Antibody-drug conjugate for use in methods of treating chemotherapy-resistant cancer

Abstract

To provide a pharmaceutical composition and a pharmaceutical combination for treating a cancer that may be resistant to chemotherapy.SOLUTION: A pharmaceutical composition and a pharmaceutical combination are provided, the pharmaceutical composition comprising a platinum-based drug, and an antibody-drug conjugate in which an anticancer agent such as a topoisomerase I inhibitor is connected via a linker to an anti-cadherin-6 (CDH6) antibody.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 244,458, filed on September 15, 2021. The entire content of this application is incorporated herein by reference.

[0002] Description of the Sequence Listing The sequence listing related to this application is provided in text format instead of a paper copy and is incorporated herein by reference. The name of the text file containing the sequence listing is 098065 - 0296_SL.txt. The size of the text file is approximately 112 kb, it was created on September 9, 2021, and was electronically submitted via EFS - Web.

[0003] This disclosure relates to fields such as treatment methods, the use of antibody - drug conjugates (ADCs), and ADC pharmaceuticals for treating cancer.

Background Art

[0004] Cadherin is a glycoprotein present on the cell membrane surface. It functions as an intercellular adhesion molecule and as a signal molecule responsible for intercellular interactions by the extracellular domains at the N - terminal side binding to each other in a calcium - ion - dependent manner. Among the cadherin superfamily, the group of molecules classified as classical cadherin is a single - pass transmembrane protein composed of five extracellular domains (EC domains), one transmembrane region, and an intracellular domain outside the cell. Classical cadherin is classified into the type I family represented by E - cadherin and N - cadherin and the type II family based on amino acid sequence homology.

[0005] ​​​​​​​​​​​​ Cadherin-6 (CDH6) is a single-pass transmembrane protein consisting of 790 amino acids, which is classified into the type II cadherin family, with the N-terminal side outside the cell and the C-terminal side inside the cell. The human CDH6 gene was first cloned in 1995 (Non-Patent Document 1) and can be referenced by accession numbers such as NM_004932 and NP_004923 (NCBI). CDH6 is specifically expressed in the brain and kidneys during development and plays important roles in the formation of central nervous system circuits (Non-Patent Documents 2 and 3) and during the development of renal nephrons (Non-Patent Documents 4 and 5). In normal adult tissues, the expression of CDH6 is restricted to renal tubules and bile duct epithelial cells, etc. On the other hand, CDH6 is known to be specifically overexpressed in tumor sites in several types of human adult cancers.

[0006] In human renal cell carcinoma, especially clear cell renal cell carcinoma, the correlation between CDH6 expression and poor prognosis, as well as its potential use as a tumor marker, has been reported (Non-Patent Documents 6 and 7). High expression of CDH6 has also been reported for human ovarian cancer (Non-Patent Document 8). In addition, it has been reported that CDH6 is involved in the epithelial-mesenchymal transition of human thyroid cancer (Non-Patent Document 9). CDH6 has also been reported to be expressed in human cholangiocarcinoma and human small cell lung cancer (Non-Patent Documents 12 and 13).

[0007] Cancer ranks high among the causes of death. The number of cancer patients is expected to increase with the aging of the population, but the treatment needs have not yet been fully met. Conventional chemotherapeutic agents (Non-Patent Document 12, 13). Cancer is ranked high among the causes of death. The number of cancer patients is expected to increase with the aging of the population, but the treatment needs have not yet been fully met. Conventional chemotherapeutic agents

[0008] ​​​​​Due to its low selectivity, it has cytotoxicity not only to tumor cells but also to normal cells, resulting in side effects and the inability to fully obtain the drug effect due to the inability to administer a sufficient drug dose are problems. Therefore, in recent years, the development of more selective molecular target drugs and antibody drugs targeting molecules, cells showing specific mutations or overexpression characteristic of cancer cells, or specific molecules involved in carcinogenesis has been carried out.

[0009] Furthermore, a common cancer treatment using conventional chemotherapeutic agents (such as platinum-based chemotherapy) often results in the emergence of cancer cells resistant to one or more chemotherapeutic agents, which is also a major problem. Chemotherapy-resistant cancer cells cause cancer recurrence or relapse, which is the cause of cancer spread .

[0010] Antibodies have high blood stability and specifically bind to target antigens. For these reasons, side effects are expected to be reduced, and many antibody drugs against molecules highly expressed on the surface of cancer cells have been developed . As one of the technologies utilizing the antigen-specific binding ability of antibodies, antibody-drug conjugate (Antibody-Drug Conjugate; ADC) can be mentioned. A DC is an antibody that binds to an antigen expressed on the surface of cancer cells and can internalize the antigen into the cell by this binding, to which a drug having cytotoxic activity is conjugated. ADC can efficiently deliver drugs to cancer cells , thereby accumulating the drug in cancer cells and killing cancer cells is expected (Non-Patent Document 10, Patent Documents 1 and 2). As an ADC, for example, ado-trastuzumab emtansine ( trademark) (brentuximab vedotin), in which monomethyl auristatin E is conjugated to an anti-CD30 monoclonal antibody, is used for the treatment of Hodgkin lymphoma and anaplastic large cell lymphoma It has also been approved as a treatment for HER2. Kadcyla (trastuzumab emtansine), a combination of HER2-positive It is used to treat breast cancer.

[0011] The characteristics of target antigens suitable for ADC as antitumor drugs are that they are specifically and highly expressed on the surface of cancer cells. It is expressed in a low level or not expressed in normal cells, can be internalized in cells, and the antigen is The internalization ability of antibodies is dependent on both the target antigen and the antibody. It depends on the nature of the target molecule. It is difficult to predict which antibodies have high internalization ability based on their binding strength or physical properties. Therefore, obtaining an antibody with high internalization ability against a target antigen is important for increasing efficacy. This remains an important issue in developing new ADCs (Non-Patent Document 11).

[0012] ADCs targeting CDH6 are specific to the EC domain 5 (EC5) of CDH6. An ADC in which DM4 is linked to an anti-CDH6 antibody that binds to Patent documents 14 and 15). [Prior art documents] [Patent documents]

[0013] [Patent Document 1] International Publication No. 2014 / 057687 [Patent Document 2] US Patent No. 2016 / 0297890 [Patent Document 3] International Publication No. 2016 / 024195 [Patent Document 4] International Publication No. 2018 / 212136 [Non-patent literature]

[0014] [Non-Patent Document 1] Shimoyama Y, et al., Cancer Research, 2206 - 2211, 55, May 15, 1995 [Non-Patent Document 2] Inoue T, et al., Developmental Biology, 183 - 194, 1997 [Non-Patent Document 3] Osterhout J A, et al., Neuron, 632 - 639, 71, Aug 25, 2011 [Non-Patent Document 4] Cho E A, et al., Developmental, 803 - 812, 125, 1998 [Non-Patent Document 5] Mah S P, et al., Developmental Biology, 38 - 53, 223, 2000 [Non-Patent Document 6] Paul R, et al., Cancer Research, 2741 - 2748, July 1, 57, 1997 [Non-Patent Document 7] Shimazui T, et al., Cancer, 963 - 968, 101(5), Sep. 1, 2004 [Non-Patent Document 8] Koebel M, et al., PLoS Medicine, 1749 - 1760, 5(12), e232, Dec. 2008 [Non-Patent Document 9] Gugnoni M, et al., Oncogene, 667 - 677, 36, 2017 [Non-Patent Document 10] Polakis P., Pharmacological Reviews, 3 - 19, 68, 2016 [Non-Patent Document 11] Peters C, et al., Bioscience Reports, 1 - 20, 35, 2015 [Non-Patent Document 12] Goeppert B,et al.,Epigenetics,780-790,11(11),2016

Non-Patent Document 13

Non-Patent Document 14

Non-Patent Document 15

Summary of the Invention

Problems to be Solved by the Invention

[0015] The object of the present disclosure is to provide a treatment method for treating cancer using an ADC, and a pharmaceutical product containing an ADC for treating cancer. More specifically, the ADC is an anti-cadherin-6 (CDH6) antibody connected via a linker to a topoisomerase I inhibitor such as a derivative of exatecan, and the cancer can be resistant to chemotherapy.

Means for Solving the Problems

[0016] The inventors of the present invention conducted intensive studies to achieve the above object, and surprisingly found that the ADC of the present disclosure exhibits excellent antitumor effects and safety. More specifically, the inventors of the present invention found that an anti-CDH6 antibody-drug conjugate that specifically binds to the extracellular domain 3 (also referred to as EC3 herein) of the antibody exhibits excellent antitumor effects and safety.

[0017] ​​​​​​​The present disclosure includes the following aspects of the present invention. [1] A treatment method for treating cancer, comprising administering an antibody-drug conjugate (ADC) to a subject in need thereof. A treatment method. [2] The antibody-drug conjugate (ADC) has a structure represented by the following formula:

Chemical formula

[10] The antibody is an antibody or a functional fragment of an antibody comprising a light chain consisting of the 21st to 233rd amino acid sequences of SEQ ID NO: 61 and a heavy chain consisting of the 20th to 471st amino acid sequences of SEQ ID NO: 69, the therapeutic method according to any one of [1] to [9].

[11] The antibody is an antibody or a functional fragment of an antibody comprising a light chain consisting of the 21st to 233rd amino acid sequences of SEQ ID NO: 61 and a heavy chain consisting of the 20th to 471st amino acid sequences of SEQ ID NO: 77, the therapeutic method according to any one of [1] to [9].

[12] The heavy chain or the light chain is subjected to one or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, asparagine isomerization, methionine oxidation, addition of a methionine residue to the N-terminus, amidation of a proline residue, pyroglutaminylation of an N-terminal glutamine or N-terminal glutamic acid, and deletion of one or two amino acids at the carboxyl terminus, the therapeutic method according to any one of [1] to

[0011] . or pyroglutaminylation of N-terminal glutamine or N-terminal glutamic acid and one or two amino acid deletions at the carboxyl terminus, the therapeutic method according to any one of [1] to

[0011] .

[13] The heavy or light chain has undergone two or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, asparagine isomerization, methionine oxidation, addition of a methionine residue to the N-terminus, amidation of a proline residue, pyroglutamylation of an N-terminal glutamine or N-terminal glutamic acid, and deletion of one or two amino acids at the carboxyl terminus, the treatment method according to any one of [1] to

[0011] .

[14] The average number of binding per antibody of one selected drug-linker structure is in the range of 1 to 10 , the treatment method according to any one of [1] to

[13] .

[15] The average number of binding per antibody of one selected drug-linker structure is in the range of 2 to 8 , the treatment method according to any one of [1] to

[14] .

[16] The average number of binding per antibody of one selected drug-linker structure is in the range of 5 to 8 , the treatment method according to any one of [1] to

[14] .

[17] The average number of binding per antibody of one selected drug-linker structure is in the range of 7 to 8 , the treatment method according to any one of [1] to

[14] .

[18] The cancer includes one or more tumors expressing CDH6, the treatment method according to any one of [1] to

[17] .

[19] The subject has a history of treatment with a chemotherapy regimen containing a platinum-based drug, the treatment method according to any one of [1] to

[18] .

[20] The subject has a history of treatment with a chemotherapy regimen containing a platinum-based drug and a taxane, the treatment method according to any one of [1] to

[18] .

[21] The subject has been previously treated with a chemotherapy regimen containing a platinum-based drug, the treatment method according to any one of [1] to

[20] .​​​​

[22] The treatment method according to any one of [1] to

[20] , wherein the subject has been previously treated with a chemotherapy regimen comprising a platinum-based drug and a taxane.

[23] The treatment method according to any one of [1] to

[22] , wherein the antibody-drug conjugate (ADC) is administered in combination with one or more chemotherapeutic agents simultaneously or at different times.

[24] The treatment method according to

[23] , wherein the antibody-drug conjugate (ADC) is administered after one or more chemotherapeutic agents.

[25] The treatment method according to

[23] , wherein the antibody-drug conjugate (ADC) and one or more chemotherapeutic agents are separately included as active ingredients in different formulations and are administered simultaneously or at different times.

[26] The treatment method according to

[23] , wherein the antibody-drug conjugate (ADC) and one or more chemotherapeutic agents are included together as active ingredients in the same formulation and are administered simultaneously.

[27] The treatment method according to any one of

[23] to

[26] , wherein the one or more chemotherapeutic agents are antimetabolites, platinum-based drugs, taxanes, or both platinum-based drugs and taxanes.

[28] The treatment method according to any one of [1] to

[27] , wherein the subject shows complete response (CR), partial response (PR), or stable disease (SD) to treatment with a chemotherapy regimen comprising a platinum-based drug.

[29] The treatment method according to any one of [1] to

[27] , wherein the subject shows complete response (CR) or partial response (PR) to treatment with a chemotherapy regimen comprising a platinum-based drug.

[30] The treatment method according to any one of [1] to

[27] , wherein the subject shows complete response (CR), partial response (PR), or stable disease (SD) to treatment with a chemotherapy regimen comprising a platinum-based drug and a taxane. ​​​​​​​​​​​​​The treatment method according to any one of the above.

[31] The treatment method according to any one of [1] to

[27] , wherein the subject shows complete response (CR) or partial response (PR) to treatment with a chemotherapy regimen including a platinum-based drug and a taxane.

[32] The treatment method according to any one of [1] to

[31] , wherein the subject has cancer resistant to platinum-based chemotherapy.

[33] The treatment method according to any one of [1] to

[32] , wherein the subject has cancer resistant to a chemotherapy regimen including a platinum-based drug and a taxane.

[34] The treatment method according to any one of [1] to

[33] , wherein the subject shows cancer recurrence before administration of the ADC.

[35] The treatment method according to

[34] , wherein the cancer recurrence occurs within about 6 months before or within about 6 months after completion of a chemotherapy regimen including a platinum-based drug.

[36] The treatment method according to

[34] , wherein the cancer recurrence occurs within about 6 months before or within about 6 months after completion of a chemotherapy regimen including a platinum-based drug and a taxane.

[37] The treatment method according to

[34] , wherein the cancer recurrence occurs after completion of a chemotherapy regimen including a platinum-based drug or about 6 months later. About 6 months

[38] The treatment method according to

[34] , wherein the cancer recurrence occurs after completion of a chemotherapy regimen including a platinum-based drug and a taxane or about 6 months later. About 6 months

[39] The treatment method according to any one of [1] to

[38] , wherein the ADC is administered to the subject together with a second drug.

[40] The treatment method according to

[39] , wherein the ADC is administered before the second drug.

[41] The treatment method according to

[39] , wherein the ADC is administered after the second drug.

[42] The treatment method according to

[39] , wherein the ADC is administered simultaneously with the second drug.

[43] A method for treating cancer, comprising administering a pharmaceutical composition to a subject having platinum-resistant ovarian cancer and / or a subject showing recurrence of ovarian cancer before administration of the pharmaceutical composition. The pharmaceutical composition contains an antibody-drug conjugate (ADC) having a structure represented by the following formula: wherein AB represents an antibody or a functional fragment of an antibody, n represents the average number of conjugations per antibody of the drug-linker structure bound to the antibody, and the antibody is bound to the linker via a sulfhydryl group derived from the antibody;

Chemical formula

[44] A method for treating cancer, comprising administering a pharmaceutical composition to a subject having ovarian cancer and who has been previously treated with a chemotherapy regimen containing a platinum drug, a taxane, or both a platinum drug and a taxane. The pharmaceutical composition contains an antibody-drug conjugate (ADC) having a structure represented by the following formula: wherein AB represents an antibody or a functional fragment of an antibody, n represents the average number of conjugations per antibody of the drug-linker structure bound to the antibody, and the antibody is bound to the linker via a sulfhydryl group derived from the antibody;

Chemical formula

[45] The method of treatment according to any one of [1] to

[44] , comprising detecting the presence or absence of CDH6 in a biological sample derived from a subject and administering a pharmaceutical composition to the subject in whom CDH6 has been detected.

[46] The method of treatment according to any one of [1] to

[45] , wherein the cancer has acquired resistance to a chemotherapy regimen comprising a platinum-based drug.

[47] The method of treatment according to any one of [1] to

[45] , wherein the cancer has acquired resistance to a chemotherapy regimen comprising a platinum-based drug and a taxane.

[48] The method of treatment according to any one of [1] to

[47] , wherein the antimetabolite is gemcitabine.

[49] The method of treatment according to any one of [1] to

[47] , wherein the platinum-based drug is carboplatin.

[50] The method of treatment according to any one of [1] to

[47] , wherein the platinum-based drug is carboplatin and the taxane is paclitaxel.

[0018]

[51] A therapeutic agent for cancer, comprising an antibody-drug conjugate (ADC) disclosed herein.

[52] The antibody-drug conjugate (ADC) is of the following formula:

Chemical formula

[51] .

[53] The antibody-drug conjugate (ADC) is an anti-CDH6 antibody-drug conjugate the therapeutic agent described in

[51] or

[52] .

[54] The cancer is selected from the group consisting of renal cell carcinoma, ovarian cancer, mesothelioma, thyroid cancer, uterine cancer, cholangiocarcinoma, pancreatic cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, breast cancer, bladder cancer, uterine endometrial cancer, and castration-resistant prostate cancer, the therapeutic agent described in any one of

[51] to

[53] .

[55] The cancer is selected from the group consisting of ovarian cancer, non-small cell lung cancer, breast cancer, bladder cancer, uterine endometrial cancer, and castration-resistant prostate cancer, the therapeutic agent described in any one of

[51] to

[53] .

[56] The cancer is ovarian cancer, the therapeutic agent described in any one of

[51] to

[53] .

[57] The ovarian cancer is selected from the group consisting of epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, the therapeutic agent described in

[56] .

[58] The ovarian cancer is metastatic, the therapeutic agent described in

[56] or

[57] .

[59] The antibody is the following combination (1) to (4): (1) a light chain consisting of the amino acid sequence of positions 21 to 233 of SEQ ID NO: 61 and a heavy chain consisting of the amino acid sequence of positions 20 to 471 of SEQ ID NO: 69 (2) a light chain consisting of the amino acid sequence of positions 21 to 233 of SEQ ID NO: 61 and a heavy chain consisting of the amino acid sequence of positions 20 to 471 of SEQ ID NO: 73 (3) a light chain consisting of the amino acid sequence of positions 21 to 233 of SEQ ID NO: 65 and a heavy chain consisting of the amino acid sequence of positions 20 to 471 of SEQ ID NO: 73 (4) a light chain consisting of the amino acid sequence of positions 21 to 233 of SEQ ID NO: 65 and a heavy chain consisting of the amino acid sequence of positions 20 to 471 of SEQ ID NO: 77 (4) a light chain consisting of the amino acid sequence of positions 21 to 233 of SEQ ID NO: 65 and a heavy chain consisting of the amino acid sequence of positions 20 to 471 of SEQ ID NO: 77, the therapeutic agent described in any one of

[51] to

[53] .

[59] The antibody is the following combination (1) to (4): (1) a light chain consisting of the amino acid sequence of positions 21 to 233 of SEQ ID NO: 61 and a heavy chain consisting of the amino acid sequence of positions 20 to 471 of SEQ ID NO: 69 a heavy chain consisting of the 20th to 471st amino acid sequences, and (4) a light chain consisting of the 21st to 233rd amino acid sequences of SEQ ID NO: 61 and SEQ ID NO: 77 a heavy chain consisting of the 20th to 471st amino acid sequences, an antibody comprising a light chain and a heavy chain selected from any one combination selected from the group consisting of or a functional fragment of the antibody, the therapeutic agent according to any one of

[51] to

[58] .

[60] The antibody is an antibody or a functional fragment of an antibody comprising a light chain consisting of the 21st to 233rd amino acid sequences of SEQ ID NO: 61 and a heavy chain consisting of the 20th to 471st amino acid sequences of SEQ ID NO: 69, the therapeutic agent according to any one of

[51] to

[59] .

[61] The antibody is an antibody or a functional fragment of an antibody comprising a light chain consisting of the 21st to 233rd amino acid sequences of SEQ ID NO: 61 and a heavy chain consisting of the 20th to 471st amino acid sequences of SEQ ID NO: 77, the therapeutic agent according to any one of

[51] to

[59] .

