BR122023026673A2 - USE OF AN ANTIBODY-DRUG CONJUGATE - Google Patents

Abstract

A therapeutic agent for a metastatic brain tumor that contains, as an active component, an antibody-drug conjugate in which a drug-connector represented by the following formula (1) (wherein A represents a connection position to an antibody) is conjugated to the antibody via a thioether linkage and/or a method of treating a metastatic brain tumor, comprising administering the antibody-drug conjugate to a subject in need of treatment for a metastatic brain tumor.

Description

Technical Field:

[001] The present invention relates to a therapeutic agent for a metastatic brain tumor comprising a specific antibody-drug conjugate, and/or a method of treatment for a metastatic brain tumor comprising administering to a subject an antibody conjugate -specific drug.

Fundamentals of the Invention:

[002] A metastatic brain tumor is a disease that develops when a primary cancer metastasizes to the brain and is known to occur in 20 to 40% of cancer patients. Cancer metastasis to the brain not only has a significant influence on prognosis but also results in notable decline in QOL, and therefore the development of an effective method of treatment for a metastatic brain tumor is required (Non-Patent References 1, 2 ).

[003] As the primary cancer for metastatic brain tumors can be exemplified: lung cancer, breast cancer, melanoma, renal cell cancer, kidney cancer, colorectal cancer, gastric cancer, head and neck cancer, hepatocellular cancer, liver cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, endometrial cancer, thyroid cancer, malignant lymphoma and sarcoma. Among these, it is known that particularly metastatic brain tumors originating from lung cancer, breast cancer and melanoma as primary cancers are present in high percentages (Non-Patent References 1, 2).

[004] For the treatment of metastatic brain tumors originating from lung cancer as a primary cancer, clinical studies using gefitinib (Non-Patent Reference 3), erlotinib (Non-Patent Reference 4), afatinib (Non-Patent Reference 5) are known. and osimertinib (Non-Patent Reference 6), which are epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, and crizotinib (Non-Patent Reference 7), which is an ALK inhibitor, or similar.

[005] For the treatment of metastatic brain tumors originating from breast cancer as a primary cancer, clinical studies are known that use trastuzumab, which is an anti-HER2 antibody (Non-Patent Reference 8), and lapatinib, which is an inhibitor of Human epidermal growth factor receptor tyrosine kinase 2 (HER2) (Non-Patent Reference 9), or the like.

[006] For the treatment of metastatic brain tumors originating from melanoma as a primary cancer, clinical studies using vemurafenib, which is a BRAF inhibitor (Non-Patent Reference 10), or the like are known.

[007] However, these drug therapies have not been proven as standard therapies, and radiotherapy and surgical therapy are considered to be more preferred.

[008] An antibody-drug conjugate (ADC) having a drug with cytotoxicity conjugated to an antibody capable of binding to an antigen expressed on the surface of cancer cells and cellular internalization, can selectively deliver the drug to cancer cells and can It can therefore be predicted to cause accumulation of the drug within cancer cells and to kill cancer cells (Non-Patent References 11 to 15).

[009] As such an antibody-drug conjugate, an antibody-drug conjugate comprising an antibody and an exatecan derivative, which is a topoisomerase I inhibitor, as its components is known (Patent References 1 to 5, References No. Patents 16 to 19). These antibody-drug conjugates, which exert superior antitumor effect and superior safety, are currently under clinical studies.

[0010] For the treatment of metastatic brain tumors using an antibody-drug conjugate, clinical and non-clinical studies of the treatment of metastatic brain tumors arising from breast cancer as a primary cancer using trastuzumab emtansine, which is a conjugate, are known. of anti-HER2 antibody-drug having, as a component, DM1, which is a tubulin inhibitor, (Non-Patent References 20 to 23).

LIST OF QUOTES Patent Literature:

[0011] Patent Reference 1: International Publication No. WO 2014/057687 Patent Reference 2: International Publication No. WO 2015/098099 Patent Reference 3: International Publication No. WO 2015/115091 Patent Reference 4: International Publication No. WO 2015/ 155998 Patent Reference 5: International Publication No. WO 2018/066626 Non-Patent Literature:

[0012] Non-Patent Reference 1: Lorenzo R., et al., Ther. Adv. Med. Oncol. 2017 Dec; 9(12): 781-796.

[0013] Non-Patent Reference 2: Rahmathulla G., et al., Journal of Oncology 2012, Article ID 723541.

[0014] Non-Patent Reference 3: Kim J-E., et al., Lung Cancer 2009; 65: 351-354.

[0015] Non-Patent Reference 4: Iuchi T., et al., Cancer 2013; 82: 282-287.

[0016] Non-Patent Reference 5: Hoffknecht P., et al., J. Thorac. Oncol. 2015; 10: 156-163.

[0017] Non-Patent Reference 6: Ahn MJ., et al., Eur. J. Cancer 2015; 51: S625-S626.

[0018] Non-Patent Reference 7: Costa DB., et al., J. Clin. Oncol. 2015; 33: 1881-1888.

[0019] Non-Patent Reference 8: Bartsch R., et al., J. Neurooncol. 2007; 85: 311-317.

[0020] Non-Patent Reference 9: Lin NU., et al., Clin. Cancer Res. 2009; 15: 1452-1459.

[0021] Non-Patent Reference 10: Dummer R., et al., Eur. J. Cancer 2014; 50: 611-621.

[0022] Non-Patent Reference 11: Ducry L., et al., Bioconjugate Chem. (2010) 21, 5-13.

[0023] Non-Patent Reference 12: Alley S. C., et al., Current Opinion in Chemical Biology (2010) 14, 529-537.

[0024] Non-Patent Reference 13: Damle N. K., Expert Opin. Biol. The R. (2004) 4, 1445-1452.

[0025] Non-Patent Reference 14: Senter P. D., et al., Nature Biotechnology (2012) 30, 631-637.

[0026] Non-Patent Reference 15: Howard A., et al., J. Clin. Oncol. 29: 398-405.

[0027] Non-Patent Reference 16: Ogitani Y., et al., Clinical Cancer Research (2016) 22(20), 5097-5108.

[0028] Non-Patent Reference 17: Ogitani Y., et al., Cancer Science (2016) 107, 1039-1046.

[0029] Non-Patent Reference 18: Doi T., et al., Lancet Oncol. 2017; 18: 1512-22.

[0030] Non-Patent Reference 19: Takegawa N., et al., Int. J. Cancer: 141, 1682-1689 (2017).

[0031] Non-Patent Reference 20: Bartsch R., et al., Clin. Exp Metastasis (2015) 32:729–737.

[0032] Non-Patent Reference 21: Askoxylakis V., et al., J. Natl. Cancer Inst. (2016) 108(2): djv313.

[0033] Non-Patent Reference 22: Ricciardi GRR., et al., BMC Cancer (2018) 18:97.

[0034] Non-Patent Reference 23: Okines A., et al., Breast J. 2018; 24:253-259.

SUMMARY OF THE INVENTION Technical problem:

[0035] Low molecular weight compounds and antibodies are used as therapeutic agents against cancer but it is usually difficult for them to pass through the blood-brain barrier (BBB). In particular, since antibodies have extremely high molecular weight, it cannot be substantially predicted that they will pass through the blood-brain barrier (Bendell JC., et al., Cancer 2003; 97(12):2972-7). On the other hand, there is a report that an antibody administered intravenously for the purpose of treating a metastatic brain tumor passed through the blood-brain barrier (Tamura K., et al., J. Nucl. Med. 2013; 54(11) :1869-75). It is inferred that the reason for this is that the blood-brain barrier had been destroyed by the tumor that had metastasized to the brain, and therefore the ability of the antibody to migrate to the brain relatively increased.

[0036] However, there is also a report that even in the case in which intracerebral concentrations of small molecular compound and antibody showed considerable values, a predicted therapeutic effect was not obtained. It is inferred that the reason for this is that the tumor that had metastasized to the brain had acquired drug resistance (e.g., a gene mutation that affects drug elimination and downstream signaling mechanisms, or the like, such as glycoprotein -P) (Saunus JM., et al., J. Pathol. 2015; 237:363-78, Brastianos PK., et al., Cancer Discov. 2015; 5:1164-77).

[0037] Furthermore, it is also known that a blood-tumor barrier (BHT) is formed between a tumor that metastasizes to the brain and normal tissues in the brain, whereby drug resistance appears (Quail DF. et al., Cancer Cell 2017 ; 31:326-41).

[0038] An object of the present invention is to verify whether or not a specific antibody-drug conjugate including an exatecan derivative as a component passes through the blood-brain barrier and whether or not it exerts a purported antitumor effect on a metastatic brain tumor that has acquired drug resistance. Additionally, another object is to provide a therapeutic agent for a metastatic brain tumor comprising the antibody-drug conjugate, and/or a method of treatment for a metastatic brain tumor comprising administering to a subject the antibody-drug conjugate.

Solution of the problem:

[0039] As a result of diligent studies for the purpose of solving the above problems, the present inventors have discovered that a specific antibody-drug conjugate including an exatecan derivative as a component exhibits an excellent antitumor effect on metastatic brain tumors, concluding thus, the present invention.

[0040] Therefore, the present invention provides the following [1] to [272]: [1] A therapeutic agent for a metastatic brain tumor comprising, as an active component, an antibody-drug conjugate in which a drug-connector represented by the following formula: [Formula 1] wherein A represents a connection position to an antibody; it is conjugated to the antibody via a thioether bond.

[0041] [2] The therapeutic agent according to [1], wherein the primary cancer for the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer, melanoma, renal cell, kidney cancer, colorectal cancer, gastric cancer, head and neck cancer, hepatocellular cancer, liver cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, endometrial cancer, thyroid cancer, malignant lymphoma and sarcoma.

[0042] [3] The therapeutic agent according to [1], wherein the primary cancer for the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer and melanoma.

[0043] [4] The therapeutic agent according to [1], wherein the primary cancer for the metastatic brain tumor is breast cancer.

[0044] [5] The therapeutic agent according to [1], wherein the primary cancer for the metastatic brain tumor is lung cancer.

[0045] [6] The therapeutic agent according to [1], wherein the primary cancer for the metastatic brain tumor is melanoma.

[0046] [7] The therapeutic agent according to any one of [1] to [6], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti- TROP2, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[0047] [8] The therapeutic agent according to [7], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[0048] [9] The therapeutic agent according to [8], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2.

[0049] [10] The therapeutic agent according to [8], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 1 and a light chain consisting of a amino acid sequence represented by SEQ ID NO: 2.

[0050] [11] The therapeutic agent according to any one of [8] to [10], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.

[0051] [12] The therapeutic agent according to [7], wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[0052] [13] The therapeutic agent according to [12], wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 3 and a light chain consisting of a amino acid sequence represented by SEQ ID NO: 4.

[0053] [14] The therapeutic agent according to [13], wherein the anti-HER3 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[0054] [15] The therapeutic agent according to any one of [12] to [14], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.

[0055] [16] The therapeutic agent according to [7], wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[0056] [17] The therapeutic agent according to [16], wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 5 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 6.

