. [Solution] The present invention provides a combination administration of anti-HER2 antibody-drug conjugates with other agents, such as immune checkpoint inhibitors.

Description

Combination of anti-HER2 antibody-drug conjugates with other agents

[0001] The present invention relates to a pharmaceutical composition characterized by the use of a specific anti-HER2 antibody-drug conjugate in combination with another drug such as an immune checkpoint inhibitor, a treatment method characterized by administering a specific anti-HER2 antibody-drug conjugate in combination with another drug such as an immune checkpoint inhibitor to a subject, and the like.

[0002] In cancer treatment, removal of the cancerous tissue through surgery or killing of cancer cells with anticancer drugs or radiation is expected to result in a cure or prolong life. However, for many cancers, a single anticancer drug treatment alone is insufficient, and therefore treatments using combinations with various drugs have been attempted. Anticancer drugs include chemotherapeutic agents such as paclitaxel, capecitabine, irinotecan, doxorubicin, carboplatin, taxol, or camptothecin (Non-Patent Document 1), molecularly targeted drugs such as imatinib, crizotinib, dasatinib, and lapatinib, cancer therapeutic antibodies such as trastuzumab (Patent Document 1), bevacizumab, cetuximab, and ramucirumab, and antibody-drug conjugates such as trastuzumab emtansine (Patent Document 2). The anticancer drug and combination therapy used are determined depending on the type and stage of cancer and the treatment status.

[0003] Immune checkpoint inhibitors, which have recently become standard therapeutic agents, are drugs that inhibit the immunosuppressive system and activate antitumor immunity (Non-Patent Documents 2 to 4). Examples of immune checkpoint inhibitors include anti-PD-1 antibodies such as nivolumab (Patent Document 3), pembrolizumab (Patent Document 4), spartalizumab (Patent Document 5), cemiplimab (Patent Document 6), and dostarlimab, as well as anti-PD-L1 antibodies such as atezolizumab (Patent Document 7) and durvalumab. b) (Patent Document 8), Avelumab (Patent Document 9), anti-CTLA-4 antibodies Ipilimumab (Patent Document 10) and Tremelimumab (Patent Document 11), anti-TIGIT antibodies Tiragolumab (Patent Document 12) and Vibostolimab (Patent Document 13), and anti-LAG-3 antibody Relatlimab (Patent Document 14), etc. are known.

[0004] STING (Stimulator of Interferon Genes) is a transmembrane adaptor protein localized in the endoplasmic reticulum (Non-Patent Document 5). STING functions as a central molecule in innate immune activation in mammals and serves as the first line of defense against the invasion of pathogens such as bacteria and viruses. It is known that STING activation is triggered by signals generated when multiple cytoplasmic DNA sensors sense exogenous and endogenous DNA (Non-Patent Documents 6-8). Recent studies have shown that STING not only promotes host defense against microorganisms but also antitumor immunity (Non-Patent Document 9). Patent Documents 15-18 describe conjugates in which a STING agonist is used as an immunostimulatory compound and is linked to an antibody via a linker, and include examples of in vivo administration. Patent Document 19 describes an example in which a conjugate in which a STING agonist and an antibody are linked via a linker is combined with trastuzumab or an anti-PD-1 antibody in vivo and administered.

[0005] However, the effect of combining a conjugate of a STING agonist having a specific cyclic dinucleotide structure with an antibody (Patent Document 17) with other drugs is unknown.

[0006] U.S. Patent No. 5,821,337, International Publication No. WO 2001 / 000244, International Publication No. WO 2006 / 121168, International Publication No. WO 2008 / 156712, International Publication No. WO 2015 / 112900, International Publication No. WO 2015 / 196051, International Publication No. WO 2010 / 077634, International Publication No. WO 2011 / 066389, International Publication No. WO 2013 / 079174, International Publication No. WO 2001 / 014424 International Publication No. 2000 / 037504 International Publication No. 2017 / 053748 International Publication No. 2016 / 028656 International Publication No. 2014 / 008218 International Publication No. 2021 / 202984 International Publication No. 2022 / 097117 International Publication No. 2020 / 050406 International Publication No. 2021 / 177438 International Publication No. 2023 / 172906

[0007] Genes & Diseases 2023, 10, 1367-1401. Cancers 2016, 8, 106. Nat. Rev. Cancer 2012, 12, 252-264. Cell 2015, 162, 937. Nature 2008, 455, 674-678. Mol. Cell 2013, 51, 226-235. Science 2015, 347, aaa2630. J. Virol. 2014, 88, 5328-5341. Immunity 2014, 41, 830-842.

[0008] An objective of the present invention is to provide a novel drug combination therapy for diseases, particularly cancer.

[0009] The present inventors have conducted extensive research to solve the above problems and have found that the combined administration of an anti-HER2 antibody-drug conjugate of the following formula (I) with another drug such as an immune checkpoint inhibitor safely exhibits excellent combined effects (particularly, significant antitumor effects), thereby completing the present invention. Specifically, the present invention provides the following [A1] to [D28].