[62] The heavy chain or the light chain is N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue to the N-terminus, amidation of a proline residue, N-terminal glutamine or pyroglutamic acid oxidation of N-terminal glutamic acid and one or two amino acid deletions at the carboxyl terminus, and the therapeutic agent according to any one of

[51] to

[0061] which has undergone one or more modifications selected from the group consisting of

[63] The heavy chain or the light chain is N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue to the N-terminus, amidation of a proline residue, N-terminal glutamine or or two or more modifications selected from the group consisting of pyroglutamination of N-terminal glutamic acid and deletion of one or two amino acids at the carboxyl terminus The therapeutic agent according to any one of

[51] to

[0061] , which has undergone two or more modifications selected from the group consisting of pyroglutamination of N-terminal glutamic acid and deletion of one or two amino acids at the carboxyl terminus

[64] The average number of conjugations per antibody of one selected drug-linker structure is 1 to 10 The therapeutic agent according to any one of

[51] to

[63] , wherein the average number of conjugations per antibody of one selected drug-linker structure is in the range of 1 to 10

[65] The average number of conjugations per antibody of one selected drug-linker structure is 2 to 8 The therapeutic agent according to any one of

[51] to

[64] , wherein the average number of conjugations per antibody of one selected drug-linker structure is in the range of 2 to 8

[66] The average number of conjugations per antibody of one selected drug-linker structure is 5 to 8 The therapeutic agent according to any one of

[51] to

[64] , wherein the average number of conjugations per antibody of one selected drug-linker structure is in the range of 5 to 8

[67] The average number of conjugations per antibody of one selected drug-linker structure is 7 to 8 The therapeutic agent according to any one of

[51] to

[64] , wherein the average number of conjugations per antibody of one selected drug-linker structure is in the range of 7 to 8

[68] The cancer comprises one or more tumors that express CDH6, the therapeutic agent according to any one of

[51] to

[67] The therapeutic agent according to any one of

[51] to

[67]

[69] The subject has a history of treatment with a chemotherapy regimen containing a platinum-based drug, the therapeutic agent according to any one of

[51] to

[68]

[70] The subject has a history of treatment with a chemotherapy regimen containing a platinum-based drug and a taxane, the therapeutic agent according to any one of

[51] to

[68] The therapeutic agent according to any one of

[51] to

[68]

[71] The subject has been previously treated with a chemotherapy regimen containing a platinum-based drug, the therapeutic agent according to any one of

[0051] to

[70]

[72] The subject has been previously treated with a chemotherapy regimen containing a platinum-based drug and a taxane, the therapeutic agent according to any one of

[51] to

[70] The therapeutic agent according to any one of

[51] to

[70]

[73] The antibody-drug conjugate (ADC) is one or more at the same time or at different times The treatment according to any one of

[51] to

[72] , administered in combination with a chemotherapeutic agent agent.

[74] The therapeutic agent according to

[73] , wherein an antibody-drug conjugate (ADC) is administered after one or more chemotherapeutic agents are administered.

[75] The therapeutic agent according to

[73] , wherein an antibody-drug conjugate (ADC) and one or more chemotherapeutic agents are separately included as active ingredients in different formulations and are administered simultaneously or at different times are administered.

[76] The therapeutic agent according to

[73] , wherein an antibody-drug conjugate (ADC) and one or more chemotherapeutic agents are included together as active ingredients in the same formulation and are administered simultaneously

[77] The therapeutic agent according to any one of

[73] to

[76] , wherein one or more chemotherapeutic agents are antimetabolites, platinum-based drugs, taxanes, or both platinum -based drugs and taxanes

[78] The therapeutic agent according to any one of

[51] to

[77] , wherein the subject shows complete response (CR), partial response (PR) or stable disease (SD) to treatment with a chemotherapy regimen containing a platinum-based drug are administered.

[79] The therapeutic agent according to any one of

[51] to

[77] , wherein the subject shows complete response (CR) or partial response (PR) to treatment with a chemotherapy regimen containing a platinum-based drug

[80] The therapeutic agent according to any one of

[51] to

[77] , wherein the subject shows complete response (CR), partial response (PR) or stable disease (SD) to treatment with a chemotherapy regimen containing a platinum-based drug and a taxane are administered.

[81] The therapeutic agent according to any one of

[51] to

[77] , wherein the subject shows complete response (CR) or partial response (PR) to treatment with a chemotherapy regimen containing a platinum-based drug and a taxane are administered.

[82] The subject has cancer resistant to platinum-based chemotherapy, the therapeutic agent according to any one of

[51] to

[81] .

[83] The subject has cancer resistant to a chemotherapy regimen containing a platinum-based drug and a taxane, the therapeutic agent according to any one of

[51] to

[82] .

[84] The subject shows cancer recurrence before administration of the ADC, the therapeutic agent according to any one of

[51] to

[83] .

[85] The cancer recurrence occurs within about 6 months before or about 6 months after completion of a chemotherapy regimen containing a platinum-based drug, the therapeutic agent according to

[84] .

[86] The cancer recurrence occurs within about 6 months before or about 6 months after completion of a chemotherapy regimen containing a platinum-based drug and a taxane, the therapeutic agent according to

[84] .

[87] The cancer recurrence occurs after completion of a chemotherapy regimen containing a platinum-based drug or about 6 months later, the therapeutic agent according to

[84] . About 6 months

[88] The cancer recurrence occurs after completion of a chemotherapy regimen containing a platinum-based drug and a taxane or about 6 months later, the therapeutic agent according to

[84] . About 6 months

[89] Administering the ADC to the subject together with a second drug, the therapeutic agent according to any one of

[51] to

[88] .

[90] Administering the ADC before the second drug, the therapeutic agent according to

[89] .

[91] Administering the ADC after the second drug, the therapeutic agent according to

[89] .

[92] Administering the ADC simultaneously with the second drug, the therapeutic agent according to

[89] .

Chemical formula

[94] A subject having ovarian cancer, and for administration to a subject who has previously been treated with a platinum-based drug, a taxane, or a chemotherapy regimen comprising both a platinum-based drug and a taxane A therapeutic agent for treating cancer, comprising a pharmaceutical composition, wherein the pharmaceutical composition has the following formula:

Chemical formula

[95] Using a biological sample derived from a test subject, in the test subject in which CDH6 is detected Before administering the pharmaceutical composition, detecting the presence or absence of CDH6 in the biological sample, the therapeutic agent according to any one of

[0051] ~

[94] .

[96] The cancer has acquired resistance to a chemotherapy regimen containing a platinum-based drug, the therapeutic agent according to any one of

[0051] ~

[95] .

[97] The cancer has acquired resistance to a chemotherapy regimen containing a platinum-based drug and a taxane The therapeutic agent according to any one of

[51] ~

[95] .

[98] The antimetabolite is gemcitabine, the therapeutic agent according to any one of

[51] ~

[97] . described.

[99] The platinum-based drug is carboplatin, the therapeutic agent according to any one of

[51] ~

[97] . described.

[0100] The platinum-based drug is carboplatin and the taxane is paclitaxel, the therapeutic agent according to any one of

[0051] ~

[97] .

[0019]

[0101] An antibody-drug conjugate (ADC) disclosed herein for use in the treatment of cancer (ADC).

[0102] The antibody-drug conjugate (ADC) has the structure represented by the following formula:

Chemical formula

[0101] . bound.

[0103] An antibody-drug conjugate (ADC) that is an anti-CDH6 antibody-drug conjugate The antibody-drug conjugate (ADC) according to

[0101] or

[0102] , which is an anti-CDH6 antibody-drug conjugate.

[0104] The cancer is selected from the group consisting of renal cell carcinoma, ovarian cancer, mesothelioma, thyroid cancer, uterine cancer, cholangiocarcinoma, pancreatic cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, breast cancer, bladder cancer, endometrial cancer, and castration-resistant prostate cancer. The antibody-drug conjugate (ADC) according to any one of

[0101] to

[0103] . The cancer is selected from the group consisting of ovarian cancer, non-small cell lung cancer, breast cancer, bladder cancer, endometrial cancer, and castration-resistant prostate cancer. The antibody-drug conjugate (ADC) according to any one of

[0101] to

[0103] . The cancer is ovarian cancer. The antibody-drug conjugate (ADC) according to any one of

[0101] to

[0103] . The antibody-drug conjugate (ADC) according to any one of

[0101] to

[0103] , wherein the ovarian cancer is selected from the group consisting of epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

[0105] The antibody-drug conjugate (ADC) according to any one of

[0101] to

[0103] , wherein the ovarian cancer is metastatic. The antibody is one of the following combinations (1) to (4): The antibody-drug conjugate (ADC) according to any one of

[0106] or

[0107] , wherein the ovarian cancer is metastatic.

[0106] The antibody-drug conjugate (ADC) according to any one of

[0101] to

[0103] , wherein the antibody is one of the following combinations (1) to (4): The antibody-drug conjugate (ADC) according to any one of

[0101] to

[0103] , wherein the antibody is one of the following combinations (1) to (4):

[0107] The antibody-drug conjugate (ADC) according to

[0106] , wherein the ovarian cancer is selected from the group consisting of epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. The antibody-drug conjugate (ADC) according to

[0106] , wherein the ovarian cancer is selected from the group consisting of epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

[0108] The antibody-drug conjugate (ADC) according to

[0106] or

[0107] , wherein the ovarian cancer is metastatic. The antibody-drug conjugate (ADC) according to

[0106] or

[0107] , wherein the ovarian cancer is metastatic.

[0109] The antibody is one of the following combinations (1) to (4): (1) A light chain consisting of the amino acid sequence from positions 21 to 233 of SEQ ID NO: 61 and a heavy chain consisting of the amino acid sequence from positions 20 to 471 of SEQ ID NO: 69. The antibody-drug conjugate (ADC) according to any one of

[0101] to

[0103] , wherein the antibody is one of the following combinations (1) to (4): (2) A light chain consisting of the amino acid sequence from positions 21 to 233 of SEQ ID NO: 61 and a heavy chain consisting of the amino acid sequence from positions 20 to 471 of SEQ ID NO: 73. The antibody-drug conjugate (ADC) according to any one of

[0101] to

[0103] , wherein the antibody is one of the following combinations (1) to (4): (3) A light chain consisting of the amino acid sequence from positions 21 to 233 of SEQ ID NO: 65 and a heavy chain consisting of the amino acid sequence from positions 20 to 471 of SEQ ID NO: 73. a heavy chain consisting of the 20th to 471st amino acid sequences, and (4) a light chain consisting of the 21st to 233rd amino acid sequences of SEQ ID NO: 61 and SEQ ID NO: 77 a heavy chain consisting of the 20th to 471st amino acid sequences, an antibody comprising any one combination selected from the group consisting of a light chain and a heavy chain as described in or a functional fragment of the antibody, the antibody-drug conjugate (ADC) according to any one of

[0101] to

[0108] . Substance conjugate (ADC).

[0110] The antibody is an antibody or a functional fragment of an antibody comprising a light chain consisting of the 21st to 233rd amino acid sequences of SEQ ID NO: 61 and a heavy chain consisting of the 20th to 471st amino acid sequences of SEQ ID NO: 69, the antibody-drug conjugate (ADC) according to any one of

[0101] to

[0109] . Conjugate (ADC).

[0111] The antibody is an antibody or a functional fragment of an antibody comprising a light chain consisting of the 21st to 233rd amino acid sequences of SEQ ID NO: 61 and a heavy chain consisting of the 20th to 471st amino acid sequences of SEQ ID NO: 77, the antibody-drug conjugate (ADC) according to any one of

[0101] to

[0109] . Conjugate (ADC).

[0112] The heavy chain or light chain is subjected to one or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue to the N-terminus, amidation of a proline residue, pyroglutaminylation of N-terminal glutamine or N-terminal glutamic acid, and deletion of one or two amino acids at the carboxyl terminus, the antibody-drug conjugate (ADC) according to any one of

[0101] to

[0111] .

[0111] .

[0113]

[0111] .

[0113] The heavy or light chain has undergone two or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue to the N-terminus, amidation of a proline residue, pyroglutaminylation of an N-terminal glutamine or N-terminal glutamic acid, and deletion of one or two amino acids at the carboxyl terminus, the antibody-drug conjugate (ADC) according to any one of

[0101] ~

[0111] . The average number of conjugations per antibody of one selected drug-linker structure is in the range of 1 to 1 0, the antibody-drug conjugate (ADC) according to any one of

[0101] ~

[0113] . The average number of conjugations per antibody of one selected drug-linker structure is in the range of 2 to 8 , the antibody-drug conjugate (ADC) according to any one of

[0101] ~

[0114] . The average number of conjugations per antibody of one selected drug-linker structure is in the range of 5 to 8

[0114] , the antibody-drug conjugate (ADC) according to any one of

[0101] ~

[0114] . The average number of conjugations per antibody of one selected drug-linker structure is in the range of 7 to 8 , the antibody-drug conjugate (ADC) according to any one of

[0101] ~

[0114] .

[0115] The cancer comprises one or more tumors expressing CDH6, the antibody-drug conjugate (ADC) according to any one of

[0101] ~

[0117] .

[0116]

[0117]

[0118]

[0119] ​​​​​​​​​The subject has a treatment history with a chemotherapy regimen containing a platinum-based drug, and the antibody-drug conjugate (ADC) according to any one of

[0101] to

[0118] .

[0120] The subject has a treatment history with a chemotherapy regimen containing a platinum-based drug and a taxane and is the antibody-drug conjugate (AD C) according to any one of

[0101] to

[0118] .

[0121] The subject has been previously treated with a chemotherapy regimen containing a platinum-based drug, and the antibody-drug conjugate (ADC) according to any one of

[0101] to

[0120] .

[0122] The subject has been previously treated with a chemotherapy regimen containing a platinum-based drug and a taxane and is the antibody-drug conjugate (A DC) according to any one of

[0101] to

[0120] .

[0123] The antibody-drug conjugate (ADC) is administered in combination with one or more chemotherapeutic agents simultaneously or at different times, and is the antibody-drug conjugate (ADC) according to any one of

[0101] to

[0122] .

[0124] The antibody-drug conjugate (ADC) is administered after one or more chemotherapeutic agents and is the antibody-drug conjugate (ADC) according to

[0123] .

[0125] The antibody-drug conjugate (ADC) and one or more chemotherapeutic agents are separately included as active ingredients in different formulations and are administered simultaneously or at different times, and is the antibody-drug conjugate (ADC) according to

[0123] .

[0126] The antibody-drug conjugate (ADC) and one or more chemotherapeutic agents are included together as active ingredients in the same formulation and are administered simultaneously, and is the antibody-drug conjugate (ADC) according to

[0123] .

[0127] One or more chemotherapeutic agents are antimetabolites, platinum-based drugs, taxanes, or both platinum-based drugs and taxanes, the antibody-drug conjugate (ADC) according to any one of

[0123] ~

[0126] . The antibody-drug conjugate (ADC) according to any one of

[0101] ~

[0127] , wherein the subject shows complete response (CR), partial response (PR) or stable disease (SD) to treatment with a chemotherapy regimen containing a platinum-based drug.

[0128] The antibody-drug conjugate (ADC) according to any one of

[0101] ~

[0127] , wherein the subject shows complete response (CR) or partial response (PR) to treatment with a chemotherapy regimen containing a platinum-based drug.

[0129] The antibody-drug conjugate (ADC) according to any one of

[0101] ~

[0127] , wherein the subject shows complete response (CR) or partial response (PR) to treatment with a chemotherapy regimen containing a platinum-based drug and a taxane.

[0130] The antibody-drug conjugate (ADC) according to any one of

[0101] ~

[0127] , wherein the subject shows complete response (CR), partial response (PR) or stable disease (SD) to treatment with a chemotherapy regimen containing a platinum-based drug and a taxane.

[0131] The antibody-drug conjugate (ADC) according to any one of

[0101] ~

[0127] , wherein the subject has cancer resistant to platinum-based chemotherapy.

[0132] The antibody-drug conjugate (ADC) according to any one of

[0101] ~

[0131] , wherein the subject has cancer resistant to a chemotherapy regimen containing a platinum-based drug and a taxane.

[0133] The antibody-drug conjugate (ADC) according to any one of

[0101] ~

[0132] , wherein the subject has cancer resistant to a chemotherapy regimen containing a platinum-based drug and a taxane. C).

[0134] ​​​​​​​​​​The subject shows cancer recurrence before administration of the ADC, an antibody-drug conjugate (ADC) according to any one of

[0101] to

[0133] .

[0135] The cancer recurrence occurs within about 6 months before or within about 6 months after completion of a chemotherapy regimen containing a platinum-based drug, an antibody-drug conjugate (ADC) according to

[0134] .

[0136] The cancer recurrence occurs within about 6 months before or within about 6 months after completion of a chemotherapy regimen containing a platinum-based drug and a taxane, an antibody-drug conjugate (ADC) according to

[0134] . DC).

[0137] The cancer recurrence occurs after completion of a chemotherapy regimen containing a platinum-based drug About 6 months or about 6 months later, an antibody-drug conjugate (ADC) according to

[0134] .

[0138] The cancer recurrence occurs after completion of a chemotherapy regimen containing a platinum-based drug and a taxane About 6 months or about 6 months later, an antibody-drug conjugate (ADC) according to

[0134] .

[0139] Administering the ADC to the subject together with a second drug, an antibody-drug conjugate (ADC) according to any one of

[0101] to

[0138] .

[0140] Administering the ADC before the second drug, an antibody-drug conjugate (ADC) according to

[0139] .

[0141] Administering the ADC after the second drug, an antibody-drug conjugate (ADC) according to

[0139] .

[0142] Administering the ADC simultaneously with the second drug, an antibody-drug conjugate (ADC) according to

[0139] .

[0143] Subjects having platinum-resistant ovarian cancer and / or administration of a pharmaceutical composition​​​​​​​ An antibody-drug conjugate (ADC) for treating cancer in a subject previously showing recurrence of ovarian cancer, having the following formula: DC

Chemical formula

[0144] A subject having ovarian cancer, and an antibody-drug conjugate (ADC) for treating cancer in a subject who has previously been treated with a chemotherapy regimen comprising a platinum-based drug, a taxane, or both a platinum-based drug and a taxane, having the following formula: DC having a structure represented by: :

Chemical formula

[0145] Before administering the ADC to a subject in which CDH6 has been detected using a biological sample derived from the subject, detecting the presence or absence of CDH6 in the biological sample, the ADC according to any one of

[0101] to

[0144] . Before administering the ADC to a subject in which CDH6 has been detected using a biological sample derived from the subject, detecting the presence or absence of CDH6 in the biological sample, the ADC according to any one of

[0101] to

[0144] .

[0146] The cancer has acquired resistance to a chemotherapy regimen containing a platinum-based drug, the antibody-drug conjugate (ADC) according to any one of

[0101] to

[0145] . The cancer has acquired resistance to a chemotherapy regimen containing a platinum-based drug, the antibody-drug conjugate (ADC) according to any one of

[0101] to

[0145] .

[0147] The cancer has acquired resistance to a chemotherapy regimen containing a platinum-based drug and a taxane, the antibody-drug conjugate according to any one of

[0101] to

[0145] . The cancer has acquired resistance to a chemotherapy regimen containing a platinum-based drug and a taxane, the antibody-drug conjugate according to any one of

[0101] to

[0145] . (ADC).

[0148] The antimetabolite is gemcitabine, the antibody-drug conjugate (ADC) according to any one of

[0101] to

[0147] . The antimetabolite is gemcitabine, the antibody-drug conjugate (ADC) according to any one of

[0101] to

[0147] .

[0149] The platinum-based drug is carboplatin, the antibody-drug conjugate (ADC) according to any one of

[0101] to

[0147] . The platinum-based drug is carboplatin, the antibody-drug conjugate (ADC) according to any one of

[0101] to

[0147] .

[0150] The platinum-based drug is carboplatin and the taxane is paclitaxel, the treatment method according to any one of

[0101] to

[0147] .

[0020]

[0151] Activating the antibody-drug conjugate (ADC) or a salt thereof disclosed in the present specification. A pharmaceutical composition for treating cancer, which contains a sex component and a pharmaceutically acceptable formulation component 。

[0152] An antibody-drug conjugate (ADC) has the structure represented by the following formula:

Chemical formula

[0151] .

[0153] The antibody-drug conjugate (ADC) is an anti-CDH6 antibody-drug conjugate -tor, the pharmaceutical composition according to

[0151] or

[0152] .

[0154] The cancer is selected from the group consisting of renal cell carcinoma, ovarian cancer, mesothelioma, thyroid cancer, uterine cancer, cholangiocarcinoma, pancreatic cancer, non small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, breast cancer, bladder cancer, endometrial cancer, and castration-resistant prostate cancer, the pharmaceutical composition according to any one of

[0151] to

[0153] 。

[0155] The cancer is selected from the group consisting of ovarian cancer, non-small cell lung cancer, breast cancer, bladder cancer, endometrial cancer, and castration-resistant pro state cancer, the pharmaceutical composition according to any one of

[0151] to

[0153] composition.

[0156] The cancer is ovarian cancer, the pharmaceutical composition according to any one of

[0151] to

[0153] composition.

[0157] The ovarian cancer is selected from the group consisting of epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer selected, the pharmaceutical composition according to

[0156] .

[0158] The ovarian cancer is metastatic, the pharmaceutical composition according to

[0156] or

[0157] .