[0057] [18] The therapeutic agent according to [17], in which the anti-TROP2 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[0058] [19] The therapeutic agent according to any one of [16] to [18], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 3 .5 to 4.5.

[0059] [20] The therapeutic agent according to [7], wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[0060] [21] The therapeutic agent according to [20], wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO : 7 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 8.

[0061] [22] The therapeutic agent according to [21], wherein the anti-B7-H3 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[0062] [23] The therapeutic agent according to any one of [20] to [22], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 3 .5 to 4.5.

[0063] [24] The therapeutic agent according to [7], wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[0064] [25] The therapeutic agent according to [24], wherein the anti-GPR20 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 472 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 10.

[0065] [26] The therapeutic agent according to [25], wherein the anti-GPR20 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[0066] [27] The therapeutic agent according to any one of [24] to [26], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.

[0067] [28] The therapeutic agent according to [7], wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[0068] [29] The therapeutic agent according to [28], wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 11 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 12.

[0069] [30] The therapeutic agent according to [29], in which the anti-CDH6 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[0070] [31] The therapeutic agent according to any one of [28] to [30], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.

[0071] [32] A therapeutic agent for a metastatic brain tumor comprising, as an active component, an antibody-drug conjugate represented by the following formula: [Formula 2] where the drug-connector is conjugated with the antibody via a thioether bond, and n is the average number of drug-connector units conjugated per antibody molecule.

[0072] [33] The therapeutic agent according to [32], wherein the primary cancer for the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer, melanoma, breast cancer renal cell, kidney cancer, colorectal cancer, gastric cancer, head and neck cancer, hepatocellular cancer, liver cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, endometrial cancer, thyroid cancer, malignant lymphoma and sarcoma.

[0073] [34] The therapeutic agent according to [32], wherein the primary cancer for the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer and melanoma.

[0074] [35] The therapeutic agent according to [32], wherein the primary cancer for the metastatic brain tumor is breast cancer.

[0075] [36] The therapeutic agent according to [32], wherein the primary cancer for the metastatic brain tumor is lung cancer.

[0076] [37] The therapeutic agent according to [32], wherein the primary cancer for the metastatic brain tumor is melanoma.

[0077] [38] The therapeutic agent according to any one of [32] to [37], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti- TROP2, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.

[0078] [39] The therapeutic agent according to [38], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[0079] [40] The therapeutic agent according to [39], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2.

[0080] [41] The therapeutic agent according to [39], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 1 and a light chain consisting of a amino acid sequence represented by SEQ ID NO: 2.

[0081] [42] The therapeutic agent according to any one of [39] to [41], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.

[0082] [43] The therapeutic agent according to [38], wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[0083] [44] The therapeutic agent according to [43], wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 3 and a light chain consisting of a amino acid sequence represented by SEQ ID NO: 4.

[0084] [45] The therapeutic agent according to [44], wherein the anti-HER3 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[0085] [46] The therapeutic agent according to any one of [43] to [45], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.

[0086] [47] The therapeutic agent according to [38], wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[0087] [48] The therapeutic agent according to [47], wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 5 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 6.

[0088] [49] The therapeutic agent according to [48], in which the anti-TROP2 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[0089] [50] The therapeutic agent according to any one of 47 to 49, wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 3.5 to 4 .5.

[0090] [51] The therapeutic agent according to [38], wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[0091] [52] The therapeutic agent according to [51], wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO : 7 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 8.

[0092] [53] The therapeutic agent according to [52], wherein the anti-B7-H3 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[0093] [54] The therapeutic agent according to any one of [51] to [53], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 3 .5 to 4.5.

[0094] [55] The therapeutic agent according to [38], wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[0095] [56] The therapeutic agent according to [55], wherein the anti-GPR20 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 472 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 10.

[0096] [57] The therapeutic agent according to [56], wherein the anti-GPR20 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[0097] [58] The therapeutic agent according to any one of [55] to [57], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.

[0098] [59] The therapeutic agent according to [38], wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[0099] [60] The therapeutic agent according to [59], wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 11 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 12.

[00100] [61] The therapeutic agent according to [60], wherein the anti-CDH6 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[00101] [62] The therapeutic agent according to any one of [59] to [61], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.

[00102] [63] A method of treatment for a metastatic brain tumor, comprising administering an antibody-drug conjugate in which a drug-connector represented by the following formula: [Formula 3] wherein A represents a connection position to an antibody, is conjugated to the antibody via a thioether bond; to a subject requiring treatment for a metastatic brain tumor.

[00103] [64] The treatment method according to [63], wherein the primary cancer for the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer, melanoma, cancer renal cell cancer, kidney cancer, colorectal cancer, gastric cancer, head and neck cancer, hepatocellular cancer, liver cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, endometrial cancer, thyroid cancer, lymphoma malignant and sarcoma.

[00104] [65] The treatment method according to [63], wherein the primary cancer for the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer and melanoma.

[00105] [66] The treatment method according to [63], wherein the primary cancer for the metastatic brain tumor is breast cancer.

[00106] [67] The treatment method according to [63], wherein the primary cancer for the metastatic brain tumor is lung cancer.

[00107] [68] The treatment method according to [63], wherein the primary cancer for the metastatic brain tumor is melanoma.

[00108] [69] The treatment method according to any one of [63] to [68], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti- -TROP2, an anti-B7-H3 antibody, an anti-GPR20 antibody or an anti-CDH6 antibody.

[00109] [70] The treatment method according to [69], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[00110] [71] The treatment method according to [70], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2.

[00111] [72] The treatment method according to [70], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 1 and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 2.

[00112] [73] The treatment method according to any one of [70] to [72], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.

[00113] [74] The treatment method according to [69], wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[00114] [75] The treatment method according to [74], wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 3 and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 4.

[00115] [76] The treatment method according to [75], in which the anti-HER3 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[00116] [77] The treatment method according to any one of [74] to [76], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.

[00117] [78] The treatment method according to [69], wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[00118] [79] The treatment method according to [78], wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 5 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 6.

[00119] [80] The treatment method according to [79], in which the anti-TROP2 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[00120] [81] The treatment method according to any one of [78] to [80], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[00121] [82] The treatment method according to [69], wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[00122] [83] The treatment method according to [82], wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 7 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 8.

[00123] [84] The treatment method according to [83], in which the anti-B7-H3 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[00124] [85] The treatment method according to any one of [82] to [84], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 3.5 to 4.5.

[00125] [86] The treatment method according to [69], wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[00126] [87] The treatment method according to [86], wherein the anti-GPR20 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 472 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 10.

[00127] [88] The treatment method according to [87], in which the anti-GPR20 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[00128] [89] The treatment method according to any one of [86] to [88], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.

[00129] [90] The treatment method according to [69], wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[00130] [91] The treatment method according to [90], wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 11 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 12.

[00131] [92] The treatment method according to [91], in which the anti-CDH6 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[00132] [93] The treatment method according to any one of [90] to [92], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.

[00133] [94] A method of treatment for a metastatic brain tumor, comprising administering an antibody-drug conjugate represented by the following formula: [Formula 4] where the drug-connector is conjugated with the antibody via a thioether bond, and n is the average number of drug-connector units conjugated per antibody molecule; to a subject requiring treatment for a metastatic brain tumor.

[00134] [95] The treatment method according to [94], wherein the primary cancer for the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer, melanoma, cancer renal cell cancer, kidney cancer, colorectal cancer, gastric cancer, head and neck cancer, hepatocellular cancer, liver cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, endometrial cancer, thyroid cancer, lymphoma malignant and sarcoma.PCT/JP2019/029765[96] The treatment method according to [94], wherein the primary cancer for the metastatic brain tumor is at least one selected from the group consisting of breast cancer, cancer of lung and melanoma.PCT/JP2019/029765[97] The treatment method according to [94], in which the primary cancer for metastatic brain tumor is breast cancer.PCT/JP2019/029765[98] The method of treatment according to [94], wherein the primary cancer for the metastatic brain tumor is lung cancer.PCT/JP2019/029765[99] The treatment method according to [94], wherein the primary cancer for the metastatic brain tumor is melanoma.PCT/JP2019/029765[100] The method of treatment according to any one of [94] to [99], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody , an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody or an anti-CDH6 antibody.PCT/JP2019/029765[101] The treatment method according to [100 ], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.PCT/JP2019/029765[102] The method of treatment according to [101], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2.PCT/JP2019 /029765[103] The treatment method according to [101], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 1 and a light chain consisting of a amino acid sequence represented by SEQ ID NO: 2.PCT/JP2019/029765[104] The treatment method according to any one of [101] to [103], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.PCT/JP2019/029765[105] The treatment method according to [100], wherein the antibody in the antibody-drug conjugate is an anti- -HER3.PCT/JP2019/029765[106] The treatment method according to [105], wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 3 and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 4.PCT/JP2019/029765[107] The treatment method according to [106], wherein the anti-HER3 antibody does not have a lysine residue in the carboxyl terminus of the heavy chain.PCT/JP2019/029765[108] The method of treatment according to any one of [105] to [107], wherein the average number of drug-connector units conjugated per antibody molecule in the conjugate of antibody-drug is in the range of 7 to 8.PCT/JP2019/029765[109] The treatment method according to [100], wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.PCT/ JP2019/029765[110] The treatment method according to [109], wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 5 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 6.PCT/JP2019/029765[111] The treatment method according to [110], wherein the anti- -TROP2 does not have a lysine residue at the carboxyl terminus of the heavy chain.PCT/JP2019/029765[112] The treatment method according to any one of [109] to [111], wherein the average number of drug units -connector conjugated per antibody molecule in the antibody-drug conjugate is in the range of 3.5 to 4.5.PCT/JP2019/029765[113] The treatment method according to [100], in which the antibody in the conjugate of antibody-drug is an anti-B7-H3 antibody.PCT/JP2019/029765[114] The treatment method according to [113], wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 7 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 8.PCT/JP2019/029765[115 ] The treatment method according to [114], wherein the anti-B7-H3 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.PCT/JP2019/029765[116] The treatment method according to any one from [113] to [115], where the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 3.5 to 4.5.PCT/JP2019/029765[ 117] The treatment method according to [100], wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.PCT/JP2019/029765[118] The treatment method according to [117], in that the anti-GPR20 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 472 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 10.PCT/JP2019/029765[119] The treatment method according to [118], wherein the anti-GPR20 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.PCT/JP2019 /029765[120] The method of treatment according to any one of [117] to [119], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.PCT/JP2019/029765[121] The method of treatment according to [100], wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.PCT/JP2019/029765[122] The method of treatment according to [121], wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 11 and a light chain consisting of a sequence of amino acids consisting of amino acid residues 21 to 233 of SEQ ID NO: 12.PCT/JP2019/029765[123] The treatment method according to [122], wherein the anti-CDH6 antibody does not have a lysine residue in the carboxyl terminus of the heavy chain.PCT/JP2019/029765[124] The method of treatment according to any one of [121] to [123], wherein the average number of drug-connector units conjugated per antibody molecule in the conjugate of antibody-drug is in the range of 7 to 8.PCT/JP2019/029765[125] An antibody-drug conjugate, for use in the treatment of a metastatic brain tumor, in which a drug-connector represented by the following formula:PCT /JP2019/029765[Formula 5]PCT/JP2019/029765 wherein A represents a connection position to an antibody; it is conjugated to the antibody via a thioether bond.