[0010] [A1] a) A pharmaceutical composition comprising an anti-HER2 antibody-drug conjugate, wherein a) the anti-HER2 antibody-drug conjugate and b) one or more selected from immune checkpoint inhibitors, chemotherapeutic agents, molecular targeted drugs, anti-HER2 antibodies, and anti-HER2 antibody-containing compounds (excluding the anti-HER2 antibody-drug conjugate described in a) and anti-HER2 antibody-deruxtecan) are used in combination, and the anti-HER2 antibody-drug conjugate is represented by the following formula (I): (In the formula, m ２ represents an integer of 1 or 2, L represents a linker connecting the N297 sugar chain and D, -Lb-La-Lp-Lc-* (where the asterisk indicates binding to drug D, and Lb is: (In the structural formula of Lb shown above, the asterisk indicates bonding to La, and the wavy line indicates bonding to the N297 sugar chain), where La is -C(=O)-CH ２ CH ２Lp represents -GGFG- or -GGPI-, Lc represents -NH-CH ２ Ab is an anti-HER2 antibody or an antigen-binding fragment thereof, comprising a heavy chain consisting of an amino acid sequence including CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 4, and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 5, and a light chain consisting of an amino acid sequence including CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of the amino acid sequence represented by SAS, and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 7, wherein the N297 sugar chain is N297-(Fuc)MSG1 having the structure represented by the following formula: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of the 1-3 chain side of the branched chain of β-Man in the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1- or 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５ represents an integer of 2 to 5), or N297-(Fuc)SG: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５ represents an integer of 2 to 5), and D represents (wherein the asterisk indicates binding to L, and W represents -NH-). [A1'] The pharmaceutical composition according to [A1], wherein Ab is an anti-HER2 antibody comprising an Fc region (wild-type or mutant-type) of the antibody, or an antigen-binding fragment of the antibody. [A2] The pharmaceutical composition according to [A1], wherein D is (wherein the asterisk indicates binding to L). [A3] The pharmaceutical composition according to [A1], wherein the anti-HER2 antibody-drug conjugate is represented by the following formula: (Wherein Ab, N297 sugar chain and m ２ is as defined above). [A4] The pharmaceutical composition according to [A1], wherein the anti-HER2 antibody-drug conjugate is represented by the following formula: In the formula, m ２ is 2, the Ab comprises a heavy chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence represented by the 1st to 119th amino acid residues of SEQ ID NO: 1, and a light chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence represented by the 1st to 108th amino acid residues of SEQ ID NO: 2, and the N297 sugar chain is N297-(Fuc)SG having a structure represented by the following formula: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, the asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring, and n ５[A5] The pharmaceutical composition according to any one of [A1] to [A4], wherein Ab comprises a heavy chain variable region consisting of the amino acid sequence represented by amino acid residues 1 to 119 of SEQ ID NO: 1, and a light chain variable region consisting of the amino acid sequence represented by amino acid residues 1 to 108 of SEQ ID NO: 2. [A6] The pharmaceutical composition according to any one of [A1] to [A5], wherein Ab comprises a heavy chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence represented by SEQ ID NO: 1, and a light chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence represented by SEQ ID NO: 2. [A7] The pharmaceutical composition according to any one of [A1] to [A6], wherein Ab comprises a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 1, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 2. [A8] The pharmaceutical composition according to any one of [A1] to [A5], wherein the Ab comprises an antibody or an antigen-binding fragment of the antibody contained in the pharmaceutical composition according to any one of [A1] to [A7], comprising: (i) a heavy chain consisting of an amino acid sequence in which one or two amino acids are deleted from the carboxyl terminus of the amino acid sequence of the heavy chain; and (ii) a light chain. [A9] The pharmaceutical composition according to any one of [A1] to [A8], wherein a) an anti-HER2 antibody-drug conjugate and b) an immune checkpoint inhibitor are used in combination, and the immune checkpoint inhibitor is an antibody selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-TIGIT antibody, and an anti-LAG-3 antibody, an antigen-binding fragment thereof, or a compound comprising any of them. [A10] The pharmaceutical composition according to [A9], wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, spartalizumab, cemiplimab, or dostarlimab. [A11] The pharmaceutical composition according to [A9], wherein the anti-PD-L1 antibody is atezolizumab, duvalumab, or avelumab. [A12] The pharmaceutical composition according to [A9], wherein the anti-CTLA-4 antibody is ipilimumab or tremelimumab. [A13] The pharmaceutical composition according to [A9], wherein the anti-TIGIT antibody is tiragolumab or vibostolimab.[A14] The pharmaceutical composition according to [A9], wherein the anti-LAG-3 antibody is leratolimab. [A15] The pharmaceutical composition according to any one of [A1] to [A8], wherein a) an anti-HER2 antibody-drug conjugate and b) a chemotherapeutic agent are used in combination, and the chemotherapeutic agent is an antimetabolite, a tubulin inhibitor, an alkylating agent, a platinum compound, or a topoisomerase inhibitor. [A16] The pharmaceutical composition according to [A15], wherein the antimetabolite is capecitabine or a pharmaceutically acceptable salt thereof. [A17] The pharmaceutical composition according to [A15], wherein the tubulin inhibitor is paclitaxel or a pharmaceutically acceptable salt thereof. [A18] The pharmaceutical composition according to [A15], wherein the topoisomerase inhibitor is irinotecan or a pharmaceutically acceptable salt thereof. [A19] The pharmaceutical composition according to any one of [A1] to [A8], wherein a) an anti-HER2 antibody-drug conjugate and b) an anti-HER2 antibody are used in combination, and the anti-HER2 antibody described in b) is trastuzumab, pertuzumab, or margetuximab. [A20] The pharmaceutical composition according to any one of [A1] to [A8], wherein a) an anti-HER2 antibody-drug conjugate and b) an anti-HER2 antibody-containing compound are used in combination, and the anti-HER2 antibody-containing compound is ado-trastuzumab emtansine (T-DM1), disitamab vedotin, or vic-trastuzumab duocarmazine. [A21] The pharmaceutical composition according to any one of [A1] to [A20], wherein a) an anti-HER2 antibody-drug conjugate; and b) an immune checkpoint inhibitor, a chemotherapeutic agent, a molecularly targeted drug, an anti-HER2 antibody, or an anti-HER2 antibody-containing compound are contained as active ingredients in separate formulations, and are administered simultaneously or sequentially or separately. [A22] The pharmaceutical composition according to any one of [A1] to [A21], for the treatment of cancer.[A23] The pharmaceutical composition according to [A22], wherein the cancer is at least one selected from the group consisting of lung cancer, colon cancer, prostate cancer, pancreatic cancer, ovarian cancer, breast cancer, bladder cancer, gastric cancer, esophageal cancer, uterine cancer, cervical cancer, head and neck cancer, bile duct cancer, myeloma, and sarcoma. [A24] The pharmaceutical composition according to [A23], wherein the cancer is lung cancer. [A25] The pharmaceutical composition according to [A23], wherein the cancer is colon cancer. [A26] The pharmaceutical composition according to [A23], wherein the cancer is breast cancer. [A27] The pharmaceutical composition according to [A23], wherein the cancer is gastric cancer. [A28] The pharmaceutical composition according to [A23], wherein the cancer is bladder cancer. [B1] An anti-HER2 antibody-drug conjugate for use in combination with one or more selected from immune checkpoint inhibitors, chemotherapeutic agents, molecular targeted drugs, anti-HER2 antibodies, and anti-HER2 antibody-containing compounds (excluding anti-HER2 antibody-drug conjugates represented by formula (I) below and anti-HER2 antibody-deruxtecan) for the treatment of cancer, wherein the anti-HER2 antibody-drug conjugate is represented by the following formula (I): (In the formula, m ２ represents an integer of 1 or 2, L represents a linker connecting the N297 sugar chain and D, -Lb-La-Lp-Lc-* (wherein the asterisk indicates binding to drug D, and Lb is: (In the structural formula of Lb shown above, the asterisk indicates bonding to La, and the wavy line indicates bonding to the N297 sugar chain), where La is -C(=O)-CH ２ CH ２ Lp represents -GGFG- or -GGPI-, Lc represents -NH-CH ２Ab is an anti-HER2 antibody or an antigen-binding fragment thereof, comprising a heavy chain consisting of an amino acid sequence including CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 4, and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 5, and a light chain consisting of an amino acid sequence including CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of the amino acid sequence represented by SAS, and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 7, wherein the N297 sugar chain is N297-(Fuc)MSG1 having the structure represented by the following formula: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of the 1-3 chain side of the branched chain of β-Man in the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1- or 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５ represents an integer of 2 to 5), or N297-(Fuc)SG: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５ represents an integer of 2 to 5), and D represents (wherein the asterisk indicates binding to L, and W represents -NH-). [B1'] The anti-HER2 antibody-drug conjugate according to [B1], wherein Ab is an anti-HER2 antibody comprising an Fc region (wild-type or mutant-type) of the antibody, or an antigen-binding fragment of the antibody. [B2] D is (wherein the asterisk indicates binding to L). [B3] The anti-HER2 antibody-drug conjugate according to [B1], wherein the anti-HER2 antibody-drug conjugate is represented by the following formula: (Wherein Ab, N297 sugar chain and m ２ [B4] The anti-HER2 antibody-drug conjugate according to [B1], wherein the anti-HER2 antibody-drug conjugate is represented by the following formula: In the formula, m ２ is 2, the Ab comprises a heavy chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence represented by the 1st to 119th amino acid residues of SEQ ID NO: 1, and a light chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence represented by the 1st to 108th amino acid residues of SEQ ID NO: 2, and the N297 sugar chain is N297-(Fuc)SG having a structure represented by the following formula: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, the asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring, and n ５represents an integer of 3). [B5] The anti-HER2 antibody-drug conjugate according to any one of [B1] to [B4], wherein the Ab comprises a heavy chain variable region consisting of the amino acid sequence represented by amino acid residues 1 to 119 of SEQ ID NO: 1, and a light chain variable region consisting of the amino acid sequence represented by amino acid residues 1 to 108 of SEQ ID NO: 2. [B6] The anti-HER2 antibody-drug conjugate according to any one of [B1] to [B5], wherein the Ab comprises a heavy chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence represented by SEQ ID NO: 1, and a light chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence represented by SEQ ID NO: 2. [B7] The anti-HER2 antibody-drug conjugate according to any one of [B1] to [B6], wherein the Ab comprises a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1, and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2. [B8] The anti-HER2 antibody-drug conjugate according to any one of [B1] to [B5], wherein the Ab comprises the antibody or antigen-binding fragment of said antibody contained in the anti-HER2 antibody-drug conjugate according to any one of [B1] to [B7]: (i) a heavy chain consisting of an amino acid sequence in which one or two amino acids are deleted from the carboxyl terminus of the amino acid sequence of the heavy chain; and (ii) a light chain. [B9] An anti-HER2 antibody-drug conjugate for use in combination with an immune checkpoint inhibitor for the treatment of cancer, the anti-HER2 antibody-drug conjugate according to any one of [B1] to [B8], wherein the immune checkpoint inhibitor is an antibody selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-TIGIT antibody, and an anti-LAG-3 antibody, an antigen-binding fragment thereof, or a compound comprising any of them. [B10] The anti-HER2 antibody-drug conjugate according to [B9], wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, spartalizumab, cemiplimab, or dostarlimab.[B11] The anti-HER2 antibody-drug conjugate according to [B9], wherein the anti-PD-L1 antibody is atezolizumab, duvalumab, or avelumab. [B12] The anti-HER2 antibody-drug conjugate according to [B9], wherein the anti-CTLA-4 antibody is ipilimumab or tremelimumab. [B13] The anti-HER2 antibody-drug conjugate according to [B9], wherein the anti-TIGIT antibody is tiragolumab or vibostolimab. [B14] The anti-HER2 antibody-drug conjugate according to [B9], wherein the anti-LAG-3 antibody is leratolimab. [B15] An anti-HER2 antibody-drug conjugate according to any one of [B1] to [B8], for use in combination with a chemotherapeutic agent for the treatment of cancer, wherein the chemotherapeutic agent is an antimetabolite, a tubulin inhibitor, an alkylating agent, a platinum compound, or a topoisomerase inhibitor. [B16] The anti-HER2 antibody-drug conjugate according to [B15], wherein the antimetabolite is capecitabine or a pharmaceutically acceptable salt thereof. [B17] The anti-HER2 antibody-drug conjugate according to [B15], wherein the tubulin inhibitor is paclitaxel or a pharmaceutically acceptable salt thereof. [B18] The anti-HER2 antibody-drug conjugate according to [B15], wherein the topoisomerase inhibitor is irinotecan or a pharmaceutically acceptable salt thereof. [B19] An anti-HER2 antibody-drug conjugate according to any one of [B1] to [B8] for use in combination with an anti-HER2 antibody for the treatment of cancer, wherein the anti-HER2 antibody used in combination with the anti-HER2 antibody-drug conjugate is trastuzumab, pertuzumab, or margetuximab. [B20] An anti-HER2 antibody-drug conjugate according to any one of [B1] to [B8] for use in combination with an anti-HER2 antibody-containing compound for the treatment of cancer, wherein the anti-HER2 antibody-containing compound is ado-trastuzumab emtansine (T-DM1), disitamab vedotin, or vic-trastuzumab duocarmazine.[B21] The anti-HER2 antibody-drug conjugate according to any one of [B1] to [B20], wherein the anti-HER2 antibody-drug conjugate; and the immune checkpoint inhibitor, chemotherapeutic agent, molecularly targeted drug, anti-HER2 antibody, or anti-HER2 antibody-containing compound are contained as active ingredients in different formulations and administered simultaneously or sequentially or separately. [B22] The anti-HER2 antibody-drug conjugate according to any one of [B1] to [B21], wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, prostate cancer, pancreatic cancer, ovarian cancer, breast cancer, bladder cancer, gastric cancer, esophageal cancer, uterine cancer, cervical cancer, head and neck cancer, bile duct cancer, myeloma, and sarcoma. [B23] The anti-HER2 antibody-drug conjugate according to [B22], wherein the cancer is lung cancer. [B24] The anti-HER2 antibody-drug conjugate according to [B22], wherein the cancer is colorectal cancer. [B25] The anti-HER2 antibody-drug conjugate according to [B22], wherein the cancer is breast cancer. [B26] The anti-HER2 antibody-drug conjugate according to [B22], wherein the cancer is gastric cancer. [B27] The anti-HER2 antibody-drug conjugate according to [B22], wherein the cancer is bladder cancer. [C1] Use of an anti-HER2 antibody-drug conjugate in combination with one or more selected from immune checkpoint inhibitors, chemotherapeutic agents, molecular targeted drugs, anti-HER2 antibodies, and anti-HER2 antibody-containing compounds (excluding anti-HER2 antibody-drug conjugates represented by formula (I) below and anti-HER2 antibody-deruxtecan) in the manufacture of a medicament for treating cancer, wherein the anti-HER2 antibody-drug conjugate is represented by the following formula (I): (In the formula, m ２ represents an integer of 1 or 2, L represents a linker connecting the N297 sugar chain and D, -Lb-La-Lp-Lc-* (wherein the asterisk indicates binding to drug D, and Lb is: (In the structural formula of Lb shown above, the asterisk indicates bonding to La, and the wavy line indicates bonding to the N297 sugar chain), where La is -C(=O)-CH２ CH ２ Lp represents -GGFG- or -GGPI-, Lc represents -NH-CH ２ Ab is an anti-HER2 antibody or an antigen-binding fragment thereof, comprising a heavy chain consisting of an amino acid sequence including CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 4, and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 5, and a light chain consisting of an amino acid sequence including CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of the amino acid sequence represented by SAS, and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 7, wherein the N297 sugar chain is N297-(Fuc)MSG1 having the structure represented by the following formula: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of the 1-3 chain side of the branched chain of β-Man in the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1- or 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５ represents an integer of 2 to 5), or N297-(Fuc)SG: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５represents an integer of 2 to 5), and D represents (wherein the asterisk indicates binding to L, and W represents -NH-). [C1'] The use according to [C1], wherein Ab is an anti-HER2 antibody comprising an Fc region (wild-type or mutant-type) of the antibody, or an antigen-binding fragment of the antibody. [C2] The use according to [C1], wherein D is (wherein the asterisk indicates binding to L). [C3] The use according to [C1], wherein the anti-HER2 antibody-drug conjugate is represented by the following formula: (Wherein Ab, N297 sugar chain and m ２ [C4] The use according to [C1], wherein the anti-HER2 antibody-drug conjugate is represented by the following formula: In the formula, m ２ is 2, the Ab comprises a heavy chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence represented by the 1st to 119th amino acid residues of SEQ ID NO: 1, and a light chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence represented by the 1st to 108th amino acid residues of SEQ ID NO: 2, and the N297 sugar chain is N297-(Fuc)SG having a structure represented by the following formula: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, the asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring, and n ５The use according to any one of [C1] to [C3], wherein the Ab comprises a heavy chain variable region consisting of the amino acid sequence shown by amino acid residues 1 to 119 of SEQ ID NO: 1, and a light chain variable region consisting of the amino acid sequence shown by amino acid residues 1 to 108 of SEQ ID NO: 2. [C6] The use according to any one of [C1] to [C5], wherein the Ab comprises a heavy chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown by SEQ ID NO: 1, and a light chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown by SEQ ID NO: 2. [C7] The use according to any one of [C1] to [C6], wherein the Ab comprises a heavy chain consisting of the amino acid sequence shown by SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown by SEQ ID NO: 2. [C8] The use according to any one of [C1] to [C5], wherein the Ab is comprised in the antibody or antigen-binding fragment of the antibody contained in the anti-HER2 antibody-drug conjugate according to any one of [C1] to [C7], and comprises: (i) a heavy chain consisting of an amino acid sequence in which one or two amino acids are deleted from the carboxyl terminus of the amino acid sequence of the heavy chain; and (ii) a light chain. [C9] The use according to any one of [C1] to [C8], wherein the use is an anti-HER2 antibody-drug conjugate in combination with an immune checkpoint inhibitor in the manufacture of a medicament for treating cancer, wherein the immune checkpoint inhibitor is an antibody selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-TIGIT antibody, and an anti-LAG-3 antibody, an antigen-binding fragment thereof, or a compound comprising any of them. [C10] The use according to [C9], wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, spartalizumab, cemiplimab, or dostarlimab. [C11] The use according to [C9], wherein the anti-PD-L1 antibody is atezolizumab, duvalumab, or avelumab. [C12] The use according to [C9], wherein the anti-CTLA-4 antibody is ipilimumab or tremelimumab. [C13] The use according to [C9], wherein the anti-TIGIT antibody is tiragolumab or vibostolimab.[C14] The use according to [C9], wherein the anti-LAG-3 antibody is leratolimab. [C15] The use according to any one of [C1] to [C8], wherein the anti-HER2 antibody-drug conjugate is used in combination with a chemotherapeutic agent in the manufacture of a medicament for the treatment of cancer, wherein the chemotherapeutic agent is an antimetabolite, a tubulin inhibitor, an alkylating agent, a platinum compound, or a topoisomerase inhibitor. [C16] The use according to [C15], wherein the antimetabolite is capecitabine or a pharmaceutically acceptable salt thereof. [C17] The use according to [C15], wherein the tubulin inhibitor is paclitaxel or a pharmaceutically acceptable salt thereof. [C18] The use according to [C15], wherein the topoisomerase inhibitor is irinotecan or a pharmaceutically acceptable salt thereof. [C19] The use according to any one of [C1] to [C8], wherein the anti-HER2 antibody used in combination with the anti-HER2 antibody-drug conjugate is trastuzumab, pertuzumab, or margetuximab, in the manufacture of a medicament for treating cancer. [C20] The use according to any one of [C1] to [C8], wherein the anti-HER2 antibody-drug conjugate is combined with an anti-HER2 antibody-containing compound in the manufacture of a medicament for treating cancer, wherein the anti-HER2 antibody-containing compound is ado-trastuzumab emtansine (T-DM1), disitamab vedotin, or vic-trastuzumab duocarmazine. [C21] The use according to any one of [C1] to [C20], wherein the anti-HER2 antibody-drug conjugate; and the immune checkpoint inhibitor, chemotherapeutic agent, molecular targeted drug, anti-HER2 antibody, or anti-HER2 antibody-containing compound are contained as active ingredients in separate formulations, and are administered simultaneously or sequentially or separately.[C22] The use according to any one of [C1] to [C21], wherein the cancer is selected from the group consisting of lung cancer, colon cancer, prostate cancer, pancreatic cancer, ovarian cancer, breast cancer, bladder cancer, gastric cancer, esophageal cancer, uterine cancer, cervical cancer, head and neck cancer, bile duct cancer, myeloma, and sarcoma. [C23] The use according to [C22], wherein the cancer is lung cancer. [C24] The use according to [C22], wherein the cancer is colon cancer. [C25] The use according to [C22], wherein the cancer is breast cancer. [C26] The use according to [C22], wherein the cancer is gastric cancer. [C27] The use according to [C22], wherein the cancer is bladder cancer. [D1] A method for treating a disease, comprising administering in combination to a subject in need of disease treatment one or more selected from a) an anti-HER2 antibody-drug conjugate; and b) an immune checkpoint inhibitor, a chemotherapeutic agent, a molecular targeted drug, an anti-HER2 antibody, and an anti-HER2 antibody-containing compound (excluding the anti-HER2 antibody-drug conjugate and anti-HER2 antibody-deruxtecan described in a), wherein the anti-HER2 antibody-drug conjugate is represented by the following formula (I): (In the formula, m ２ represents an integer of 1 or 2, L represents a linker connecting the N297 sugar chain and D, -Lb-La-Lp-Lc-* (wherein the asterisk indicates binding to drug D, and Lb is: (In the structural formula of Lb shown above, the asterisk indicates bonding to La, and the wavy line indicates bonding to the N297 sugar chain), where La is -C(=O)-CH ２ CH ２ Lp represents -GGFG- or -GGPI; Lc represents -NH-CH ２Ab is an anti-HER2 antibody or an antigen-binding fragment thereof, comprising a heavy chain consisting of an amino acid sequence including CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 4, and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 5, and a light chain consisting of an amino acid sequence including CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of the amino acid sequence represented by SAS, and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 7, wherein the N297 sugar chain is N297-(Fuc)MSG1 having the structure represented by the following formula: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of the 1-3 chain side of the branched chain of β-Man in the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1- or 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５ represents an integer of 2 to 5), or N297-(Fuc)SG: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５ represents an integer of 2 to 5), and D represents (wherein the asterisk indicates binding to L, and W represents -NH-). [D1'] The method according to [D1], wherein Ab is an anti-HER2 antibody comprising an Fc region (wild-type or mutant-type) of the antibody, or an antigen-binding fragment of the antibody. [D2] The method according to [D1], wherein D is (wherein the asterisk indicates binding to L). [D3] The method according to [D1], wherein the anti-HER2 antibody-drug conjugate is represented by the following formula: (Wherein Ab, N297 sugar chain and m ２ [D4] The method according to [D1], wherein the anti-HER2 antibody-drug conjugate is represented by the following formula: In the formula, m ２ is 2, the Ab comprises a heavy chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence represented by the 1st to 119th amino acid residues of SEQ ID NO: 1, and a light chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence represented by the 1st to 108th amino acid residues of SEQ ID NO: 2, and the N297 sugar chain is N297-(Fuc)SG having a structure represented by the following formula: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, the asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring, and n ５[D5] The method of any one of [D1] to [D4], wherein the Ab comprises a heavy chain variable region consisting of the amino acid sequence shown by amino acid residues 1 to 119 of SEQ ID NO: 1, and a light chain variable region consisting of the amino acid sequence shown by amino acid residues 1 to 108 of SEQ ID NO: 2. [D6] The method of any one of [D1] to [D5], wherein the Ab comprises a heavy chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown by SEQ ID NO: 1, and a light chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown by SEQ ID NO: 2. [D7] The method of any one of [D1] to [D6], wherein the Ab comprises a heavy chain consisting of the amino acid sequence shown by SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown by SEQ ID NO: 2. [D8] The method of any one of [D1] to [D5], wherein the Ab is comprised in the antibody or antigen-binding fragment of the antibody contained in the anti-HER2 antibody-drug conjugate of any one of [D1] to [D7], and comprises: (i) a heavy chain consisting of an amino acid sequence in which one or two amino acids are deleted from the carboxyl terminus of the amino acid sequence of the heavy chain; and (ii) a light chain. [D9] The method of any one of [D1] to [D8], wherein the method comprises administering in combination to a subject in need of disease treatment a) an anti-HER2 antibody-drug conjugate; and b) an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is an antibody selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-TIGIT antibody, and an anti-LAG-3 antibody, an antigen-binding fragment thereof, or a compound comprising any of them. [D10] The method according to [D9], wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, spartalizumab, cemiplimab, or dostarlimab. [D11] The method according to [D9], wherein the anti-PD-L1 antibody is atezolizumab, duvalumab, or avelumab. [D12] The method according to [D9], wherein the anti-CTLA-4 antibody is ipilimumab or tremelimumab.[D13] The method of [D9], wherein the anti-TIGIT antibody is tiragolumab or vibostolimab. [D14] The method of [D9], wherein the anti-LAG-3 antibody is leratolimab. [D15] The method of any one of [D1] to [D8], wherein the method comprises administering in combination to a subject in need of disease treatment a) an anti-HER2 antibody-drug conjugate; and b) a chemotherapeutic agent, wherein the chemotherapeutic agent is an antimetabolite, a tubulin inhibitor, an alkylating agent, a platinum compound, or a topoisomerase inhibitor. [D16] The method of [D15], wherein the antimetabolite is capecitabine or a pharmaceutically acceptable salt thereof. [D17] The method of [D15], wherein the tubulin inhibitor is paclitaxel or a pharmaceutically acceptable salt thereof. [D18] The method of [D15], wherein the topoisomerase inhibitor is irinotecan or a pharmaceutically acceptable salt thereof. [D19] The method according to any one of [D1] to [D8], comprising administering in combination to a subject in need of disease treatment a) an anti-HER2 antibody-drug conjugate; and b) an anti-HER2 antibody, wherein the anti-HER2 antibody described in b) is trastuzumab, pertuzumab, or marjetuximab. [D20] The method according to any one of [D1] to [D8], comprising administering in combination to a subject in need of disease treatment a) an anti-HER2 antibody-drug conjugate; and b) an anti-HER2 antibody-containing compound, wherein the anti-HER2 antibody-containing compound is ado-trastuzumab emtansine (T-DM1), disitamab vedotin, or vic-trastuzumab duocarmazine. [D21] The method according to any one of [D1] to [D20], wherein the anti-HER2 antibody-drug conjugate; and the immune checkpoint inhibitor, chemotherapeutic agent, molecular targeted drug, anti-HER2 antibody, or anti-HER2 antibody-containing compound are contained as active ingredients in separate formulations, and are administered simultaneously or sequentially or separately.[D22] The method according to any one of [D1] to [D21], wherein the disease is cancer. [D23] The method according to [D22], wherein the cancer is selected from the group consisting of lung cancer, colon cancer, prostate cancer, pancreatic cancer, ovarian cancer, breast cancer, bladder cancer, gastric cancer, esophageal cancer, uterine cancer, cervical cancer, head and neck cancer, bile duct cancer, myeloma, and sarcoma. [D24] The method according to [D22], wherein the cancer is lung cancer. [D25] The method according to [D22], wherein the cancer is colon cancer. [D26] The method according to [D22], wherein the cancer is breast cancer. [D27] The method according to [D22], wherein the cancer is gastric cancer. [D28] The method according to [D22], wherein the cancer is bladder cancer.

[0011] The present invention provides a novel, safe drug combination therapy that exhibits significant antitumor effects in the treatment of diseases, particularly cancer.