[0159] The antibody is any one of the following combinations (1) to (4): (1) a light chain consisting of the amino acid sequence of positions 21 to 233 of SEQ ID NO: 61 and a heavy chain consisting of the amino acid sequence of positions 20 to 471 of SEQ ID NO: 69 (2) a light chain consisting of the amino acid sequence of positions 21 to 233 of SEQ ID NO: 61 and a heavy chain consisting of the amino acid sequence of positions 20 to 471 of SEQ ID NO: 73 (3) a light chain consisting of the amino acid sequence of positions 21 to 233 of SEQ ID NO: 65 and a heavy chain consisting of the amino acid sequence of positions 20 to 471 of SEQ ID NO: 73, and (4) a light chain consisting of the amino acid sequence of positions 21 to 233 of SEQ ID NO: 61 and a heavy chain consisting of the amino acid sequence of positions 20 to 471 of SEQ ID NO: 77 An antibody comprising a light chain and a heavy chain as described in any one combination selected from the group consisting of or a functional fragment of the antibody, the pharmaceutical composition according to any one of

[0151] to

[0158] .

[0160] The antibody is an antibody or a functional fragment of an antibody comprising a light chain consisting of the amino acid sequence of positions 21 to 233 of SEQ ID NO: 61 and a heavy chain consisting of the amino acid sequence of positions 20 to 471 of SEQ ID NO: 69, the pharmaceutical composition according to any one of

[0151] to

[0159] .

[0161] The antibody is an antibody or a functional fragment of an antibody comprising a light chain consisting of the amino acid sequence of positions 21 to 233 of SEQ ID NO: 61 and a heavy chain consisting of the amino acid sequence of positions 20 to 471 of SEQ ID NO: 77, the pharmaceutical composition according to any one of

[0151] to

[0159] .

[0162] The heavy chain or light chain is subject to N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, asparagine isomerization, methionine ​​​​​Oxidation of N, addition of a methionine residue to the N-terminus, amidation of a proline residue, pyroglutamination of N-terminal glutamine or N-terminal glutamic acid, and one or two amino acid deletions at the carboxyl terminus, or one or more modifications selected from the group consisting of pyroglutamination of N-terminal glutamine or N-terminal glutamic acid and one or two amino acid deletions at the carboxyl terminus, the pharmaceutical composition according to any one of

[0151] to

[0161] . Or the heavy chain or light chain has undergone two or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue to the N-terminus, amidation of a proline residue, pyroglutamination of N-terminal glutamine or N-terminal glutamic acid, and one or two amino acid deletions at the carboxyl terminus, the pharmaceutical composition according to any one of

[0151] to

[0161] . Or the heavy chain or light chain has undergone two or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue to the N-terminus, amidation of a proline residue, pyroglutamination of N-terminal glutamine or N-terminal glutamic acid, and one or two amino acid deletions at the carboxyl terminus, the pharmaceutical composition according to any one of

[0151] to

[0161] . The pharmaceutical composition according to any one of

[0151] to

[0161] .

[0163] The average number of binding per antibody of one selected drug-linker structure is in the range of 1 to 10, the pharmaceutical composition according to any one of

[0151] to

[0163] . The average number of binding per antibody of one selected drug-linker structure is in the range of 2 to 8, the pharmaceutical composition according to any one of

[0151] to

[0164] . The average number of binding per antibody of one selected drug-linker structure is in the range of 5 to 8, the pharmaceutical composition according to any one of

[0151] to

[0164] . The average number of binding per antibody of one selected drug-linker structure is in the range of 7 to 8, the pharmaceutical composition according to any one of

[0151] to

[0164] . The average number of binding per antibody of one selected drug-linker structure is in the range of 7 to 8, the pharmaceutical composition according to any one of

[0151] to

[0164] . The pharmaceutical composition according to any one of

[0151] to

[0164] .

[0164] The average number of binding per antibody of one selected drug-linker structure is in the range of 1 to 10, the pharmaceutical composition according to any one of

[0151] to

[0163] . The pharmaceutical composition according to any one of

[0151] to

[0163] .

[0165] The average number of binding per antibody of one selected drug-linker structure is in the range of 2 to 8, the pharmaceutical composition according to any one of

[0151] to

[0164] . The pharmaceutical composition according to any one of

[0151] to

[0164] .

[0166] The average number of binding per antibody of one selected drug-linker structure is in the range of 5 to 8, the pharmaceutical composition according to any one of

[0151] to

[0164] . The pharmaceutical composition according to any one of

[0151] to

[0164] .

[0167] The average number of binding per antibody of one selected drug-linker structure is in the range of 7 to 8, the pharmaceutical composition according to any one of

[0151] to

[0164] . The pharmaceutical composition according to any one of

[0151] to

[0164] .

[0168] The pharmaceutical composition according to any one of

[0151] to

[0167] , wherein the cancer comprises one or more tumors expressing CDH6.

[0169] The pharmaceutical composition according to any one of

[0151] to

[0168] , wherein the subject has a history of treatment with a chemotherapy regimen comprising a platinum-based drug.

[0170] The subject has a history of treatment with a chemotherapy regimen comprising a platinum-based drug and a taxane The pharmaceutical composition according to any one of

[0151] to

[0168] .

[0171] The pharmaceutical composition according to any one of

[0151] to

[0170] , wherein the subject has been previously treated with a chemotherapy regimen comprising a platinum-based drug.

[0172] The subject has been previously treated with a chemotherapy regimen comprising a platinum-based drug and a taxane The pharmaceutical composition according to any one of

[0151] to

[0170] .

[0173] The antibody-drug conjugate (ADC) is administered in combination with one or more chemotherapeutic agents simultaneously or at different times, according to any one of

[0151] to

[0172] The pharmaceutical composition described. The pharmaceutical composition according to any one of

[0151] to

[0172] .

[0174] The antibody-drug conjugate (ADC) is administered after one or more chemotherapeutic agents The pharmaceutical composition according to

[0173] .

[0175] The antibody-drug conjugate (ADC) and one or more chemotherapeutic agents are separately included as active ingredients in different formulations and administered simultaneously or at different times, according to

[0173] The pharmaceutical composition described.

[0176] The antibody-drug conjugate (ADC) and one or more chemotherapeutic agents are included together as active ingredients in the same formulation and administered simultaneously, according to the pharmaceutical composition described in

[0173] The pharmaceutical composition described.

[0177] One or more chemotherapeutic agents are antimetabolites, platinum-based drugs, taxanes, or white The pharmaceutical composition according to any one of

[0173] to

[0176] , which is both a gold drug and a taxane. Pharmaceutical composition.

[0178] The subjects achieved complete response (CR) to chemotherapy regimens including platinum-based drugs. , showing partial response (PR) or stable disease (SD),

[0151] to

[0177] The pharmaceutical composition described in any one of the above.

[0179] The subjects achieved complete response (CR) to chemotherapy regimens including platinum-based drugs. or partial response (PR), Pharmaceutical composition.

[0180] Subjects were completely treated with chemotherapy regimens including platinum-based drugs and taxanes. The pharmaceutical composition according to any one of

[0151] to

[0177] , which shows a response (CR), partial response (PR) or stable disease (SD).

[0181] Subjects were completely treated with chemotherapy regimens including platinum-based drugs and taxanes. Any one of

[0151] to

[0177] showing response (CR) or partial response (PR) The pharmaceutical composition described above.

[0182] The subject has a cancer resistant to platinum-based chemotherapy, 13. The pharmaceutical composition according to any one of claims 1 to 12.

[0183] The subject has cancer that is resistant to chemotherapy regimens that include platinum-based drugs and taxanes. The pharmaceutical composition according to any one of

[0151] to

[0182] .

[0184] Any of

[0151] to

[0183] , in which the subject shows a recurrence of cancer prior to administration of the ADC. The pharmaceutical composition described in any one of the above.

[0185] Cancer recurrence occurs within about 6 months of completion of a platinum-based chemotherapy regimen or A pharmaceutical composition according to

[0184] , which occurs within about 6 months.

[0186] A pharmaceutical composition according to

[0184] , wherein cancer recurrence occurs within less than about 6 months or within about 6 months after completion of a chemotherapy regimen comprising a platinum-based drug and a taxane. A pharmaceutical composition according to

[0184] , wherein cancer recurrence occurs within less than about 6 months or within about 6 months after completion of a chemotherapy regimen comprising a platinum-based drug.

[0187] A pharmaceutical composition according to

[0184] , wherein cancer recurrence occurs after completion of a chemotherapy regimen comprising a platinum-based drug About 6 months or about 6 months later.

[0188] A pharmaceutical composition according to

[0184] , wherein cancer recurrence occurs after completion of a chemotherapy regimen comprising a platinum-based drug and a taxane About 6 months or about 6 months later.

[0189] A pharmaceutical composition according to any one of

[0151] to

[0188] , wherein an ADC is administered to a subject together with a second drug. A pharmaceutical composition according to any one of

[0151] to

[0188] , wherein an ADC is administered to a subject together with a second drug.

[0190] A pharmaceutical composition according to

[0189] , wherein an ADC is administered before a second drug.

[0191] A pharmaceutical composition according to

[0189] , wherein an ADC is administered after a second drug.

[0192] A pharmaceutical composition according to

[0189] , wherein an ADC is administered simultaneously with a second drug.

[0193] A pharmaceutical composition for treating cancer in a subject having platinum-resistant ovarian cancer and / or a subject who has shown recurrence of ovarian cancer prior to administration of the pharmaceutical composition, comprising an antibody-drug conjugate (ADC) having a structure represented by the following formula: In the formula, AB represents an antibody or a functional fragment of an antibody, and n represents the average number of conjugations per antibody of a drug-linker structure bound to the antibody. The antibody is via a sulfhydryl group derived from the antibody.

Chemical formula

[0194] In a subject having ovarian cancer and in a subject who has previously been treated with a chemotherapy regimen comprising a platinum-based drug, a taxane, or both a platinum-based drug and a taxane, for treating cancer, the pharmaceutical composition comprising an antibody-drug conjugate (ADC) having a structure represented by the following formula: wherein AB represents an antibody or a functional fragment of an antibody, n represents the average number of conjugations per antibody of the drug-linker structure bound to the antibody, the antibody is bound to the linker via a sulfhydryl group derived from the antibody; the ADC is a salt thereof or a hydrate of the ADC or the salt; the drug-

Chemical formula

[0195] Detecting the presence or absence of CDH6 in a biological sample before administering the pharmaceutical composition to a test subject in whom CDH6 has been detected using a biological sample derived from the test subject before administering the pharmaceutical composition to a test subject in whom CDH6 has been detected using a biological sample derived from the test subject, The pharmaceutical composition according to any one of

[0151] to

[0194] .

[0196] The cancer has acquired resistance to a chemotherapy regimen containing a platinum-based drug. The pharmaceutical composition according to any one of

[0151] to

[0195] .

[0197] The cancer has acquired resistance to a chemotherapy regimen containing a platinum-based drug and a taxane. The pharmaceutical composition according to any one of

[0151] to

[0195] , which has acquired resistance.

[0198] The metabolic antagonist is gemcitabine. The pharmaceutical composition according to any one of

[0151] to

[0197] . One of the pharmaceutical compositions described.

[0199] The platinum-based drug is carboplatin. The pharmaceutical composition according to any one of

[0151] to

[0197] . One of the pharmaceutical compositions described.

[0200] The platinum-based drug is carboplatin and the taxane is paclitaxel. The pharmaceutical composition according to any one of

[0151] to

[0197] .

[0021]

[0201] Use of the antibody-drug conjugate (ADC) disclosed herein in the manufacture of a medicament for treating cancer. Conjugate (ADC).

[0202] The antibody-drug conjugate (ADC) has the structure represented by the following formula:

Chemical formula

[0201] . One of the uses described in

[0201] .

[0203] The antibody-drug conjugate (ADC) is an anti-CDH6 antibody-drug conjugate. The use according to

[0201] or

[0202] .

[0204] The cancer is selected from the group consisting of renal cell carcinoma, ovarian cancer, mesothelioma, thyroid cancer, uterine cancer, cholangiocarcinoma, pancreatic cancer, non- small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, breast cancer, bladder cancer, endometrial cancer, and castration-resistant prostate cancer, the use according to any one of

[0201] to

[0203] as described in any one of

[0201] to

[0203] .

[0205] The cancer is selected from the group consisting of ovarian cancer, non-small cell lung cancer, breast cancer, bladder cancer, endometrial cancer, and castration-resistant prostate cancer, the use according to any one of

[0201] to

[0203] .

[0206] The cancer is ovarian cancer, the use according to any one of

[0201] to

[0203] .

[0207] The ovarian cancer is selected from the group consisting of epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, the use according to

[0206] .

[0208] The ovarian cancer is metastatic, the use according to

[0206] or

[0207] .

[0209] The antibody is the following combinations (1) to (4): (1) a light chain consisting of the amino acid sequence from positions 21 to 233 of SEQ ID NO: 61 and a heavy chain consisting of the amino acid sequence from positions 20 to 471 of SEQ ID NO: 69 , (2) a light chain consisting of the amino acid sequence from positions 21 to 233 of SEQ ID NO: 61 and a heavy chain consisting of the amino acid sequence from positions 20 to 471 of SEQ ID NO: 73 , (3) a light chain consisting of the amino acid sequence from positions 21 to 233 of SEQ ID NO: 65 and a heavy chain consisting of the amino acid sequence from positions 20 to 471 of SEQ ID NO: 73, and (4) a light chain consisting of the amino acid sequence from positions 21 to 233 of SEQ ID NO: 61 and a heavy chain consisting of the amino acid sequence from positions 20 to 471 of SEQ ID NO: 77 , an antibody comprising a light chain and a heavy chain described in any one combination selected from the group consisting of ​The use according to any one of

[0201] ~

[0208] , which is a functional fragment of an antibody.

[0210] The use according to any one of

[0201] ~

[0209] , wherein the antibody is an antibody or a functional fragment of an antibody comprising a light chain consisting of the amino acid sequence of positions 21 to 233 of SEQ ID NO: 61 and a heavy chain consisting of the amino acid sequence of positions 20 to 471 of SEQ ID NO: 69. The use according to any one of

[0201] ~

[0209] , which is an antibody or a functional fragment of an antibody comprising a light chain consisting of the amino acid sequence of positions 21 to 233 of SEQ ID NO: 61 and

[0211] a heavy chain consisting of the amino acid sequence of positions 20 to 471 of SEQ ID NO: 77. The use according to any one of

[0201] ~

[0209] , which is an antibody or a functional fragment of an antibody comprising a light chain consisting of the amino acid sequence of positions 21 to 233 of SEQ ID NO: 61 and a heavy chain consisting of the amino acid sequence of positions 20 to 471 of SEQ ID NO: 77.

[0212] The use according to any one of

[0201] ~

[0211] , wherein the heavy chain or the light chain has undergone one or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue at the N-terminus, amidation of a proline residue, pyroglutamination of N-terminal glutamine or N-terminal glutamic acid, and deletion of one or two amino acids at the carboxyl terminus. The use according to any one of

[0201] ~

[0211] , wherein the heavy chain or the light chain has undergone two or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue at the N-terminus, amidation of a proline residue, pyroglutamination of N-terminal glutamine or N-terminal glutamic acid, and deletion of one or two amino acids at the carboxyl terminus. The use according to any one of

[0201] ~

[0211] , wherein the heavy chain or the light chain has undergone one or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue at the N-terminus, amidation of a proline residue, pyroglutamination of N-terminal glutamine or N-terminal glutamic acid, and deletion of one or two amino acids at the carboxyl terminus. The use according to any one of

[0201] ~

[0211] , wherein the heavy chain or the light chain has undergone one or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue at the N-terminus, amidation of a proline residue, pyroglutamination of N-terminal glutamine or N-terminal glutamic acid, and deletion of one or two amino acids at the carboxyl terminus. The use according to any one of

[0201] ~

[0211] , wherein the heavy chain or the light chain has undergone one or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue at the N-terminus, amidation of a proline residue, pyroglutamination of N-terminal glutamine or N-terminal glutamic acid, and deletion of one or two amino acids at the carboxyl terminus. The use according to any one of

[0201] ~

[0211] , wherein the heavy chain or the light chain has undergone one or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue at the N-terminus, amidation of a proline residue, pyroglutamination of N-terminal glutamine or N-terminal glutamic acid, and deletion of one or two amino acids at the carboxyl terminus.

[0213] The use according to any one of

[0201] ~

[0211] , wherein the heavy chain or the light chain has undergone one or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue at the N-terminus, amidation of a proline residue, pyroglutamination of N-terminal glutamine or N-terminal glutamic acid, and deletion of one or two amino acids at the carboxyl terminus. The use according to any one of

[0201] ~

[0211] , wherein the heavy chain or the light chain has undergone one or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue at the N-terminus, amidation of a proline residue, pyroglutamination of N-terminal glutamine or N-terminal glutamic acid, and deletion of one or two amino acids at the carboxyl terminus. The use according to any one of

[0201] ~

[0211] , wherein the heavy chain or the light chain has undergone one or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue at the N-terminus, amidation of a proline residue, pyroglutamination of N-terminal glutamine or N-terminal glutamic acid, and deletion of one or two amino acids at the carboxyl terminus. The use according to any one of

[0201] ~

[0211] , wherein the heavy chain or the light chain has undergone one or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue at the N-terminus, amidation of a proline residue, pyroglutamination of N-terminal glutamine or N-terminal glutamic acid, and deletion of one or two amino acids at the carboxyl terminus. The use according to any one of

[0201] ~

[0211] , wherein the heavy chain or the light chain has undergone two or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue at the N-terminus, amidation of a proline residue, pyroglutamination of N-terminal glutamine or N-terminal glutamic acid, and deletion of one or two amino acids at the carboxyl terminus. The use according to any one of

[0201] ~

[0211] , wherein the heavy chain or the light chain has undergone two or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue at the N-terminus, amidation of a proline residue, pyroglutamination of N-terminal glutamine or N-terminal glutamic acid, and deletion of one or two amino acids at the carboxyl terminus.

[0214] The average number of conjugations per antibody of one selected drug-linker structure is in the range of 1 to 1 0, and the use according to any one of

[0201] to

[0213] .

[0215] The average number of conjugations per antibody of one selected drug-linker structure is in the range of 2 to 8 and the use according to any one of

[0201] to

[0214] .

[0216] The average number of conjugations per antibody of one selected drug-linker structure is in the range of 5 to 8 and the use according to any one of

[0201] to

[0214] .

[0217] The average number of conjugations per antibody of one selected drug-linker structure is in the range of 7 to 8 and the use according to any one of

[0201] to

[0214] .

[0218] The cancer includes one or more tumors expressing CDH6, and the use according to any one of

[0201] to

[0217] .

[0219] The subject has a treatment history with a chemotherapy regimen including a platinum-based drug, and the use according to any one of

[0201] to

[0218] .

[0220] The subject has a treatment history with a chemotherapy regimen including a platinum-based drug and a taxane and the use according to any one of

[0201] to

[0218] .

[0221] The subject has been previously treated with a chemotherapy regimen including a platinum-based drug, and the use according to any one of

[0201] to

[0220] .

[0222] The subject has been previously treated with a chemotherapy regimen including a platinum-based drug and a taxane and the use according to any one of

[0201] to

[0220] .

[0223] The antibody-drug conjugate (ADC) is administered in combination with one or more chemotherapeutic agents simultaneously or at different times, and the use according to any one of

[0201] to

[0222] .

[0224] The use according to

[0223] , wherein the antibody-drug conjugate (ADC) is administered after one or more chemotherapeutic agents. The use according to

[0223] , wherein the antibody-drug conjugate (ADC) and one or more chemotherapeutic agents are separately included as active ingredients in different formulations and are administered simultaneously or at different times.

[0225] The use according to

[0223] , wherein the antibody-drug conjugate (ADC) and one or more chemotherapeutic agents are included together as active ingredients in the same formulation and are administered simultaneously. The use according to

[0223] , wherein the antibody-drug conjugate (ADC) and one or more chemotherapeutic agents are included together as active ingredients in the same formulation and are administered simultaneously. The use according to

[0223] , wherein the antibody-drug conjugate (ADC) and one or more chemotherapeutic agents are included together as active ingredients in the same formulation and are administered simultaneously.

[0226] The use according to

[0223] , wherein the antibody-drug conjugate (ADC) and one or more chemotherapeutic agents are included together as active ingredients in the same formulation and are administered simultaneously. The use according to

[0223] , wherein the antibody-drug conjugate (ADC) and one or more chemotherapeutic agents are included together as active ingredients in the same formulation and are administered simultaneously.

[0227] The use according to any one of

[0223] to

[0226] , wherein the one or more chemotherapeutic agents are antimetabolites, platinum-based drugs, taxanes, or both platinum-based drugs and taxanes. The use according to any one of

[0223] to

[0226] , wherein the one or more chemotherapeutic agents are antimetabolites, platinum-based drugs, taxanes, or both platinum-based drugs and taxanes. The use according to any one of

[0223] to

[0226] , wherein the one or more chemotherapeutic agents are antimetabolites, platinum-based drugs, taxanes, or both platinum-based drugs and taxanes.