[00135] [126] The antibody-drug conjugate according to [125], wherein the primary cancer for the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer, melanoma , renal cell cancer, kidney cancer, colorectal cancer, gastric cancer, head and neck cancer, hepatocellular cancer, liver cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, endometrial cancer, thyroid cancer , malignant lymphoma and sarcoma.PCT/JP2019/029765[127] The antibody-drug conjugate according to [125], wherein the primary cancer for the metastatic brain tumor is at least one selected from the group consisting of cancer breast cancer, lung cancer and melanoma.PCT/JP2019/029765[128] The antibody-drug conjugate according to [125], wherein the primary cancer for the metastatic brain tumor is breast cancer.PCT/JP2019/ 029765[129] The antibody-drug conjugate according to [125], wherein the primary cancer for the metastatic brain tumor is lung cancer.PCT/JP2019/029765[130] The antibody-drug conjugate according to [125], wherein the primary cancer for the metastatic brain tumor is melanoma.PCT/JP2019/029765[131] The antibody-drug conjugate according to any one of [125] to [130], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.PCT/JP2019/029765 [132] The antibody-drug conjugate according to [131], wherein the antibody in the antibody-drug conjugate is an anti-HER2PCT antibody/JP2019/029765[133] The antibody-drug conjugate according to [132 ], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of residues of amino acids 1 to 214 of SEQ ID NO: 2.PCT/JP2019/029765[134] The antibody-drug conjugate according to [132], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of a sequence of amino acids represented by SEQ ID NO: 1 and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 2.PCT/JP2019/029765[135] The antibody-drug conjugate according to any one of [132] to [134], where the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8. PCT/JP2019/029765[136] The antibody-drug conjugate of according to [131], wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.PCT/JP2019/029765[137] The antibody-drug conjugate according to [136], wherein the anti-HER3 antibody HER3 is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 3 and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 4.PCT/JP2019/029765[138] The conjugate of antibody-drug according to [137], wherein the anti-HER3 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain. PCT/JP2019/029765[139] The antibody-drug conjugate according to any of [136] to [138], where the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.PCT/JP2019/029765[140] The antibody conjugate -drug according to [131], wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.PCT/JP2019/029765[141] The antibody-drug conjugate according to [140], wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 5 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 6.PCT/JP2019/029765[142] The antibody-drug conjugate according to [141], wherein the anti-TROP2 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.PCT/JP2019 /029765[143] The antibody-drug conjugate according to any one of [140] to [142], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range from 3.5 to 4.5.PCT/JP2019/029765[144] The antibody-drug conjugate according to [131], wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.PCT /JP2019/029765[145] The antibody-drug conjugate according to [144], wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 7 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 8.PCT/JP2019/029765[146] The antibody-drug conjugate according to [145 ], wherein the anti-B7-H3 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.PCT/JP2019/029765[147] The antibody-drug conjugate according to any one of [144] to [146 ], where the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 3.5 to 4.5.PCT/JP2019/029765[148] The antibody-drug conjugate according to [131], wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.PCT/JP2019/029765[149] The antibody-drug conjugate according to [148], wherein the anti-GPR antibody -GPR20 is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 472 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 10.PCT/JP2019/029765[150] The antibody-drug conjugate according to [149], wherein the anti-GPR20 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.PCT/JP2019/029765 [151] The antibody-drug conjugate according to any one of [148] to [150], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.PCT/JP2019/029765[152] The antibody-drug conjugate according to [131], wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.PCT/JP2019/029765[153] antibody-drug conjugate according to [152], wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 11 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 12.PCT/JP2019/029765[154] The antibody-drug conjugate according to [153], wherein the anti-CDH6 antibody does not has a lysine residue at the carboxyl terminus of the heavy chain.PCT/JP2019/029765[155] The antibody-drug conjugate according to any one of [152] to [154], wherein the average number of units of the drug- connector conjugates per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.PCT/JP2019/029765[156] An antibody-drug conjugate, for use in the treatment of a metastatic brain tumor, represented by the following formula :PCT/JP2019/029765[Formula 6] where the drug-connector is conjugated with the antibody via a thioether bond, and n is the average number of drug-connector units conjugated per antibody molecule.

[00136] [157] The antibody-drug conjugate according to [156], wherein the primary cancer for the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer, melanoma , renal cell cancer, kidney cancer, colorectal cancer, gastric cancer, head and neck cancer, hepatocellular cancer, liver cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, endometrial cancer, thyroid cancer , malignant lymphoma and sarcoma.

[00137] [158] The antibody-drug conjugate according to [156], wherein the primary cancer for the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer and melanoma .

[00138] [159] The antibody-drug conjugate according to [156], wherein the primary cancer for the metastatic brain tumor is breast cancer.

[00139] [160] The antibody-drug conjugate according to [156], wherein the primary cancer for the metastatic brain tumor is lung cancer.

[00140] [161] The antibody-drug conjugate according to [156], wherein the primary cancer for the metastatic brain tumor is melanoma.

[00141] [162] The antibody-drug conjugate according to any one of [156] to [161], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody or an anti-CDH6 antibody.

[00142] [163] The antibody-drug conjugate according to [162], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[00143] [164] The antibody-drug conjugate according to [163], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2.

[00144] [165] The antibody-drug conjugate according to [163], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 1 and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 2.

[00145] [166] The antibody-drug conjugate according to any one of [163] to [165], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range from 7 to 8.

[00146] [167] The antibody-drug conjugate according to [162], wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[00147] [168] The antibody-drug conjugate according to [167], wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 3 and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 4.

[00148] [169] The antibody-drug conjugate according to [168], wherein the anti-HER3 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[00149] [170] The antibody-drug conjugate according to any one of [167] to [169], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range from 7 to 8.

[00150] [171] The antibody-drug conjugate according to [162], wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[00151] [172] The antibody-drug conjugate according to [171], wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 5 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 6.

[00152] [173] The antibody-drug conjugate according to [172], wherein the anti-TROP2 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[00153] [174] The antibody-drug conjugate according to any one of [171] to [173], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range from 3.5 to 4.5.

[00154] [175] The antibody-drug conjugate according to [162], wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[00155] [176] The antibody-drug conjugate according to [175], wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 7 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 8.

[00156] [177] The antibody-drug conjugate according to [176], wherein the anti-B7-H3 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[00157] [178] The antibody-drug conjugate according to any one of [175] to [177], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range from 3.5 to 4.5.

[00158] [179] The antibody-drug conjugate according to [162], wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[00159] [180] The antibody-drug conjugate according to [179], wherein the anti-GPR20 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 472 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 10.

[00160] [181] The antibody-drug conjugate according to [180], wherein the anti-GPR20 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[00161] [182] The antibody-drug conjugate according to any one of [179] to [181], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range from 7 to 8.

[00162] [183] The antibody-drug conjugate according to [162], wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[00163] [184] The antibody-drug conjugate according to [183], wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 11 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 12.

[00164] [185] The antibody-drug conjugate according to [184], wherein the anti-CDH6 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[00165] [186] The antibody-drug conjugate according to any one of [183] to [185], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range from 7 to 8.

[00166] [187] Use of an antibody-drug conjugate for the manufacture of a medicine for the treatment of a metastatic brain tumor, in which a drug-connector represented by the following formula: [Formula 7] where A represents a position of connection to an antibody; it is conjugated to the antibody via a thioether bond.

[00167] [188] The use according to [187], wherein the primary cancer for the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer, melanoma, cell cancer renal, kidney cancer, colorectal cancer, gastric cancer, head and neck cancer, hepatocellular cancer, liver cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, endometrial cancer, thyroid cancer, malignant lymphoma and sarcoma.

[00168] [189] The use according to [187], wherein the primary cancer for the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer and melanoma.

[00169] [190] The use according to [187], wherein the primary cancer for the metastatic brain tumor is breast cancer.

[00170] [191] The use according to [187], wherein the primary cancer for the metastatic brain tumor is lung cancer.

[00171] [192] The use according to [187], wherein the primary cancer for the metastatic brain tumor is melanoma.

[00172] [193] The use according to any one of [187] to [192], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody , an anti-B7-H3 antibody, an anti-GPR20 antibody or an anti-CDH6 antibody.

[00173] [194] The use according to [193], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[00174] [195] The use according to [194], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2.

[00175] [196] The use according to [194], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 1 and a light chain consisting of a sequence of amino acids represented by SEQ ID NO: 2.

[00176] [197] The use according to any one of [194] to [196], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.

[00177] [198] The use according to [193], wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[00178] [199] The use according to [198], wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 3 and a light chain consisting of a sequence of amino acids represented by SEQ ID NO: 4.

[00179] [200] The use according to [199], in which the anti-HER3 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[00180] [201] The use according to any one of [198] to [200], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.

[00181] [202] The use according to [193], wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[00182] [203] The use according to [202], wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 5 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 6.

[00183] [204] The use according to [203], in which the anti-TROP2 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[00184] [205] The use according to any one of [202] to [204], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 3, 5 to 4.5.

[00185] [206] The use according to [193], wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[00186] [207] The use according to [206], wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 7 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 8.

[00187] [208] The use according to [207], in which the anti-B7-H3 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[00188] [209] The use according to any one of [206] to [208], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 3, 5 to 4.5.

[00189] [210] The use according to [193], wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[00190] [211] The use according to [210], wherein the anti-GPR20 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 472 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 10.

[00191] [212] The use according to [211], in which the anti-GPR20 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[00192] [213] The use according to any one of [210] to [212], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.

[00193] [214] The use according to [193], wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[00194] [215] The use according to [214], wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 11 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 12.

[00195] [216] The use according to [215], in which the anti-CDH6 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[00196] [217] The use according to any one of [214] to [216], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.

[00197] [218] Use of an antibody-drug conjugate for the manufacture of a medicine for the treatment of a metastatic brain tumor, represented by the following formula: [Formula 8] where the drug-connector is conjugated with the antibody via a thioether bond, and n is the average number of drug-connector units conjugated per antibody molecule.

[00198] [219] The use according to [218], wherein the primary cancer for the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer, melanoma, cell cancer renal, kidney cancer, colorectal cancer, gastric cancer, head and neck cancer, hepatocellular cancer, liver cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, endometrial cancer, thyroid cancer, malignant lymphoma and sarcoma.

[00199] [220] The use according to [218], wherein the primary cancer for the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer and melanoma.

[00200] [221] The use according to [218], wherein the primary cancer for the metastatic brain tumor is breast cancer.

[00201] [222] The use according to [218], wherein the primary cancer for the metastatic brain tumor is lung cancer.

[00202] [223] The use according to [218], wherein the primary cancer for the metastatic brain tumor is melanoma.

[00203] [224] The use according to any one of [218] to [223], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody , an anti-B7-H3 antibody, an anti-GPR20 antibody or an anti-CDH6 antibody.

[00204] [225] The use according to [224], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

[00205] [226] The use according to [225], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2.

[00206] [227] The use according to [225], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 1 and a light chain consisting of a sequence of amino acids represented by SEQ ID NO: 2.