[0012]

[0033] Figure 1 shows the amino acid sequence of the heavy chain of anti-HER2 antibody 1 (SEQ ID NO: 1). Figure 2 shows the amino acid sequence of the light chain of anti-HER2 antibody 1 (SEQ ID NO: 2). Figure 3 shows the amino acid sequence of CDRH1 (SEQ ID NO: 3), CDRH2 (SEQ ID NO: 4), CDRH3 (SEQ ID NO: 5), CDRL1 (SEQ ID NO: 6), CDRL2, and CDRL3 (SEQ ID NO: 7) of anti-HER2 antibody 1. Figure 4 shows the amino acid sequence of the heavy chain of anti-HER2 antibody 2 (SEQ ID NO: 8). Figure 5 shows the amino acid sequence of the light chain of anti-HER2 antibody 2 (SEQ ID NO: 9). Figure 6 shows the amino acid sequence of CDRH1 (SEQ ID NO: 10), CDRH2 (SEQ ID NO: 11), CDRH3 (SEQ ID NO: 12), CDRL1 (SEQ ID NO: 13), CDRL2, and CDRL3 (SEQ ID NO: 14) of anti-HER2 antibody 2.

[0033] Figure 1 shows the amino acid sequence (SEQ ID NO: 15) of the heavy chain of anti-HER2 antibody 3. Figure 1 shows the amino acid sequence (SEQ ID NO: 16) of the light chain of anti-HER2 antibody 3. Figure 1 shows the amino acid sequence of CDRH1 (SEQ ID NO: 17), CDRH2 (SEQ ID NO: 18), CDRH3 (SEQ ID NO: 19), CDRL1 (SEQ ID NO: 20), CDRL2, and CDRL3 (SEQ ID NO: 21) of anti-HER2 antibody 3.

[0034] Figure 1 shows the antitumor effect of intravenous administration of HER2-ADC(1) and trastuzumab in mice subcutaneously implanted with CT26.WT-HER2 cells, a mouse colon cancer cell line CT26.WT introduced with the human HER2 gene. In the figure, the black circle line indicates the vehicle group, the black square line indicates the HER2-ADC(1) administration group, the black triangle line indicates the trastuzumab administration group, and the black inverted triangle line indicates the HER2-ADC(1) and trastuzumab co-administration group. The vertical axis indicates tumor volume (mm ３ The horizontal axis represents the number of days after tumor implantation. This figure shows the antitumor combined effect of intravenous administration of HER2-ADC(1) and trastuzumab in mice subcutaneously implanted with the human breast cancer cell line JIMT-1. In the figure, the black circle line represents the vehicle group, the black square line represents the HER2-ADC(1) administration group, the black triangle line represents the trastuzumab administration group, and the black inverted triangle line represents the HER2-ADC(1) and trastuzumab combination administration group. The vertical axis represents tumor volume (mm ３The horizontal axis represents the number of days after tumor implantation. This figure shows the antitumor combined effect of intravenous administration of HER2-ADC(1) and trastuzumab in mice subcutaneously implanted with the human gastric cancer cell line NCI-N87. In the figure, the black circle line represents the vehicle group, the black square line represents the HER2-ADC(1) administration group, the black triangle line represents the trastuzumab administration group, and the black inverted triangle line represents the HER2-ADC(1) and trastuzumab combination administration group. The vertical axis represents tumor volume (mm ３ The horizontal axis represents the number of days after tumor implantation. Figure 1 shows the antitumor effect of intravenous administration of HER2-ADC(3) and T-DM1 in mice subcutaneously implanted with the human breast cancer cell line KPL-4. In the figure, the black circle line represents the vehicle group, the black square line represents the HER2-ADC(3)-administered group, the black triangle line represents the T-DM1-administered group, and the black inverted triangle line represents the HER2-ADC(3) and T-DM1 combined administration group. The vertical axis represents tumor volume (mm ３ The horizontal axis represents the number of days after tumor implantation. Figure 1 shows the antitumor effect of intravenous administration of HER2-ADC(1) and T-DM1 in mice subcutaneously implanted with the human gastric cancer cell line NCI-N87. In the figure, the black circle line represents the vehicle group, the black square line represents the HER2-ADC(1)-administered group, the black triangle line represents the T-DM1-administered group, and the black inverted triangle line represents the HER2-ADC(1) and T-DM1 combined administration group. The vertical axis represents tumor volume (mm ３ ), and the horizontal axis indicates the number of days after tumor implantation. This figure shows the antitumor combined effect of intravenous administration of HER2-ADC (1) and an anti-PD-1 surrogate antibody in mice subcutaneously implanted with LL / 2-HER2 cells, which were mouse lung cancer cell line LL / 2 introduced with the human HER2 gene. In the figure, the black circle line indicates the vehicle group, the black square line indicates the HER2-ADC (1) administration group, the black triangle line indicates the anti-PD-1 surrogate antibody administration group, and the black inverted triangle line indicates the group administered with a combination of HER2-ADC (1) and an anti-PD-1 surrogate antibody. The vertical axis indicates tumor volume (mm ３The horizontal axis indicates the number of days after tumor implantation. Figure 1 shows the antitumor combination effect of intravenous administration of HER2-ADC(1) and an anti-PD-1 surrogate antibody in mice subcutaneously implanted with CT26.WT-chimeraHER2 cells, a mouse colon cancer cell line created by introducing a human-mouse chimeric HER2 gene in which the epitope site of the anti-HER2 antibody was replaced with a human type. In the figure, the black circle line indicates the vehicle group, the black square line indicates the HER2-ADC(1) administration group, the black triangle line indicates the anti-PD-1 surrogate antibody administration group, and the black inverted triangle line indicates the group administered with a combination of HER2-ADC(1) and an anti-PD-1 surrogate antibody. The vertical axis indicates tumor volume (mm ３ The horizontal axis represents the number of days after tumor implantation. This figure shows the antitumor combination effect of intravenous administration of HER2-ADC(1) and an anti-PD-L1 surrogate antibody in mice subcutaneously implanted with CT26.WT-HER2 cells, a mouse colon cancer cell line CT26.WT introduced with the human HER2 gene. In the figure, the black circle line represents the vehicle group, the black square line represents the HER2-ADC(1) administration group, the black triangle line represents the anti-PD-L1 surrogate antibody administration group, and the black inverted triangle line represents the HER2-ADC(1) and anti-PD-L1 surrogate antibody combination administration group. The vertical axis represents tumor volume (mm ３ The horizontal axis represents the number of days after tumor implantation. Figure 1 shows the survival benefit of intravenous administration of HER2-ADC(1) and an anti-CTLA-4 surrogate antibody in mice subcutaneously implanted with CT26.WT-chimeraHER2 cells, a mouse colon cancer cell line created by introducing a human-mouse chimeric HER2 gene in which the epitope site of the anti-HER2 antibody had been replaced with a human form. In the figure, the black circle line represents the vehicle group, the black square line represents the HER2-ADC(1)-administered group, the black triangle line represents the anti-CTLA-4 surrogate antibody-administered group, and the black inverted triangle line represents the group administered with a combination of HER2-ADC(1) and an anti-CTLA-4 surrogate antibody. The vertical axis represents survival rate (%), and the horizontal axis represents the number of days after tumor implantation. This figure shows the antitumor effect of intravenously administered HER2-ADC(2) and paclitaxel in mice subcutaneously implanted with the human breast cancer cell line KPL-4. In the figure, the black circle line represents the vehicle group, the black square line represents the HER2-ADC(2) administration group, the black triangle line represents the paclitaxel administration group, and the black inverted triangle line represents the HER2-ADC(2) and paclitaxel combination administration group. The vertical axis represents tumor volume (mm ３The horizontal axis represents the number of days after tumor implantation. This figure shows the antitumor combined effect of intravenous administration of HER2-ADC(2) and oral administration of capecitabine in mice subcutaneously implanted with the human breast cancer cell line KPL-4. In the figure, the black circle line represents the vehicle group, the black square line represents the HER2-ADC(2) administration group, the black triangle line represents the capecitabine administration group, and the black inverted triangle line represents the HER2-ADC(2) and capecitabine combined administration group. The vertical axis represents tumor volume (mm ３ The horizontal axis represents the number of days after tumor implantation. This figure shows the combined antitumor effect of intravenous administration of HER2-ADC(1) and oral administration of capecitabine in mice subcutaneously implanted with the human gastric cancer cell line NCI-N87. In the figure, the black circle line represents the vehicle group, the black square line represents the HER2-ADC(1) administration group, the black triangle line represents the capecitabine administration group, and the black inverted triangle line represents the HER2-ADC(1) and capecitabine combination administration group. The vertical axis represents tumor volume (mm ３ The horizontal axis represents the number of days after tumor implantation. Figure 1 shows the antitumor effect of intravenous administration of HER2-ADC(1) and paclitaxel in mice subcutaneously implanted with the human gastric cancer cell line NCI-N87. In the figure, the black circle line represents the vehicle group, the black square line represents the HER2-ADC(1) administration group, the black triangle line represents the paclitaxel administration group, and the black inverted triangle line represents the HER2-ADC(1) and paclitaxel combination administration group. The vertical axis represents tumor volume (mm ３ The horizontal axis represents the number of days after tumor implantation. This figure shows the antitumor combined effect of intravenous administration of HER2-ADC(1) and irinotecan in mice subcutaneously implanted with the human gastric cancer cell line NCI-N87. In the figure, the black circle line represents the vehicle group, the black square line represents the HER2-ADC(1) administration group, the black triangle line represents the irinotecan administration group, and the black inverted triangle line represents the HER2-ADC(1) and irinotecan combination administration group. The vertical axis represents tumor volume (mm ３ ), the horizontal axis indicates the number of days after tumor implantation.

[0013] Preferred embodiments for carrying out the present invention will be described below. Note that the embodiment described below shows one example of a typical embodiment of the present invention, and the scope of the present invention should not be construed as being narrow.

[0014] 1. Anti-HER2 antibody-drug conjugate The anti-HER2 antibody-drug conjugate used in the present invention is represented by the following formula (I): It is expressed as:

[0015] Ab represents an anti-HER2 antibody or an antigen-binding fragment of the antibody, N297 sugar chain represents an N-linked sugar chain bound to the side chain of Asn at position 297 of the IgG heavy chain contained in Ab, L represents a linker connecting the N297 sugar chain and D, D represents a drug that is a cyclic dinucleotide derivative, and m ２ represents an integer of 1 or 2.

[0016] 1-1. Anti-HER2 Antibody The anti-HER2 antibody in the antibody-drug conjugate used in the present invention may be derived from any species, but is preferably an antibody derived from human, rat, mouse, or rabbit. When the antibody is derived from a species other than human, it is preferably chimerized or humanized using well-known techniques. The anti-HER2 antibody in the antibody-drug conjugate used in the present invention may be a polyclonal or monoclonal antibody, but is preferably a monoclonal antibody.

[0017] It is known that the heavy and light chains of an antibody molecule each contain three complementarity determining regions (CDRs). CDRs, also known as hypervariable regions, are located within the variable regions of the heavy and light chains of an antibody and are particularly highly variable in their primary structure. They are separated into three regions in the primary structure of the heavy and light chain polypeptide chains. In this specification, the CDRs of an antibody are represented as CDRH1, CDRH2, and CDRH3 from the amino-terminus of the heavy chain amino acid sequence, and CDRL1, CDRL2, and CDRL3 from the amino-terminus of the light chain amino acid sequence. These regions are close to each other in the three-dimensional structure and determine the specificity for the antigen to which they bind. In the present invention, the positions and lengths of CDRs were determined according to the IMGT definition (Developmental and Comparative Immunology 27 (2003) 55-77).

[0018] It is known that there are multiple allotypes of antibody constant regions. For example, for IgG1 heavy chains, allotypes include G1m17, G1m3, G1m1, and G1m2. The antibody constant region used in the present invention is not particularly limited, but it is preferable to use G1m17 or G1m3.

[0019] In the present invention, "antigen-binding fragment of anti-HER2 antibody" means an antibody fragment having antigen-binding activity, and has a well-conserved N-linked glycan (referred to as "Asn297 glycan" or "N297 glycan" in the present specification and claims) at the 297th asparagine residue in the Fc region of the IgG heavy chain (hereinafter referred to as "Asn297 or N297"). However, the antigen-binding fragment is not limited to these molecules as long as it has antigen-binding ability. Furthermore, these antigen-binding fragments include not only those obtained by treating the full-length antibody protein molecule with an appropriate enzyme, but also proteins produced in appropriate host cells using genetically engineered antibody genes.

[0020] The "anti-HER2 antibody" in the antibody-drug conjugate used in the present invention is an antibody that specifically binds to HER2 (Human Epidermal Growth Factor Receptor Type 2; ErbB-2), and preferably has the activity of being internalized into HER2-expressing cells upon binding to HER2.

[0021] Examples of anti-HER2 antibodies include trastuzumab (US Pat. No. 5,821,337) and pertuzumab (WO 2001 / 00245), with pertuzumab being preferred.

[0022] Substitution of some amino acid residues in the constant region can adjust effector function (see WO88 / 07089, WO94 / 28027, WO94 / 29351). An example of an IgG1 mutant is the IgG1 LALA mutation (IgG1-L234A, L235A). L234A and L235A represent substitutions of leucine with alanine at positions 234 and 235, as defined by the EU index (Proceedings of the National Academy of Sciences of the United States of America, Vol. 63, No. 1 (May 15, 1969), pp. 78-85).

[0023] Examples of anti-HER2 antibodies include antibodies whose heavy chain constant region is that of human IgG1, in which the leucines at positions 234 and 235 according to the EU index are substituted with alanine, and preferred examples include antibodies 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.

[0024] Furthermore, it is known that when antibodies are produced in cultured mammalian cells, the lysine residue at the carboxyl terminus of the heavy chain is deleted (Journal of Chromatography A, 705:129-134 (1995)), and that two amino acid residues, glycine and lysine, are deleted from the carboxyl terminus of the heavy chain, and a proline residue newly positioned at the carboxyl terminus is amidated (Analytical Biochemistry, 360:75-83 (2007)). Thus, the antibodies of the present invention also include deletion antibodies in which one or two amino acids are deleted from the carboxy terminus of the heavy chain, as well as amidated versions of such deletion antibodies (for example, antibodies in which the proline residue at the carboxyl terminus of the heavy chain is amidated).