[0228] The use according to any one of

[0201] to

[0227] , wherein the subject shows complete response (CR), partial response (PR), or stable disease (SD) to treatment with a chemotherapy regimen containing a platinum-based drug. The use according to any one of

[0201] to

[0227] , wherein the subject shows complete response (CR), partial response (PR), or stable disease (SD) to treatment with a chemotherapy regimen containing a platinum-based drug. The use according to any one of

[0201] to

[0227] , wherein the subject shows complete response (CR), partial response (PR), or stable disease (SD) to treatment with a chemotherapy regimen containing a platinum-based drug.

[0229] The use according to any one of

[0201] to

[0227] , wherein the subject shows complete response (CR) or partial response (PR) to treatment with a chemotherapy regimen containing a platinum-based drug. The use according to any one of

[0201] to

[0227] , wherein the subject shows complete response (CR) or partial response (PR) to treatment with a chemotherapy regimen containing a platinum-based drug. The use according to any one of

[0201] to

[0227] , wherein the subject shows complete response (CR) or partial response (PR) to treatment with a chemotherapy regimen containing a platinum-based drug.

[0230] The use according to any one of

[0201] to

[0227] , wherein the subject shows complete response (CR), partial response (PR), or stable disease (SD) to treatment with a chemotherapy regimen containing a platinum-based drug and a taxane. The use according to any one of

[0201] to

[0227] , wherein the subject shows complete response (CR), partial response (PR), or stable disease (SD) to treatment with a chemotherapy regimen containing a platinum-based drug and a taxane.

[0231] The use according to any one of

[0201] to

[0227] , wherein the subject shows complete response (CR) or partial response (PR) to treatment with a chemotherapy regimen containing a platinum-based drug and a taxane. The use according to any one of

[0201] to

[0227] , wherein the subject shows complete response (CR) or partial response (PR) to treatment with a chemotherapy regimen containing a platinum-based drug and a taxane. The use according to any one of

[0201] to

[0227] , wherein the subject shows complete response (CR) or partial response (PR) to treatment with a chemotherapy regimen containing a platinum-based drug and a taxane.

[0232] The subject has cancer resistant to platinum-based chemotherapy, as described in any one of

[0201] to

[0231] Use according to any one of the above.

[0233] The subject has cancer resistant to chemotherapy regimens containing platinum-based drugs and taxanes Use according to any one of

[0201] to

[0232]

[0234] The subject shows cancer recurrence before administration of the ADC, use according to any one of

[0201] to

[0233] Use according to any one of the above.

[0235] Cancer recurrence occurs within about 6 months before or within about 6 months after completion of a chemotherapy regimen containing platinum-based drugs, use according to

[0234] Use according to

[0234]

[0236] Cancer recurrence occurs within about 6 months before or within about 6 months after completion of a chemotherapy regimen containing platinum-based drugs and taxanes Use according to

[0234]

[0237] Cancer recurrence occurs after completion of a chemotherapy regimen containing platinum-based drugs About 6 months or about 6 months later, use according to

[0234]

[0238] Cancer recurrence occurs after completion of a chemotherapy regimen containing platinum-based drugs and taxanes About 6 months or about 6 months later, use according to

[0234]

[0239] Administer the ADC to the subject together with a second drug, use according to any one of

[0201] to

[0238] Use according to any one of the above.

[0240] Administer the ADC before the second drug, use according to

[0239]

[0241] Administer the ADC after the second drug, use according to

[0239]

[0242] Administer the ADC simultaneously with the second drug, use according to

[0239]

[0243] Administration of a pharmaceutical composition to a subject having platinum-resistant ovarian cancer and / or A method for treating cancer, comprising administering a pharmaceutical composition to a subject who has previously shown recurrence of ovarian cancer Use of a pharmaceutical composition, wherein the pharmaceutical composition comprises an antibody-drug conjugate (ADC) having a structure represented by the following formula:

Chem.

[0244] A subject having ovarian cancer and who has previously been treated with a chemotherapy regimen comprising a platinum-based drug, a taxane, or both a platinum-based drug and a taxane, and a method for treating cancer, comprising administering a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises an antibody-drug conjugate (ADC) having a structure represented by the following formula: wherein AB represents an antibody or a functional fragment of an antibody, n represents the average number of conjugations per antibody of the drug-linker structure bound to the antibody, and the antibody is bound to the linker via a sulfhydryl group derived from the antibody; the ADC is a salt thereof or a hydrate of the ADC or the salt; the average number of conjugations per antibody of the drug-linker structure is 7 to 8, and the antibody comprises a heavy-chain amino acid sequence represented by SEQ ID NO: 87 or an amino acid sequence derived from the amino acid sequence represented by SEQ ID NO: 87 with one or two amino acids deleted from its carboxyl terminus; and a light-chain amino acid sequence represented by SEQ ID NO: 88. wherein AB represents an antibody or a functional fragment of an antibody, n represents the average number of conjugations per antibody of the drug-linker structure bound to the antibody, and the antibody is bound to the linker via a sulfhydryl group derived from the antibody;

Chem.

[0201] to

[0244] , comprising detecting the presence or absence of CDH6 in a biological sample derived from a subject to be tested and administering a pharmaceutical composition to the subject in which CDH6 has been detected.

[0245] Use according to any one of

[0201] to

[0245] , wherein the cancer has acquired resistance to a chemotherapy regimen comprising a platinum-based drug. Use according to any one of

[0201] to

[0245] , wherein the cancer has acquired resistance to a chemotherapy regimen comprising a platinum-based drug and a taxane. Use according to any one of

[0201] to

[0247] , wherein the antimetabolite is gemcitabine.

[0246] Use according to any one of

[0201] to

[0247] , wherein the platinum-based drug is carboplatin. Use according to any one of

[0201] to

[0247] , wherein the platinum-based drug is carboplatin and the taxane is paclitaxel.

[0247] In some embodiments, the disclosed treatment relates broadly to a therapeutic use or method for treating cancer and comprises administering an antibody-drug conjugate (ADC) to a subject in need thereof.

[0248]

[0249]

[0250] ​​​​​​​​​In some embodiments, an antibody-drug conjugate (ADC) has the following formula: [Chemical Structure] having a structure represented by wherein AB represents an antibody or a functional fragment of an antibody, n represents the average number of conjugations per antibody of the drug-linker -structure, and the antibody is linked to the linker via a sulfhydryl group derived from the antibody. In some embodiments, the antibody-drug conjugate (ADC) is an anti-CDH6 antibody-drug conjugate. In some embodiments, the antibody-drug conjugate (ADC) is an anti-CDH6 antibody-drug conjugate in which the antibody specifically binds to extracellular domain 3. In some embodiments, the cancer is selected from the group consisting of renal cell carcinoma, ovarian cancer, mesothelioma, thyroid cancer, uterine cancer, cholangiocarcinoma, pancreatic cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, breast cancer , bladder cancer, endometrial cancer, and castration-resistant prostate cancer. In some embodiments , the cancer is selected from the group consisting of ovarian cancer, non-small cell lung cancer, breast cancer, bladder cancer, endometrial cancer, and castration-resistant prostate cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments , the ovarian cancer is selected from the group consisting of epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. In some embodiments, the ovarian cancer is metastatic. In some embodiments, the antibody is one of the following combinations (1)-(4): (1) a light chain consisting of the amino acid sequence of positions 21-233 of SEQ ID NO: 61 and a heavy chain consisting of the amino acid sequence of positions 20-471 of SEQ ID NO: 69, (2) a light chain consisting of the amino acid sequence of positions 21-233 of SEQ ID NO: 61 and a heavy chain consisting of the amino acid sequence of positions 20-471 of SEQ ID NO: 73, (3) a sequence of the light chain consisting of the amino acid sequence of positions 21-233 of SEQ ID NO: 61 and a heavy chain consisting of the amino acid sequence of positions 20-471 of SEQ ID NO: 73, (4) a sequence ​A light chain consisting of the 21st to 233rd amino acid sequences of No. 65 and the 20th to 47th of SEQ ID NO: 73 A heavy chain consisting of the 1st amino acid sequence, and (4) a light chain consisting of the 21st to 233rd amino acid sequences of SEQ ID NO: 61 And a heavy chain consisting of the 20th to 471st amino acid sequences of SEQ ID NO: 77, and an antibody or antibody functional fragment comprising any one combination selected from the group consisting of The light chain and heavy chain described in any one combination selected from the group consisting of An antibody or a functional fragment of an antibody. In some embodiments, the antibody is an antibody or antibody functional fragment comprising a light chain consisting of the 21st to 233rd amino acid sequences of SEQ ID NO: 61 And a heavy chain consisting of the 20th to 471st amino acid sequences of SEQ ID NO: 69. In some embodiments, the antibody is an antibody or antibody functional fragment comprising a light chain consisting of the 21st to 233rd Amino acid sequences of SEQ ID NO: 61 and a heavy chain consisting of the 20th to 471st amino acid sequences of SEQ ID NO: 77. In some embodiments, the antibody is an antibody or antibody functional fragment comprising a light chain consisting of the 21st to 233rd Amino acid sequences of SEQ ID NO: 61 and a heavy chain consisting of the 20th to 471st amino acid sequences of SEQ ID NO: 77. An antibody or a functional fragment of an antibody. In some embodiments, the heavy chain or light chain is subjected to one or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation , N-terminal processing, C-terminal processing, deamidation, asparagine isomerization , methionine oxidation, addition of a methionine residue to the N-terminus, amidation of a proline residue, N-terminal glutamine Or pyroglutaminylation of N-terminal glutamine or N-terminal glutamate and one or two amino acid deletions at the carboxyl terminus Selected from the group consisting of. In some embodiments, the heavy chain or light chain is subjected to two or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation , N-terminal processing, C-terminal processing, deamidation, asparagine isomerization , methionine oxidation, addition of a methionine residue to the N-terminus, amidation of a proline residue, N-terminal glutamine Or pyroglutaminylation of N-terminal glutamine or N-terminal glutamate and one or two amino acid deletions at the carboxyl terminus Selected from the group consisting of. In some embodiments, the average binding per antibody of one selected drug-linker structure is in the range of 1 to 10. In some embodiments, the average binding per antibody of one selected drug-linker structure is in the range of 2 to 8. In some embodiments, the average binding per antibody of one selected drug-linker structure is in the range of 5 to 8. In some embodiments, the average binding per antibody of one selected drug-linker structure is in the range of 7 to 8. In some embodiments, the cancer comprises one or more tumors that express CDH6. In some embodiments, the subject has a history of treatment with a chemotherapy regimen comprising a platinum-based drug. In some embodiments, the subject has a history of treatment with a chemotherapy regimen comprising a platinum-based drug and a taxane. In some embodiments, the subject has been previously treated with a chemotherapy regimen comprising a platinum-based drug. In some embodiments, the subject has been previously treated with a chemotherapy regimen comprising a platinum-based drug and a taxane. In some embodiments, the antibody-drug conjugate (ADC) is administered in combination with one or more chemotherapeutic agents either simultaneously or at different times. In some embodiments, the antibody-drug conjugate (ADC) is administered after one or more chemotherapeutic agents. In some embodiments, the antibody-drug conjugate (ADC) is administered after the antibody-drug conjugate (ADC) has been administered in combination with one or more chemotherapeutic agents. In some embodiments, the antibody-drug conjugate (ADC) and one or more chemotherapeutic agents are separately included as active ingredients in different formulations and are administered either simultaneously or at different times. ​​​​​In some embodiments, an antibody-drug conjugate (ADC) and one or more chemotherapeutic agents are included together as active ingredients in the same formulation and are administered simultaneously. In some embodiments, the one or more chemotherapeutic agents are antimetabolites, platinum-based drugs, taxanes, or both platinum-based drugs and taxanes. In some embodiments, the one or more chemotherapeutic agents are antimetabolites. In some embodiments, the one or more chemotherapeutic agents are platinum-based drugs. In some embodiments, the one or more chemotherapeutic agents are both platinum-based drugs and taxanes. In some embodiments, the subject has achieved complete response (CR), partial response (PR), or stable disease (SD) to treatment with a chemotherapy regimen comprising a platinum-based drug. In some embodiments, the subject has achieved complete response (CR) or partial response (PR) to treatment with a chemotherapy regimen comprising a platinum-based drug. In some embodiments, the subject has achieved complete response (CR), partial response (PR), or stable disease (SD) to treatment with a chemotherapy regimen comprising a platinum-based drug and a taxane. In some embodiments, the subject has achieved complete response (CR) or partial response (PR) to treatment with a chemotherapy regimen comprising a platinum-based drug and a taxane. In some embodiments, the subject has cancer that is resistant to platinum-based chemotherapy. In some embodiments, the subject has cancer that is resistant to a chemotherapy regimen comprising a platinum-based drug and a taxane. In some embodiments, the subject exhibits Occurs within less than about 6 months. In some embodiments, cancer recurrence occurs within less than about 6 months of completion of a chemotherapy regimen that includes a platinum-based drug. In some embodiments, cancer recurrence occurs within less than about 6 months of completion of a chemotherapy regimen that includes a platinum-based drug. In some embodiments, cancer recurrence occurs within about 6 months of completion of a chemotherapy regimen that includes a platinum-based drug. In some embodiments, cancer recurrence occurs within less than or about 6 months of completion of a chemotherapy regimen that includes a platinum-based drug and a taxane. In some embodiments, cancer recurrence occurs within less than 6 months of completion of a chemotherapy regimen that includes a platinum-based drug and a taxane. In some embodiments, cancer recurrence occurs within less than 6 months of completion of a chemotherapy regimen that includes a platinum-based drug and a taxane. In some embodiments, cancer recurrence occurs within 6 months of completion of a chemotherapy regimen that includes a platinum-based drug and a taxane. In some embodiments, cancer recurrence occurs about 6 months or about 6 months after completion of a chemotherapy regimen that includes a platinum-based drug. In some embodiments, cancer recurrence occurs about 6 months after completion of a chemotherapy regimen that includes a platinum-based drug. In some embodiments, cancer recurrence occurs about 6 months after completion of a chemotherapy regimen that includes a platinum-based drug. In some embodiments, cancer recurrence occurs about 6 months after completion of a chemotherapy regimen that includes a platinum-based drug. In some embodiments, cancer recurrence occurs within less than or about 6 months of completion of a chemotherapy regimen that includes a platinum-based drug and a taxane. In some embodiments, cancer recurrence occurs within less than about 6 months of completion of a chemotherapy regimen that includes a platinum-based drug and a taxane. In some embodiments, cancer recurrence occurs within less than about 6 months of completion of a chemotherapy regimen that includes a platinum-based drug and a taxane. In some embodiments, cancer recurrence occurs about 6 months after completion of a chemotherapy regimen that includes a platinum-based drug and a taxane. In some embodiments, cancer recurrence occurs within about 6 months of completion of a chemotherapy regimen that includes a platinum-based drug and a taxane. In some embodiments, cancer recurrence occurs within less than or 6 months of completion of a chemotherapy regimen that includes a platinum-based drug. In some embodiments, cancer recurrence occurs within less than 6 months of completion of a chemotherapy regimen that includes a platinum-based drug. In some embodiments, cancer recurrence occurs within less than 6 months of completion of a chemotherapy regimen that includes a platinum-based drug. In some embodiments, cancer recurrence occurs within 6 months of completion of a chemotherapy regimen that includes a platinum-based drug. ​In some embodiments, cancer recurrence occurs about 6 months or about 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs and taxanes. In some embodiments, cancer recurrence occurs about 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs and taxanes. In some embodiments, cancer recurrence occurs about 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs and taxanes. In some embodiments, cancer recurrence occurs about 6 months or about 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs and taxanes. In some embodiments, cancer recurrence occurs about 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs and taxanes. In some embodiments, cancer recurrence occurs about 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs and taxanes. In some embodiments, cancer recurrence occurs about 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs and taxanes. In some embodiments, cancer recurrence occurs about 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs and taxanes. In some embodiments, cancer recurrence occurs about 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs and taxanes. In some embodiments, cancer recurrence occurs about 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs and taxanes. In some embodiments, cancer recurrence occurs about 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs and taxanes. In some embodiments, cancer recurrence occurs about 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs and taxanes. occurs. In some embodiments, cancer recurrence occurs 6 months or 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs. In some embodiments, cancer recurrence occurs 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs. In some embodiments, cancer recurrence occurs 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs. In some embodiments, cancer recurrence occurs 6 months or 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs. In some embodiments, cancer recurrence occurs 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs. In some embodiments, cancer recurrence occurs 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs. In some embodiments, cancer recurrence occurs 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs. In some embodiments, cancer recurrence occurs 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs. In some embodiments, cancer recurrence occurs 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs. In some embodiments, cancer recurrence occurs 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs. In some embodiments, cancer recurrence occurs 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs. In some embodiments, cancer recurrence occurs 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs. In some embodiments, cancer recurrence occurs 6 months or 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs and taxanes. In some embodiments, cancer recurrence occurs 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs and taxanes. In some embodiments, cancer recurrence occurs 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs and taxanes. In some embodiments, cancer recurrence occurs 6 months or 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs and taxanes. In some embodiments, cancer recurrence occurs 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs and taxanes. In some embodiments, cancer recurrence occurs 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs and taxanes. In some embodiments, cancer recurrence occurs 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs and taxanes. In some embodiments, cancer recurrence occurs 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs and taxanes. In some embodiments, cancer recurrence occurs 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs and taxanes. In some embodiments, cancer recurrence occurs 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs and taxanes. In some embodiments, cancer recurrence occurs 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs and taxanes. In some embodiments, cancer recurrence occurs 6 months after the completion of a chemotherapy regimen that includes platinum-based drugs and taxanes. In some embodiments, the ADC is administered to the subject together with a second drug. In some embodiments, the ADC is administered before the second drug. In some embodiments, the ADC is administered after the second drug. In some embodiments, the ADC is administered simultaneously with the second drug. In some embodiments, the ADC is administered to the subject together with a second drug. In some embodiments, the ADC is administered before the second drug. In some embodiments, the ADC is administered after the second drug. In some embodiments, the ADC is administered simultaneously with the second drug. In some embodiments, the ADC is administered to the subject together with a second drug. In some embodiments, the ADC is administered before the second drug. In some embodiments, the ADC is administered after the second drug. In some embodiments, the ADC is administered simultaneously with the second drug. In some embodiments, the present disclosure generally relates to a method of treating cancer, comprising administering a pharmaceutical composition to a subject having ovarian cancer resistant to platinum-based chemotherapy and / or a subject showing recurrence of ovarian cancer prior to administration of the pharmaceutical composition, wherein the pharmaceutical composition has the following formula: In some embodiments, the present disclosure generally relates to a method of treating cancer, comprising administering a pharmaceutical composition to a subject having ovarian cancer resistant to platinum-based chemotherapy and / or a subject showing recurrence of ovarian cancer prior to administration of the pharmaceutical composition, wherein the pharmaceutical composition has the following formula: In some embodiments, the present disclosure generally relates to a method of treating cancer, comprising administering a pharmaceutical composition to a subject having ovarian cancer resistant to platinum-based chemotherapy and / or a subject showing recurrence of ovarian cancer prior to administration of the pharmaceutical composition, wherein the pharmaceutical composition has the following formula:

Chemical formula

Chemical formula

[24] Administering the ADC simultaneously with the second drug, The treatment method according to [21A]. [25A] Administering a pharmaceutical composition to a subject having platinum-resistant ovarian cancer and / or a subject showing recurrence of ovarian cancer before administration of the pharmaceutical composition, A treatment method for treating cancer, comprising: The pharmaceutical composition is represented by the following formula:

Chemical formula

Advantages of the Invention

[0022] The present disclosure provides a therapeutic method for treating cancer using an ADC, and a pharmaceutical product containing an ADC for treating cancer. The present disclosure also provides an anti-tumor effect that exhibits and maintains both a tumor regression effect and safety using an anti-CD6 antibody-drug conjugate in which the antibody specifically binds to EC3 A therapeutic method for treating chemotherapy-resistant cancer. The present disclosure also provides a pharmaceutical composition containing an anti-CD6 antibody-drug conjugate. An excellent anti-tumor effect. The present disclosure provides a therapeutic method for treating chemotherapy-resistant cancer having an excellent anti-tumor effect that exhibits and maintains both a tumor regression effect and safety using an anti-CD6 antibody-drug conjugate. The present disclosure also provides a pharmaceutical composition containing an anti-CD6 antibody-drug conjugate.

Brief Description of the Drawings

[0023]

Figure 1

Figure 2-1

Figure 2-2

Figure 2-3

Figure 2-4

Figure 2-5

Figure 2-6

Figure 3

Figure 4

Figure 5

Figure 6-1

Figure 6-2

Figure 7-1

Figure 7-2

Figure 7-3

Figure 7-4

Figure 7-5

Figure 7-6

Figure 8

Figure 9

Figure 10-1

Figure 10-2

Figure 10-3

Figure 11

Figure 12

Figure 13

Figure 14

Figure 15

Figure 16

Figure 17

Figure 18

Figure 19

Figure 20

Figure 21

Mode for Carrying Out the Invention

[0024] Hereinafter, preferred embodiments for carrying out the present invention will be described with reference to the drawings. Note that the embodiments described below show an example of a typical embodiment of the present invention, and thus the scope of the present invention should not be construed narrowly.