[00207] [228] The use according to any one of [225] to [227], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.

[00208] [229] The use according to [224], wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

[00209] [230] The use according to [229], wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 3 and a light chain consisting of a sequence of amino acids represented by SEQ ID NO: 4.

[00210] [231] The use according to [230], in which the anti-HER3 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[00211] [232] The use according to any one of [229] to [231], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.

[00212] [233] The use according to [224], wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

[00213] [234] The use according to [233], wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 5 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 6.

[00214] [235] The use according to [234], in which the anti-TROP2 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[00215] [236] The use according to any one of [233] to [235], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 3, 5 to 4.5.

[00216] [237] The use according to [224], wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

[00217] [238] The use according to [237], wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 7 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 8.

[00218] [239] The use according to [238], in which the anti-B7-H3 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[00219] [240] The use according to any one of [237] to [239], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 3, 5 to 4.5.

[00220] [241] The use according to [224], wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

[00221] [242] The use according to [241], wherein the anti-GPR20 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 472 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 10.

[00222] [243] The use according to [242], in which the anti-GPR20 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[00223] [244] The use according to any one of [241] to [243], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.

[00224] [245] The use according to [244], wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.

[00225] [246] The use according to [245], wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 11 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 12.

[00226] [247] The use according to [246], in which the anti-CDH6 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain.

[00227] [248] The use according to any one of [245] to [247], wherein the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.

[00228] [249] A therapeutic agent for metastatic cancer comprising, as an active component, an antibody-drug conjugate in which a drug-connector represented by the following formula: [Formula 9] wherein A represents a connection position to an antibody; it is conjugated to the antibody via a thioether bond.

[00229] [250] The therapeutic agent according to [249], wherein the metastatic cancer is at least one selected from the group consisting of a metastatic brain tumor, a metastatic bone tumor, a metastatic lung tumor and metastatic lung cancer. metastatic liver.

[00230] [251] The therapeutic agent according to [250], wherein the metastatic cancer is a metastatic bone tumor.

[00231] [252] A therapeutic agent for metastatic cancer comprising, as an active component, an antibody-drug conjugate represented by the following formula: [Formula 10] where the drug-connector is conjugated with the antibody via a thioether bond, and n is the average number of drug-connector units conjugated per antibody molecule.

[00232] [253] The therapeutic agent according to [252], wherein the metastatic cancer is at least one selected from the group consisting of a metastatic brain tumor, a metastatic bone tumor, a metastatic lung tumor and metastatic lung cancer. metastatic liver.

[00233] [254] The therapeutic agent according to [253], wherein the metastatic cancer is a metastatic bone tumor.

[00234] [255] A method of treatment for metastatic cancer, comprising administering an antibody-drug conjugate in which a drug-connector represented by the following formula: [Formula 11] wherein A represents a connection position to an antibody, is conjugated to the antibody via a thioether bond; to a subject who needs treatment for metastatic cancer.

[00235] [256] The treatment method according to [255], wherein the metastatic cancer is at least one selected from the group consisting of a metastatic brain tumor, a metastatic bone tumor, a metastatic lung tumor and cancer of metastatic liver.

[00236] [257] The treatment method according to [256], wherein the metastatic cancer is a metastatic bone tumor.

[00237] [258] A method of treatment for metastatic cancer, comprising administering an antibody-drug conjugate represented by the following formula: [Formula 12] where the drug-connector is conjugated with the antibody via a thioether bond, and n is the average number of drug-connector units conjugated per antibody molecule; to a subject who needs treatment for metastatic cancer.

[00238] [259] The treatment method according to [258], wherein the metastatic cancer is at least one selected from the group consisting of a metastatic brain tumor, a metastatic bone tumor, a metastatic lung tumor and cancer of metastatic liver.

[00239] [260] The treatment method according to [259], wherein the metastatic cancer is a metastatic bone tumor.

[00240] [261] An antibody-drug conjugate for use in the treatment of metastatic cancer, in which a drug-connector is represented by the following formula: [Formula 13] wherein A represents a connection position to an antibody; it is conjugated to the antibody via a thioether bond.

[00241] [262] The antibody-drug conjugate according to [261], wherein the metastatic cancer is at least one selected from the group consisting of a metastatic brain tumor, a metastatic bone tumor, a metastatic lung tumor and metastatic liver cancer.

[00242] [263] The antibody-drug conjugate according to [262], wherein the metastatic cancer is a metastatic bone tumor.

[00243] [264] An antibody-drug conjugate for use in the treatment of metastatic cancer, represented by the following formula: [Formula 14] where the drug-connector is conjugated with the antibody via a thioether bond, and n is the average number of drug-connector units conjugated per antibody molecule.

[00244] [265] The antibody-drug conjugate according to [264], wherein the metastatic cancer is at least one selected from the group consisting of a metastatic brain tumor, a metastatic bone tumor, a metastatic lung tumor and metastatic liver cancer.

[00245] [266] The antibody-drug conjugate according to [265], wherein the metastatic cancer is a metastatic bone tumor.

[00246] [267] Use of an antibody-drug conjugate for the manufacture of a medicine for the treatment of metastatic cancer, in which a drug-connector represented by the following formula: [Formula 15] wherein A represents a connection position to an antibody; it is conjugated to the antibody via a thioether bond. [268] The use according to [267], wherein the metastatic cancer is at least one selected from the group consisting of a metastatic brain tumor, a metastatic bone tumor, a metastatic lung tumor and metastatic liver cancer. [269] The use according to [268], wherein the metastatic cancer is a metastatic bone tumor. [270] Use of an antibody-drug conjugate for the manufacture of a medicine for the treatment of metastatic cancer, represented by the following formula: [Formula 16] where the drug-connector is conjugated with the antibody via a thioether bond, and n is the average number of drug-connector units conjugated per antibody molecule. [271] The use according to [270], wherein the metastatic cancer is at least one selected from the group consisting of a metastatic brain tumor, a metastatic bone tumor, a metastatic lung tumor and metastatic liver cancer. [272] The use according to [271], wherein the metastatic cancer is a metastatic bone tumor.

ADVANTAGEOUS EFFECTS OF THE INVENTION

[00247] The present invention provides a therapeutic agent for a metastatic brain tumor comprising a specific antibody-drug conjugate, and/or a method of treatment for a metastatic brain tumor comprising administering to a subject a specific antibody-drug conjugate .

BRIEF DESCRIPTION OF THE DRAWINGS

[00248] [Figure 1] Figure 1 is a diagram showing the amino acid sequence of a heavy chain of an anti-HER2 antibody (SEQ ID NO: 1).

[00249] [Figure 2] Figure 2 is a diagram showing the amino acid sequence of a light chain of an anti-HER2 antibody (SEQ ID NO: 2).

[00250] [Figure 3] Figure 3 is a diagram showing the amino acid sequence of a heavy chain of an anti-HER3 antibody (SEQ ID NO: 3).

[00251] [Figure 4] Figure 4 is a diagram showing the amino acid sequence of a light chain of an anti-HER3 antibody (SEQ ID NO: 4).

[00252] [Figure 5] Figure 5 is a diagram showing the amino acid sequence of a heavy chain of an anti-TROP2 antibody (SEQ ID NO: 5).

[00253] [Figure 6] Figure 6 is a diagram showing the amino acid sequence of a light chain of an anti-TROP2 antibody (SEQ ID NO: 6).

[00254] [Figure 7] Figure 7 is a diagram showing the amino acid sequence of a heavy chain of an anti-B7-H3 antibody (SEQ ID NO: 7).

[00255] [Figure 8] Figure 8 is a diagram showing the amino acid sequence of a light chain of an anti-B7-H3 antibody (SEQ ID NO: 8).

[00256] [Figure 9] Figure 9 is a diagram showing the life-prolonging effects of an antibody-drug conjugate (1) on mice with intracranially transplanted KPL-4-Luc.

[00257] [Figure 10] Figure 10 is a diagram showing the antitumor effects of an antibody-drug conjugate (1) on mice with intracranially transplanted KPL-4-Luc. The amount of tumor is confirmed by the luminescence intensity of KPL-4-Luc.

[00258] [Figure 11] Figure 11 are diagrams showing the pathological images of the brain by hematoxylin and eosin staining in mice (No.1 and No.2) from a solvent administered group. The center images show the full pathological images, and the left and right images show the enlarged pathological images. Tumor masses are found in the area surrounded by a dashed line or in the area shown by arrows.

[00259] [Figure 12] Figure 12 is a diagram showing the amino acid sequence of a heavy chain of an anti-GPR20 antibody (SEQ ID NO: 9).

[00260] [Figure 13] Figure 13 is a diagram showing the amino acid sequence of a light chain of an anti-GPR20 antibody (SEQ ID NO: 10).

[00261] [Figure 14] Figure 14 is a diagram showing the amino acid sequence of a heavy chain of an anti-CDH6 antibody (SEQ ID NO: 11).

[00262] [Figure 15] Figure 15 is a diagram showing the amino acid sequence of a light chain of an anti-CDH6 antibody (SEQ ID NO: 12).

DESCRIPTION OF MODALITIES

[00263] Hereinafter, preferred modalities for carrying out the invention are described. The embodiments described below are provided merely to illustrate an example of a typical embodiment of the present invention and are not intended to limit the scope of the present invention.

1. Metastatic Brain Tumor:

[00264] In the present invention, the term “metastatic brain tumor” means a tumor developed by the metastasis of a primary cancer (a cancer developed in biological tissues other than the brain) to the brain. The metastatic brain tumor in the present invention includes not only tumors that metastasize into the brain parenchyma, but also tumors that invade the pia mater and the arachnoid membrane (meningeal carcinomatosis). The site of metastasis can be one or several sites. Furthermore, metastatic brain tumors are predominantly found after symptoms of a primary cancer, but can also be found before symptoms of a primary cancer.

[00265] Symptoms of metastatic brain tumor can be exemplified, for example, headache, vomiting, visual impairment, disturbance of consciousness, seizure, paralysis and language disturbance. It is inferred that these symptoms are caused by direct damage of brain tissues by a tumor and an increased intracranial pressure.

[00266] Examination of the metastatic brain tumor can be carried out, for example, by CT (Computed Tomography), PTE (Positron Emission Tomography), MRI (Magnetic Resonance Imaging), or similar.

[00267] For primary cancer, metastatic brain tumors, lung cancer, breast cancer, melanoma, renal cell cancer, kidney cancer, colorectal cancer, gastric cancer, head and neck cancer, hepatocellular cancer, cancer liver cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, endometrial cancer, thyroid cancer, malignant lymphoma and sarcoma. Among these, lung cancer, breast cancer and melanoma are particularly found as primary cancers for metastatic brain tumors in high percentages.

2. Antibody-Drug Conjugate:

[00268] The antibody-drug conjugate used in the present invention is an antibody-drug conjugate in which a drug-connector is represented by the following formula: [Formula 17] wherein A represents a connection position to an antibody; it is conjugated to the antibody via a thioether bond.

[00269] In the present invention, the partial structure of a connector and a drug in the antibody-drug conjugate is called a “drug-connector”. The drug-linker is connected to a thiol group (in other words, the sulfur atom of a cysteine residue) formed at an interchain disulfide bond site (two sites between the heavy chains, and two sites between a heavy chain and a light chain) in the antibody.