[0025] In the present invention, examples of the heavy chain and light chain contained in an anti-HER2 antibody, i.e., an antibody that binds to HER2, or an antigen-binding fragment of the antibody include the following (i) to (xvi): (i) (i-H) a heavy chain consisting of an amino acid sequence comprising CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 4, and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 5, and (i-L) a light chain consisting of an amino acid sequence comprising CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of the amino acid sequence represented by SAS, and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 7; (ii) a combination of heavy and light chains according to (i), wherein (ii-H) a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, more preferably 95% or more identical to the amino acid sequence represented by amino acid residues 1 to 119 of SEQ ID NO: 1, and (ii-L) a light chain comprising a light chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in the 1st to 108th amino acid residues of SEQ ID NO: 2; (iii) a combination of heavy chains and light chains according to (i) or (ii), (iii-H) a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence shown in the 1st to 119th amino acid residues of SEQ ID NO: 1, and (iii-L) a light chain comprising a light chain variable region consisting of the amino acid sequence shown in the 1st to 108th amino acid residues of SEQ ID NO: 2; (iv) a combination of heavy chains and light chains according to (i), (ii), or (iii), (iv-H) a heavy chain comprising an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 1, and (iv-L) a light chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 2; (v) a combination of a heavy chain and a light chain according to (i), (ii), (iii) or (iv), comprising: (v-H) a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1; and (v-L) a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2;(vi) (vi-H) a heavy chain consisting of an amino acid sequence comprising CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 10, CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 11, and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 12, and (vi-L) a light chain consisting of an amino acid sequence comprising CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 13, CDRL2 consisting of the amino acid sequence represented by SAS, and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 14; (vii) a combination of heavy and light chains according to (vi), wherein: (vii-H) a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence represented by amino acid residues 1 to 119 of SEQ ID NO: 8, and (vii-L) a light chain comprising a light chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence represented by amino acid residues 1 to 108 of SEQ ID NO: 9; (viii) A combination of heavy and light chains according to (vi) or (vii), comprising: (viii-H) a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 8, amino acid residues 1 to 119; and (viii-L) a light chain comprising a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 9, amino acid residues 1 to 108; (ix) A combination of heavy and light chains according to (vi), (vii), or (viii), comprising: (ix-H) a heavy chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 8; and (ix-L) a light chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 9; (x) A combination of heavy and light chains according to (vi), (vii), (viii), or (ix), comprising: (x-H) a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 8, and (x-L) a light chain consisting of the amino acid sequence shown in SEQ ID NO: 9;(xi) (xi-H) a heavy chain consisting of an amino acid sequence comprising CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 17, CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 18, and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 19, and (xi-L) a light chain consisting of an amino acid sequence comprising CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 20, CDRL2 consisting of the amino acid sequence represented by SAS, and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 21; (xii) a combination of heavy and light chains according to (xi), (xii-H) a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence represented by amino acid residues 1 to 120 of SEQ ID NO: 15, and (xii-L) a light chain comprising a light chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence represented by amino acid residues 1 to 108 of SEQ ID NO: 16; (xiii) A combination of heavy and light chains according to (xi) or (xii), comprising: (xiii-H) a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 15, amino acid residues 1 to 120; and (xiii-L) a light chain comprising a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 16, amino acid residues 1 to 108; (xiv) A combination of heavy and light chains according to (xi), (xii), or (xiii), comprising: (xiv-H) a heavy chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 15; and (xiv-L) a light chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 16; (xv) A combination of a heavy chain and a light chain according to (xi), (xii), (xiii) or (xiv), wherein (xv-H) a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 15, and (xv-L) a light chain consisting of the amino acid sequence shown in SEQ ID NO: 16;(xvi) (xvi-a) A heavy chain consisting of an amino acid sequence in which 1 or 2 amino acids are deleted from the carboxyl terminus of the amino acid sequence of the heavy chain (heavy chain a) described in any one of (i-H) to (v-H), and a light chain (light chain a) combined with heavy chain a in (i) to (v); (xvi-b) A heavy chain consisting of an amino acid sequence in which 1 or 2 amino acids are deleted from the carboxyl terminus of the amino acid sequence of the heavy chain (heavy chain b) described in any one of (vi-H) to (x-H), and a light chain (light chain b) combined with heavy chain b in (vi) to (x); (xvi-c) A heavy chain consisting of an amino acid sequence in which 1 or 2 amino acids are deleted from the carboxyl terminus of the amino acid sequence of the heavy chain (heavy chain c) described in any one of (xi-H) to (xv-H), and a light chain (light chain c) combined with heavy chain c in (xi) to (xv): Examples include, but are not limited to, (i) to (v), (xv), (xvi-a) and (xvi-c), preferably (i) to (v) and (xvi-a), and even more preferably (v) and (xvi-a). The anti-HER2 antibody or antigen-binding fragment of the antibody of the present invention may preferably comprise an antibody Fc region (wild-type or mutant), more preferably an Fc region derived from IgG (same), and even more preferably an Fc region derived from human IgG (preferably human IgG1) (same). The mutant Fc region may be either naturally occurring or artificially created.

[0026] In the above (ii), (iv), (vii), (ix), (xii) or (xiv), the numerical values ​​"80%, " "90%" or "95%" are not limited thereto and may be, for example, any of 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, and may preferably be any of the numerical values ​​of 90% or more, and more preferably be any of the numerical values ​​of 95% or more.

[0027] 1-2. Antibody N297 Glycan Chain IgG has a well-conserved N-linked glycan (hereinafter referred to as "Asn297 glycan" or "N297 glycan") at the 297th asparagine residue (hereinafter referred to as "Asn297" or "N297") in the Fc region of its heavy chain, and is known to contribute to the activity, kinetics, etc. of antibody molecules (Eon-Duval, A. et al., Biotechnol. Prog. 2012, 28, 608-622; Sanglier-Cianferani, S., Anal. Chem. 2013, 85, 715-736).

[0028] The amino acid sequence in the constant region of IgG is well conserved, and in a report by Edelman et al. (Proc. Natl. Acad. Sci. U.S.A., 63, 78-85, (1969)), each amino acid is identified by an EU number (EU INDEX). For example, Asn297, to which an N-linked sugar chain is added in the Fc region, corresponds to position 297 in the EU numbering. Even if the actual amino acid position changes due to molecular fragmentation or region deletion, the amino acid can be uniquely identified by displaying it by EU numbering.

[0029] The N297 sugar chain used in the antibody-drug conjugate of the present invention is N297-(Fuc)SG or N297-(Fuc)MSG1, preferably N297-(Fuc)SG.

[0030] N297-(Fuc)SG is represented by the following structural formula or sequence formula:

[0031]

[0032]

[0033] In the above formula, the wavy line indicates binding to Asn297 of the antibody, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２-NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, and the asterisk indicates that the linker L is bonded to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring of Lb, where n ５ is an integer of 2 to 5, preferably 3.

[0034] N297-(Fuc)MSG1 is represented by the following structural formula or sequence formula:

[0035]

[0036]

[0037] In the above formula, the wavy line indicates binding to Asn297 of the antibody, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, which indicates that the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2nd position of the sialic acid at the non-reducing end of the 1-3 chain side of the branched chain of β-Man in the N297 sugar chain; an asterisk indicates that the linker L is bonded to the nitrogen atom at the 1st or 3rd position on the 1,2,3-triazole ring of Lb; ５ is an integer of 2 to 5, preferably 3.

[0038] When the N297 sugar chain of the antibody in the antibody-drug conjugate of the present invention is N297-(Fuc)SG, the antibody-drug conjugate is a molecule to which four linkers L and four drugs D are bound (the above m ２ = 2).

[0039] When the N297 sugar chain of the antibody in the antibody-drug conjugate of the present invention is N297-(Fuc)MSG1, the antibody-drug conjugate is a molecule to which two linkers L and two drugs D are bound (the above m ２ = 1).

[0040] When the N297 sugar chain of the antibody in the antibody-drug conjugate of the present invention is N297-(Fuc)SG or N297-(Fuc)MSG1, a highly homogeneous ADC can be obtained.

[0041] 1-3. Drug The drug of the anti-HER2 antibody-drug conjugate used in the present invention (D in formula (I) above, also referred to as drug D) is (wherein the asterisk indicates bonding to L, and W represents —NH—).

[0042] Preferably, and more preferably, (where the asterisk indicates binding to L).

[0043] 1-4. Linker The linker connecting the N297 sugar chain and drug D is represented by -Lb-La-Lp-Lc-*, where the asterisk indicates binding to drug D, Lp is -GGGFG- or -GGPI-, preferably -GGGFG-, and La is -C(=O)-CH ２ CH ２ Lb represents —C(═O)—; (In the structural formula of Lb shown above, the asterisk indicates bonding to La, and the wavy line indicates bonding to the N297 sugar chain), and Lc represents -NH-CH ２ Indicates -.

[0044] In the present invention, a drug linker refers to a compound in which a drug D in an antibody-drug conjugate is bound to a linker moiety, and a drug linker of the following formula x1, x2, y1, or y2 is preferably used, and a drug linker of formula x1 or x2 is more preferably used. (In the above formulae x1, x2, y1 and y2, the wavy lines indicate binding to the N297 sugar chain).

[0045] 2. Production of anti-HER2 antibody-drug conjugates 2-1. Production of antibodies The anti-HER2 antibodies described in 1-1 can be obtained by known means (for example, US Pat. No. 5,821,337, WO 2001 / 00245, etc.).

[0046] Recently, a method has been reported in which heterogeneous antibody sugar chains are remodeled (modified) by enzymatic reaction to uniformly introduce sugar chains bearing functional groups (ACS Chem. Biol. 2012, 7, 110-122, ACS Med. Chem. Lett. 2016, 7, 1005-1008). Attempts have also been made to use this sugar chain remodeling technique to site-specifically introduce drugs and synthesize homogeneous ADCs (Bioconjugate Chem. 2015, 26, 2233-2242, Angew. Chem. Int. Ed. 2016, 55, 2361-2367, US2016361436).

[0047] The antibody having an N297 sugar chain used in the present invention can be produced by applying sugar chain remodeling technology to the antibody described in 1-1., for example, in accordance with the methods described in WO2018 / 003983, WO2020 / 050406, WO2021 / 177438, WO2022 / 050300, WO2023 / 167238, PLos ONE 2018, 13, e0193534, etc.

[0048] 2-2. Production of Drugs and Linkers The drugs and linkers used in the present invention can be produced with reference to the descriptions in WO 2020 / 050406, WO 2021 / 177438, WO 2022 / 163846, and the like.

[0049] 2-3. Production of Drug Linker Intermediate (Conjugation Precursor) The drug linker intermediate (conjugation precursor) used in the production of the anti-HER2 antibody-drug conjugate used in the present invention is represented by the following formula:

[0050] Preferably, a drug linker intermediate (conjugation precursor) represented by the following formula is used:

[0051] More preferably, a drug linker intermediate (conjugation precursor) represented by the following formula is used:

[0052] The above drug linker intermediate (conjugation precursor) can be produced with reference to the descriptions in WO 2020 / 050406, WO 2021 / 177438, WO 2022 / 163846, etc.

[0053] 2-4. Production of anti-HER2 antibody-drug conjugates The anti-HER2 antibody-drug conjugates used in the present invention can be produced by linking the aforementioned drug linker intermediate (conjugation precursor) with an antibody having an N297 sugar chain via a cycloaddition reaction. Examples of cycloaddition reactions include the Diels-Alder reaction and the 1,3-dipolar cycloaddition reaction, and preferably the 1,3-dipolar cycloaddition reaction. Examples of the 1,3-dipolar cycloaddition reaction include the cycloaddition reaction of an azide with a terminal alkyne, and the SPAAC (strain-promoted azide-alkyne cycloaddition: J. Am. Chem. Soc. 2004, 126, 15046-15047) reaction, and preferably the SPAAC reaction.

[0054] The above anti-HER2 antibody-drug conjugate can be produced with reference to the descriptions in WO 2020 / 050406, WO 2021 / 177438, WO 2022 / 163846, etc.

[0055] 3. Immune Checkpoint Inhibitors In the present invention, the term "immune checkpoint inhibitor" refers to a drug that inhibits the immunosuppressive system and activates tumor immunity. The immune checkpoint inhibitor used in the present invention is not particularly limited, but preferred examples include anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA-4 antibodies, anti-TIGIT antibodies, and anti-LAG-3 antibodies, and more preferred examples include anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-CTLA-4 antibodies.

[0056] In the present invention, the term "anti-PD-1 antibody" refers to an antibody that specifically binds to PD-1 (programmed cell death-1; CD279; PDCD1), and preferably refers to an antibody that has the effect of reducing, inhibiting, and / or interfering with signal transduction resulting from the interaction between PD-1 and its binding partners, PD-L1 and PD-L2. The anti-PD-1 antibody used in the present invention is not particularly limited as long as its clinical efficacy and safety have been confirmed. Preferred examples include nivolumab (WO 2006 / 121168, etc.), pembrolizumab (WO 2008 / 156712, etc.), dostarlimab, spartalizumab (WO 2015 / 112900, etc.), and cemiplimab (WO 2015 / 196051, etc.). Furthermore, for the purpose of confirming the combined effect of the anti-HER2 antibody-drug conjugate used in the present invention in preclinical studies, commercially available anti-PD-1 antibodies for research use (e.g., clone RMP1-14, Anti-mPD-1 mIgG1e3), etc. These anti-PD-1 antibodies are commonly used as surrogate antibodies that inhibit PD-1 signaling in mice.

[0057] In the present invention, the term "anti-PD-L1 antibody" refers to an antibody that specifically binds to PD-L1 (Programmed cell death ligand 1; CD274; B7-H1), and preferably refers to an antibody that has the effect of reducing, inhibiting, and / or interfering with signal transduction resulting from the interaction between PD-L1 and its binding partners, PD-1 and B7.1 (CD80). The anti-PD-L1 antibody used in the present invention is not particularly limited as long as its clinical efficacy and safety have been confirmed, but preferred examples include atezolizumab (WO 2010 / 077634, etc.), durvalumab (WO 2011 / 066389, etc.), and avelumab (WO 2013 / 079174, etc.). Furthermore, for the purpose of confirming the combined effect of the anti-HER2 antibody-drug conjugate used in the present invention in preclinical studies, commercially available anti-PD-L1 antibodies for research use (e.g., clone 10F.9G2) can also be used. These anti-PD-L1 antibodies are commonly used as surrogate antibodies that inhibit PD-L1 signaling in mice.

[0058] In the present invention, the term "anti-CTLA-4 antibody" refers to an antibody that specifically binds to CTLA-4 (cytotoxic T-lymphocyte-associated protein 4; CD152), and preferably refers to an antibody that has the effect of reducing, inhibiting, and / or interfering with signal transduction resulting from the interaction between CTLA-4 and its binding partners, B7.1 (CD80) and B7.2 (CD86). The anti-CTLA-4 antibody used in the present invention is not particularly limited as long as its clinical efficacy and safety have been confirmed, but preferred examples include ipilimumab (WO 2001 / 014424, etc.) and tremelimumab (WO 2000 / 037504, etc.). Furthermore, for the purpose of confirming the combined effect of the anti-HER2 antibody-drug conjugate used in the present invention in preclinical studies, commercially available anti-CTLA-4 antibodies for research use (e.g., clones 9D9 and 9H10) can also be used. These anti-CTLA-4 antibodies are commonly used as surrogate antibodies that inhibit CTLA-4 signaling in mice.

[0059] In the present invention, the term "anti-TIGIT antibody" refers to an antibody that specifically binds to TIGIT (T cell immunoreceptor with Ig and ITIM domains), and preferably refers to an antibody that has the effect of reducing, inhibiting, and / or interfering with signal transduction resulting from the interaction between TIGIT and its binding partner, CD155 or the like. The anti-TIGIT antibody used in the present invention is not particularly limited as long as its clinical efficacy and safety have been confirmed, but preferred examples include tiragolumab (WO 2017 / 053748) and vibostolimab (WO 2016 / 028656). Furthermore, for the purpose of confirming the combined effect of the antibody-drug conjugate used in the present invention in preclinical studies, commercially available anti-TIGIT antibodies for research use (e.g., clone 1G9) can also be used.

[0060] In the present invention, the term "anti-LAG-3 antibody" refers to an antibody that specifically binds to LAG-3 (lymphocyte-activation gene 3), and preferably refers to an antibody that has the effect of reducing, inhibiting, and / or interfering with signal transduction resulting from the interaction between LAG-3 and its binding partner, major histocompatibility complex (MHC) class II. The anti-LAG-3 antibody used in the present invention is not particularly limited as long as its clinical efficacy and safety have been confirmed, and a preferred example is relatlimab. Furthermore, for the purpose of confirming the combined effect of the antibody-drug conjugate used in the present invention in preclinical studies, commercially available anti-LAG-3 antibodies for research use (e.g., clone C9B7W) and the like can also be used.

[0061] In the present invention, the immune checkpoint inhibitor used in combination with the anti-HER2 antibody-drug conjugate may be an antigen-binding fragment of any of the above antibodies, or a compound containing the antibody or the antigen-binding fragment. Here, the antigen-binding fragment means a fragment of an antibody that has antigen-binding activity, and includes Fab, F(ab')2, Fv, scFv, diabody, linear antibody, and multispecific antibody formed from antibody fragments. However, the antigen-binding fragment is not limited to these molecules as long as it has antigen-binding ability.

[0062] 4. Chemotherapeutic Agents In the present invention, the term "chemotherapeutic agent" refers to a chemically synthesized drug among compounds having anticancer or antitumor activity. The chemotherapeutic agent used in the present invention is not particularly limited, but suitable examples include topoisomerase inhibitors, tubulin inhibitors, antimetabolites, platinum compounds, DNA demethylating agents, anticancer antibiotics, and alkylating agents, and may also be pharmaceutically acceptable salts of these drugs.

[0063] Examples of topoisomerase inhibitors include irinotecan, topotecan, etoposide, sacituzumab govitecan, and the like, with irinotecan being preferred.

[0064] Examples of tubulin inhibitors include paclitaxel, docetaxel, vincristine, vinblastine, vindesine, eribulin, vinorelbine, albumin-suspended paclitaxel (Nab-paclitaxel), and the like, with paclitaxel being preferred.

[0065] Examples of the antimetabolite include fluorouracil (also called 5-FU), mercaptopurine, decitabine, gemcitabine (also called GEM), azacitidine (also called 5-Aza), methotrexate, tegafur, UFT, S-1, carmofur, doxifluridine, and capecitabine, with capecitabine being preferred.

[0066] Examples of platinum agents include oxaliplatin, carboplatin, cisplatin, nedaplatin, etc., with cisplatin being preferred.

[0067] Examples of DNA demethylating agents include azacytidine and decitabine.

[0068] Examples of anticancer antibiotics include doxorubicin, bleomycin, and liposomal doxorubicin.