[0025] In this specification, "cancer" and "tumor" are used interchangeably.

[0026] In this specification, the term "gene" includes not only DNA but also its mRNA, cDNA, and its cRNA.

[0027] In this specification, "polynucleotide" or "nucleotide" is used interchangeably with nucleic acid and includes DNA, RNA, probes, oligonucleotides, and primers. In this specification, "polynucleotide" and "nucleotide" can be used interchangeably unless otherwise specified.

[0028] In this specification, "polypeptide" and "protein" can be used interchangeably.

[0029] In this specification, "cell" includes cells in an animal body and cultured cells.

[0030] In this specification, "CDH6" can be used interchangeably with CDH6 protein. In this specification, human CDH6 may be referred to as "hCDH6".

[0031] In this specification, the term "cytotoxic activity" is used to mean that cells are pathologically changed by any given method. This term refers not only to direct trauma but also to DNA cleavage, formation of base dimers, chromosome breakage, damage to the cell division apparatus, and any other damage to the structure and function of cells, such as a decrease in various

[0032] In this specification, "exhibiting toxicity intracellularly" means showing toxicity intracellularly in some form. This term does not only refer to direct trauma, but also includes DNA cleavage, formation of base dimers, chromosome cleavage, damage to the cell division apparatus, decrease in various enzyme activities, suppression of the action of cell growth factors, and any other effects on the structure, function, and metabolism of cells.

[0033] In this specification, "functional fragment of an antibody" is also referred to as "antigen-binding fragment of an antibody", and means a partial fragment of an antibody having antigen-binding activity. It includes Fab, F(ab’)2, scFv, diabody, linear antibody, bispecific antibody formed from antibody fragments, etc. Also, Fab’, which is a monovalent fragment of the variable region of an antibody obtained by treating F(ab’)2 under reducing conditions, is also included in the antigen-binding fragments of antibodies. However, the antigen-binding fragments of antibodies are not limited to these molecules as long as they have the ability to bind to an antigen. In addition, these antigen-binding fragments include not only those obtained by treating the full-length molecule of an antibody protein with an appropriate enzyme, but also proteins produced in appropriate host cells using genetically engineered antibody genes.

[0034] In this specification, "epitope" means a partial peptide or partial three-dimensional structure of CDH6 to which a specific anti-CDH6 antibody binds. The epitope, which is the partial peptide of CDH6 mentioned above, can be determined by methods well known to those skilled in the art, such as immunoassay methods. First, various partial structures of the antigen are prepared. In preparing the partial structures, known oligonucleotide synthesis techniques can be used. For example, a series of polypeptides sequentially shortened by an appropriate length from the C-terminus or N-terminus of CDH6 can be prepared using genetic recombination techniques well known to those skilled in the art. They are then produced. Thereafter, the reactivity of antibodies thereto is examined to determine the approximate recognition site. Thereafter, shorter peptides are further synthesized and their reactivity with these peptides is examined. By doing so, the epitope can be determined. Also, when an antibody that binds to a membrane protein composed of multiple extracellular domains has a three-dimensional structure composed of multiple domains as the epitope, it is possible to determine which domain binds by modifying the amino acid sequence of a specific extracellular domain to modify the three-dimensional structure. The epitope, which is the partial three-dimensional structure of the antigen to which a specific antibody binds, can also be determined by identifying the amino acid residues of the antigen adjacent to the antibody by X-ray structural analysis. In this specification, "binding to the same epitope" means an antibody that binds to a common epitope. If a second antibody binds to the partial peptide or partial three-dimensional structure to which the first antibody binds, it can be determined that the first antibody and the second antibody bind to the same epitope. Alternatively, by confirming that the second antibody competes with the binding of the first antibody to the antigen (i.e., the second antibody hinders the binding of the first antibody to the antigen), even if the sequence or structure of the specific epitope has not been determined, it can be determined that the first antibody and the second antibody bind to the same epitope. In this specification, "binding to the same epitope"

[0035] means that the first antibody and the second antibody are determined to bind to a common epitope by either one or both of the determination methods. When the first antibody and the second antibody bind to the same epitope and the first antibody has a special effect such as antitumor activity or internalization activity, it can be expected that the second antibody also has the same activity. ​

[0036] In this specification, "CDR" means Complementary Determining Region (CDR). It is known that there are three CDRs each in the heavy and light chains of an antibody molecule. Such CDRs are also called hypervariable regions and are located in the variable regions of the heavy and light chains of the antibody. These regions have a particularly highly variable primary structure and are separated into three sites on the primary structure of the polypeptide chain in each of the heavy and light chains. In this specification, regarding the CDRs of an antibody, the CDRs of the heavy chain are denoted as CDRH1, CDRH2, and CDRH3 from the amino-terminal side of the heavy chain amino acid sequence, and the CDRs of the light chain are denoted as CDRL1, CDRL2, and CDRL3 from the amino-terminal side of the light chain amino acid sequence. These sites are close to each other in terms of three-dimensional structure and determine the specificity for the antigen to which they bind. ty Determining Region) means. It is known that there are three CDRs each in the heavy and light chains of an antibody molecule. are each known to have three CDRs. Such CDRs are also called hypervariable regions and are located in the variable regions of the heavy and light chains of the antibody. These regions have a particularly highly variable primary structure and are separated into three sites on the primary structure of the polypeptide chain in each of the heavy and light chains. These regions have a particularly highly variable primary structure and are separated into three sites on the primary structure of the polypeptide chain in each of the heavy and light chains. These regions have a particularly highly variable primary structure and are separated into three sites on the primary structure of the polypeptide chain in each of the heavy and light chains. In this specification, regarding the CDRs of an antibody, the CDRs of the heavy chain are denoted as CDRH1, CDRH2, and CDRH3 from the amino-terminal side of the heavy chain amino acid sequence, and the CDRs of the light chain are denoted as CDRL1, CDRL2, and CDRL3 from the amino-terminal side of the light chain amino acid sequence. These sites are close to each other in terms of three-dimensional structure and determine the specificity for the antigen to which they bind. These sites are close to each other in terms of three-dimensional structure and determine the specificity for the antigen to which they bind.

[0037] In this specification, "hybridizing under stringent conditions" means hybridizing at 68°C in a commercially available hybridization solution ExpressHyb Hybridization Solut ion (manufactured by Clontech Laboratories), or performing hybridization at 68°C in the presence of 0.7 - 1.0 M NaCl using a filter to which DNA is immobilized, and then washing at 68°C with an SSC solution at 0.1 - 2 times the concentration (1× concentration SSC consists of 150 mM NaCl and 15 mM sodium citrate). It refers to the conditions that can be identified by hybridizing under such conditions or equivalent conditions. ion (manufactured by Clontech Laboratories), or performing hybridization at 68°C in the presence of 0.7 - 1.0 M NaCl using a filter to which DNA is immobilized, and then washing at 68°C with an SSC solution at 0.1 - 2 times the concentration (1× concentration SSC consists of 150 mM NaCl and 15 mM sodium citrate). It refers to the conditions that can be identified by hybridizing under such conditions or equivalent conditions. 1× concentration SSC consists of 150 mM NaCl and 15 mM sodium citrate). It refers to the conditions that can be identified by hybridizing under such conditions or equivalent conditions. It refers to the conditions that can be identified by hybridizing under such conditions or equivalent conditions.

[0038] In this specification, "one to several" means one to ten, one to nine, one to eight, one to seven, one to six to five, one to four, one to three, or one to two.

[0039] In this specification, the term "resistant" is used to mean having non-responsiveness to treatment with an anticancer agent. This term can also be expressed as "refractory", "non-responsive", or "unresponsive". Furthermore, since this term cannot prevent tumor growth due to non-responsiveness, it can also be expressed as "intolerant". In this specification, "resistance" may mean "having resistance acquired by cancer through treatment with an anticancer agent", or may mean "having intrinsic resistance to cancer independent of treatment with an anticancer agent". In this specification, the term "chemotherapy-resistant" is used to mean having non-responsiveness to treatment with chemotherapy. In this specification, the term "chemotherapy regimen-resistant" is used to mean having non-responsiveness to chemotherapy performed according to a chemotherapy regimen. In this specification, the term "platinum-based chemotherapy-resistant" is used to mean having non-responsiveness to treatment with platinum-based chemotherapy. In this specification, the term "chemotherapy" refers to one or more used for treating cancer

[0040] In this specification, "resistance" may also mean "having resistance acquired by cancer through treatment with an anticancer agent", or may mean "having intrinsic resistance to cancer independent of treatment with an anticancer agent". In this specification, "resistance" may also mean "having resistance acquired by cancer through treatment with an anticancer agent", or may mean "having intrinsic resistance to cancer independent of treatment with an anticancer agent". In this specification, "resistance" may also mean "having resistance acquired by cancer through treatment with an anticancer agent", or may mean "having intrinsic resistance to cancer independent of treatment with an anticancer agent".

[0041] In this specification, the term "chemotherapy-resistant" is used to mean having non-responsiveness to treatment with chemotherapy. In this specification, the term "chemotherapy-resistant" is used to mean having non-responsiveness to treatment with chemotherapy.

[0042] In this specification, the term "chemotherapy regimen-resistant" is used to mean having non-responsiveness to chemotherapy performed according to a chemotherapy regimen. In this specification, the term "chemotherapy regimen-resistant" is used to mean having non-responsiveness to chemotherapy performed according to a chemotherapy regimen.

[0043] In this specification, the term "platinum-based chemotherapy-resistant" is used to mean having non-responsiveness to treatment with platinum-based chemotherapy. In this specification, the term "platinum-based chemotherapy-resistant" is used to mean having non-responsiveness to treatment with platinum-based chemotherapy.

[0044] In this specification, the term "chemotherapy" refers to one or more used for treating cancer The term is used to mean a therapy using chemotherapy agents.

[0045] As used herein, the term "chemotherapeutic agent" refers to a chemotherapy agent used to treat cancer. The term "chemotherapeutic agent" is used to mean an agent that inhibits the inflammatory process. Chemotherapeutic agents include alkylating agents (e.g., mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, hexamethasone Lumelamine, thiotepa, busulfan, carmustine, lomustine, semustine, streptomycin, putozocin, dacarbazine), antimetabolites (e.g., gemcitabine, methotrexate , fluorouracil, doxifluridine, capecitabine, floxuridine, cytarabine , mercaptopurine, thioguanine, pentostatin), vinca alkaloids (e.g., vinblastine, vincristine), epipodophyllotoxins (e.g., etoposide, tetanus, niposide), antibiotics (e.g., dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin, mitomycin), platinum complexes (e.g., cisplatin , carboplatin, oxaliplatin), taxanes (e.g., paclitaxel, docetaxel cell), anthracenediones (e.g., mitoxantrone), substituted ureas (e.g., hydrochloride xyurea), methylhydrazines (e.g., procarbazine hydrochloride), vitamin A metabolites ( For example, tretinoin) but are not limited to these.

[0046] As used herein, the term "platinum-based chemotherapy" refers to chemotherapy that involves one or more other chemotherapeutic agents. is used to mean a cancer therapy using one or more platinum-based drugs with or without platinum-based drugs.

[0047] As used herein, the term "platinum-based drug" refers to platinum complexes used in the treatment of cancer. It is used for tasting. Platinum-based drugs include, but are not limited to, cisplatin, carboplatin, and oxaliplatin. It includes, but is not limited to, these.

[0048] In this specification, the term "cancer recurrence" is used to mean that the cancer returns to the same location as the primary tumor or to another location in the body after a period when the cancer could not be detected. This term is defined based on "recurrence" in the following references. NCI Dictionaries, "recurrence", NCI Dictionary of Cancer Terms [online]. National Cancer Institute [searched: 2022-09-06]. <cancer.gov / publications / dictionaries / cancer-terms / def / recurrence> obtained from.

[0049] In this specification, the term "chemotherapy regimen" is used to mean a treatment plan for chemotherapy that defines the drug(s), dosage, frequency, etc.

[0050] In this specification, the term "complete response (CR)" is used to mean all signs of cancer that have disappeared in response to treatment. "Complete response (CR)" does not necessarily mean that the cancer has been cured. This term can also be expressed as "complete remission". This term is defined based on "complete response" in the following references. NCI Dictionaries, "complete response", NC I Dictionary of Cancer Terms [online]. National Cancer Institute [searched: 2022-09-06]. <ca ncer.gov / publications / dictionaries / cance r - terms / def / complete - response>.

[0051] In this specification, the term "partial response (PR)" is used to mean that the size of the tumor in the body or the degree of cancer decreases in response to treatment. This term can also be expressed as "partial remission". This term is defined based on "partial response" in the following reference. NCI Dictionaries, "partial response", NCI Dictionary of Cancer Terms [online]. National Cancer Institute [searched: 2022 - 09 - 06]. <can cer.gov / publications / dictionaries / cancer - terms / def / partial - response>. Retrieved from ncer.gov / publications / dictionaries / cancer - terms / def / partial - response>.

[0052] In this specification, the term "stable disease (SD)" is used to mean that the degree or severity of cancer neither decreases nor increases. This term is defined based on "partial response" in the following reference. NCI Dictionaries, "stable disease", NCI D ictionary of Cancer Terms [online]. National Cancer Institute [searched: 2022 - 09 - 06]. <cance r.gov / publications / dictionaries / cancer - t erms / def / stable - disease>. Retrieved from r.gov / publications / dictionaries / cancer - t erms / def / stable - disease>.

[0053] 1.CDH6 Cadherins are glycoproteins present on the cell membrane surface that bind to the N-terminus in a calcium ion-dependent manner. The binding of the extracellular domains at the two ends of the protein functions as an intercellular adhesion molecule and as a mediator of cell-cell interactions. It functions as a signaling molecule that carries out the functions of the cadherin superfamily. Cadherins are a group of molecules that have five extracellular domains (EC domains) and one extracellular domain. It is a single-pass transmembrane protein consisting of two transmembrane domains and an intracellular domain.

[0054] CDH6 (Cadherin-6) is classified into the type II cadherin family. It is a single-pass transmembrane protein consisting of 790 amino acids, with the N-terminus at the extracellular side and the C-terminus at the The human CDH6 gene was first cloned in 1995 (Non-Patent Document 1), NM_004932, NP_004923 (NCBI), etc. It is more accessible.

[0055] The CDH6 protein used in the present invention may be derived from a human or non-human mammal (e.g., rat). Alternatively, the CDH6-expressing cells may be purified directly from CDH6-expressing cells of a mammalian animal (such as a mouse or monkey) and used. A cell membrane fraction of the cells can be prepared and used as the CDH6 protein. CDH6 can be synthesized in vitro or expressed in host cells by genetic engineering. Alternatively, it can be obtained by producing CDH6 in cells. We inserted CDH6 cDNA into a vector capable of expressing CDH6 cDNA and then transfected it. CDH6 is synthesized in a solution containing the enzymes, substrates, and energy materials required for transcription and translation. or by transforming other prokaryotic or eukaryotic host cells. By expressing it, the CDH6 protein can be obtained. Also, the above gene CDH6-expressing cells obtained by manipulation, or cell lines expressing CDH6, can also be used as the CDH6 protein It is also possible to directly administer an expression vector incorporating the cDNA of CDH6 to an immunized animal to express CDH6 in the body of the immunized animal.

[0056] Also, in the amino acid sequence of the above CDH6, a protein consisting of an amino acid sequence in which one or several amino acids are substituted, deleted and / or added, and having biological activity equivalent to that of the CDH6 protein is also included in the term "CDH6".

[0057] The human CDH6 protein has the amino acid sequence set forth in SEQ ID NO: 1. The extracellular region of the human CDH6 protein is extracellular domain 1 having the amino acid sequence of positions 54 to 159 of the amino acid sequence set forth in SEQ ID NO: 1 (also referred to as EC1 herein), extracellular domain 2 having the amino acid sequence of positions 160 to 268 of the amino acid sequence set forth in SEQ ID NO: 1 (also referred to as EC2 in this specification), extracellular domain 3 having the amino acid sequence of positions 269 to 383 of the amino acid sequence set forth in SEQ ID NO: 1 (also referred to as EC3 in this specification), extracellular domain 4 having the amino acid sequence of positions 384 to 486 of the amino acid sequence set forth in SEQ ID NO: 1 (also referred to as EC4 in this specification), and extracellular domain 5 having the amino acid sequence of positions 487 to 608 of the amino acid sequence set forth in SEQ ID NO: 1 (also referred to as EC5 in this specification). The amino acid sequences of EC1 to EC5 are set forth as SEQ ID NOs: 2 to 6, respectively (Table 1).

[0058] 2. Production of anti-CDH6 antibody ​​​​​​​​​​​​​As an example of the anti-CDH6 antibody of the present invention, an amino acid containing the amino acid sequence shown in SEQ ID NO: 4 sequence can be mentioned, which recognizes the sequence and has internalization activity. As an example of the anti-CDH6 antibody of the present invention, an anti-CDH6 antibody that specifically recognizes the amino acid sequence containing the amino acid sequence shown in SEQ ID NO: 4 and has internalization activity can be mentioned. As an example of the anti-CDH6 antibody of the present invention, an anti-CDH6 antibody that recognizes the amino acid sequence consisting of the amino acid sequence shown in SEQ ID NO: 4 and has internalization activity can be mentioned. As an example of the anti-CDH6 antibody of the present invention, an anti-CDH6 antibody that specifically recognizes the amino acid sequence consisting of the amino acid sequence shown in SEQ ID NO: 4 and has internalization activity can be mentioned. When the antibody "specifically recognizes the amino acid sequence containing the amino acid sequence shown in SEQ ID NO: 4" or "specifically recognizes the EC3 domain", it means that the antibody strongly recognizes or strongly binds to the EC3 domain of CDH6 as compared to other extracellular domains of CDH6. The anti-CDH6 antibody of the present invention can be derived from any species. Preferred examples of the species may include humans, monkeys, rats, mice, and rabbits. When the anti-CDH6 antibody of the present invention is derived from a species other than humans, it is preferable to chimerize or humanize the anti-CDH6 antibody by well-known techniques.

[0059] The anti-CDH6 antibody of the present invention can be a polyclonal antibody or a monoclonal antibody, but a monoclonal antibody is preferred.

[0060] The anti-CDH6 antibody of the present invention is an antibody that can target tumor cells. Specifically, the anti-CDH6 antibody of the present invention has the property of being able to recognize tumor cells and the property of being able to bind to tumor cells. ​​​​​​and / or has characteristics such as being incorporated and internalized into tumor cells. Therefore, the anti-CDH6 antibody of the present invention and a compound having anti-tumor activity can be conjugated via a linker to form an antibody -drug conjugate.

[0061] The binding of the antibody to tumor cells can be confirmed using flow cytometry. The uptake of the antibody into tumor cells can be confirmed by (1) an assay (Cell Death and Differentiation, 2008, 15, 751-761) in which the antibody incorporated into the cells is visualized with a fluorescence microscope using a secondary antibody (fluorescently labeled) that binds to the therapeutic antibody, (2) an assay (Molecular Biology of the Cell Vol. 15, 5268-5282, December 2004) in which the amount of fluorescence incorporated into the cells is measured using a secondary antibody (fluorescently labeled) that binds to the therapeutic antibody, or (3) a Mab-ZAP assay (Bio Techniques 28:162-165, January 2000) in which when the immunotoxin that binds to the therapeutic antibody is incorporated into the cells, the toxin is released and cell proliferation is inhibited. As the immunotoxin, a recombinant complex protein of the catalytic region of diphtheria toxin and protein G can also be used. The so-called "high internalization ability" referred to in this specification means that the survival rate of CDH6-expressing cells administered with the antibody and a saporin-labeled anti-rat IgG antibody (expressed as a relative rate with the cell survival rate without the addition of the antibody being 100%) is preferably 70% or less, more preferably 60% or less.

[0062]

[0063] The anti-tumor antibody-drug conjugate of the present invention contains a conjugated compound that exhibits an anti-tumor effect. Therefore, it is preferable that the antibody itself has an anti-tumor effect, but it is not essential. For the purpose of specifically and / or selectively exerting the cytotoxicity of the anti-tumor compound in tumor cells, it is important and preferable that the antibody has the property of internalizing and migrating into tumor cells. The anti-CDH6 antibody can be obtained by immunizing an animal with an antigenic polypeptide using methods commonly practiced in this field and collecting and purifying the antibodies produced in vivo. It is preferable to use CDH6 with its three-dimensional structure retained as the antigen. Such methods include, for example, the DNA immunization method. The origin of the antigen is not limited to humans, and antigens derived from non-human animals such as mice and rats can also be used to immunize animals. In this case, antibodies applicable to human diseases can be selected by testing the cross-reactivity between the obtained antibodies that bind to the heterologous antigen and human antigens. Also, hybridomas can be established and monoclonal antibodies can be obtained by fusing antibody-producing cells that produce antibodies against an antigen with myeloma cells according to known methods (e.g., Kohler and Milstein, Nature (1975) 256, 495-497; Kennet, R., ed., Monoclonal Antibodies, 365-367, Plenum Press, N.Y. (1980)). Hereinafter, a method for obtaining an antibody against CDH6 will be specifically described.