[00270] The drug-connector of the present invention includes, as a component, exatecan (IUPAC name: (1S,9S)-1-amino-9-ethyl-5-fluoro-1,2,3,9,12,15 -hexahydro-9-hydroxy-4-methyl-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10,13-dione, ( also called with the chemical name: (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyran [3',4':6,7]indolizino[1,2- b]quinolin-10,13(9H,15H)-dione)), which is an inhibitor of topoisomerase I. Exatecan is a camptothecin derivative that has antitumor effect, represented by the following formula: [Formula 18]

[00271] The antibody-drug conjugate used in the present invention can also be represented by the following formula: [Formula 19] in which the drug-connector is conjugated with an antibody via a thioether bond. The meaning of n is the same as what is called the average number of drug molecules conjugated (RFA; Ratio of Drug to Antibody), and indicates the average number of drug-connector units conjugated per antibody molecule.

[00272] After migration into cancer cells, the antibody-drug conjugate used in the present invention releases the compound represented by the following formula: [Formula 20] and thus exerts an antitumor effect.

[00273] It is inferred that the aforementioned compound is the original source of the antitumor activity of the antibody-drug conjugate used in the present invention, and it has been confirmed that it has a topoisomerase I inhibitory effect (Ogitani Y. et al., Clinical Cancer Research, 2016, Oct 15; 22(20):5097-5108, Epub 2016 Mar 29).

[00274] It is also known that the antibody-drug conjugate used in the present invention has a bystander effect (Ogitani Y. et al., Cancer Science (2016) 107, 1039-1046).

[00275] The bystander effect is exerted through a process such that the antibody-drug conjugate used in the present invention is internalized in cancer cells expressing the target and the aforementioned compound is released and then exerts an antitumor effect on the cancer cells that are present around and that do not express the target.

3. Antibody in Antibody-Drug Conjugate:

[00276] The antibody in the antibody-drug conjugate used in the present invention can be derived from any species, and is preferably an antibody derived from a human, a rat, a mouse, or a rabbit. In cases where the antibody is derived from species other than human, it is preferably chimerized or humanized using a well-known technique. The antibody of the present invention may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody.

[00277] The antibody in the antibody-drug conjugate used in the present invention is an antibody preferably having the property of being able to target cancer cells, and is preferably an antibody having the property of being able to recognize a cancer cell, a property of being able to bind to a cancer cell, the property of being incorporated and internalized into a cancer cell, and is preferably an antibody having the property of being able to recognize a cancer cell, the property of being able to bind to a cancer cell, the property of being incorporated and internalized into a cancer cell, and/or cytocidal activity against cancer cells.

[00278] The binding activity of the antibody against cancer cells can be confirmed using flow cytometry. Antibody internalization into cancer cells can be confirmed using (1) an assay to visualize a cell-incorporated antibody under a fluorescence microscope using a secondary (fluorescently labeled) antibody that binds to the therapeutic antibody (Cell Death and Differentiation (2008) 15, 751-761), (2) an assay measuring a cell-embedded fluorescence intensity using a secondary (fluorescently labeled) antibody that binds to the therapeutic antibody (Molecular Biology of the Cell, Vol. 15, 5268-5282, December 2004), or (3) a Mab-ZAP assay that uses an immunotoxin that binds to the therapeutic antibody in which the toxin is released upon incorporation into cells to inhibit cell growth (Bio Techniques 28 : 162-165, January 2000). As the immunotoxin, a recombinant complex protein of a diphtheria toxin catalytic domain and G-protein can be used.

[00279] The antitumor activity of the antibody can be confirmed in vitro by determining the inhibitory activity against cell growth. For example, a cancer cell line is cultured that overexpresses a target protein for the antibody, and the antibody is added in varying concentrations to the culture system that is capable of determining inhibitory activity against focus formation, colony formation, and spheroid growth. Antitumor activity can be confirmed in vivo, for example, by administering the antibody to a nude mouse with a transplanted cancer cell line that highly expresses the target protein, and by determining changes in the cancer cells.

[00280] Since the conjugated compound in the antibody-drug conjugate exerts an antitumor effect, it is preferred, but not essential, that the antibody itself should have an antitumor effect. For the purpose of specifically and selectively exerting the cytotoxic activity of the antitumor compound against cancer cells, it is important and also preferred that the antibody should have the property of being internalized to migrate into cancer cells.

[00281] The antibody in the antibody-drug conjugate used in the present invention can be obtained by a procedure known in the art. For example, the antibody of the present invention can be obtained using a method commonly performed in the art, which involves immunizing animals with an antigenic polypeptide and collecting and purifying antibodies produced in vivo. The origin of the antigen is not limited to humans, and animals can be immunized with an antigen derived from a non-human animal such as a mouse, a rat and the like. In this case, the cross-reactivity of antibodies, which bind to the obtained heterologous antigen, with human antigens, can be tested to screen for an antibody applicable to a human disease.

[00282] Alternatively, antibody-producing cells that produce antibodies against the antigen can be fused with myeloma cells according to a method known in the art (e.g., Kohler and Milstein, Nature (1975) 256, p. 495-497 ; Kennet, R. ed., Monoclonal Antibodies, p. 365-367, Plenum Press, N.Y., USA (1980)) to establish hybridomas, from which monoclonal antibodies can in turn be obtained.

[00283] The antigen can be obtained by host cells genetically engineered to produce a gene that encodes the antigenic protein. Specifically, vectors that allow expression of the antigen-coding gene are prepared and transferred into host cells so that the gene is expressed. The antigen thus expressed can be purified. The antibody can also be obtained by a method of immunizing animals with the genetically engineered antigen-expressing cells described above, or by a cell line that expresses the antigen.

[00284] The antibody in the antibody-drug conjugate used in the present invention is preferably a recombinant antibody obtained by artificial modification for the purpose of decreasing heterologous antigenicity to humans as a chimeric antibody or a humanized antibody, or is preferably an antibody having only the gene sequence of a human-derived antibody, i.e., a human antibody. These antibodies can be produced using a known method.

[00285] As the chimeric antibody, an antibody in which the variable and constant regions of the antibody are derived from different species can be exemplified, for example, a chimeric antibody in which a mouse or rat derived antibody variable region is connected to a human-derived antibody constant region (Proc. Natl. Acad. Sci. USA, 81, 6851-6855, (1984)).

[00286] As the humanized antibody, an antibody obtained by integrating only the complementarity determining region (CDR) of a heterologous antibody into a human-derived antibody can be exemplified (Nature (1986) 321, pp. 522-525), an antibody obtained by grafting a portion of the amino acid residues of the framework region of a heterologous antibody and also of the CDR sequence of the heterologous antibody onto a human antibody by a CDR grafting method (WO 90 /07861), and a humanized antibody using a gene conversion mutagenesis strategy (U.S. Patent No. 5,821,337).

[00287] Like the human antibody, an antibody generated by the use of a human antibody-producing mouse having a chromosome fragment including genes for a heavy chain and a light chain of a human antibody can be exemplified (see Tomizuka, K. et. al., Nature Genetics (1997) 16, p.133-143; Kuroiwa, Y. et al., Nucl. Acids Res. (1998) 26, p.3447-3448; Cell Technology: Basic and Applied Aspects” vol.10, p.69-73 (Kitagawa, Y., Matsuda, T. and Iijima, S. eds.), Kluwer Academic Publishers, 1999; Proc. Natl. Acad. Sci. USA (2000) 97, p.722-727, etc.). As an alternative, an antibody obtained by phage display may be exemplified, the antibody being selected from a library of human antibodies (see Wormstone, I. M. et al., Investigative Ophthalmology & Visual Science. (2002)43 (7), p. 2301-2308; Carmen, S. et al., Briefings in Functional Genomics and Proteomics (2002), 1(2), p.189-203; p.427-431, etc.).

[00288] In the antibody in the antibody-drug conjugate used in the present invention, modified variants of the antibody are also included. The modified variant refers to a variant obtained by subjecting the antibody according to the present invention to chemical or biological modification. Examples of the chemically modified variant include variants including a linkage of a chemical moiety to an amino acid backbone, variants including a linkage of a chemical moiety to an N-linked or O-linked carbohydrate chain, etc. Examples of biologically modified variants include variants obtained by post-translational modification (such as N-linked or O-linked glycosylation, N-terminal or C-terminal processing, deamidation, aspartic acid isomerization, or methionine oxidation), and variants in which a methionine residue is added to the N-terminus by being expressed in a prokaryotic host cell. Furthermore, an antibody labeled so as to permit detection or isolation of the antibody or antigen according to the present invention, for example, an enzyme-linked antibody, an antibody labeled as a fluorescent agent, and an antibody labeled as a fluorescent agent. affinity are also included in the meaning of the modified variant. Such a modified variant of the antibody according to the present invention is useful for improving the stability and blood retention of the antibody, reducing the antigenicity thereof, detecting or isolating an antibody or an antigen, and so on.

[00289] Furthermore, by regulating the modification of a glycan that is linked to the antibody according to the present invention (glycosylation, defucosylation, etc.), it is possible to enhance antibody-dependent cellular cytotoxic activity. As the technique for regulating the modification of an antibody glycan, WO 99/54342, WO 00/61739, WO 02/31140, WO 2007/133855, WO 2013/120066, etc. are known. However, the technique is not limited to them. In the antibody according to the present invention, antibodies in which the modification of a glycan is regulated are also included.

[00290] It is known that a lysine residue is deleted at the carboxyl terminus of the heavy chain of an antibody produced in a cultured mammalian cell (Journal of Chromatography A, 705: 129-134 (1995)), and it is also known that they are Two amino acid residues (glycine and lysine) are deleted at the carboxyl terminus of the heavy chain of an antibody produced in a cultured mammalian cell and a newly located proline residue at the carboxyl terminus is amidated (Analytical Biochemistry, 360: 75 83 (2007) ). However, such deletion and modification of the heavy chain sequence do not affect the antigen binding affinity and effector function (complement activation, antibody-dependent cellular cytotoxicity, etc.) of the antibody. Therefore, in the antibody according to the present invention, also included are antibodies subjected to such modification and functional fragments of the antibody, and deletion variants in which one or two amino acids are deleted from the carboxyl terminus of the heavy chain, variants obtained by amidation of the deletion variants (e.g., a heavy chain in which the carboxyl-terminal proline residue is amidated), and the like. The type of deletion variant having a deletion in the carboxyl terminus of the heavy chain of the antibody according to the present invention is not limited to the above variants as long as the antigen binding affinity and effector function are conserved. The two heavy chains constituting the antibody according to the present invention may be of a type selected from the group consisting of full-length heavy chain and the deletion variant described above, or may be of two types in combination selected thereof. . The ratio between the amounts of each deletion variant can be affected by the type of cultured mammalian cells that produce the antibody according to the present invention and the culture conditions; however, an antibody in which an amino acid residue at the carboxyl terminus is deleted in both two heavy chains in the antibody according to the present invention may preferably be exemplified.