[0069] Examples of the alkylating agent include ifosfamide, cyclophosphamide, dacarbazine, etc., and preferably cyclophosphamide.

[0070] However, the chemotherapeutic agents that can be used in combination with the anti-HER2 antibody-drug conjugates of the present invention are not limited to these.

[0071] 5. Anti-HER2 Antibodies In the present invention, examples of anti-HER2 antibodies used in combination with the anti-HER2 antibody-drug conjugate include trastuzumab, pertuzumab, margetuximab, etc., and preferably trastuzumab. The anti-HER2 antibodies also include biosimilars or biobetters thereof.

[0072] 6. Anti-HER2 Antibody-Containing Compounds In the present invention, examples of anti-HER2 antibody-containing compounds used in combination with anti-HER2 antibody-drug conjugates include ado-trastuzumab emtansine (T-DM1), disitamab vedotin, and vic-trastuzumab duocarmazine, with T-DM1 being preferred (excluding anti-HER2 antibody-drug conjugates represented by formula (I) and anti-HER2 antibody-deruxtecan). Anti-HER2 antibody-containing compounds also include biosimilars or biobetters thereof. Examples of the anti-HER2 antibody in anti-HER2 antibody-deruxtecan include trastuzumab, as well as fragments, variants, derivatives, and constructs of trastuzumab.

[0073] 7. Molecularly Targeted Drugs In the present invention, the term "molecularly targeted drug" refers to a drug designed to attack genes or proteins present in or around cancer cells, particularly those involved in cancer cell proliferation, with the main targets being cell surface antigens, signaling molecules, ligands, and the like. The molecularly targeted drug used in the present invention is not particularly limited, but preferred examples include tyrosine kinase inhibitors such as EGFR inhibitors, VEGF inhibitors, and FGFR inhibitors, as well as multikinase inhibitors. Examples of EGFR inhibitors include gefitinib, erlotinib, afatinib, osimertinib, cetuximab, panitumumab, necitumumab, matuzumab, nimotuzumab, zalutumumab, and the like. Suitable examples of VEGF inhibitors include bevacizumab, ramucirumab, aflibercept beta, and axitinib. Suitable examples of FGFR inhibitors include pemigatinib, futibatinib, and the like. Suitable examples of multikinase inhibitors include sorafenib, sunitinib, pazopanib, regorafenib, lenvatinib, etc. Furthermore, examples of tyrosine kinase inhibitors targeting HER2 include tucatinib, etc., and examples of tyrosine kinase inhibitors targeting HER2, etc. include neratinib, lapatinib, etc.

[0074] 8. Pharmaceutical compositions, treatment methods, etc.

[0075] Hereinafter, the pharmaceutical composition used in the combination therapy of the anti-HER2 antibody-drug conjugate according to the present invention with an immune checkpoint inhibitor, a chemotherapeutic agent, a molecular targeted drug, an anti-HER2 antibody, or an anti-HER2 antibody-containing compound, and the combination therapy (treatment method) will be described.

[0076] In the present invention, "used in combination" means that a recipient takes in multiple drugs into their body over a certain period of time. Furthermore, multiple drugs do not need to be present in the body at the same time; they may be taken into the body over a certain period of time (e.g., one month, preferably one week, more preferably several days, and even more preferably one day), and the other active ingredient may have disappeared from the body by the time one of the drugs is administered. In the present invention, the anti-HER2 antibody-drug conjugate and the immune checkpoint inhibitor, chemotherapeutic agent, molecularly targeted drug, anti-HER2 antibody, or anti-HER2 antibody-containing compound may each be contained as active ingredients in separate formulations. In such cases, the timing and number of administrations are not particularly limited, and may be, for example, administered simultaneously (simultaneously) or at different times (sequentially or separately). When administered at different times, they may be administered consecutively or discontinuously. When administered at different times, the administration interval and order can be changed as appropriate. Furthermore, in the present invention, the anti-HER2 antibody-drug conjugate and the immune checkpoint inhibitor, chemotherapeutic agent, molecular targeted drug, anti-HER2 antibody, or anti-HER2 antibody-containing compound may be contained as active ingredients in a single preparation.

[0077] The present invention also encompasses embodiments in which an anti-HER2 antibody-drug conjugate is used in combination with two or more drugs selected from immune checkpoint inhibitors, chemotherapeutic agents, molecularly targeted drugs, anti-HER2 antibodies, and anti-HER2 antibody-containing compounds. In this case, the two or more drugs may be selected from drugs belonging to the same category (e.g., two drugs belonging to immune checkpoint inhibitors) or from drugs belonging to different categories (e.g., a drug belonging to immune checkpoint inhibitors and a drug belonging to chemotherapeutic agents). For example, in one aspect of the present invention, a pharmaceutical composition comprising an anti-HER2 antibody-drug conjugate can be used in combination with two or more drugs selected from an immune checkpoint inhibitor, a chemotherapeutic agent, a molecular targeted drug, an anti-HER2 antibody, and an anti-HER2 antibody-containing compound; and a pharmaceutical composition comprising an immune checkpoint inhibitor, a chemotherapeutic agent, a molecular targeted drug, an anti-HER2 antibody, or an anti-HER2 antibody-containing compound can be used in combination with, in addition to the anti-HER2 antibody-drug conjugate, one or more other drugs selected from an immune checkpoint inhibitor, a chemotherapeutic agent, a molecular targeted drug, an anti-HER2 antibody, and an anti-HER2 antibody-containing compound. In another aspect of the present invention, the pharmaceutical composition comprising the anti-HER2 antibody-drug conjugate further comprises two or more drugs selected from an immune checkpoint inhibitor, a chemotherapeutic agent, a molecular targeted drug, an anti-HER2 antibody, and an anti-HER2 antibody-containing compound; and in yet another aspect of the present invention, the pharmaceutical composition comprising the anti-HER2 antibody-drug conjugate and an immune checkpoint inhibitor, a chemotherapeutic agent, a molecular targeted drug, an anti-HER2 antibody, or an anti-HER2 antibody-containing compound may be used in combination with one or more other drugs selected from an immune checkpoint inhibitor, a chemotherapeutic agent, a molecular targeted drug, an anti-HER2 antibody, and an anti-HER2 antibody-containing compound.

[0078] The pharmaceutical composition and treatment method of the present invention can be used for the treatment of cancer, and can preferably be used for the treatment of at least one cancer selected from the group consisting of lung cancer, renal cancer, urothelial cancer, colorectal cancer, prostate cancer, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric cancer, esophageal cancer, uterine cancer, testicular cancer, cervical cancer, placental choriocarcinoma, glioblastoma multiforme, brain tumor, head and neck cancer, thyroid cancer, mesothelioma, gastrointestinal stromal tumor (GIST), gallbladder cancer, bile duct cancer, adrenal cancer, squamous cell carcinoma, leukemia, malignant lymphoma, plasmacytoma, myeloma, and sarcoma.

[0079] In another aspect, the pharmaceutical composition and treatment method of the present invention can be used for the treatment of at least one cancer selected from the group consisting of lung cancer, colon cancer, prostate cancer, pancreatic cancer, ovarian cancer, breast cancer, bladder cancer, gastric cancer, esophageal cancer, uterine cancer, cervical cancer, head and neck cancer, bile duct cancer, myeloma, and sarcoma.

[0080] In another embodiment, the pharmaceutical compositions and treatment methods of the present invention can be used to treat lung cancer.

[0081] In another embodiment, the pharmaceutical compositions and treatment methods of the present invention can be used to treat breast cancer.

[0082] In another embodiment, the pharmaceutical compositions and treatment methods of the present invention can be used to treat gastric cancer.

[0083] In another embodiment, the pharmaceutical compositions and treatment methods of the present invention can be used to treat colon cancer.

[0084] In another embodiment, the pharmaceutical compositions and treatment methods of the present invention can be used to treat bladder cancer.

[0085] In one aspect, the present invention relates to a pharmaceutical composition comprising an anti-HER2 antibody-drug conjugate used in combination with an immune checkpoint inhibitor, a chemotherapeutic agent, a molecularly targeted drug, an anti-HER2 antibody, or an anti-HER2 antibody-containing compound.

[0086] In one aspect, the present invention relates to an anti-HER2 antibody-drug conjugate for use in combination with an immune checkpoint inhibitor, a chemotherapeutic agent, a molecularly targeted drug, an anti-HER2 antibody, or an anti-HER2 antibody-containing compound for the treatment of cancer.

[0087] In one aspect, the present invention relates to the use of an anti-HER2 antibody-drug conjugate in combination with an immune checkpoint inhibitor, a chemotherapeutic agent, a molecular targeted drug, an anti-HER2 antibody, or an anti-HER2 antibody-containing compound in the manufacture of a medicament for the treatment of cancer. In another aspect of the present invention, the present invention relates to the use of an anti-HER2 antibody-drug conjugate in combination with an immune checkpoint inhibitor, a chemotherapeutic agent, a molecular targeted drug, an anti-HER2 antibody, or an anti-HER2 antibody-containing compound in the manufacture of a medicament for the treatment of cancer. The present invention relates to the use of an anti-HER2 antibody-drug conjugate and an immune checkpoint inhibitor, a chemotherapeutic agent, a molecular targeted drug, an anti-HER2 antibody, or an anti-HER2 antibody-containing compound in the manufacture of a medicament for the combination treatment of cancer; the use of an anti-HER2 antibody-drug conjugate in the manufacture of a cancer therapeutic drug in combination with an immune checkpoint inhibitor, a chemotherapeutic agent, a molecular targeted drug, an anti-HER2 antibody, or an anti-HER2 antibody-containing compound; or the use of an immune checkpoint inhibitor, a chemotherapeutic agent, a molecular targeted drug, an anti-HER2 antibody, or an anti-HER2 antibody-containing compound in the manufacture of a cancer therapeutic drug in combination with an anti-HER2 antibody-drug conjugate.

[0088] In one aspect, the present invention relates to a method for treating a disease, comprising administering to a subject in need of treatment an anti-HER2 antibody-drug conjugate and an immune checkpoint inhibitor, a chemotherapeutic agent, a molecularly targeted drug, an anti-HER2 antibody, or an anti-HER2 antibody-containing compound in combination.

[0089] In one aspect, the present invention relates to a pharmaceutical composition for the treatment of cancer, comprising an anti-HER2 antibody-drug conjugate, for use in combination with an immune checkpoint inhibitor, a chemotherapeutic agent, a molecularly targeted drug, an anti-HER2 antibody, or an anti-HER2 antibody-containing compound; and in another aspect, the present invention relates to a pharmaceutical composition for the treatment of cancer, comprising an immune checkpoint inhibitor, a chemotherapeutic agent, a molecularly targeted drug, an anti-HER2 antibody, or an anti-HER2 antibody-containing compound, for use in combination with an anti-HER2 antibody-drug conjugate.

[0090] In one aspect, the present invention relates to a cancer therapeutic agent which is used in combination with an immune checkpoint inhibitor, a chemotherapeutic agent, a molecular targeted drug, an anti-HER2 antibody, or an anti-HER2 antibody-containing compound, the cancer therapeutic agent comprising an anti-HER2 antibody-drug conjugate as an active ingredient and which is intended for patients undergoing treatment with the immune checkpoint inhibitor, a chemotherapeutic agent, a molecular targeted drug, an anti-HER2 antibody, or an anti-HER2 antibody-containing compound. In another aspect, the present invention relates to a cancer therapeutic agent which is used in combination with an anti-HER2 antibody-drug conjugate, the cancer therapeutic agent comprising an immune checkpoint inhibitor, a chemotherapeutic agent, a molecular targeted drug, an anti-HER2 antibody, or an anti-HER2 antibody-containing compound as an active ingredient and which is intended for patients undergoing treatment with the anti-HER2 antibody-drug conjugate.

[0091] In one aspect, the present invention relates to a cancer therapeutic agent for use in the treatment of cancer, which comprises an anti-HER2 antibody-drug conjugate as an active ingredient, wherein the treatment comprises administering an immune checkpoint inhibitor, a chemotherapeutic agent, a molecularly targeted drug, an anti-HER2 antibody, or an anti-HER2 antibody-containing compound in addition to the anti-HER2 antibody-drug conjugate. In another aspect, the present invention relates to a cancer therapeutic agent for use in the treatment of cancer, which comprises an immune checkpoint inhibitor, a chemotherapeutic agent, a molecularly targeted drug, an anti-HER2 antibody, or an anti-HER2 antibody-containing compound as an active ingredient, wherein the treatment comprises administering the anti-HER2 antibody-drug conjugate in addition to the immune checkpoint inhibitor, a chemotherapeutic agent, a molecularly targeted drug, an anti-HER2 antibody, or an anti-HER2 antibody-containing compound.

[0092] The pharmaceutical composition and treatment method of the present invention can be suitably used when HER2 expression has been confirmed in cancer.

[0093] HER2 expression can be confirmed, for example, by detection at the level of the HER2 gene product (protein) using immunohistochemistry (IHC), a flow cytometer, Western blotting, or the like, or by detection at the gene transcription level using in situ hybridization (ISH) or quantitative PCR (q-PCR).

[0094] As used herein, a "subject" or "patient" refers to a human or other animal in need of such treatment, and in one embodiment, a human in need of such treatment.

[0095] The antitumor effect of the pharmaceutical composition and treatment method of the present invention can be confirmed, for example, by preparing a model in which cancer cells are transplanted into a test animal and measuring the reduction in tumor volume and the life-prolonging effect caused by administering the pharmaceutical composition and treatment method of the present invention.The combined effect of the anti-HER2 antibody-drug conjugate used in the present invention and the immune checkpoint inhibitor, chemotherapeutic agent, molecular targeted drug, anti-HER2 antibody, or anti-HER2 antibody-containing compound used in the present invention can be confirmed by comparing the antitumor effect with that of each of the anti-HER2 antibody-drug conjugate, immune checkpoint inhibitor, chemotherapeutic agent, molecular targeted drug, anti-HER2 antibody, or anti-HER2 antibody-containing compound used in the present invention when administered alone.

[0096] The antitumor effects of the pharmaceutical composition and treatment method of the present invention can be confirmed in clinical trials by the Response Evaluation Criteria in Solid Tumors (RECIST) evaluation method, the WHO evaluation method, the Macdonald evaluation method, weight measurement, and other methods, and the results can be evaluated for complete response (CR), partial response (PR), progressive disease (PD), objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and other important parameters. The survival rate can be determined by an index such as OS (Optical Survival Rate).

[0097] By the above-mentioned method, it is possible to confirm the superiority of the antitumor effect of the pharmaceutical composition and treatment method of the present invention over existing pharmaceutical compositions and treatment methods for cancer treatment.

[0098] The pharmaceutical composition and treatment method of the present invention can suppress the proliferation of cancer cells and even eliminate cancer cells. These actions can relieve cancer patients from cancer-related symptoms and improve their quality of life, thereby achieving a therapeutic effect while preserving the life of the cancer patient. Even if the cancer cells are not eliminated, the suppression and control of cancer cell proliferation can enable cancer patients to achieve a higher quality of life and longer survival.

[0099] The pharmaceutical composition of the present invention can be administered containing one or more pharmaceutically compatible ingredients. The pharmaceutically compatible ingredients can be appropriately selected from formulation additives and others commonly used in this field depending on the dose and administration concentration of the anti-HER2 antibody-drug conjugate, immune checkpoint inhibitor, chemotherapeutic agent, molecular targeted drug, anti-HER2 antibody, or anti-HER2 antibody-containing compound used in the present invention.

[0100] The pharmaceutical composition and treatment method of the present invention may further comprise a cancer therapeutic agent other than the anti-HER2 antibody-drug conjugate, immune checkpoint inhibitor, chemotherapeutic agent, molecular targeted drug, anti-HER2 antibody, or anti-HER2 antibody-containing compound of the present invention. The pharmaceutical composition of the present invention can also be administered in combination with other cancer therapeutic agents, thereby enhancing the anti-tumor effect. The other cancer therapeutic agent used for such a purpose may be administered simultaneously with the pharmaceutical composition of the present invention or at different times (sequentially or separately). When administered at different times, the other cancer therapeutic agents may be administered consecutively or discontinuously. When administered at different times, the administration interval and order can be changed as appropriate. Such cancer therapeutic agents are not limited as long as they have anti-tumor activity, but examples include at least one selected from the group consisting of endocrine therapy agents, immunotherapeutic agents such as interferon preparations or BCG, and antibodies other than anti-HER2 antibodies or antigen-binding fragments of such antibodies. Here, the antigen-binding fragment refers to a fragment of an antibody that has binding activity to an antigen, and includes Fab, F(ab')2, Fv, scFv, diabody, linear antibody, and multispecific antibody formed from antibody fragments, etc. However, it is not limited to these molecules as long as it has the ability to bind to an antigen.