[0064] The anti-CD6 antibody can be obtained by immunizing an animal with an antigenic polypeptide using methods commonly practiced in this field and collecting and purifying the antibodies produced in vivo. It is preferable to use CDH6 with its three-dimensional structure retained as the antigen. Such methods include, for example, the DNA immunization method. The origin of the antigen is not limited to humans, and antigens derived from non-human animals such as mice and rats can also be used to immunize animals. In this case, antibodies applicable to human diseases can be selected by testing the cross-reactivity between the obtained antibodies that bind to the heterologous antigen and human antigens. Also, hybridomas can be established and monoclonal antibodies can be obtained by fusing antibody-producing cells that produce antibodies against an antigen with myeloma cells according to known methods (e.g., Kohler and Milstein, Nature (1975) 256, 495-497; Kennet, R., ed., Monoclonal Antibodies, 365-367, Plenum Press, N.Y. (1980)). Hereinafter, a method for obtaining an antibody against CDH6 will be specifically described.

[0065] The origin of the antigen is not limited to humans, and antigens derived from non-human animals such as mice and rats can also be used to immunize animals. In this case, antibodies applicable to human diseases can be selected by testing the cross-reactivity between the obtained antibodies that bind to the heterologous antigen and human antigens. Also, hybridomas can be established and monoclonal antibodies can be obtained by fusing antibody-producing cells that produce antibodies against an antigen with myeloma cells according to known methods (e.g., Kohler and Milstein, Nature (1975) 256, 495-497; Kennet, R., ed., Monoclonal Antibodies, 365-367, Plenum Press, N.Y. (1980)). Hereinafter, a method for obtaining an antibody against CDH6 will be specifically described.

[0066] Also, hybridomas can be established and monoclonal antibodies can be obtained by fusing antibody-producing cells that produce antibodies against an antigen with myeloma cells according to known methods (e.g., Kohler and Milstein, Nature (1975) 256, 495-497; Kennet, R., ed., Monoclonal Antibodies, 365-367, Plenum Press, N.Y. (1980)). (1975)256,495-497,Kennet,R.ed.,Monoclona l Antibodies,365-367,Plenum Press,N.Y.(1 980)) to fuse antibody-producing cells that produce antibodies against an antigen with myeloma cells to establish hybridomas and obtain monoclonal antibodies. Hereinafter, a method for obtaining an antibody against CDH6 will be specifically described. The anti-CD6 antibody can be obtained by immunizing an animal with an antigenic polypeptide using methods commonly practiced in this field and collecting and purifying the antibodies produced in vivo. It is preferable to use CDH6 with its three-dimensional structure retained as the antigen. Such methods include, for example, the DNA immunization method.

[0067] Hereinafter, a method for obtaining an antibody against CDH6 will be specifically described.

[0068] (1) Preparation of antigen The antigen can be obtained by genetically engineering a host cell to produce a gene encoding the antigen protein. Specifically, a vector capable of expressing the antigen gene is prepared, introduced into a host cell to express the gene, and the expressed antigen is purified. The antigen-expressing cells obtained by the above gene manipulation, or cell lines expressing the antigen, can also be used to immunize animals to obtain antibodies.

[0069] Alternatively, without using the antigen protein, the cDNA of the antigen protein is incorporated into an expression vector and administered to immunized animals to express the antigen protein in the immunized animals and produce antibodies against the antigen protein to obtain antibodies.

[0070] (2) Production of anti-CDH6 monoclonal antibody The anti-CDH6 antibody used in the present invention is not particularly limited. For example, an antibody identified by the amino acid sequence shown in the sequence listing of the present application can be preferably used. The anti-CDH6 antibody used in the present invention is preferably an antibody having the following characteristics. The anti-CDH6 antibody used in the present invention is preferably an antibody having the following characteristics. (1) Antibodies having the following characteristics: (a) Specifically binds to CDH6, and (b) Has the activity of internalizing into CDH6-expressing cells by binding to CDH6; (2) The antibody according to (1) above, wherein CDH6 is human CDH6; or (3) The antibody according to (1) or (2) above, which specifically recognizes EC3 of human CDH6 and has internalization activity. The method for obtaining the antibody against CDH6 of the present invention is not limited as long as an anti-CDH6 antibody can be obtained It is not particularly limited. It is preferable to use CDH6 that retains its higher-order structure as an antigen. .

[0071] As an example of a preferable method for obtaining an antibody, the DNA immunization method can be mentioned. DNA immunization The method is a technique for inducing immunity against an antigen by introducing an antigen-expression plasmid into an animal individual such as a mouse or a rat and expressing the antigen in vivo. Methods of gene introduction include a method of directly injecting a plasmid into muscle, a method of intravenously injecting an introduction reagent such as liposome or polyethyleneimine, a technique using a viral vector, a technique of shooting gold particles attached with a plasmid by a Gene Gun, a Hydrodynamic method of rapidly intravenously injecting a large amount of plasmid solution, etc. Regarding the method of gene introduction by intramuscular injection of an expression plasmid, as a technique for improving the expression level, there is a technique called in vivo electroporation in which electroporation is applied to the same site after intramuscular injection of the plasmid (Aihara H, Miyazaki J. Nat Biotechnol nol. 1998 Sep;16(9):867-70 or Mir LM, Bure au MF, Gehl J, Rangara R, Rouy D, Caillaud J M, Delaere P, Branellec D, Schwartz B, Scher man D. Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4262-7). This technique further improves the expression level by treating the muscle with hyaluronidase before intramuscular injection of the plasmid (McMahon JM1, Sig nori E, Wells KE, Fazio VM, Wells DJ., Gene nori E, Wells KE, Fazio VM, Wells DJ., Gene nori E, Wells KE, Fazio VM, Wells DJ., Gene man D. Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4262-7). This technique further improves the expression level by treating the muscle with hyaluronidase before intramuscular injection of the plasmid (McMahon JM1, Sig nori E, Wells KE, Fazio VM, Wells DJ., Gene nori E, Wells KE, Fazio VM, Wells DJ., Gene ​(Ther. 2001 Aug;8(16):1264 - 70). Also, the production of hybridomas can be carried out by known methods. For example, it can also be carried out using the Hybrimune Hybrid oma Production System (Cyto Pulse Science s).

[0072] Specific examples of obtaining monoclonal antibodies can include the following procedures. (a) Incorporate the cDNA of CDH6 into an expression vector (e.g., pcDNA3.1: Thermo Fisher Scientific), and administer the vector directly to an immunized animal (e.g., rat or mouse) by methods such as electroporation or gene gun, etc., to express CDH6 in the animal body and thereby induce an immune response. Administration of the vector by electroporation or the like may be performed one or more times, preferably multiple times, if necessary to enhance the antibody titer. (b) Collection of tissues containing antibody - producing cells (e.g., lymph nodes) from the above - mentioned animals in which an immune response has been induced; (c) Preparation of myeloma cells (hereinafter referred to as "myeloma") (e.g., mouse myeloma SP 2 / 0 - ag14 cells); (d) Cell fusion between antibody - producing cells and myeloma; (e) Selection of a group of hybridomas that produce the target antibody; (f) Splitting (cloning) into single - cell clones; (g) In some cases, culturing of hybridomas for mass production of monoclonal antibodies, or breeding of animals transplanted with hybridomas; and / or (h) Examination of the biological activity (internalization activity) and binding specificity of the produced monoclonal antibodies (i) (g) In some cases, culturing of hybridomas for mass production of monoclonal antibodies, or breeding of animals transplanted with hybridomas; and / or (h) Examination of the biological activity (internalization activity) and binding specificity of the produced monoclonal antibodies (h) Examination of the biological activity (internalization activity) and binding specificity of the produced monoclonal antibodies , or examination of the properties of an antibody as a labeling reagent.

[0073] Examples of the method for measuring the antibody titer used herein include, but are not limited to, flow cytometry or Cel l-ELISA method.

[0074] Examples of the hybridoma strains established in this way include anti-CDH6 antibody-producing hybrid omas rG019, rG055, rG056 and rG061. Incidentally, in this specification, the antibody produced by the anti-CDH6 antibody-producing hybridoma rG019 is described as "rG019 antibody" or simply "rG019", and the antibody produced by the hybridoma rG055 is described as "rG055 antibody" or simply "rG055", and the antibody produced by the hybridoma rG056 is described as "rG056 antibody" or simply "rG056", and the antibody produced by the hybridoma rG061 is described as "rG061 antibody" or simply "rG061 ".

[0075] The light chain variable region of the rG019 antibody consists of the amino acid sequence shown in SEQ ID NO: 10. The amino acid sequence of the light chain variable region of the rG019 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 11. The light chain variable region of the rG019 antibody has CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 13, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 14. The heavy chain variable region of the rG019 antibody consists of the amino acid sequence shown in SEQ ID NO: 15. The amino acid sequence of the heavy chain variable region of the rG019 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 16. 。The heavy-chain variable region of the rG019 antibody consists of CDR RH1 consisting of the amino acid sequence shown in SEQ ID NO: 17, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 18, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 19. The sequence of the rG019 antibody is shown in Table 1.

[0076] The light-chain variable region of the rG055 antibody consists of the amino acid sequence shown in SEQ ID NO: 20. The amino acid sequence of the light-chain variable region of the rG055 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 21. The light-chain variable region of the rG055 antibody consists of CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 22, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 23, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 24. The heavy-chain variable region of the rG055 antibody consists of the amino acid sequence shown in SEQ ID NO: 25. The amino acid sequence of the heavy-chain variable region of the rG055 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 26. The heavy-chain variable region of the rG055 antibody consists of CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 27, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 28, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 29. The sequence of the rG055 antibody is shown in Table 1. The heavy-chain variable region of the rG056 antibody consists of the amino acid sequence shown in SEQ ID NO: 30. The amino acid sequence of the heavy-chain variable region of the rG056 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 31. The light-chain variable region of the rG056 antibody consists of CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 32, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 33, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 34. The heavy-chain variable region of the rG056 antibody consists of CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 35, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 36, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 37. The sequence of the rG056 antibody is shown in Table 1.

[0077] The light-chain variable region of the rG056 antibody consists of the amino acid sequence shown in SEQ ID NO: 30. The amino acid sequence of the light-chain variable region of the rG056 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 31. The light-chain variable region of the rG056 antibody consists of CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 32, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 33, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 34. The heavy-chain variable region of the rG056 antibody consists of CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 35, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 36, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 37. The heavy chain variable region consists of the amino acid sequence shown in SEQ ID NO: 35. The heavy chain variable region amino acid sequence of the rG056 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 36 . The heavy chain variable region of the rG056 antibody consists of CD RH1 consisting of the amino acid sequence shown in SEQ ID NO: 37, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 38, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 39. The sequence of the rG056 antibody is shown in Table 1.

[0078] The light chain variable region of the rG061 antibody consists of the amino acid sequence shown in SEQ ID NO: 40. The amino acid sequence of the light chain variable region of the rG061 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 41. The light chain variable region of the rG061 antibody consists of CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 42, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 43, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 44. The heavy chain variable region of the rG061 antibody consists of the amino acid sequence shown in SEQ ID NO: 45. The amino acid sequence of the heavy chain variable region of the rG061 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 46 . The heavy chain variable region of the rG061 antibody consists of CD RH1 consisting of the amino acid sequence shown in SEQ ID NO: 47, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 48, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 49. The sequence of the rG061 antibody is shown in Table 1.

[0079] Furthermore, when the steps of "(2. Production of anti-CDH6 antibody)" (a) to (h) are carried out again to separately obtain monoclonal antibodies independently, or when monoclonal antibodies are separately obtained by other methods Even when the body is obtained, it is possible to obtain an antibody having internalization activity equivalent to that of the rG019 antibody, rG055 antibody, rG056 antibody or r G061 antibody. As an example of such an antibody, an antibody that binds to the same epitope as the rG019 antibody, rG055 antibody, rG056 antibody or rG061 anti body can be mentioned. If the newly produced monoclonal antibody binds to the binding partial peptide or partial three-dimensional structure of the rG019 antibody, rG055 antibody, rG056 antibody or rG061 antibody, the monoclonal antibody binds to the same epitope as the rG01 9 antibody, rG055 antibody, rG056 antibody or rG061 antibody. can be determined. In addition, the monoclonal antibody competes with the binding of the rG019 antibody, rG055 antibody, rG056 antibody or rG061 antibody to CDH6 ( That is, the monoclonal antibody inhibits the binding of the rG019 antibody, rG055 antibody, rG056 antibody or rG061 antibody to CDH6). By confirming this, even if the sequence or structure of the specific epi top is not determined, it can be determined that the monoclonal antibody binds to the same epitope as the anti-CDH6 antibody . If it is confirmed that the monoclonal antibody binds to the same epitope as the epitope to which the rG0 19 antibody, rG055 antibody, rG056 antibody or rG061 antibody binds, the monoclonal antibody has antigen-binding ability, biological activity and is strongly expected to have the same internalization activity as the rG019 antibody, rG055 antibody, rG056 antibody or rG061 antibody. (3) Other antibodies In addition to the monoclonal antibodies against CDH6 described above, the antibodies of the present invention are different from humans In addition to the monoclonal antibodies against CDH6 described above, the antibodies of the present invention are different from humans In addition to the monoclonal antibodies against CDH6 described above, the antibodies of the present invention are different from humans In addition to the monoclonal antibodies against CDH6 described above, the antibodies of the present invention are different from humans

[0080] (3) Other antibodies In addition to the monoclonal antibodies against CDH6, the antibodies of the present invention include those different from humans Genetically engineered antibodies artificially modified for the purpose of reducing antigenicity, etc., such as , chimeric antibodies, humanized antibodies, or human antibodies, etc. are also included. These antibodies can be produced using known methods.

[0081] Examples of chimeric antibodies include antibodies in which the variable region and the constant region of the antibody are heterologous to each other, such as chimeric antibodies in which the variable region of a mouse or rat-derived antibody is conjugated to a human-derived constant region (see Proc. Natl. Acad. Sci. U.S.A., 81, 6851- 6855, (1984)).

[0082] Examples of chimeric antibodies derived from rat anti-human CDH6 antibodies include, for example, those described herein rat anti-human CDH6 antibodies (e.g., rG019 antibody, rG055 antibody, rG056 antibody or rG061 antibody), a light chain containing each light chain variable region and a human-derived constant region, and each heavy chain an antibody consisting of a heavy chain containing a variable region and a human-derived constant region.

[0083] Another example of a chimeric antibody derived from a rat anti-human CDH6 antibody includes, for example, those described herein rat anti-human CDH6 antibodies (e.g., rG019 antibody, rG055 antibody, rG056 antibody or rG061 antibody), 1 to several residues, 1 to 3 residues, 1 to 2 residues, preferably 1 residue of amino acid in each light chain variable region substituted with another amino acid residue, a light chain containing the light chain variable region, and and, 1 to several residues, 1 to 3 residues, 1 to 2 residues, preferably 1 residue of amino acid in each heavy chain variable region substituted with another amino acid residue, an antibody consisting of a heavy chain containing the heavy chain variable region. This antibody can have any given human-derived constant region.

[0084] As another example of a chimeric antibody derived from a rat anti-human CDH6 antibody, for example, as described herein any one to three of the CDRs in each light chain variable region of the rat anti-human CDH6 antibody (e.g., rG019 antibody, rG055 antibody, rG056 antibody or rG061 antibody), one to two residues, preferably one residue, of the amino acid are substituted with another amino acid residue, and a light chain variable region containing the substituted light chain variable region , and one to two residues, preferably one residue, of the amino acid in any one to three of the CDRs in each heavy chain variable region are substituted with another amino acid residue, and a heavy chain containing the substituted heavy chain variable region . Such antibodies may have any given human-derived constant region.

[0085] As an example of a chimeric antibody derived from the rG019 antibody, for example, a light chain containing a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 10, and a heavy chain containing a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 15 . Such antibodies may have any given human-derived constant region.

[0086] As another example of a chimeric antibody derived from the rG019 antibody, for example, one to several residues, one to three residues, one to two residues, preferably one residue, of the amino acid in the light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 10 are substituted with another amino acid residue, and a light chain containing the substituted light chain variable region, and one to several residues, one to three residues, one to two residues, preferably one residue, of the amino acid in the heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 15 are substituted with another amino acid residue, and a heavy chain containing the substituted heavy chain variable region . Such antibodies may have any given human-derived constant region.

[0087] As another example of a chimeric antibody derived from the rG019 antibody, for example, as shown in SEQ ID NO: 10​​​​​​ A light chain comprising a light chain variable region in which one or two residues (preferably one residue) of any one to three CDRs in the light chain variable region consisting of an amino acid sequence are replaced with another amino acid residue, and also, an antibody consisting of a heavy chain comprising a heavy chain variable region in which one or two residues (preferably one residue) of any one to three CDRs in the heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 15 are replaced with another amino acid residue. This antibody may have any given human-derived constant region. Another example of a chimeric antibody derived from the rG019 antibody is, for example, an antibody consisting of a light chain comprising a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 10, and a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 58. This antibody may have any given human-derived constant region. The amino acid sequence shown in SEQ ID NO: 58 is a sequence in which the cysteine residue in CDRH2 in the amino acid sequence shown in SEQ ID NO: 1

[0088] 5 is replaced with a proline residue. A specific example of a chimeric antibody derived from the rG019 antibody is an antibody consisting of a light chain consisting of the full-length light chain amino acid sequence shown in SEQ ID NO: 53 and a heavy chain consisting of the full-length heavy chain amino acid sequence shown in SEQ ID NO: 56. In the present specification, this chimeric anti-human CDH6 antibody is referred to as "chimeric G0 19 antibody", "chG019 antibody" or "chG019". The full-length light chain amino acid sequence of the chG019 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 54, and the full-length heavy chain amino acid sequence of the chG0 19 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 57.

[0089]

[0090] ​​​​​​​​​The amino acid sequence of the light chain variable region of the chG019 antibody is identical to the amino acid sequence of the light chain variable region of the rG019 antibody and consists of the amino acid sequence shown in SEQ ID NO: 10. The light chain of the chG019 antibody consists of CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 13, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 14, and is identical to CDRL1, CDRL2, and CDRL3 of the light chain of rG019, respectively. The amino acid sequence of the light chain variable region of the chG019 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 55. The light chain of the chG019 antibody consists of CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 13, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 14, and is identical to CDRL1, CDRL2, and CDRL3 of the light chain of rG019, respectively. The amino acid sequence of the light chain variable region of the chG019 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 55. The light chain of the chG019 antibody consists of CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 13, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 14, and is identical to CDRL1, CDRL2, and CDRL3 of the light chain of rG019, respectively. The amino acid sequence of the light chain variable region of the chG019 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 55. The light chain of the chG019 antibody consists of CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 13, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 14, and is identical to CDRL1, CDRL2, and CDRL3 of the light chain of rG019, respectively. The amino acid sequence of the light chain variable region of the chG019 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 55. The light chain of the chG019 antibody consists of CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 13, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 14, and is identical to CDRL1, CDRL2, and CDRL3 of the light chain of rG019, respectively. The amino acid sequence of the light chain variable region of the chG019 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 55. The amino acid sequence of the light chain variable region of the chG019 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 55. The amino acid sequence of the light chain variable region of the chG019 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 55.