[00291] As isotypes of the antibody according to the present invention, for example, IgG (IgG1, IgG2, IgG3, IgG4) can be exemplified, and IgG1 or IgG2 can preferably be exemplified.

[00292] Examples of antibodies in the antibody-drug conjugate used in the present invention may include, but are not particularly limited to, an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7- H3, an anti-CD3 antibody, an anti-CD30 antibody, an anti-CD33 antibody, an anti-CD37 antibody, an anti-CD56 antibody, an anti-CD98 antibody, an anti-DR5 antibody, an anti-EGFR antibody, an anti-EPHA2 antibody, an anti-FGFR2 antibody, an anti-FGFR4 antibody, an anti-FOLR1 antibody, an anti-VEGF antibody, an anti-CD20 antibody, an anti-CD22 antibody, an anti-CD70 antibody, an anti-PSMA, an anti-CEA antibody, an anti-Mesothelin antibody, an anti-A33 antibody, an anti-CanAg antibody, an anti-Cripto antibody, an anti-G250 antibody, an anti-MUC1 antibody, an anti- GPNMB, an anti-Integrin antibody, an anti-Tenascin-C antibody, an anti-SLC44A4 antibody, an anti-GPR20 antibody, and an anti-CDH6 antibody. Furthermore, an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, and an anti-CDH6 antibody may be preferably exemplified, and may be more preferably An anti-HER2 antibody is exemplified.

[00293] In the present invention, the term “anti-HER2 antibody” refers to an antibody that specifically binds to HER2 (Human Epidermal Growth Factor Receptor Type 2; ErbB-2) , and preferably has an internalization activity in cells that express HER2 by binding to HER2.

[00294] Examples of the anti-HER2 antibody include trastuzumab (U.S. Patent No. 5,821,337) and pertuzumab (International Publication No. WO 01/00245). Preferably, trastuzumab can be exemplified.

[00295] In the present invention, the term “anti-HER3 antibody” refers to an antibody that specifically binds to HER3 (Human Epidermal Growth Factor Receptor Type 3; ErbB-3) , and preferably has an internalization activity in cells expressing HER3 by binding to HER3.

[00296] Examples of the anti-HER3 antibody include patritumab (U3-1287), U1-59 (International Publication No. WO 2007/077028), MM-121 (seribantumab), an anti-ERBB3 antibody described in International Publication No. WO 2008/100624, RG-7116 (lumretuzumab), and LJM-716 (elgemtumab). Preferably, patritumab and U1-59 can be exemplified.

[00297] In the present invention, the term “anti-TROP2 antibody” refers to an antibody that specifically binds to TROP2 (TACSTD2: Tumor-Associated Calcium Signal Transducer 2; EGP- 1), and preferably has an internalization activity in cells that express TROP2 by binding to TROP2.

[00298] Example of the anti-TROP2 antibody includes hTINA1-H1L1 (International Publication No. WO 2015/098099).

[00299] In the present invention, the term “anti-B7-H3 antibody” refers to an antibody that specifically binds to B7-H3 (B cell antigen no. B; PD-L3; CD276), and preferably has an internalization activity in cells expressing B7-H3 by binding to B7-H3.

[00300] Example of the anti-B7-H3 antibody includes M30-H1-L4 (International Publication No. WO 2014/057687).

[00301] In the present invention, the term “anti-GPR20 antibody” refers to an antibody that specifically binds to GPR20 (G Protein-Coupled Receptor 20), and preferably has an activity of internalization in GPR20-expressing cells by binding to GPR20.

[00302] Example of the anti-GPR20 antibody includes h046-H4e/L7 (International Publication No. WO 2018/135501).

[00303] In the present invention, the term “anti-CDH6 antibody” refers to an antibody that specifically binds to CDH6 (Cadherin-6), and preferably has an internalization activity in cells that express CDH6 by binding to CDH6.

[00304] Examples of the anti-CDH6 antibody include H01L02 (International Publication No. WO 2018/212136). 4. Production of Antibody-Drug Conjugate:

[00305] A drug-connector intermediate for use in the production of the antibody-drug conjugate used in the present invention is represented by the following formula. [Formula 21] OH O

[00306] The drug-connector intermediate can be called with the chemical name N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-hexanoyl]glycylglycyl-L -phenylalanyl-N-[(2-{[(1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15 -hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl]amino}-2-oxoethoxy)methyl]glycinamide, and may be produced with reference to the descriptions in International Publication No. WO 2014/057687, International Publication No. WO 2015/098099, International Publication No. WO 2015/115091, International Publication No. WO 2015/155998, International Publication No. WO 2019/044947, and so on.

[00307] The antibody-drug conjugate used in the present invention can be produced by reacting the drug-connector intermediate described above and an antibody having a thiol group (alternatively called a sulfhydryl group).

[00308] The antibody having a sulfhydryl group can be obtained by a method known in the art (Hermanson, G. T, Bioconjugate Techniques, pp. 56-136, pp. 456-493, Academic Press (1996)). For example, by using 0.3 to 3 molar equivalents of a reducing agent such as tris(carboxyethyl)phosphine hydrochloride (TCEP.HCl, Tris(2-Carboxyethyl)Phosphine Hydrochloride) by interchain disulfide within the antibody and reacting with the antibody In a buffer solution containing a chelating agent such as ethylenediaminetetraacetic acid (EDTA), an antibody having a sulfhydryl group with interchain disulfides partially or completely reduced within the antibody can be obtained.

[00309] Furthermore, by using 2 to 20 molar equivalents of drug-connector intermediate per antibody having a sulfhydryl group, an antibody-drug conjugate can be produced in which 2 to 8 drug molecules are conjugated per antibody molecule.

[00310] The average number of drug molecules per antibody molecule of the antibody-drug conjugate produced can be determined, for example, by a calculation method based on measuring the UV absorbance of the anti-HER2 antibody-drug conjugate and of its conjugation precursor at the two wavelengths of 280 nm and 370 nm (UV method), or by a calculation method based on quantification through HPLC measurement of the fragments obtained by treating the antibody-drug conjugate with a reducing agent (HPLC method).

[00311] The conjugation between the antibody and the drug-connector intermediate and the calculation of the average number of drug molecules conjugated per antibody molecule of the antibody-drug conjugate can be carried out with reference to the descriptions in International Publication No. WO 2014/ 057687, International Publication No. WO 2015/098099, International Publication No. WO 2015/115091, International Publication No. WO 2015/155998, International Publication No. WO 2018/135501, International Publication No. WO 2018/212136, and so on against.

[00312] In the present invention, the term “anti-HER2 antibody-drug conjugate” refers to an antibody-drug conjugate such that the antibody in the antibody-drug conjugate according to the present invention is an anti-HER2 antibody. HER2.

[00313] The anti-HER2 antibody is preferably an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of residues of amino acids 1 to 214 of SEQ ID NO: 2, or an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 1 and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 2.

[00314] The average number of drug-connector units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 8, even more preferably 7 to 8, even more preferably from 7.5 to 8, and even more preferably from about 8.

[00315] The anti-HER2 antibody-drug conjugate can be produced with reference to the descriptions in International Publication No. WO 2015/115091 and so on.

[00316] In the present invention, the term “anti-HER3 antibody-drug conjugate” refers to an antibody-drug conjugate such that the antibody in the antibody-drug conjugate according to the present invention is an anti-HER3 antibody. .

[00317] The anti-HER3 antibody is preferably an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence consisting of amino acid residues 26 to 35 of SEQ ID NO: 3, CDRH2 consisting of an amino acid sequence consisting of residues of amino acids 50 to 65 of SEQ ID NO: 3, and CDRH3 consisting of an amino acid sequence consisting of amino acid residues 98 to 106 of SEQ ID NO: 3 and a light chain comprising CDRL1 consisting of an amino acid sequence consisting of amino acid residues 24 to 39 of SEQ ID NO: 4, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 56 to 62 of SEQ ID NO: 4, and CDRL3 consisting of an amino acid sequence consisting of amino acid residues 95 to 103 of SEQ ID NO: 4, more preferably an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 117 of SEQ ID NO: 3 and a light chain comprising a chain variable region light chain consisting of an amino acid sequence consisting of amino acid residues 1 to 113 of SEQ ID NO: 4, and even more preferably an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 3 and a light chain consisting of in an amino acid sequence represented by SEQ ID NO: 4, or a variant of the antibody in which a lysine residue at the carboxyl terminus of the heavy chain is deleted.

[00318] The average number of drug-connector units conjugated per antibody molecule in the anti-HER3 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 8, even more preferably 7 to 8, even more preferably from 7.5 to 8, and even more preferably about 8.

[00319] The anti-HER3 antibody-drug conjugate can be produced with reference to the descriptions in International Publication No. WO 2015/155998 and so on.

[00320] In the present invention, the term “anti-TROP2 antibody-drug conjugate” refers to an antibody-drug conjugate such that the antibody in the antibody-drug conjugate according to the present invention is an anti-TROP2 antibody. .

[00321] The anti-TROP2 antibody is preferably an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence consisting of amino acid residues 50 to 54 of SEQ ID NO: 5, CDRH2 consisting of an amino acid sequence consisting of residues of amino acids 69 to 85 of SEQ ID NO: 5, and CDRH3 consisting of an amino acid sequence consisting of amino acid residues 118 to 129 of SEQ ID NO: 5 and a light chain comprising CDRL1 consisting of an amino acid sequence consisting of amino acid residues 44 to 54 of SEQ ID NO: 6, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 70 to 76 of SEQ ID NO: 6, and CDRL3 consisting of an amino acid sequence consisting of amino acid residues 109 to 117 of SEQ ID NO: 6, more preferably an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 140 of SEQ ID NO: 5 and a light chain comprising a variable chain region light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 129 of SEQ ID NO: 6, and even more preferably an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO : 5 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 6, or a variant of the antibody in which a lysine residue at the carboxyl terminus of the heavy chain is deleted.

[00322] The average number of drug-connector units conjugated per antibody molecule in the anti-TROP2 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 5, even more preferably 3.5 to 4, 5, and even more preferably about 4.

[00323] The anti-TROP2 antibody-drug conjugate can be produced with reference to the descriptions in International Publication No. WO 2015/098099 and so on.

[00324] In the present invention, the term “anti-B7-H3 antibody-drug conjugate” refers to an antibody-drug conjugate such that the antibody in the antibody-drug conjugate according to the present invention is an anti-B7-H3 antibody. -B7-H3.

[00325] The anti-B7-H3 antibody is preferably an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence consisting of amino acid residues 50 to 54 of SEQ ID NO: 7, CDRH2 consisting of an amino acid sequence consisting of amino acid residues 69 to 85 of SEQ ID NO: 7, and CDRH3 consisting of an amino acid sequence consisting of amino acid residues 118 to 130 of SEQ ID NO: 7 and a light chain comprising CDRL1 consisting of an amino acid sequence consisting of residues of amino acids 44 to 53 of SEQ ID NO: 8, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 69 to 75 of SEQ ID NO: 8, and CDRL3 consisting of an amino acid sequence consisting of amino acid residues 108 to 116 of SEQ ID NO: 8, more preferably an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 141 of SEQ ID NO: 7 and a light chain comprising a variable region of a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 128 of SEQ ID NO: 8, and even more preferably an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 7 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 8, or a variant of the antibody in which a lysine residue at the carboxyl terminus of the heavy chain is deleted

[00326] The average number of drug-connector units conjugated per antibody molecule in the anti-B7-H3 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 5, even more preferably 3.5 to 4.5, and even more preferably about 4.