[0101] The pharmaceutical composition and treatment method of the present invention can also be used in combination with radiation therapy and / or cellular immunotherapy. For example, a cancer patient may receive radiation therapy and / or cellular immunotherapy before and / or after, or simultaneously with, treatment with the pharmaceutical composition of the present invention.

[0102] The pharmaceutical composition and treatment method of the present invention can also be used as adjuvant chemotherapy in combination with surgery. The pharmaceutical composition of the present invention can be administered before surgery to reduce tumor size (neoadjuvant chemotherapy, or neoadjuvant therapy), or after surgery to prevent tumor recurrence (postoperative adjuvant chemotherapy, or adjuvant therapy). The pharmaceutical composition and treatment method of the present invention can also be used as maintenance therapy.

[0103] In addition to the therapeutic uses described above, the pharmaceutical composition and treatment method of the present invention can also be expected to have a preventive effect, such as suppressing the proliferation and even eliminating microscopic metastatic cancer cells. For example, they can be expected to have an effect of suppressing the proliferation and eliminating cancer cells present in body fluids during the metastasis process, as well as an effect of suppressing the proliferation and eliminating microscopic cancer cells immediately after implantation in any tissue. Therefore, they can be expected to have an inhibitory and preventive effect on cancer metastasis, particularly after surgical removal of cancer.

[0104] The pharmaceutical compositions of the present invention can be administered as pharmaceutical compositions containing one or more pharmaceutically compatible ingredients. The substances used in the pharmaceutical compositions of the present invention can be appropriately selected from formulation additives and other substances commonly used in this field, depending on the dosage and administration concentration. For example, the pharmaceutical composition typically contains one or more pharmaceutical carriers (e.g., a sterile liquid). Liquids include, for example, water and oils (petroleum, animal, plant, or synthetic). Oils may include, for example, peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is a more typical carrier when the pharmaceutical composition is administered intravenously. Saline solutions, as well as aqueous dextrose and glycerol solutions, can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients can be appropriately selected from those known in the art. The pharmaceutical composition may also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired. Examples of suitable pharmaceutical carriers are described in E. W. The formulation corresponds to the mode of administration.

[0105] Various delivery systems are known and can be used to administer the pharmaceutical compositions of the present invention. Routes of introduction can 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, administration of the antibody-drug conjugate is by infusion. Parenteral administration is a preferred route of administration.

[0106] When the anti-HER2 antibody-drug conjugate used in the present invention is administered to a human, the dose and interval of administration are not limited, and for example, about 0.001 to 100 mg / kg can be administered once or multiple times at intervals of once every 1 to 180 days.

[0107] The immune checkpoint inhibitor, chemotherapeutic agent, molecular targeted drug, anti-HER2 antibody, or anti-HER2 antibody-containing compound used in the present invention can be administered at a single dose of 0.1 mg to 3000 mg, and preferably at a single dose of 50 mg to 2000 mg.

[0108] The immune checkpoint inhibitor, anti-HER2 antibody, or anti-HER2 antibody-containing compound according to the present invention can be administered to a human at intervals of 1 to 4 times every 1 to 56 days, and preferably at intervals of once every 7 days, once every 14 days, once every 21 days, once every 28 days, or once every 42 days. The chemotherapeutic agent or molecular targeted drug can be administered to a human at intervals of 1 to 3 times per day, or 1 to 4 times per 1 to 56 days, and preferably at intervals of once per day, twice per day, or once every 7 days, once every 14 days, once every 21 days, once every 28 days, or once every 42 days.

[0109] The present invention will be specifically described with reference to the following examples, but the present invention is not limited to these examples. Furthermore, these examples should not be construed as limiting in any sense.

[0110] (Production Example 1) Preparation of anti-HER2 antibody-drug conjugate In accordance with the production method described in WO 2020 / 050406, an anti-HER2 antibody (referred to in the present invention as "anti-HER2 antibody 1") comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 (FIG. 1) and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2 (FIG. 2) was prepared by the following formula: (wherein the N297 sugar chain is [N297-(Fuc)SG]) An anti-HER2 antibody-drug conjugate represented by the formula: ２ The anti-HER2 antibody-drug conjugate of m = 2 is referred to as "HER2-ADC(1)", ２The anti-HER2 antibody-drug conjugate of m = 1 is referred to as "HER2-ADC(2)". Similarly, an anti-HER2 antibody (referred to as "anti-HER2 antibody 2" in the present invention) comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 8 (FIG. 4) and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 9 (FIG. 5) was used to ２ An anti-HER2 antibody-drug conjugate ("HER2-ADC(3)") of 1 was prepared.

[0111] (Antitumor test) Measurement and calculation formula: In all studies, the major and minor diameters of the tumor were measured twice a week using an electronic digital caliper (CD-15CX, Mitutoyo Corp.), and the tumor volume (mm ３ The calculation formula is as follows: Tumor volume (mm ３ ) = 1 / 2 x major axis (mm) x [minor axis (mm)] ２

[0112] In the following test examples, the tumor volume was 50 mm ３ The following individuals are referred to as "CR individuals".

[0113] (Test Example 1) Antitumor Test (1) CT26.WT-HER2 cells were prepared by introducing the human HER2 gene into the mouse colon cancer cell line CT26.WT purchased from American Type Culture Collection. CT26.WT-HER2 cells were subcutaneously implanted into the right axilla of BALB / c mice (Day 0), and seven days later, mice were randomly assigned to groups. HER2-ADC(1) was administered intravenously at a dose of 0.4 mg / kg once on Day 7. Trastuzumab was administered intravenously at a dose of 15 mg / kg twice on Day 7 and Day 10. Each group contained 10 mice. The results are shown in Figure 10. In the figure, the black circle line indicates the vehicle group, the black square line indicates the HER2-ADC(1) administration group, the black triangle line indicates the trastuzumab administration group, and the black inverted triangle line indicates the HER2-ADC(1) and trastuzumab co-administration group. The vertical axis indicates tumor volume (mm ３), the horizontal axis indicates the number of days after tumor implantation. Tumor growth progressed in the vehicle group and the trastuzumab-administered group. Tumor growth was suppressed in the HER2-ADC(1)-administered group, with 3 out of 10 mice achieving CR as of Day 22. In contrast, tumor growth was significantly suppressed in the HER2-ADC(1) and trastuzumab-administered group, with 10 out of 10 mice achieving CR as of Day 22. From the above, a strong antitumor combined effect of HER2-ADC(1) and trastuzumab was confirmed.

[0114] (Test Example 2) Antitumor Test (2) Human breast cancer cell line JIMT-1 purchased from DSMZ was subcutaneously transplanted into the right axilla of BALB / c-nu mice (Day 0), and 11 days later, the mice were randomly assigned to groups. HER2-ADC(1) was administered into the tail vein at a dose of 0.04 mg / kg once on Day 11. Trastuzumab was administered into the tail vein at a dose of 10 mg / kg three times on Days 11, 18, and 25. Each group consisted of five mice. The results are shown in Figure 11. In the figure, the black circle line indicates the vehicle group, the black square line indicates the HER2-ADC(1)-administered group, the black triangle line indicates the trastuzumab-administered group, and the black inverted triangle line indicates the group administered with a combination of HER2-ADC(1) and trastuzumab. The vertical axis represents tumor volume (mm ３ ), the horizontal axis indicates the number of days after tumor implantation. Tumor growth progressed in the vehicle group. At day 45, tumor volume was 20% smaller in the trastuzumab-administered group compared to the vehicle-administered group, and tumor volume was almost unchanged in the HER2-ADC(1)-administered group. In contrast, tumor growth was significantly suppressed in the HER2-ADC(1) and trastuzumab-administered group, and tumor volume at day 45 was 63% smaller than that in the vehicle-administered group. From the above, a strong antitumor effect of the combined use of HER2-ADC(1) and trastuzumab was confirmed.

[0115] (Test Example 3) Antitumor Test (3) Human gastric cancer cell line NCI-N87 purchased from American Type Culture Collection was subcutaneously transplanted into the right axilla of BALB / c-nu mice (Day 0), and seven days later, the mice were randomly assigned to groups. HER2-ADC (1) was administered into the tail vein at a dose of 0.4 mg / kg once on Day 7. Trastuzumab was administered into the tail vein at a dose of 10 mg / kg three times on Days 7, 14, and 21. Each group consisted of six mice. The results are shown in Figure 12. In the figure, the black circle line indicates the vehicle group, the black square line indicates the HER2-ADC(1) administration group, the black triangle line indicates the trastuzumab administration group, and the black inverted triangle line indicates the HER2-ADC(1) and trastuzumab co-administration group. The vertical axis indicates tumor volume (mm ３ ), the horizontal axis indicates the number of days after tumor implantation. Tumor growth progressed in the vehicle group. Tumor growth was suppressed in the HER2-ADC(1) administration group and the trastuzumab administration group, but as of Day 27, 0 out of 6 mice in each group had achieved CR. In contrast, tumor growth was significantly suppressed in the HER2-ADC(1) and trastuzumab combination administration group, and as of Day 27, 6 out of 6 mice had achieved CR. From the above, a strong antitumor combined effect of HER2-ADC(1) and trastuzumab was confirmed.

[0116] Test Example 4: Antitumor test (4) The human breast cancer cell line KPL-4, provided by Kawasaki Medical School, was subcutaneously implanted into the right axilla of BALB / c-nu mice (Day 0), and 14 days later, the mice were randomly assigned to groups. HER2-ADC(3) was administered into the tail vein at a dose of 0.1 mg / kg three times in total on Days 14, 21, and 28. T-DM1 was administered into the tail vein at a dose of 3 mg / kg three times in total on Days 14, 21, and 28. Each group consisted of six mice. The results are shown in Figure 13. In the figure, the black circle line indicates the vehicle group, the black square line indicates the HER2-ADC(3)-administered group, the black triangle line indicates the T-DM1-administered group, and the black inverted triangle line indicates the HER2-ADC(3) and T-DM1 co-administered group. The vertical axis represents tumor volume (mm ３), the horizontal axis indicates the number of days after tumor implantation. Tumor growth progressed in the vehicle group. Tumor growth was suppressed in the HER2-ADC(3) and T-DM1 groups, but 0 of 6 mice achieved CR as of Day 42. In contrast, tumor growth was significantly suppressed in the HER2-ADC(3) and T-DM1 combination group, with 4 of 6 mice achieving CR as of Day 42. These findings demonstrate the strong antitumor effect of the combined use of HER2-ADC(3) and T-DM1.

[0117] (Test Example 5) Antitumor Test (5) Human gastric cancer cell line NCI-N87 purchased from American Type Culture Collection was subcutaneously implanted into the right axilla of BALB / c-nu mice (Day 0), and seven days later, the mice were randomly assigned to groups. HER2-ADC (1) was administered into the tail vein at a dose of 0.4 mg / kg once on Day 7. T-DM1 was administered into the tail vein at a dose of 3 mg / kg three times on Days 7, 14, and 21. Each group consisted of six mice. The results are shown in Figure 14. In the figure, the black circle line represents the vehicle group, the black square line represents the HER2-ADC(1) administration group, the black triangle line represents the T-DM1 administration group, and the black inverted triangle line represents the HER2-ADC(1) and T-DM1 combination administration group. The vertical axis represents tumor volume (mm ３ ), the horizontal axis indicates the number of days after tumor implantation. Tumor growth progressed in the vehicle group. Tumor growth was suppressed in the HER2-ADC(1) and T-DM1 groups, but 0 out of 6 mice in each group achieved CR as of Day 27. In contrast, tumor growth was significantly suppressed in the HER2-ADC(1) and T-DM1 combination group, with 6 out of 6 mice achieving CR as of Day 27. These findings demonstrate the strong antitumor effect of the combined use of HER2-ADC(1) and T-DM1.

[0118] (Test Example 6) Antitumor Test (6) LL / 2-HER2 cells were prepared by introducing the human HER2 gene into the mouse lung cancer cell line LL / 2 purchased from American Type Culture Collection. LL / 2-HER2 cells were subcutaneously transplanted into the right axilla of C57BL / 6 mice (Day 0), and 10 days later, the mice were randomly assigned to groups. HER2-ADC (1) was administered intravenously at a dose of 0.4 mg / kg once on Day 10. An anti-PD-1 surrogate antibody (Anti-mPD-1 mIgG1e3, Invivogen) was administered intravenously at a dose of 5 mg / kg twice on Day 10 and Day 14. Each group contained six mice. The results are shown in Figure 15. In the figure, the black circle line represents the vehicle group, the black square line represents the HER2-ADC(1) administration group, the black triangle line represents the anti-PD-1 surrogate antibody administration group, and the black inverted triangle line represents the HER2-ADC(1) and anti-PD-1 surrogate antibody combined administration group. The vertical axis represents tumor volume (mm ３ The horizontal axis indicates the number of days after tumor implantation. In the vehicle group and the anti-PD-1 surrogate antibody administration group, tumor growth progressed, and the tumor volume reached 2500 mm on Day 17. ３ Since more than 100 individuals were confirmed to have a tumor growth rate exceeding 100%, the measurement was terminated from the perspective of a humane endpoint. Tumor growth was suppressed in the HER2-ADC (1) administration group, but 0 out of 6 individuals achieved CR as of Day 22. In contrast, tumor growth was significantly suppressed in the HER2-ADC (1) and anti-PD-1 surrogate antibody combination administration group, with 2 out of 6 individuals achieving CR as of Day 22. From the above, the strong anti-tumor combined effect of HER2-ADC (1) and anti-PD-1 surrogate antibody was confirmed.

[0119] (Test Example 7) Antitumor Test (7) CT26.WT-chimeraHER2 cells were prepared by introducing a human-mouse chimeric HER2 gene, in which the epitope site of the anti-HER2 antibody was humanized, into the mouse colon cancer cell line CT26.WT purchased from American Type Culture Collection. CT26.WT-chimeraHER2 cells were subcutaneously implanted into the right axilla of BALB / c mice (Day 0), and 6 days later, the mice were randomly assigned to groups. HER2-ADC(1) was administered once into the tail vein at a dose of 0.4 mg / kg on Day 6. Anti-PD-1 surrogate antibody (Anti-mPD-1 mIgG1e3, Invivogen) was administered at a dose of 5 mg / kg into the tail vein a total of three times on Day 6, Day 9, and Day 13. Each group had seven mice. The results are shown in Figure 16. In the figure, the black circle line indicates the vehicle group, the black square line indicates the HER2-ADC(1) administration group, the black triangle line indicates the anti-PD-1 surrogate antibody administration group, and the black inverted triangle line indicates the group administered with a combination of HER2-ADC(1) and anti-PD-1 surrogate antibody. The vertical axis indicates tumor volume (mm ３ The horizontal axis indicates the number of days after tumor transplantation. In the vehicle group and the anti-PD-1 surrogate antibody administration group, tumor growth progressed, and the tumor volume reached 2500 mm on Day 13. ３ Since more than 100 individuals were confirmed to have a tumor growth rate exceeding 100%, the measurement was terminated from the perspective of a humane endpoint. Tumor growth was suppressed in the HER2-ADC (1) administration group, but as of Day 17, 0 out of 7 individuals had a CR. In contrast, tumor growth was significantly suppressed in the HER2-ADC (1) and anti-PD-1 surrogate antibody combination administration group, with 3 out of 7 individuals having a CR as of Day 17. From the above, the strong anti-tumor combined effect of HER2-ADC (1) and anti-PD-1 surrogate antibody was confirmed.

[0120] (Test Example 8) Antitumor Test (8) CT26.WT-HER2 cells prepared in Test Example 1 were subcutaneously transplanted into the right axilla of BALB / c mice (Day 0), and eight days later, the mice were randomly assigned to groups. HER2-ADC (1) was administered intravenously at a dose of 0.3 mg / kg once on Day 8. Anti-PD-L1 surrogate antibody (clone number 10F.9G2, BioXcell) was administered intravenously at a dose of 10 mg / kg once on Day 8. Each group contained seven mice. The results are shown in Figure 17. In the figure, the black circle line indicates the vehicle group, the black square line indicates the HER2-ADC(1) administration group, the black triangle line indicates the anti-PD-L1 surrogate antibody administration group, and the black inverted triangle line indicates the HER2-ADC(1) and anti-PD-L1 surrogate antibody combined administration group. The vertical axis indicates tumor volume (mm ３ ), the horizontal axis indicates the number of days after tumor implantation. Tumor growth progressed in the vehicle group and the anti-PD-L1 surrogate antibody administration group. Tumor growth was suppressed in the HER2-ADC(1) administration group, but 0 out of 7 mice achieved CR as of Day 25. In contrast, tumor growth was significantly suppressed in the group administered a combination of HER2-ADC(1) and anti-PD-L1 surrogate antibody, with 3 out of 7 mice achieving CR as of Day 25. These results confirmed the strong anti-tumor effect of the combination of HER2-ADC(1) and anti-PD-L1 surrogate antibody.