[0091] The amino acid sequence of the heavy chain variable region of the chG019 antibody consists of the amino acid sequence shown in SEQ ID NO: 58. The heavy chain of the chG019 antibody has CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 17, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 60, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 19. The amino acid sequence shown in SEQ ID NO: 58 is a sequence in which the cysteine residue in CDRH2 in the amino acid sequence shown in SEQ ID NO: 15 is substituted with a proline residue. CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 60 is a sequence in which the cysteine residue in rG019 CDRH2 shown in SEQ ID NO: 18 is substituted with a proline residue. The amino acid sequence of the heavy chain variable region of the chG019 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 59. The heavy chain of the chG019 antibody has CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 17, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 60, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 19. The amino acid sequence shown in SEQ ID NO: 58 is a sequence in which the cysteine residue in CDRH2 in the amino acid sequence shown in SEQ ID NO: 15 is substituted with a proline residue. CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 60 is a sequence in which the cysteine residue in rG019 CDRH2 shown in SEQ ID NO: 18 is substituted with a proline residue. The amino acid sequence of the heavy chain variable region of the chG019 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 59. The heavy chain of the chG019 antibody has CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 17, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 60, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 19. The amino acid sequence shown in SEQ ID NO: 58 is a sequence in which the cysteine residue in CDRH2 in the amino acid sequence shown in SEQ ID NO: 15 is substituted with a proline residue. CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 60 is a sequence in which the cysteine residue in rG019 CDRH2 shown in SEQ ID NO: 18 is substituted with a proline residue. The amino acid sequence of the heavy chain variable region of the chG019 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 59. The heavy chain of the chG019 antibody has CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 17, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 60, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 19. The amino acid sequence shown in SEQ ID NO: 58 is a sequence in which the cysteine residue in CDRH2 in the amino acid sequence shown in SEQ ID NO: 15 is substituted with a proline residue. CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 60 is a sequence in which the cysteine residue in rG019 CDRH2 shown in SEQ ID NO: 18 is substituted with a proline residue. The amino acid sequence of the heavy chain variable region of the chG019 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 59. The amino acid sequence shown in SEQ ID NO: 58 is a sequence in which the cysteine residue in CDRH2 in the amino acid sequence shown in SEQ ID NO: 15 is substituted with a proline residue. CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 60 is a sequence in which the cysteine residue in rG019 CDRH2 shown in SEQ ID NO: 18 is substituted with a proline residue. The amino acid sequence of the heavy chain variable region of the chG019 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 59. The amino acid sequence shown in SEQ ID NO: 58 is a sequence in which the cysteine residue in CDRH2 in the amino acid sequence shown in SEQ ID NO: 15 is substituted with a proline residue. CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 60 is a sequence in which the cysteine residue in rG019 CDRH2 shown in SEQ ID NO: 18 is substituted with a proline residue. The amino acid sequence of the heavy chain variable region of the chG019 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 59. CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 60 is a sequence in which the cysteine residue in rG019 CDRH2 shown in SEQ ID NO: 18 is substituted with a proline residue. The amino acid sequence of the heavy chain variable region of the chG019 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 59. CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 60 is a sequence in which the cysteine residue in rG019 CDRH2 shown in SEQ ID NO: 18 is substituted with a proline residue. The amino acid sequence of the heavy chain variable region of the chG019 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 59. The amino acid sequence of the heavy chain variable region of the chG019 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 59.

[0092] The sequence of the chG019 antibody is shown in Table 1.

[0093] Examples of chimeric antibodies derived from the rat anti-human CDH6 antibody rG055 antibody include, for example, SEQ ID NO: a light chain comprising a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 20; and a chimeric antibody having a heavy chain comprising a heavy chain variable region having the amino acid sequence shown in The antibody may have any given human-derived constant region.

[0094] Chimeric antibodies derived from the rat anti-human CDH6 antibody rG056 include, for example, those having the sequence a light chain comprising a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 30; and a chimeric antibody having a heavy chain comprising a heavy chain variable region having the amino acid sequence shown in The antibody may have any given human-derived constant region.

[0095] Chimeric antibodies derived from the rat anti-human CDH6 antibody rG061 include, for example, those having the sequence a light chain comprising a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 40; and a chimeric antibody having a heavy chain comprising a heavy chain variable region having the amino acid sequence shown in The antibody may have any given human-derived constant region.

[0096] Humanized antibodies are characterized by the complementarity determining regions (CDRs). An antibody that incorporates only the terminating region into a human antibody (Nat (see ure (1986) 321, p. 522-525), and CDR grafting method In addition to the sequence of the antibody, some of the framework amino acid residues were also transplanted into a human antibody (International Publication No. 90 / 07861), and further, the amino acid sequence of some of the CDRs can be modified while maintaining the antigen-binding ability. Examples of such antibodies include antibodies in which the amino acid sequence has been modified.

[0097] As used herein, rG019 antibody, rG055 antibody, rG056 antibody, rG061 antibody A humanized antibody derived from the body or chG019 antibody refers to any one of the rG019 antibody, rG055 antibody, rG 056 antibody, rG061 antibody or chG019 antibody, as long as it retains all six CDR sequences unique to each and is a humanized antibody with internalization activity, and is not limited to a specific humanized antibody. As long as the humanized antibody has internalization activity, even a part of the amino acid sequence of some CDRs may be modified.

[0098] Examples of humanized antibodies of chG019 antibody include: (1) the amino acid sequence described in SEQ ID NO: 63 or 67, (2) an amino acid sequence having at least 95% identity to the amino acid sequence of (1) above (preferably, having at least 95% sequence identity to the sequence of the framework region other than each CDR sequence), and (3) an amino acid sequence in which one or several amino acids are deleted, substituted or added in the amino acid sequence of (1) above A light chain containing a light chain variable region selected from any one of the groups consisting of, and (4) the amino acid sequence described in SEQ ID NO: 71, 75 or 79, (5) an amino acid sequence having at least 95% identity to the amino acid sequence of (4) above (preferably, having at least 95% sequence identity to the sequence of the framework region other than each CDR sequence), and (6) an amino acid sequence in which one or several amino acids are deleted, substituted or added in the amino acid sequence of (4) above. Any combination of a heavy chain containing a heavy chain variable region selected from any one of the groups consisting of can be mentioned. In addition, one of the heavy chain or light chain is humanized, and the other is a light chain or heavy chain of a rat antibody or a chimeric antibody with respect to at least 95% identity to the amino acid sequence of (4) above (preferably, having at least 95% sequence identity to the sequence of the framework region other than each CDR sequence), and (6) an amino acid sequence in which one or several amino acids are deleted, substituted or added in the amino acid sequence of (4) above. Any combination of a heavy chain containing a heavy chain variable region selected from any one of the groups consisting of can be mentioned. can be mentioned.

[0099] Also, one of the heavy chain or light chain is humanized, and the other is a light chain or heavy chain of a rat antibody or a chimeric antibody Antibodies thus obtained can also be used. Examples of such antibodies include: (1) the amino acid sequence set forth in SEQ ID NO: 63 or 67, (2) an amino acid sequence having at least 95% identity or more with the amino acid sequence of (1) above (preferably, an amino acid sequence having at least 95% sequence identity with the sequence of the framework region other than each CDR sequence), and ( 3) a light chain comprising a light chain variable region selected from any one of the groups consisting of amino acid sequences in which one or several amino acids are deleted, substituted or added in the amino acid sequence of (1) above , and (4) the amino acid sequence set forth in SEQ ID NO: 15, 25, 35, 45 or 58, (5) an amino acid sequence having at least 95% identity or more with the amino acid sequence of (4) above (preferably, an amino acid sequence having at least 95% sequence identity or more with the sequence of the framework region other than each CDR sequence), and (6) any combination of heavy chains comprising a heavy chain variable region selected from any one of the groups consisting of amino acid sequences in which one or several amino acids are deleted, substituted or added in the amino acid sequence of (4) above . Other examples include: (1) the amino acid sequence set forth in SEQ ID NO: 10, 20, 30 or 40, ( 2) an amino acid sequence having at least 95% identity or more with the amino acid sequence of (1) above (preferably, an amino acid sequence having at least 95% sequence identity or more with the sequence of the framework region other than each CDR sequence), and (3) a light chain comprising a light chain variable region selected from any one of the groups consisting of amino acid sequences in which one or several amino acids are deleted, substituted or added in the amino acid sequence of (1) above, and (4) the amino acid sequence set forth in SEQ ID NO: 71, 7 . (5) the amino acid sequence set forth in SEQ ID NO: 75 or 79, (6) an amino acid sequence having at least 95% identity or more with the amino acid sequence of (4) above (preferably, an amino acid sequence having at least 95% sequence identity or more with the sequence of the framework region other than each CDR sequence), and (3) any amino acid sequence in which one or several amino acids are deleted, substituted or added in the amino acid sequence of (1) above selected from any one of the groups consisting of amino acid sequences, and (4) a light chain comprising a light chain variable region described in any one of (3) above, and (5) the amino acid sequence set forth in SEQ ID NO: 71, 7 5 or 79, (6) at least to the amino acid sequence of (4) above 95% identity or more of the amino acid sequence, and any combination of heavy chains comprising a heavy chain variable region selected from any one of the groups consisting of amino acid sequences in which one or several amino acids are deleted, substituted or added in the amino acid sequence of (4) above can be mentioned. An amino acid sequence having 95% or more identity (preferably an amino acid sequence having at least 95% sequence identity to the sequence of the framework region other than each CDR sequence), and (6) Any combination of heavy chains comprising a heavy chain variable region selected from the group consisting of an amino acid sequence in which one or several amino acids are deleted, substituted or added in the amino acid sequence of (4) above can be mentioned. Also, conservative amino acid substitutions are preferred as the amino acid substitutions in the present specification. Conservative amino acid substitution is a substitution that occurs within an amino acid group related to the amino acid side chain. Preferred amino acid groups are as follows: acidic group = aspartic acid, glutamic acid; basic group = lysine, arginine, histidine; non-polar group = alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan; and uncharged polar family = glycine, asparagine, glutamine, cysteine, serine, threonine, tyrosine. Other preferred amino acid groups are as follows: aliphatic hydroxy group = serine and threonine; amide-containing group = asparagine and glutamine; aliphatic group = alanine, valine, leucine and isoleucine; and aromatic group = phenylalanine, tryptophan and tyrosine. Such amino acid substitutions are preferably made within a range that does not reduce the properties of the substance having the original amino acid sequence.

[0100] As a preferred combination of the above light chain and heavy chain antibodies, there is an antibody having the light chain variable region amino acid sequence shown in SEQ ID NO: 63 (also referred to as the hL02 light chain variable region amino acid sequence in the present specification).

[0101] ​​​​​​​​​​​​A light chain having a light chain variable region amino acid sequence shown in SEQ ID NO: 67 (also referred to as the hL03 light chain variable region amino acid sequence herein), and a heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO: 71 (also referred to as the hH01 heavy chain variable region amino acid sequence herein), a heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO: 75 (also referred to as the hH02 heavy chain variable region amino acid sequence herein), or a heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO: 79 (also referred to as the hH04 heavy chain variable region amino acid sequence herein). Examples of preferred antibodies include an antibody consisting of a light chain having a light chain variable region amino acid sequence shown in SEQ ID NO: 63 and a heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO: 71; an antibody consisting of a light chain having a light chain variable region amino acid sequence shown in SEQ ID NO: 63 and a heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO: 75; an antibody consisting of a light chain having a light chain variable region amino acid sequence shown in SEQ ID NO: 63 and a heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO: 79; an antibody consisting of a light chain having a light chain variable region amino acid sequence shown in SEQ ID NO: 67 and a heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO: 71; an antibody consisting of a light chain having a light chain variable region amino acid sequence shown in SEQ ID NO: 67 and a heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO: 75; or an antibody consisting of a light chain having a light chain variable region amino acid sequence shown in SEQ ID NO: 67 and a heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO: 79. More preferred examples include an antibody consisting of a light chain having a light chain variable region amino acid sequence shown in SEQ ID NO: 63 and a heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO: 71; an antibody consisting of a light chain having a light chain variable region amino acid sequence shown in SEQ ID NO: 63 and a heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO: 71; an antibody consisting of a light chain having a light chain variable region amino acid sequence shown in SEQ ID NO: 63 and a heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO: 71; (also referred to as variable region amino acid sequence) and a heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO: 71 (also referred to as the hH01 heavy chain variable region amino acid sequence herein) A heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO: 75 (also referred to as the hH02 heavy chain variable region amino acid sequence herein), or a heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO: 79 (also referred to as the hH04 heavy chain variable region amino acid sequence herein) (also referred to as variable region amino acid sequence) and a heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO: 79 (also referred to as the hH04 heavy chain variable region amino acid sequence herein) Examples of preferred antibodies include an antibody consisting of a light chain having a light chain variable region amino acid sequence shown in SEQ ID NO: 63 and a heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO: 71 and a heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO: 71 ; an antibody consisting of a light chain having a light chain variable region amino acid sequence shown in SEQ ID NO: 63 and a heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO: 75 ; an antibody consisting of a light chain having a light chain variable region amino acid sequence shown in SEQ ID NO: 63 and a heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO: 79 ; an antibody consisting of a light chain having a light chain variable region amino acid sequence shown in SEQ ID NO: 67 and a heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO: 71 ; an antibody consisting of a light chain having a light chain variable region amino acid sequence shown in SEQ ID NO: 67 and a heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO: 75 ; or an antibody consisting of a light chain having a light chain variable region amino acid sequence shown in SEQ ID NO: 67 and a heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO: 79 ; an antibody consisting of a light chain having a light chain variable region amino acid sequence shown in SEQ ID NO: 63 and a heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO: 71 A light chain having the amino acid sequence of the light chain variable region shown in SEQ ID NO: 63 and a heavy chain having the amino acid sequence of the heavy chain variable region shown in SEQ ID NO: 75 An antibody consisting of a heavy chain having the amino acid sequence of the heavy chain variable region shown in SEQ ID NO: 75; the light chain variable region shown in SEQ ID NO: 63 A light chain having the amino acid sequence shown in SEQ ID NO: 63 and a heavy chain having the amino acid sequence of the heavy chain variable region shown in SEQ ID NO: 79 An antibody consisting of a heavy chain; or, a light chain having the amino acid sequence of the light chain variable region shown in SEQ ID NO: 67 An antibody consisting of a heavy chain having the amino acid sequence of the heavy chain variable region shown in SEQ ID NO: 75 is listed.

[0102] As another example of an antibody with a preferred combination of the above light chain and heavy chain, the 21st to 233rd amino acid sequence of the full-length light chain amino acid sequence shown in SEQ ID NO: 61 (also referred to as the hL02 full-length light chain amino acid sequence in this specification) or the 21st to 233rd amino acid sequence of the full-length light chain amino acid sequence shown in SEQ ID NO: 65 (also referred to as the hL03 full-length light chain amino acid sequence in this specification), and the 20th to 233rd amino acid sequence of the full-length light chain amino acid sequence shown in SEQ ID NO: 65 (also referred to as the hL03 full-length light chain amino acid sequence in this specification), and the 20th to 471st amino acid sequence of the full-length heavy chain amino acid sequence shown in SEQ ID NO: 69 (also referred to as the hH01 full-length heavy chain amino acid sequence in this specification), the 20th to 471st amino acid sequence of the full-length heavy chain amino acid sequence shown in SEQ ID NO: 73 (also referred to as the hH02 full-length heavy chain amino acid sequence in this specification) or the 20th to 471st amino acid sequence of the full-length heavy chain amino acid sequence shown in SEQ ID NO: 77 (also referred to as the hH04 full-length heavy chain amino acid sequence in this specification) consisting of a heavy chain An antibody consisting of a heavy chain is listed. A preferred example is an antibody consisting of a light chain consisting of the 21st to 233rd amino acid sequence of the full-length light chain amino acid sequence shown in SEQ ID NO: 61 and a heavy chain consisting of the 20th to 471st amino acid sequence of the full-length heavy chain amino acid sequence shown in SEQ ID NO: 69; the full-length light chain shown in SEQ ID NO: 61 As a preferred example, the 21st to 233rd amino acid sequence of the light chain and the 20th to 471st amino acid sequence of the full-length heavy chain amino acid sequence shown in SEQ ID NO: 69 An antibody consisting of a light chain composed of the amino acid sequence at positions 21 to 233 of the amino acid sequence and a heavy chain composed of the amino acid sequence at positions 20 to 471 of the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 73; An antibody consisting of a heavy chain composed of the amino acid sequence at positions 20 to 471 of the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 73; A light chain consisting of the amino acid sequence at positions 21 to 233 of the full-length amino acid sequence of the light chain shown in SEQ ID NO: 61 and a heavy chain composed of the amino acid sequence at positions 20 to 471 of the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 77; An antibody consisting of a heavy chain composed of the amino acid sequence at positions 20 to 471 of the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 77; A light chain consisting of the amino acid sequence at positions 21 to 233 of the full-length amino acid sequence of the light chain shown in SEQ ID NO: 65 and a heavy chain composed of the amino acid sequence at positions 20 to 471 of the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 69; An antibody consisting of a heavy chain composed of the amino acid sequence at positions 20 to 471 of the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 69; A light chain consisting of the amino acid sequence at positions 21 to 233 of the full-length amino acid sequence of the light chain shown in SEQ ID NO: 65 and a heavy chain composed of the amino acid sequence at positions 20 to 471 of the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 73; An antibody consisting of a heavy chain composed of the amino acid sequence at positions 20 to 471 of the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 73; Or, a light chain consisting of the amino acid sequence at positions 21 to 233 of the full-length amino acid sequence of the light chain shown in SEQ ID NO: 65 and a heavy chain composed of the amino acid sequence at positions 20 to 471 of the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 77; An antibody consisting of a heavy chain composed of the amino acid sequence at positions 20 to 471 of the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 77; Preferably, examples include an antibody consisting of a light chain composed of the amino acid sequence at positions 21 to 233 of the full-length amino acid sequence of the light chain shown in SEQ ID NO: 61 and a heavy chain composed of the amino acid sequence at positions 20 to 471 of the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 69 (in this specification, also referred to as "H01L02 antibody" or "H01L02"); An antibody consisting of a light chain composed of the amino acid sequence at positions 21 to 233 of the full-length amino acid sequence of the light chain shown in SEQ ID NO: 61 and a heavy chain composed of the amino acid sequence at positions 20 to 471 of the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 73 (in this specification, also referred to as "H02L02 antibody" or "H02L02"); An antibody consisting of a light chain composed of the amino acid sequence at positions 21 to 233 of the full-length amino acid sequence of the light chain shown in SEQ ID NO: 61 and a heavy chain composed of the amino acid sequence at positions 20 to 471 of the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 69 (in this specification, also referred to as "H01L02 antibody" or "H01L02"); An antibody consisting of a light chain composed of the amino acid sequence at positions 21 to 233 of the full-length amino acid sequence of the light chain shown in SEQ ID NO: 61 and a heavy chain composed of the amino acid sequence at positions 20 to 471 of the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 73 (in this specification, also referred to as "H02L02 antibody" or "H02L02"); Or, a light chain consisting of the amino acid sequence at positions 21 to 233 of the full-length amino acid sequence of the light chain shown in SEQ ID NO: 65 and a heavy chain composed of the amino acid sequence at positions 20 to 471 of the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 77; An antibody consisting of a heavy chain composed of the amino acid sequence at positions 20 to 471 of the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 77; Preferably, examples include an antibody consisting of a light chain composed of the amino acid sequence at positions 21 to 233 of the full-length amino acid sequence of the light chain shown in SEQ ID NO: 61 and a heavy chain composed of the amino acid sequence at positions 20 to 471 of the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 69 (in this specification, also referred to as "H01L02 antibody" or "H01L02"); An antibody consisting of a light chain composed of the amino acid sequence at positions 21 to 233 of the full-length amino acid sequence of the light chain shown in SEQ ID NO: 61 and a heavy chain composed of the amino acid sequence at positions 20 to 471 of the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 69 (in this specification, also referred to as "H01L02 antibody" or "H01L02"); An antibody consisting of a light chain composed of the amino acid sequence at positions 21 to 233 of the full-length amino acid sequence of the light chain shown in SEQ ID NO: 61 and a heavy chain composed of the amino acid sequence at positions 20 to 471 of the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 73 (in this specification, also referred to as "H02L02 antibody" or "H02L02"); An antibody consisting of a light chain composed of the amino acid sequence at positions 21 to 233 of the full-length amino acid sequence of the light chain shown in SEQ ID NO: 61 and a heavy chain composed of the amino acid sequence at positions 20 to 471 of the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 69 (in this specification, also referred to as "H01L02 antibody" or "H01L02"); An antibody consisting of a light chain composed of the amino acid sequence at positions 21 to 233 of the full-length amino acid sequence of the light chain shown in SEQ ID NO: 61 and a heavy chain composed of the amino acid sequence at positions 20 to 471 of the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 73 (in this specification, also referred to as "H02L02 antibody" or "H02L02"); An antibody consisting of a light chain composed of the amino acid sequence at positions 21 to 233 of the full-length amino acid sequence of the light chain shown in SEQ ID NO: 61 and a heavy chain composed of the amino acid sequence at positions 20 to 471 of the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 73 (in this specification, also referred to as "H02L02 antibody" or "H02L02"); An antibody consisting of a light chain composed of the amino acid sequence at positions 21 to 233 of the full-length amino acid sequence of the light chain shown in SEQ ID NO: 61 and a heavy chain composed of the amino acid sequence at positions 20 to 471 of the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 73 (in this specification, also referred to as "H02L02 antibody" or "H02L02"); A light chain consisting of the amino acid sequence at positions 21 to 233 of the full-length amino acid sequence of the light chain shown in SEQ ID NO: 61 and a heavy chain composed of the amino acid sequence at positions 20 to 471 of the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 73 (in this specification, also referred to as "H02L02 antibody" or "H02L02"); An antibody consisting of a light chain composed of the 1st to 233rd amino acid sequences and a heavy chain composed of the 20th to 471st amino acid sequences of the heavy chain full-length amino acid sequence shown in SEQ ID NO: 77 (hereinafter, also referred to as "H04L02 antibody" or "H04L02" in this specification); or, a light chain composed of the 21st to 233rd amino acid sequences of the light chain full-length amino acid sequence shown in SEQ ID NO: 65 and a heavy chain composed of the 20th to 471st amino acid sequences of the heavy chain full-length amino acid sequence shown in SEQ ID NO: 73 An antibody consisting of a heavy chain (hereinafter, also referred to as "H02L03 antibody" or "H02L03" in this specification); The sequences of the H01L02 antibody, H02L02 antibody, H02L03 antibody or H04L02 antibody are shown in Table 1. are included. chain;

[0103] By combining sequences that show high identity with the above heavy chain amino acid sequence and light chain amino acid sequence, it is possible to select an antibody having biological activity equivalent to each of the above antibodies. Such identity is generally 80% or more identity, preferably 90% or more identity, more preferably 95% or more identity, and most preferably 99% or more identity. Also, by combining amino acid sequences in which one to several amino acid residues are substituted, deleted or added to the amino acid sequence of the heavy chain or light chain, it is also possible to select an antibody having biological activity equivalent to each of the above antibodies.