[00327] The anti-B7-H3 antibody-drug conjugate used in the present invention can be produced with reference to the descriptions in International Publication No. WO 2014/057687 and so on.

[00328] In the present invention, the term “anti-GPR20 antibody-drug conjugate” refers to an antibody-drug conjugate in which the antibody in the antibody-drug conjugate according to the present invention is an anti-GPR20 antibody .

[00329] The anti-GPR20 antibody is preferably an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence consisting of amino acid residues 45 to 54 of SEQ ID NO: 9, CDRH2 consisting of an amino acid sequence consisting of residues of amino acids 69 to 78 of SEQ ID NO: 9, and CDRH3 consisting of an amino acid sequence consisting of amino acid residues 118 to 131 of SEQ ID NO: 9 and a light chain comprising CDRL1 consisting of an amino acid sequence consisting of amino acid residues 44 to 54 of SEQ ID NO: 10, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 70 to 76 of SEQ ID NO: 10, and CDRL3 consisting of an amino acid sequence consisting of amino acid residues 109 to 117 of SEQ ID NO: 10, more preferably an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 142 of SEQ ID NO: 9 and a light chain comprising a variable chain region light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 129 of SEQ ID NO: 10, and even more preferably an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 472 of SEQ ID NO : 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 10, or a variant of the antibody in which a lysine residue at the carboxyl terminus of the heavy chain is deleted.

[00330] The average number of drug-connector units conjugated per antibody molecule in the anti-GPR20 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 8, even more preferably 7 to 8, even more preferably from 7.5 to 8, and even more preferably about 8.

[00331] The anti-GPR20 antibody-drug conjugate can be produced with reference to the descriptions in International Publication No. WO 2018/135501 and so on.

[00332] In the present invention, the term “anti-CDH6 antibody-drug conjugate” refers to an antibody-drug conjugate in which the antibody in the antibody-drug conjugate according to the present invention is an anti-CDH6 antibody .

[00333] The anti-CDH6 antibody is preferably an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence consisting of amino acid residues 45 to 54 of SEQ ID NO: 11, CDRH2 consisting of an amino acid sequence consisting of residues of amino acids 69 to 78 of SEQ ID NO: 11, and CDRH3 consisting of an amino acid sequence consisting of amino acid residues 118 to 130 of SEQ ID NO: 11, and a light chain comprising CDRL1 consisting of an amino acid sequence consisting of residues of amino acids 44 to 54 of SEQ ID NO: 12, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 70 to 76 of SEQ ID NO: 12, and CDRL3 consisting of an amino acid sequence consisting of amino acid residues 109 to 116 of SEQ ID NO: 12, more preferably an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 141 of SEQ ID NO: 11 and a light chain comprising a variable region of light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 128 of SEQ ID NO: 12, and even more preferably an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 11 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 12, or a variant of the antibody in which the lysine residue at the carboxyl terminus of the heavy chain is deleted.

[00334] The average number of drug-connector units conjugated per antibody molecule in the anti-CDH6 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 8, even more preferably 7 to 8, even more preferably from 7.5 to 8, and even more preferably about 8.

[00335] The anti-CDH6 antibody-drug conjugate can be produced with reference to the descriptions in International Publication No. WO 2018/212136 and so on. 5. Therapeutic Agent and/or Treatment Method:

[00336] The therapeutic agent of the present invention comprises the antibody-drug conjugate used in the present invention. Furthermore, the treatment method of the present invention comprises administering the antibody-drug conjugate used in the present invention. The therapeutic agent and treatment method can be used for treating a metastatic brain tumor.

[00337] Primary cancers for metastatic brain tumor for which the therapeutic agent and/or treatment method of the present invention can be used are not particularly limited as long as they have a potential to metastasize to the brain, and can be exemplified breast cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, renal cell cancer, kidney cancer, colorectal cancer (also called colon and rectal cancer, and including colon cancer and rectal cancer), gastric cancer (also called gastric adenocarcinoma), head and neck cancer, hepatocellular cancer, liver cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, cancer endometrial cancer, thyroid cancer, malignant lymphoma and sarcoma, and may be more preferably exemplified breast cancer, lung cancer and melanoma, breast cancer and may be more preferably exemplified lung cancer, and may be even more preferably exemplified breast cancer .

[00338] Among the antibody-drug conjugates used in the present invention, a preferable antibody-drug conjugate, particularly having a specific antibody, can be determined by examining the characteristics of the primary cancer and tumor markers. For example, in the case in which the primary cancer is breast cancer or lung cancer and HER2 expression is found, an anti-HER2 antibody-drug conjugate may preferably be used; in the case in which HER3 expression is found, an anti-HER3 antibody-drug conjugate may preferably be used; in the case in which TROP2 expression is found, an anti-TROP2 antibody-drug conjugate may preferably be used; and in the case in which B7-H3 expression is found, an anti-B7-H3 antibody-drug conjugate may preferably be used. Furthermore, in the case in which the primary cancer is melanoma and HER3 expression is found, an anti-HER3 antibody-drug conjugate may preferably be used; in the case in which TROP2 expression is found, an anti-TROP2 antibody-drug conjugate may preferably be used; and in the case in which B7-H3 expression is found, an anti-B7-H3 antibody-drug conjugate may preferably be used. Furthermore, in the case in which the primary cancer is kidney cancer and CDH6 expression is found, an anti-CDH6 antibody-drug conjugate may preferably be used.

[00339] The presence or absence of HER2, HER3, TROP2, B7-H3, GPR20 and CDH6, and other tumor markers, can be checked, for example, by collecting tumor tissue from a cancer patient and subjecting the formalin-fixed paraffin-embedded (FFPE) specimen to an examination at a gene product (protein) level, such as an immunohistochemistry (IHC) method, a flow cytometry, a Western blot method (Western blot), or an examination at a gene transcription level, such as an in situ hybridization (HIS) method, a quantitative polymerase chain reaction (q-PCR) method, or a microarray analysis; Alternatively, it can also be checked by collecting circulating tumor DNA (ctDNA) from cell-free blood from a cancer patient and subjecting it to a test using a method such as Next-Generation Sequencing (NGS). sequencing).

[00340] The therapeutic agent and treatment method of the present invention can preferably be used in mammals, and can be more preferably used in humans.

[00341] The antitumor effect of the therapeutic agent and treatment method of the present invention can be confirmed, for example, by generating a model in which cancer cells derived from a primary cancer transfected with a marker gene (e.g., luciferase gene ) are transplanted into the brain of a test animal, and measuring, using any imaging technique, the life-prolonging effects and luminescence intensity transition of the tracer when the therapeutic agent or treatment method of the present invention is applied. invention. For example, in the case of transplantation of cells transfected with a luciferase gene, luciferin is administered to investigate the luminescence intensity, and in the case in which the luminescence intensity is decreased compared to a control group when the therapeutic agent is applied or the treatment method of the present invention, an antitumor effect is recognized.

[00342] Alternatively, the antitumor effect of the therapeutic agent and treatment method of the present invention can also be confirmed by generating a model in which a test animal is transplanted with a biopsy derived from a patient with a metastatic brain tumor ( for example, a PDX [Patient Derived Xenograft] brain transplant model and application of the therapeutic agent or treatment method of the present invention, and may additionally also be confirmed by administration of the therapeutic agent or application of the treatment method of the present invention to a patient with a metastatic brain tumor. Measurement of the antitumor effect can be performed, for example, using CT, TEP, and/or MRI, by confirming the change in tumor volumes before and after application of the therapeutic agent or treatment method of the present invention.

[00343] Furthermore, the antitumor effect of the therapeutic agent and the treatment method of the present invention can be confirmed, in a clinical study, with the Response Evaluation Criteria in Solid Tumors (RECIST) evaluation method. Solid Tumors), WHO (World Health Organization) assessment method, Macdonald assessment method, body weight measurement, and other methods, and can be determined by indicators such as Complete Response (CR), Partial Response (PR), Progressive Disease (PD), Objective Response Rate (ORR), Duration of Response (DdR), Progression-Free Survival (SIP), and Overall Survival (ST).

[00344] The aforementioned methods can provide confirmation of superiority in terms of the antitumor effect of the therapeutic agent and the treatment method of the present invention against metastatic brain tumors compared to existing anticancer agents.

[00345] The therapeutic agent and treatment method of the present invention can show not only an antitumor effect against metastatic brain tumors, but also an antitumor effect against metastatic cancers other than metastatic brain tumors. Examples of metastatic cancers other than metastatic brain tumors may include metastatic bone tumors, metastatic lung tumors and metastatic liver cancer, and metastatic bone tumors may preferably be exemplified. Metastatic cancers other than metastatic brain tumors may occur intercurrently with a metastatic brain tumor or may occur separately from a metastatic brain tumor, and the therapeutic agent and treatment method of the present invention may exert an antitumor effect in both cases.

[00346] The therapeutic agent and treatment method of the present invention can slow down the growth of cancer cells, suppress their proliferation, and can additionally kill cancer cells. These effects can allow patients to be free from symptoms caused by cancer or can achieve an improvement in the QoL (Quality of Life) of cancer patients and achieve a therapeutic effect by prolonging the lives of cancer patients. Even if the therapeutic agent and treatment method do not kill cancer cells, they can achieve higher QoL of cancer patients while achieving longer-term survival by inhibiting or controlling the growth of cancer cells.

[00347] It can be predicted that the therapeutic agent of the present invention exerts a therapeutic effect by application as systemic therapy in patients, and additionally, by local application in cancerous tissues.

[00348] The therapeutic agent of the present invention can be administered as a pharmaceutical composition containing at least one pharmaceutically suitable ingredient. Pharmaceutically suitable ingredients can be appropriately selected and applied from formulation additives or the like that are generally used in the art, considering the dosage, administration concentration or the like of the antibody-drug conjugate used in the present invention. For example, the therapeutic agent of the present invention can be administered as a pharmaceutical composition (hereinafter, called “the pharmaceutical composition of the present invention”) containing a buffering agent such as histidine buffering agent, an excipient such as sucrose or trehalose, and a surfactant such as polysorbate 80 or 20. The pharmaceutical composition of the present invention may be preferably used as an injection, may be more preferably used as an aqueous injection or a lyophilized injection, and may even more preferably be used as a lyophilized injection.

[00349] In the case in which the pharmaceutical composition of the present invention is an aqueous injection, it may preferably be diluted with a suitable diluent and then administered as an intravenous infusion. For the diluent, a dextrose solution, a physiological saline solution, and the like may be exemplified, and a dextrose solution may be preferably exemplified, and a 5% dextrose solution may be more preferably exemplified.

[00350] In the case in which the pharmaceutical composition of the present invention is a lyophilized injection, it may be preferably dissolved in water for injection, subsequently a required amount may be diluted with a suitable diluent and then administered as an intravenous infusion. For the diluent, a dextrose solution, a physiological saline solution, and the like may be exemplified, and a dextrose solution may be preferably exemplified, and a 5% dextrose solution may be more preferably exemplified.