[0121] (Test Example 9) Life Extension Test (1) CT26.WT-chimeraHER2 cells prepared in Test Example 7 were subcutaneously transplanted into the right axilla of BALB / c mice (Day 0), and seven days later, the mice were randomly assigned to groups. HER2-ADC (1) was administered into the tail vein at a dose of 0.4 mg / kg once on Day 7. Anti-CTLA-4 surrogate antibody (clone number 9D9, BioXcell) was administered into the tail vein at a dose of 5 mg / kg four times on Days 7, 10, 14, and 17. Each group consisted of six mice. The results are shown in Figure 18. In the figure, the black circle line indicates the vehicle group, the black square line indicates the HER2-ADC(1) administration group, the black triangle line indicates the anti-CTLA-4 surrogate antibody administration group, and the black inverted triangle line indicates the HER2-ADC(1) and anti-CTLA-4 surrogate antibody co-administration group. The vertical axis indicates the survival rate (%), and the horizontal axis indicates the number of days after tumor transplantation. When the tumor volume was 2500 mm ３For any individual exceeding this number, measurement was terminated, i.e., death, from the perspective of a humane endpoint. In the vehicle group and the anti-CTLA-4 surrogate antibody administration group, tumor growth progressed, with deaths occurring from Day 14, and measurement was terminated for all individuals by Day 17. In the HER2-ADC (1) administration group, tumor growth was suppressed, with deaths occurring from Day 17, and measurement was terminated for all individuals by Day 26. In contrast, tumor growth was significantly suppressed in the group administered a combination of HER2-ADC (1) and anti-CTLA-4 surrogate antibody, with deaths occurring from Day 22, and measurement was terminated for all individuals by Day 33. In other words, compared to the vehicle group, the time until the first death was observed was not extended in the anti-CTLA-4 surrogate antibody administration group, was extended by 3 days in the HER2-ADC(1) administration group, and was extended by 8 days in the HER2-ADC(1) and anti-CTLA-4 surrogate antibody combination administration group. These results confirmed the strong antitumor effect of the combination of HER2-ADC(1) and anti-CTLA-4 surrogate antibody.

[0122] (Test Example 10) Antitumor Test (9) Human breast cancer cell line KPL-4, provided by Kawasaki Medical School, was subcutaneously transplanted into the right axilla of BALB / c-nu mice (Day 0), and 14 days later, the mice were randomly divided into groups. HER2-ADC(2) was administered into the tail vein at a dose of 0.3 mg / kg twice in total, on Day 14 and Day 21. Paclitaxel was administered into the tail vein at a dose of 15 mg / kg twice in total, on Day 14 and Day 21. Each group consisted of 6 mice. The results are shown in Figure 19. In the figure, the black circle line indicates the vehicle group, the black square line indicates the HER2-ADC(2) administration group, the black triangle line indicates the paclitaxel administration group, and the black inverted triangle line indicates the group administered with a combination of HER2-ADC(2) and paclitaxel. The vertical axis indicates tumor volume (mm ３), the horizontal axis indicates the number of days after tumor implantation. Tumor growth progressed in the vehicle group. Tumor growth was suppressed in the HER2-ADC(2) administration group and the paclitaxel administration group. As of Day 42, 1 out of 6 mice in the HER2-ADC(2) administration group and 0 out of 6 mice in the paclitaxel administration group had achieved CR. In contrast, tumor growth was significantly suppressed in the HER2-ADC(2) and paclitaxel combination administration group, with 6 out of 6 mice achieving CR as of Day 42. From the above, a strong antitumor combined effect of HER2-ADC(2) and paclitaxel was confirmed.

[0123] (Test Example 11) Antitumor Test (10) Human breast cancer cell line KPL-4, provided by Kawasaki Medical School, was subcutaneously transplanted into the right axilla of BALB / c-nu mice (Day 0), and 14 days later, the mice were randomly assigned to groups. HER2-ADC (2) was administered at a dose of 0.3 mg / kg via the tail vein twice in total, on Day 14 and Day 21. Capecitabine was orally administered at a dose of 540 mg / kg daily from Day 14 to Day 18 and daily from Day 21 to Day 25, a total of 10 times. Each group consisted of 6 mice. The results are shown in Figure 20. In the figure, the black circle line indicates the vehicle group, the black square line indicates the HER2-ADC(2) administration group, the black triangle line indicates the capecitabine administration group, and the black inverted triangle line indicates the HER2-ADC(2) and capecitabine co-administration group. The vertical axis indicates tumor volume (mm ３ ), the horizontal axis indicates the number of days after tumor implantation. Tumor growth progressed in the vehicle group. Tumor growth was suppressed in the HER2-ADC(2)-administered group and the capecitabine-administered group. As of Day 42, 1 out of 6 mice in the HER2-ADC(2)-administered group and 0 out of 6 mice in the capecitabine-administered group had achieved CR. In contrast, tumor growth was significantly suppressed in the group administered a combination of HER2-ADC(2) and capecitabine, with 3 out of 6 mice achieving CR as of Day 42. From the above, a strong antitumor combined effect of HER2-ADC(2) and capecitabine was confirmed.

[0124] (Test Example 12) Antitumor Test (11) Human gastric cancer cell line NCI-N87 purchased from American Type Culture Collection was subcutaneously transplanted into the right axilla of BALB / c-nu mice (Day 0), and seven days later, the mice were randomly assigned to groups. HER2-ADC (1) was administered intravenously into the tail vein at a dose of 0.4 mg / kg once on Day 7. Capecitabine was orally administered at a dose of 360 mg / kg daily from Day 7 to Day 11 and daily from Day 14 to Day 18, a total of 10 times. Each group consisted of six mice. The results are shown in Figure 21. In the figure, the black circle line indicates the vehicle group, the black square line indicates the HER2-ADC(1) administration group, the black triangle line indicates the capecitabine administration group, and the black inverted triangle line indicates the HER2-ADC(1) and capecitabine co-administration group. The vertical axis indicates tumor volume (mm ３ ), the horizontal axis indicates the number of days after tumor implantation. Tumor growth progressed in the vehicle group. Tumor growth was suppressed in the HER2-ADC(1)-administered group and the capecitabine-administered group. As of Day 42, 0 out of 6 mice in the HER2-ADC(1)-administered group and 1 out of 6 mice in the capecitabine-administered group achieved CR. In contrast, tumor growth was significantly suppressed in the group administered a combination of HER2-ADC(1) and capecitabine, with 6 out of 6 mice achieving CR as of Day 42. From the above, a strong antitumor combined effect of HER2-ADC(1) and capecitabine was confirmed.

[0125] (Test Example 13) Antitumor Test (12) Human gastric cancer cell line NCI-N87 purchased from American Type Culture Collection was subcutaneously transplanted into the right axilla of BALB / c-nu mice (Day 0), and seven days later, the mice were randomly assigned to groups. HER2-ADC (1) was administered into the tail vein at a dose of 0.4 mg / kg once on Day 7. Paclitaxel was administered into the tail vein at a dose of 15 mg / kg three times on Day 7, Day 14, and Day 21. Each group consisted of six mice. The results are shown in Figure 22. In the figure, the black circle line indicates the vehicle group, the black square line indicates the HER2-ADC(1) administration group, the black triangle line indicates the paclitaxel administration group, and the black inverted triangle line indicates the HER2-ADC(1) and paclitaxel combination administration group. The vertical axis indicates tumor volume (mm ３), the horizontal axis indicates the number of days after tumor implantation. Tumor growth progressed in the vehicle group. Tumor growth was suppressed in the HER2-ADC(1)-administered group and the paclitaxel-administered group. As of Day 42, 0 out of 6 mice in both the HER2-ADC(1)-administered group and the paclitaxel-administered group had achieved CR. In contrast, tumor growth was significantly suppressed in the group administered a combination of HER2-ADC(1) and paclitaxel, with 5 out of 6 mice achieving CR as of Day 42. From the above, a strong antitumor combined effect of HER2-ADC(1) and paclitaxel was confirmed.

[0126] (Test Example 14) Antitumor Test (13) Human gastric cancer cell line NCI-N87 purchased from American Type Culture Collection was subcutaneously transplanted into the right axilla of BALB / c-nu mice (Day 0), and seven days later, the mice were randomly assigned to groups. HER2-ADC (1) was administered into the tail vein at a dose of 0.4 mg / kg once on Day 7. Irinotecan was administered into the tail vein at a dose of 60 mg / kg three times on Day 7, Day 14, and Day 21. Each group consisted of six mice. The results are shown in Figure 23. In the figure, the black circle line indicates the vehicle group, the black square line indicates the HER2-ADC(1) administration group, the black triangle line indicates the irinotecan administration group, and the black inverted triangle line indicates the HER2-ADC(1) and irinotecan combination administration group. The vertical axis indicates tumor volume (mm ３ ), the horizontal axis indicates the number of days after tumor implantation. Tumor growth progressed in the vehicle group. Tumor growth was suppressed in the HER2-ADC(1) administration group and the irinotecan administration group. As of Day 42, 0 out of 6 mice in both the HER2-ADC(1) administration group and the irinotecan administration group had achieved CR. In contrast, tumor growth was significantly suppressed in the HER2-ADC(1) and irinotecan combination administration group, with 2 out of 6 mice achieving CR as of Day 42. From the above, a strong antitumor combined effect of HER2-ADC(1) and irinotecan was confirmed.

[0127] In the combined administration groups of Test Examples 1 to 14, no significant weight loss was observed compared to the groups administered with each single agent, confirming that there are no safety issues associated with combined administration.

[0128] SEQ ID NO: 1: Amino acid sequence of the heavy chain of anti-HER2 antibody 1 SEQ ID NO: 2: Amino acid sequence of the light chain of anti-HER2 antibody 1 SEQ ID NO: 3: Amino acid sequence of CDRH1 of anti-HER2 antibody 1 SEQ ID NO: 4: Amino acid sequence of CDRH2 of anti-HER2 antibody 1 SEQ ID NO: 5: Amino acid sequence of CDRH3 of anti-HER2 antibody 1 SEQ ID NO: 6: Amino acid sequence of CDRL1 of anti-HER2 antibody 1 SEQ ID NO: 7: Amino acid sequence of CDRL3 of anti-HER2 antibody 1 SEQ ID NO: 8: Amino acid sequence of the heavy chain of anti-HER2 antibody 2 SEQ ID NO: 9: Amino acid sequence of the light chain of anti-HER2 antibody 2 SEQ ID NO: 10: Amino acid sequence of CDRH1 of anti-HER2 antibody 2 SEQ ID NO: 11: Amino acid sequence of CDRH2 of anti-HER2 antibody 2 SEQ ID NO: 12: Amino acid sequence of CDRH3 of anti-HER2 antibody 2 SEQ ID NO: 13: Amino acid sequence of CDRL1 of anti-HER2 antibody 2 SEQ ID NO: 14: Amino acid sequence of CDRL3 of anti-HER2 antibody 2 SEQ ID NO: 15: Amino acid sequence of the heavy chain of anti-HER2 antibody 3 SEQ ID NO: 16: Amino acid sequence of the light chain of anti-HER2 antibody 3 SEQ ID NO: 17: Amino acid sequence of CDRH1 of anti-HER2 antibody 3 SEQ ID NO: 18: Amino acid sequence of CDRH2 of anti-HER2 antibody 3 SEQ ID NO: 19: Amino acid sequence of CDRH3 of anti-HER2 antibody 3 SEQ ID NO: 20: Amino acid sequence of CDRL1 of anti-HER2 antibody 3 SEQ ID NO: 21: Amino acid sequence of CDRL3 of anti-HER2 antibody 3

Claims

1. a) A pharmaceutical composition comprising an anti-HER2 antibody-drug conjugate, wherein a) the anti-HER2 antibody-drug conjugate and b) one or more selected from immune checkpoint inhibitors, chemotherapeutic agents, molecular targeted drugs, anti-HER2 antibodies, and anti-HER2 antibody-containing compounds (excluding the anti-HER2 antibody-drug conjugate described in a) and anti-HER2 antibody-deruxtecan) are used in combination, and the anti-HER2 antibody-drug conjugate is represented by the following formula (I): (In the formula, m ２ represents an integer of 1 or 2, L represents a linker connecting the N297 sugar chain and D, -Lb-La-Lp-Lc-* (where the asterisk indicates binding to drug D, and Lb is: (In the structural formula of Lb shown above, the asterisk indicates bonding to La, and the wavy line indicates bonding to the N297 sugar chain), where La is -C(=O)-CH ２ CH ２ Lp represents -GGFG- or -GGPI-, Lc represents -NH-CH ２ Ab is an anti-HER2 antibody or an antigen-binding fragment thereof, comprising a heavy chain consisting of an amino acid sequence including CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 4, and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 5, and a light chain consisting of an amino acid sequence including CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of the amino acid sequence represented by SAS, and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 7, wherein the N297 sugar chain is N297-(Fuc)MSG1 having the structure represented by the following formula: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of the 1-3 chain side of the branched chain of β-Man in the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1- or 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５ represents an integer of 2 to 5), or N297-(Fuc)SG: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５ represents an integer of 2 to 5), and D represents (wherein the asterisk indicates bonding to L, and W represents -NH-).

2. D is The pharmaceutical composition according to claim 1, which is represented by the formula: (wherein the asterisk indicates binding to L).

3. The anti-HER2 antibody-drug conjugate has the formula: (Wherein Ab, N297 sugar chain and m ２ The pharmaceutical composition according to claim 1 , wherein 4. The anti-HER2 antibody-drug conjugate has the formula: In the formula, m ２ is 2, the Ab comprises a heavy chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence represented by the 1st to 119th amino acid residues of SEQ ID NO: 1, and a light chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence represented by the 1st to 108th amino acid residues of SEQ ID NO: 2, and the N297 sugar chain is N297-(Fuc)SG having a structure represented by the following formula: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, the asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring, and n ５ The pharmaceutical composition according to any one of claims 1 to 3, wherein R is an integer of 1 to 3.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the Ab comprises a heavy chain variable region consisting of the amino acid sequence represented by amino acid residues 1 to 119 of SEQ ID NO: 1, and a light chain variable region consisting of the amino acid sequence represented by amino acid residues 1 to 108 of SEQ ID NO:

2.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the Ab comprises a heavy chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 1, and a light chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO:

2.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the Ab comprises a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO:

2.

8. The pharmaceutical composition of any one of claims 1 to 5, wherein the Ab comprises an antibody or an antigen-binding fragment of said antibody contained in the pharmaceutical composition of any one of claims 1 to 7, and comprises: (i) a heavy chain consisting of an amino acid sequence in which one or two amino acids are deleted from the carboxyl terminus of the amino acid sequence of the heavy chain; and (ii) a light chain.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein a) an anti-HER2 antibody-drug conjugate and b) an immune checkpoint inhibitor are used in combination, and the immune checkpoint inhibitor is an antibody selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-TIGIT antibody, and an anti-LAG-3 antibody, an antigen-binding fragment thereof, or a compound comprising any of them.

10. The pharmaceutical composition according to claim 9, wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, spartalizumab, cemiplimab, or dostarlimab.

11. The pharmaceutical composition according to claim 9, wherein the anti-PD-L1 antibody is atezolizumab, duvalumab, or avelumab.

12. The pharmaceutical composition of claim 9, wherein the anti-CTLA-4 antibody is ipilimumab or tremelimumab.

13. The pharmaceutical composition according to claim 9, wherein the anti-TIGIT antibody is tiragolumab or vibostolimab.

14. The pharmaceutical composition of claim 9, wherein the anti-LAG-3 antibody is leratolimab.

15. The pharmaceutical composition according to any one of claims 1 to 8, wherein a) the anti-HER2 antibody-drug conjugate and b) a chemotherapeutic agent are used in combination, and the chemotherapeutic agent is an antimetabolite, a tubulin inhibitor, an alkylating agent, a platinum compound, or a topoisomerase inhibitor.