[00351] Examples of the administration route that can be used to administer the pharmaceutical composition of the present invention include intravenous, intradermal, subcutaneous, intramuscular and intraperitoneal routes, and preferably include an intravenous route. Furthermore, the pharmaceutical composition of the present invention can also be administered by direct injection into the parenchyma, pia mater or arachnoid membrane.

[00352] The antibody-drug conjugate used in the present invention can be administered to a human once at intervals of 1 to 180 days, and can preferably be administered once a week, once every 2 weeks, once every every 3 weeks or once every 4 weeks, and may even more preferably be administered once every 3 weeks. Also, the antibody-drug conjugate used in the present invention can be administered at a dose of about 0.001 to 100 mg/kg, and may preferably be administered at a dose of 0.8 to 12.4 mg/kg. In the case in which the antibody-drug conjugate used in the present invention is an anti-HER2 antibody-drug conjugate, it may preferably be administered once every 3 weeks at a dose of 0.8 mg/kg, 1.6 mg/kg, 3.2 mg/kg, 5.4 mg/kg, 6.4 mg/kg, 7.4 mg/kg or 8 mg/kg, may more preferably be administered once every 3 weeks in a dose of 5.4, 6.4, or 7.4 mg/kg, and may even more preferably be administered once every 3 weeks at a dose of 5.4 mg/kg or 6.4 mg/kg. In the case in which the antibody-drug conjugate used in the present invention is an anti-HER3 antibody-drug conjugate, it may preferably be administered once every 3 weeks at a dose of 1.6 mg/kg, 3.2 mg/kg, 4.8 mg/kg, 5.6 mg/kg, 6.4 mg/kg, 8.0 mg/kg, 9.6 mg/kg or 12.8 mg/kg, and may be more preferably administered once every 3 weeks at a dose of 4.8 mg/kg, 5.6 mg/kg or 6.4 mg/kg. In the case in which the antibody-drug conjugate used in the present invention is an anti-TROP2 antibody-drug conjugate, it may preferably be administered once every 3 weeks at a dose of 0.27 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 4.0 mg/kg, 6.0 mg/kg or 8.0 mg/kg, and may more preferably be administered once every 3 weeks at a dose of 4.0 mg/kg, 6.0 mg/kg or 8.0 mg/kg.

[00353] The therapeutic agent of the present invention can also be administered in combination with an anti-cancer therapeutic agent other than the antibody-drug conjugate used in the present invention, thus intensifying the anti-tumor effect. Other anticancer therapeutic agents used for such purposes can be administered to a subject simultaneously with, separately from, or subsequently to the therapeutic agent of the present invention, and can be administered while varying the interval of administration for each. Such anticancer therapeutic agents are not limited as long as they are agents having antitumor activity, and may be exemplified by at least one selected from the group consisting of irinotecan (CPT-11), cisplatin, carboplatin, oxaliplatin, fluorouracil (5-FU) , genoclytabine, capecitabine, paclitaxel, doxorubicin, epirubicin, cyclophosphamide, mitomycin C, combination of tegafur-gimeracila-otracilla, cetuximab, panitumumab, bevacizumab, ramucirumab, regofenib, combination of trifluridine-typiocil, getinib erlotinibe, afatinib, methotrexate, pemetrexed, tamoxifen, toremifene, fulvestrant, leuprorelin, goserelin, letrozole, anastrozole, progesterone formulation, trastuzumab emtansine, trastuzumab, pertuzumab, and lapatinib.

[00354] The therapeutic agent of the present invention can also be used with radiotherapy. For example, a cancer patient may receive radiotherapy before and/or after receiving, or simultaneously with, treatment by the therapeutic agent of the present invention. Examples of the radiation therapy method may include Whole Brain Radiation Therapy (WBRT), Stereotactic Irradiation (STI), and Stereotactic Radiosurgery (SRS).

[00355] The therapeutic agent of the present invention can also be used as an adjuvant chemotherapy in combination with a surgical procedure. Surgical procedures are performed, for example, by removing all or part of a brain tumor. The therapeutic agent of the present invention can be administered for the purpose of decreasing the size of a brain tumor before a surgical procedure (called preoperative adjuvant chemotherapy, or neoadjuvant therapy), or can be administered after a surgical procedure for the purpose of preventing recurrence of a brain tumor (called post-operative adjuvant chemotherapy, or adjuvant therapy).

EXAMPLES

[00356] The present invention is specifically described considering the examples shown below. However, the present invention is not limited to these examples. Furthermore, it should in no way be interpreted in a limited way.

Example 1: Production of Antibody-Drug Conjugate

[00357] According to a production method described in International Publication No. WO 2015/115091 with the use of a humanized anti-HER2 antibody (an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2), an antibody-drug conjugate was produced in which a drug-connector represented by the following formula: [Formula 22] where A represents a connection position to an antibody, is conjugated with the anti-HER2 antibody via a thioether bond (hereinafter, called the “antibody-drug conjugate (1)”). RFA of the antibody-drug conjugate (1) is 7.8.

Example 2: Life Prolongation Test:

[00358] Mouse: 5- to 6-week-old female BALB/c nude mice (“Charles River Laboratories Japan, Inc.”) were subjected to the experiment.

[00359] The antibody-drug conjugate (1) was diluted with ABS buffer solution (10 mM acetate buffering agent (pH 5.5), 5% sorbitol) and the solution was intravenously administered into the tail vein with a solution volume of 10 mL/kg.

[00360] KPL-4-Luc was used, in which a luciferase gene was transfected into KPL-4 cells, a human breast cancer cell line obtained from Dr. Junichi Kurebayashi, “Kawasaki Medical School” (British Journal of Cancer, (1999) 79 (5/6). KPL-4-Luc was suspended in physiological saline, 1 x 104 cells were intracranially transplanted into female nude mice, and mice were randomly grouped 7 days after transplantation (Day 0). The antibody-drug conjugate (1) was intravenously administered at a dose of 10 mg/kg to the tail vein on Days 0 and 21. A solvent was administered to the control groups. The number of mice in each group was five and the presence or absence of survival was observed until Day 28. From the point of view of animal ethics, in the case in which a weight loss of 30% or more and a abnormal behavior (circling movements, eating/drinking disorders, and the like), euthanasia was performed. Furthermore, luciferin was intraperitoneally administered to each mouse on Days 14, 21, and 28 to confirm tumor location and tumor quantity with the luciferase activity of KPL-4-Luc as an indicator, and head luminescence was measured using an In Vivo Imaging System (IVIS). A solvent-administered group (2 mice) was established as satellite, formalin-fixed paraffin-embedded mouse head section was produced on Day 14, and hematoxylin and eosin staining was performed.

[00361] The results are shown in Figures 9 to 11. For the control groups, death was seen from Day 14, and all mice died by Day 26. In contrast, for the groups administered with the antibody conjugate -drug (1), all mice survive until Day 28 (Figure 9). For luminescence by KPL-4-Luc, tumor growth was seen in mice from the groups administered with the antibody-drug (1) on Day 21, but decreased luminescence was seen on Day 28, which was 1 week after the second administration, suggesting that the antibody-drug conjugate (1) exerts efficacy in brain tumors (Figure 10). In the pathological images of the brain on Day 14, tumor masses were found in the olfactory bulb, nasal turbinate, brain parenchyma, base of the brain, cerebral ventricle and around the cerebellum in 2/2 cases (Figure 11).

[00362] These results suggest that the antibody-drug conjugate (1) is effective in metastatic brain tumors and has life-prolonging effects.

TEXT EXEMPT FROM SEQUENCE LISTING

[00363] SEQ ID NO: 1 - Amino acid sequence of a heavy chain of the anti-HER2 antibody, SEQ ID NO: 2 - Amino acid sequence of a light chain of the anti-HER2 antibody, SEQ ID NO: 3 - Amino acid sequence of an anti-HER3 antibody heavy chain, SEQ ID NO: 4 - Amino acid sequence of an anti-HER3 antibody light chain, SEQ ID NO: 5 - Amino acid sequence of an anti-TROP2 antibody heavy chain, SEQ ID NO: 6 - Amino acid sequence of a light chain of the anti-TROP2 antibody, SEQ ID NO: 7 - Amino acid sequence of a heavy chain of the anti-B7-H3 antibody, SEQ ID NO: 8 - Amino acid sequence of a chain anti-B7-H3 antibody light, SEQ ID NO: 9 - Amino acid sequence of an anti-GPR20 antibody heavy chain, SEQ ID NO: 10 - Amino acid sequence of an anti-GPR20 antibody light chain, SEQ ID NO : 11 - Amino acid sequence of a heavy chain of the anti-CDH6 antibody, SEQ ID NO: 12 - Amino acid sequence of a light chain of the anti-CDH6 antibody.

Claims (14)

1. Use of an antibody-drug conjugate, characterized in that it is for the manufacture of a medicament to treat a metastatic brain tumor, wherein the antibody-drug conjugate comprises a drug-connector conjugated to an antibody via a thioether bond and in which the drug-connector is represented by the following formula: where A represents an antibody connection position; and the antibody in the antibody-drug conjugate is an anti-CDH6 antibody. 2. Use according to claim 1, characterized by the fact that the primary cancer for the metastatic brain tumor is at least one selected from the group consisting of breast cancer, lung cancer, melanoma, renal cell cancer, cancer kidney cancer, colorectal cancer, gastric cancer, head and neck cancer, hepatocellular cancer, liver cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, endometrial cancer, thyroid cancer, malignant lymphoma and sarcoma. 3. Use according to claim 1, characterized by the fact that the primary cancer for the metastatic brain tumor is at least one selected from the group consisting of lung cancer, renal cell cancer, kidney cancer, colorectal cancer, gastric cancer, head and neck cancer, ovarian cancer and endometrial cancer. 4. Use according to claim 1, characterized by the fact that the primary cancer for the metastatic brain tumor is renal cell cancer. 5. Use according to claim 1, characterized by the fact that the primary cancer for the metastatic brain tumor is lung cancer. 6. Use according to claim 1, characterized by the fact that the primary cancer for the metastatic brain tumor is kidney cancer. 7. Use according to claim 1, characterized by the fact that the primary cancer for the metastatic brain tumor is gastric cancer. 8. Use according to claim 1, characterized by the fact that the primary cancer for the metastatic brain tumor is colorectal cancer. 9. Use according to claim 1, characterized by the fact that the primary cancer for the metastatic brain tumor is head and neck cancer. 10. Use according to claim 1, characterized by the fact that the primary cancer for the metastatic brain tumor is ovarian cancer. 11. Use according to claim 1, characterized by the fact that the primary cancer for the metastatic brain tumor is endometrial cancer. 12. Use according to any one of claims 1 to 11, characterized in that the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 11 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 12. 13. Use according to claim 12, characterized by the fact that the anti-CDH6 antibody does not have a lysine residue at the carboxyl terminus of the heavy chain. 14. Use according to claim 12 or 13, characterized by the fact that the average number of drug-connector units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.