16. The pharmaceutical composition of claim 15, wherein the antimetabolite is capecitabine or a pharmaceutically acceptable salt thereof.

17. The pharmaceutical composition of claim 15, wherein the tubulin inhibitor is paclitaxel or a pharmaceutically acceptable salt thereof.

18. The pharmaceutical composition of claim 15, wherein the topoisomerase inhibitor is irinotecan or a pharmaceutically acceptable salt thereof.

19. The pharmaceutical composition according to any one of claims 1 to 8, wherein a) an anti-HER2 antibody-drug conjugate and b) an anti-HER2 antibody are used in combination, and the anti-HER2 antibody described in b) is trastuzumab, pertuzumab, or marjetuximab.

20. The pharmaceutical composition according to any one of claims 1 to 8, wherein a) an anti-HER2 antibody-drug conjugate and b) an anti-HER2 antibody-containing compound are used in combination, and the anti-HER2 antibody-containing compound is ado-trastuzumab emtansine (T-DM1), disitamab vedotin, or vic-trastuzumab duocarmazine.

21. The pharmaceutical composition according to any one of claims 1 to 20, wherein a) the anti-HER2 antibody-drug conjugate; and b) the immune checkpoint inhibitor, chemotherapeutic agent, molecular targeted drug, anti-HER2 antibody, or anti-HER2 antibody-containing compound are contained as active ingredients in separate formulations and administered simultaneously or at different times.

22. A pharmaceutical composition according to any one of claims 1 to 21 for the treatment of cancer.

23. The pharmaceutical composition of claim 22, wherein the cancer is at least one selected from the group consisting of lung cancer, colon cancer, prostate cancer, pancreatic cancer, ovarian cancer, breast cancer, bladder cancer, gastric cancer, esophageal cancer, uterine cancer, cervical cancer, head and neck cancer, bile duct cancer, myeloma, and sarcoma.

24. The pharmaceutical composition of claim 23, wherein the cancer is lung cancer.

25. The pharmaceutical composition of claim 23, wherein the cancer is colon cancer.

26. The pharmaceutical composition of claim 23, wherein the cancer is breast cancer.

27. The pharmaceutical composition of claim 23, wherein the cancer is gastric cancer.

28. The pharmaceutical composition of claim 23, wherein the cancer is bladder cancer.

29. An anti-HER2 antibody-drug conjugate for use in combination with one or more selected from immune checkpoint inhibitors, chemotherapeutic agents, molecular targeted drugs, anti-HER2 antibodies, and anti-HER2 antibody-containing compounds (excluding anti-HER2 antibody-drug conjugates represented by formula (I) below and anti-HER2 antibody-deruxtecan) for the treatment of cancer, wherein the anti-HER2 antibody-drug conjugate is represented by the following formula (I): (In the formula, m ２ represents an integer of 1 or 2, L represents a linker connecting the N297 sugar chain and D, -Lb-La-Lp-Lc-* (wherein the asterisk indicates binding to drug D, and Lb is: (In the structural formula of Lb shown above, the asterisk indicates bonding to La, and the wavy line indicates bonding to the N297 sugar chain), where La is -C(=O)-CH ２ CH ２ Lp represents -GGFG- or -GGPI-, Lc represents -NH-CH ２ Ab is an anti-HER2 antibody or an antigen-binding fragment thereof, comprising a heavy chain consisting of an amino acid sequence including CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 4, and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 5, and a light chain consisting of an amino acid sequence including CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of the amino acid sequence represented by SAS, and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 7, wherein the N297 sugar chain is N297-(Fuc)MSG1 having the structure represented by the following formula: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of the 1-3 chain side of the branched chain of β-Man in the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1- or 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５ represents an integer of 2 to 5), or N297-(Fuc)SG: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５ represents an integer of 2 to 5), and D represents (wherein the asterisk indicates binding to L, and W represents -NH-)) 30. D.

30. The anti-HER2 antibody-drug conjugate of claim 29, represented by the formula: (wherein the asterisk indicates binding to L).

31. The anti-HER2 antibody-drug conjugate has the formula: (Wherein Ab, N297 sugar chain and m ２ The anti-HER2 antibody-drug conjugate of claim 29, wherein:

32. The anti-HER2 antibody-drug conjugate has the formula: In the formula, m ２ is 2, the Ab comprises a heavy chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence represented by the 1st to 119th amino acid residues of SEQ ID NO: 1, and a light chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence represented by the 1st to 108th amino acid residues of SEQ ID NO: 2, and the N297 sugar chain is N297-(Fuc)SG having a structure represented by the following formula: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, the asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring, and n ５ The anti-HER2 antibody-drug conjugate of any one of claims 29 to 31, wherein R is an integer of 1 or 2.

33. The anti-HER2 antibody-drug conjugate of any one of claims 29 to 32, wherein the Ab comprises a heavy chain variable region consisting of the amino acid sequence represented by amino acid residues 1 to 119 of SEQ ID NO: 1, and a light chain variable region consisting of the amino acid sequence represented by amino acid residues 1 to 108 of SEQ ID NO:

2.

34. The anti-HER2 antibody-drug conjugate of any one of claims 29 to 33, wherein the Ab comprises a heavy chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO: 1, and a light chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence shown in SEQ ID NO:

2.

35. The anti-HER2 antibody-drug conjugate of any one of claims 29 to 34, wherein the Ab comprises a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO:

2.

36. The anti-HER2 antibody-drug conjugate of any one of claims 29 to 33, wherein the Ab is comprised in an antibody or antigen-binding fragment of said antibody contained in the anti-HER2 antibody-drug conjugate of any one of claims 29 to 35, and comprises: (i) a heavy chain consisting of an amino acid sequence in which one or two amino acids are deleted from the carboxyl terminus of the amino acid sequence of the heavy chain; and (ii) a light chain.

37. The anti-HER2 antibody-drug conjugate of any one of claims 29 to 36, for use in combination with an immune checkpoint inhibitor for the treatment of cancer, wherein the immune checkpoint inhibitor is an antibody selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-TIGIT antibody, and an anti-LAG-3 antibody, an antigen-binding fragment thereof, or a compound comprising any of them.

38. The anti-HER2 antibody-drug conjugate of claim 37, wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, spartalizumab, cemiplimab, or dostarlimab.

39. The anti-HER2 antibody-drug conjugate of claim 37, wherein the anti-PD-L1 antibody is atezolizumab, duvalumab, or avelumab.

40. The anti-HER2 antibody-drug conjugate of claim 37, wherein the anti-CTLA-4 antibody is ipilimumab or tremelimumab.

41. The anti-HER2 antibody-drug conjugate of claim 37, wherein the anti-TIGIT antibody is tiragolumab or vibostolimab.

42. The anti-HER2 antibody-drug conjugate of claim 37, wherein the anti-LAG-3 antibody is leratolimab.

43. The anti-HER2 antibody-drug conjugate of any one of claims 29 to 36, for use in combination with a chemotherapeutic agent for the treatment of cancer, wherein the chemotherapeutic agent is an antimetabolite, a tubulin inhibitor, an alkylating agent, a platinum compound, or a topoisomerase inhibitor.

44. The anti-HER2 antibody-drug conjugate of claim 43, wherein the antimetabolite is capecitabine or a pharmaceutically acceptable salt thereof.

45. The anti-HER2 antibody-drug conjugate of claim 43, wherein the tubulin inhibitor is paclitaxel or a pharmaceutically acceptable salt thereof.

46. The anti-HER2 antibody-drug conjugate of claim 43, wherein the topoisomerase inhibitor is irinotecan or a pharmaceutically acceptable salt thereof.

47. An anti-HER2 antibody-drug conjugate according to any one of claims 29 to 36, for use in combination with an anti-HER2 antibody for the treatment of cancer, wherein the anti-HER2 antibody used in combination with the anti-HER2 antibody-drug conjugate is trastuzumab, pertuzumab, or marjetuximab.

48. The anti-HER2 antibody-drug conjugate of any one of claims 29 to 36, for use in combination with an anti-HER2 antibody-containing compound for the treatment of cancer, wherein the anti-HER2 antibody-containing compound is ado-trastuzumab emtansine (T-DM1), disitamab vedotin, or vic-trastuzumab duocarmazine.

49. The anti-HER2 antibody-drug conjugate according to any one of claims 29 to 48, wherein the anti-HER2 antibody-drug conjugate; and the immune checkpoint inhibitor, chemotherapeutic agent, molecular targeted drug, anti-HER2 antibody, or anti-HER2 antibody-containing compound are each contained as active ingredients in separate formulations and administered simultaneously or at different times.

50. The anti-HER2 antibody-drug conjugate of any one of claims 29 to 49, wherein the cancer is selected from the group consisting of lung cancer, colon cancer, prostate cancer, pancreatic cancer, ovarian cancer, breast cancer, bladder cancer, gastric cancer, esophageal cancer, uterine cancer, cervical cancer, head and neck cancer, bile duct cancer, myeloma, and sarcoma.

51. The anti-HER2 antibody-drug conjugate of claim 50, wherein the cancer is lung cancer.

52. The anti-HER2 antibody-drug conjugate of claim 50, wherein the cancer is colon cancer.

53. The anti-HER2 antibody-drug conjugate of claim 50, wherein the cancer is breast cancer.

54. The anti-HER2 antibody-drug conjugate of claim 50, wherein the cancer is gastric cancer.

55. The anti-HER2 antibody-drug conjugate of claim 50, wherein the cancer is bladder cancer.

56. A method for treating a disease, comprising administering to a subject in need of treatment a combination of one or more of: a) an anti-HER2 antibody-drug conjugate; and b) an immune checkpoint inhibitor, a chemotherapeutic agent, a molecular targeted drug, an anti-HER2 antibody, and an anti-HER2 antibody-containing compound (excluding the anti-HER2 antibody-drug conjugate and anti-HER2 antibody-deruxtecan described in a)), wherein the anti-HER2 antibody-drug conjugate is represented by the following formula (I): (In the formula, m ２ represents an integer of 1 or 2, L represents a linker connecting the N297 sugar chain and D, -Lb-La-Lp-Lc-* (wherein the asterisk indicates binding to drug D, and Lb is: (In the structural formula of Lb shown above, the asterisk indicates bonding to La, and the wavy line indicates bonding to the N297 sugar chain), where La is -C(=O)-CH ２ CH ２ Lp represents -GGFG- or -GGPI; Lc represents -NH-CH ２ Ab is an anti-HER2 antibody or an antigen-binding fragment thereof, comprising a heavy chain consisting of an amino acid sequence including CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 4, and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 5, and a light chain consisting of an amino acid sequence including CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of the amino acid sequence represented by SAS, and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 7, wherein the N297 sugar chain is N297-(Fuc)MSG1 having the structure represented by the following formula: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of the 1-3 chain side of the branched chain of β-Man in the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1- or 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５ represents an integer of 2 to 5), or N297-(Fuc)SG: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, an asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring of Lb in the linker L, and n ５ represents an integer of 2 to 5), and D represents (wherein the asterisk indicates bonding to L, and W represents -NH-).

57. D.

57. The method of claim 56, wherein the compound is represented by the formula: wherein the asterisk indicates that the compound is attached to L.

58. The anti-HER2 antibody-drug conjugate has the following formula: (Wherein Ab, N297 sugar chain and m ２ is as previously defined).

59. An anti-HER2 antibody-drug conjugate having the formula: In the formula, m ２ is 2, the Ab comprises a heavy chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence represented by the 1st to 119th amino acid residues of SEQ ID NO: 1, and a light chain variable region consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence represented by the 1st to 108th amino acid residues of SEQ ID NO: 2, and the N297 sugar chain is N297-(Fuc)SG having a structure represented by the following formula: (where the wavy line indicates binding to Asn297 of Ab, and L(PEG) is -(CH ２ -CH ２ -O)n ５ -CH ２ -CH ２ -NH-, the amino group at the right end of L(PEG) is amide-bonded to the carboxyl group at the 2-position of the sialic acid at the non-reducing end of both the 1-3 chain side and the 1-6 chain side of the branched chain of β-Man of the N297 sugar chain, the asterisk indicates bonding to the nitrogen atom at the 1-position or the 3-position on the 1,2,3-triazole ring, and n ５ The method according to any one of claims 56 to 58, wherein:

60. The method of any one of claims 56 to 59, wherein the Ab comprises a heavy chain variable region consisting of the amino acid sequence represented by amino acid residues 1 to 119 of SEQ ID NO: 1, and a light chain variable region consisting of the amino acid sequence represented by amino acid residues 1 to 108 of SEQ ID NO:

2.

61. The method of any one of claims 56 to 60, wherein the Ab comprises a heavy chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence set forth in SEQ ID NO:1, and a light chain consisting of an amino acid sequence that is 80% or more, preferably 90% or more, and more preferably 95% or more identical to the amino acid sequence set forth in SEQ ID NO:

2.

62. The method of any one of claims 56 to 61, wherein the Ab comprises a heavy chain consisting of the amino acid sequence shown in SEQ ID NO:1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO:

2.

63. The method of any one of claims 56 to 60, wherein the Ab is comprised in an antibody or antigen-binding fragment of said antibody contained in the anti-HER2 antibody-drug conjugate of any one of claims 56 to 62, and comprises: (i) a heavy chain consisting of an amino acid sequence in which one or two amino acids are deleted from the carboxyl terminus of the amino acid sequence of the heavy chain; and (ii) a light chain.

64. A method for treating a disease, comprising administering in combination to a subject in need of disease treatment a) an anti-HER2 antibody-drug conjugate; and b) an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is an antibody selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-TIGIT antibody, and an anti-LAG-3 antibody, an antigen-binding fragment thereof, or a compound comprising any of them, according to any one of claims 56 to 63.

65. The method of claim 64, wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, spartalizumab, cemiplimab, or dostarlimab.

66. The method of claim 64, wherein the anti-PD-L1 antibody is atezolizumab, duvalumab, or avelumab.

67. The method of claim 64, wherein the anti-CTLA-4 antibody is ipilimumab or tremelimumab.

68. The method of claim 64, wherein the anti-TIGIT antibody is tiragolumab or vibostolimab.

69. The method of claim 64, wherein the anti-LAG-3 antibody is leratolimab.

70. A method for treating a disease, comprising administering in combination to a subject in need of disease treatment: a) an anti-HER2 antibody-drug conjugate; and b) a chemotherapeutic agent, wherein the chemotherapeutic agent is an antimetabolite, a tubulin inhibitor, an alkylating agent, a platinum compound, or a topoisomerase inhibitor, according to any one of claims 56 to 63.

71. The method of claim 70, wherein the antimetabolite is capecitabine or a pharmaceutically acceptable salt thereof.

72. The method of claim 70, wherein the tubulin inhibitor is paclitaxel or a pharmaceutically acceptable salt thereof.

73. The method of claim 70, wherein the topoisomerase inhibitor is irinotecan or a pharmaceutically acceptable salt thereof.

74. A method for treating a disease, comprising administering in combination to a subject in need of disease treatment: a) an anti-HER2 antibody-drug conjugate; and b) an anti-HER2 antibody, wherein the anti-HER2 antibody described in b) is trastuzumab, pertuzumab, or marjetuximab. The method of any one of claims 56 to 63.

75. A method for treating a disease, comprising administering in combination to a subject in need of disease treatment: a) an anti-HER2 antibody-drug conjugate; and b) an anti-HER2 antibody-containing compound, wherein the anti-HER2 antibody-containing compound is ado-trastuzumab emtansine (T-DM1), disitamab vedotin, or vic-trastuzumab duocarmazine.

76. The method according to any one of claims 56 to 75, wherein the anti-HER2 antibody-drug conjugate; and the immune checkpoint inhibitor, chemotherapeutic agent, molecular targeted drug, anti-HER2 antibody, or anti-HER2 antibody-containing compound are each contained as active ingredients in separate formulations and administered simultaneously or at different times.

77. The method of any one of claims 56 to 76, wherein the disease is cancer.

78. The method of claim 77, wherein the cancer is selected from the group consisting of lung cancer, colon cancer, prostate cancer, pancreatic cancer, ovarian cancer, breast cancer, bladder cancer, gastric cancer, esophageal cancer, uterine cancer, cervical cancer, head and neck cancer, bile duct cancer, myeloma, and sarcoma.

79. The method of claim 77, wherein the cancer is lung cancer.

80. The method of claim 77, wherein the cancer is colon cancer.

81. The method of claim 77, wherein the cancer is breast cancer.

82. The method of claim 77, wherein the cancer is gastric cancer.

83. The method of claim 77, wherein the cancer is bladder cancer.

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