[0104] The identity between two kinds of amino acid sequences is determined by ClustalW version2 (Lark in MA, Blackshields G, Brown NP, Chenna R, M cGettigan PA, McWilliam H, Valentin F, Wall ace IM, Wilm A, Lopez R, Thompson JD, Gibson​​​​​​​​​ TJ and Higgins DG (2007), "Clustal W and Clustal X version 2.0", Bioinformatics. 23 (21): 2947 - 2948) using the default parameters to align the sequences can be determined. [

[0105] ] In addition, in the full - length amino acid sequence of hL02 light chain shown in SEQ ID NO: 61, the amino acid sequence consisting of amino acid residues 1 - 20 is a signal sequence, and the amino acid sequence consisting of amino acid residues 21 - 128 is a variable region, and the amino acid sequence consisting of amino acid residues 129 - 233 is a constant region. In the full - length nucleotide sequence of hL02 light chain shown in SEQ ID NO: 62, the nucleotide sequence consisting of nucleotides 1 - 60 encodes a signal sequence, and the nucleotide sequence consisting of nucleotides 61 - 384 encodes a variable region, and the nucleotide sequence consisting of nucleotides 385 - 699 encodes a constant region. . [

[0106] ] In the full - length amino acid sequence of hL03 light chain shown in SEQ ID NO: 65, the amino acid sequence consisting of amino acid residues 1 - 20 is a signal sequence, and the amino acid sequence consisting of amino acid residues 21 - 128 is a variable region, and the amino acid sequence consisting of amino acid residues 129 - 233 is a constant region. In the full - length nucleotide sequence of hL03 light chain shown in SEQ ID NO: 66, the nucleotide sequence consisting of nucleotides 1 - 60 encodes a signal sequence, and the nucleotide sequence consisting of nucleotides 61 - 384 encodes a variable region, and the nucleotide sequence consisting of nucleotides 385 - 699 encodes a constant region. [

[0107] ]​​​​​​​ In the full-length amino acid sequence of hH01 heavy chain shown in SEQ ID NO: 69, the amino acid sequence consisting of amino acid residues 1 to 19 is a signal sequence, and the amino acid sequence consisting of amino acid residues 20 to 141 is a variable region, and the amino acid sequence consisting of amino acid residues 142 to 471 is a constant region. In the full-length nucleotide sequence of hH01 heavy chain shown in SEQ ID NO: 70, the nucleotide sequence consisting of nucleotides 1 to 57 encodes a signal sequence, and 58 the nucleotide sequence consisting of nucleotides to 423 encodes a variable region, and 424 to the nucleotide sequence consisting of nucleotides 1413 encodes a constant region.

[0108] In the full-length amino acid sequence of hH02 heavy chain shown in SEQ ID NO: 73, the amino acid sequence consisting of amino acid residues 1 to 19 is a signal sequence, and the amino acid sequence consisting of amino acid residues 20 to 141 is a variable region, and the amino acid sequence consisting of amino acid residues 142 to 471 is a constant region. In the full-length nucleotide sequence of hH02 heavy chain shown in SEQ ID NO: 74, the nucleotide sequence consisting of nucleotides 1 to 57 encodes a signal sequence, and 58 the nucleotide sequence consisting of nucleotides to 423 encodes a variable region, and 424 to the nucleotide sequence consisting of nucleotides 1413 encodes a constant region.

[0109] In the full-length amino acid sequence of hH04 heavy chain shown in SEQ ID NO: 77, the amino acid sequence consisting of amino acid residues 1 to 19 is a signal sequence, and the amino acid sequence consisting of amino acid residues 20 to 141 is a variable region, and the amino acid sequence consisting of amino acid residues 142 to 471 is a constant region. In the full-length nucleotide sequence of hH04 heavy chain shown in SEQ ID NO: 78, The nucleotide sequence consisting of nucleotides 1 to 57 is a signal sequence, and 58 to 4 The nucleotide sequence consisting of nucleotides 23 to 23 encodes a variable region, and 424 The nucleotide sequence consisting of nucleotides ~1413 encodes a constant region.

[0110]

Table 1-1

[0111]

Table 1-2

[0112]

Table 1-3

[0113]

Table 1-4

[0114]

Table 1-5

[0115]

Table 1-6

[0116]

Table 1-7

[0117]

Table 1-8

[0118]

Table 1-9

[0119]

Table 1-10

[0120]

Table 1-11

[0121]

Table 1-12

[0122]

Table 1-13

[0123]

Table 1-14

[0124]

Table 1-15

Table 1-16

[0125] (In this specification, Tables 1-1 to 1-16 may be collectively referred to as Table 1.) Examples of the antibody of the present invention further include human antibodies that bind to CDH6 . An anti-CDH6 human antibody means a human antibody having only the gene sequence of an antibody derived from the human chromosome . An anti-CDH6 human antibody is a method using a human antibody-producing mouse having a human chromosome fragment containing the genes of the heavy and light chains of a human antibody (Tomizuka, K. et al., Na ture Genetics (1997) 16, p. 133-143,; Kuroiwa , Y. et.al., Nucl. Acids Res. (1998) 26, p. 3447 -3448; Yoshida, H. et.al., Animal Cell Techn -3448; Yoshida, H. et.al., Animal Cell Techn ology: Basic and Applied Aspects vol.10, p .69 - 73 (Kitagawa, Y., Matsuda, T. and Iijima, S. eds.), Kluwer Academic Publishers, 1999. ; Tomizuka, K. et.al., Proc. Natl. Acad. Sci. US A (2000) 97, p.722 - 727, etc. (see).) can be obtained by

[0126] Such human antibody - producing mice can be specifically created by disrupting the loci of endogenous immunoglobulin heavy and light chains and replacing them with human immunoglobulin heavy and light chain loci via a yeast artificial chromosome (YAC) vector or the like, and by producing knockout animals and transgenic animals and crossing these animals with each other.

[0127] Alternatively, the anti - CDH6 human antibody can be obtained by transforming eukaryotic cells with cDNA encoding each of the heavy and light chains of such human antibodies, or preferably with a vector containing the cDNA, according to genetic recombination techniques, and then culturing the transformed cells that produce the genetically modified human monoclonal antibody, and as a result, the antibody can be obtained from the culture supernatant.

[0128] Here, as the host, for example, eukaryotic cells, preferably mammalian cells such as CHO cells, lymphocytes, and myelomas can be used.

[0129] Also, human antibodies derived from phage display selected from a human antibody library can be obtained Methods (Wormstone, I.M. et al., Investigative O phthalmology & Visual Science. (2002) 43(7), p. 2301 - 2308; Carmen, S. et al., Briefings in Functional Genomics and Proteomics (2002 ), 1(2), p. 189 - 203; Siriwardena, D. et al., Op hthalmology (2002) 109(3), p. 427 - 431, etc. See also.) are also known to be.

[0130] For example, the variable region of a human antibody can be expressed on the phage surface as a single-chain antibody (scFv), and the phage display method (Nature Biotechnology (2005), 23, (9), p. 1105 - 1116) can be used to select phages that bind to the antigen. This can be done.

[0131] By analyzing the gene of the phage selected by binding to the antigen, the DNA sequence encoding the variable region of the human antibody that binds to the antigen can be determined.

[0132] Once the DNA sequence of the scFv that binds to the antigen is clarified, an expression vector having the said sequence is prepared, introduced into an appropriate host and expressed to obtain a human antibody (International Publication Nos. 92 / 01047, 92 / 20791, 93 / 06213, 93 / 11236, 93 / 19172, 95 / 01438, 95 / 153 888, Annu. Rev. Immunol (1994) 12, p. 433 - 455, N ature Biotechnology (2005) 23(9), p. 1105 - 11 16). ​​​​

[0133] The newly generated human antibodies include the rat anti-human CDH6 antibodies described herein, chimeric anti- Human CDH6 antibody or humanized anti-human CDH6 antibody (e.g., rG019 antibody, rG055 Antibody, rG056 antibody, rG061 antibody, chG019 antibody, H01L02 antibody, H02 L02 antibody, H02L03 antibody or H04L02 antibody) If the human antibody binds to the peptide or partial conformation, the human antibody is It binds to the same epitope as the humanized anti-human CDH6 antibody or the humanized anti-human CDH6 antibody. Alternatively, the rat anti-human CDH6 antibody, chimeric Anti-human CDH6 antibody or humanized anti-human CDH6 antibody (e.g., rG019 antibody, rG05 5 antibody, rG056 antibody, rG061 antibody, chG019 antibody, H01L02 antibody, H0 2L02 antibody, H02L03 antibody or H04L02 antibody) to CDH6 The human antibody competes with the rG019 antibody, the rG055 antibody, the rG061 antibody, the rG071 antibody, the rG081 antibody, the rG091 antibody, the rG010 antibody, the rG020 antibody, the rG030 antibody, the rG040 antibody, the rG051 antibody, the rG062 antibody, the rG073 antibody, the rG G056 antibody, rG061 antibody, chG019 antibody, H01L02 antibody, H02L02 anti antibody, H02L03 antibody or H04L02 antibody and CDH6, preferably EC3 of CDH6 By confirming that the sequence or structure of a specific epitope is Even if the chimeric antibody has not yet been determined, the human antibody may be a rat anti-human CDH6 antibody, chimeric antibody, or chimeric antibody described herein. It was found to bind to the same epitope as the humanized anti-human CDH6 antibody or humanized anti-human CDH6 antibody. In the present specification, at least one of the determination methods If the antibody is determined to "bind to the same epitope" by , the rat anti-human CDH6 antibody, chimeric anti-human CDH6 antibody, or humanized anti- human CDH6 antibody described in this specification can be said to "bind to the same epitope". If it is confirmed that the epitopes are the same , it is expected that the human antibody has biological activity equivalent to that of the rat anti-human CDH6 antibody, chimeric anti-human CDH6 antibody, or humanized anti-human CDH6 antibody (e.g., rG019 antibody, rG055 antibody, rG0 56 antibody, rG061 antibody, chG019 antibody, H01L02 antibody, H02L02 antibody, H02L03 antibody, or H04L02 antibody).

[0134] The chimeric antibody, humanized antibody, or human antibody obtained by the above method can be evaluated for binding to the antigen by known methods or the like , and a suitable antibody can be selected.

[0135] As an example of another index for comparing the properties of antibodies, the stability of the antibody can be mentioned . Differential scanning calorimetry (DSC) is a device that can quickly and accurately measure the thermal denaturation midpoint (Tm), which is a good index of the relative structural stability of proteins. By using DSC to measure the Tm value and comparing the values, the difference in thermal stability can be compared . It is known that the storage stability of antibodies shows a certain correlation with the thermal stability of antibodies (Lori Burton, et.al., Pharmaceutical Devel opment and Technology (2007) 12, p.265-273) . Based on thermal stability as an index, a suitable antibody can be selected. Other indices for selecting antibodies include high yield in a suitable host cell and low aggregability in an aqueous solution . For example, the antibody with the highest yield does not necessarily show the highest thermal stability Therefore, it is necessary to comprehensively judge based on the above-mentioned indices and select the antibody that is most suitable for administration to humans.

[0136] The antibodies of the present invention include modified antibodies. The modified antibody means an antibody obtained by chemically or biologically modifying the antibody of the present invention. Chemical modified antibodies include those in which a chemical moiety is bonded to the amino acid backbone, chemically modified N-linked or O-linked carbohydrate chains, and the like. Biologically modified antibodies include those modified post-translationally (e.g., addition of sugar chains to N-linked or O-linked, processing at the N-terminus or C-terminus, deamidation, isomerization of aspartic acid, oxidation of methionine, or pyroglutaminylation of N-terminal glutamine or N-terminal glutamic acid), those with an N-terminal methionine residue added by expression using a prokaryotic host cell, and the like. Also included are those labeled to enable detection or isolation of the antibody or antigen of the present invention, for example, enzyme-labeled, fluorescent-labeled, and affinity-labeled substances are also included in the meaning of such modified products. Such modified antibodies of the present invention are useful for improving the stability and blood retention of the antibody, reducing antigenicity, detecting or isolating the antibody or antigen, and the like.

[0137] In addition, it is possible to enhance the antibody-dependent cell cytotoxic activity by regulating the sugar chain modification bonded to the antibody of the present invention (such as glycosylation, defucosylation, etc.). As techniques for regulating the sugar chain modification of antibodies, International Publication Nos. WO1999 / 54342, WO2000 / 61739, WO2002 / 31140, etc. are known, but are not limited thereto. The antibodies of the present invention include antibodies with regulated sugar chain modifications.

[0138] When an antibody gene is isolated and then introduced into a suitable host to produce an antibody, an appropriate A combination of a host and an expression vector can be used. Specific examples of antibody genes include genes encoding the heavy chain sequences of the antibodies described herein, and those encoding the light chain sequences combined genes. When transforming host cells, the heavy chain sequence gene and the light chain sequence gene can be inserted into the same expression vector or into separate expression vectors.

[0139] When using eukaryotic cells as hosts, animal cells, plant cells, and eukaryotic microorganisms can be used In particular, as animal cells, mammalian cells, for example, COS cells, which are monkey cells (G luzman, Y. Cell (1981) 23, p. 175-182, ATCC CRL -1650), mouse fibroblast NIH3T3 (ATCC No. CRL-1658), or dihydro folate reductase-deficient strain of Chinese hamster ovary cells (CHO cells, ATCC CCL-61) (Urlaub, G. and Chasin, L. A. Proc. N atl. Acad. Sci. U.S.A. (1980) 77, p. 4126-4220) , FreeStyle 293F cells (Invitrogen) can be mentioned. .

[0140] When using prokaryotic cells, for example, Escherichia coli and Bacillus subtilis can be mentioned.

[0141] The target antibody gene is introduced into these cells by transformation, and the transformed cells are cultured in vitro to obtain an antibody. In this culture, the yield may vary depending on the sequence of the antibody. Among antibodies having equivalent binding activity, it is possible to select those that are easy to produce as pharmaceuticals based on the yield. Therefore, the antibodies of the present invention include ​ culturing the transformed host cell, and collecting the target antibody or a functional fragment of the antibody from the culture obtained in this step, and the production of the antibody is characterized by including this step The antibody obtained by the method is also included.

[0142] It is known that the lysine residue at the carboxyl terminus of the heavy chain of an antibody produced by mammalian cultured cells is deleted (Journal of Chromatography A, 705:129-134(1995)), and also, the glycine and lysine at the carboxyl terminus of the heavy chain are deleted, and the proline residue newly located at the carboxyl terminus is amidated (Analytical Biochemistry 360:75-83(2007)). However, these deletions and modifications of the heavy chain sequence do not affect the antigen-binding ability and effector functions (such as complement activation and antibody-dependent cell cytotoxicity) of the antibody. Therefore, the antibody according to the present invention also includes the antibody that has undergone such modification and a functional fragment of the antibody, and a deletion body in which one or two amino acids are deleted at the carboxyl terminus of the heavy chain, and an amidated deletion body thereof (for example, a heavy chain in which the proline residue at the carboxyl terminus is amidated), etc. are also included. However, as long as the antigen-binding ability and effector functions are maintained, the deletion bodies at the carboxyl terminus of the heavy chain of the antibody according to the present invention are not limited to the above types. The two heavy chains constituting the antibody according to the present invention may be any one of the heavy chains selected from the group consisting of the full length and the above deletion bodies, or any combination of two of them. The ratio of each deletion body may be affected by the type and culture conditions of the cultured mammalian cells that produce the antibody of the present invention. The main component of the antibody of the present invention is the carboxyl groups of the two heavy chains types and culture conditions. The main component of the antibody of the present invention is the carboxyl groups of the two heavy chains Antibodies with one amino acid residue deleted at each xylol terminus can be mentioned.

[0143] As the isotype of the antibody of the present invention, for example, IgG (IgG1, IgG2, IgG3 , IgG4), etc. can be mentioned. Among them, IgG1 and IgG4 are preferable.

[0144] As the biological activity of the antibody, generally, antigen-binding activity, the activity of internalizing into cells expressing the antigen by binding to the antigen, the activity of neutralizing the activity of the antigen, the activity of enhancing the activity of the antigen , the activity of antibody-dependent cell cytotoxicity (ADCC), the activity of complement-dependent cell cytotoxicity (CDC), and antibody-dependent cell-mediated phagocytosis (ADCP) can be mentioned. The function of the antibody according to the present invention is the binding activity to CDH6, preferably the activity of internalizing into CDH6-expressing cells by binding to CDH6. Furthermore, the antibody of the present invention may have, in addition to the cell internalization activity, ADCC activity, CDC activity, and / or ADCP activity.

[0145] The obtained antibody can be purified to homogeneity. For the separation and purification of the antibody, separation and purification methods usually used for ordinary proteins can be used. For example, column chromatography , filter filtration, ultrafiltration, salting out, dialysis, preparative polyacrylamide gel electrophoresis, isoelectric focusing electrophoresis, etc. can be appropriately selected and combined to separate and purify the antibody (S trategies for Protein Purification and C haracterization:A Laboratory Course Manu al,Daniel R.Marshak et al.eds.,Cold Spri ng Harbor Laboratory Press(1996);Antibod trategies for Protein Purification and C haracterization:A Laboratory Course Manu al,Daniel R.Marshak et al.eds.,Cold Spri ng Harbor Laboratory Press(1996);Antibod ies: A Laboratory Manual. Ed Harlow and Da vid Lane, Cold Spring Harbor Laboratory(1 988)) is not limited to these.

[0146] Examples of chromatography include affinity chromatography, ion exchange chromatography, hydrophobic chromatography, gel filtration chromatography, reverse phase chromatography, adsorption chromatography, and the like.

[0147] These chromatographies can be performed using liquid chromatography such as HPLC or FPLC.

[0148] Examples of columns used for affinity chromatography include protein A columns and protein G columns. For example, columns using protein A columns include Hyper D, POROS, Sepharose FF (Pharmacia), etc. can be mentioned.

[0149] It is also possible to purify an antibody by utilizing its binding ability to an antigen using a carrier immobilized with the antigen.

[0150] 3. Anti-CDH6 Antibody-Drug Conjugate (1) Drug The anti-CDH6 antibody obtained in the above "2. Production of anti-CDH6 antibody" can be made into an anti-CDH6 antibody-drug conjugate by binding a drug via a linker structure portion. There is no particular limitation on the drug as long as it has a substituent or partial structure that can bind to the linker structure. The anti-CDH6 antibody-drug conjugate varies depending on the drug to be bound. It can be used for various purposes. Examples of such drugs include substances having antitumor activity , substances having an effect on blood diseases, substances having an effect on autoimmune diseases, anti-inflammatory substances, antibacterial substances, antifungal substances, antiparasitic substances, antiviral substances, anti-anesthetic substances, etc. can be mentioned.

[0151] (1)-1 Antitumor compound Examples of using an antitumor compound as the compound bound to the anti-CDH6 antibody-drug conjugate of the present invention are described below. As the antitumor compound, any compound having an antitumor effect and having a substituent or partial structure that can be bound to the linker structure is not particularly limited as long as it has. The antitumor compound is such that part or all of the linker is cleaved within tumor cells and the antitumor compound moiety is released to exhibit an antitumor effect. If the linker is cleaved at the binding portion to the drug, the antitumor compound is released in its original structure and its original antitumor effect is exerted.

[0152] The anti-CDH6 antibody obtained in the above "2. Production of anti-CDH6 antibody" can be made into an anti-CDH6 antibody-drug conjugate by binding an antitumor compound via the linker structure portion.

[0153] One example of the antitumor compound used in the present invention is exatecan, a camptothecin derivative ((1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro -9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3’,4’:

[0153] One example of the antitumor compound used in the present invention is exatecan, a camptothecin derivative ((1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro -9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3’,4’: 6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione; the following formula) can be preferably used.

[0154]

Chemical formula

[0155] The same compound can be easily obtained, for example, by the method described in US Patent Publication No. US2016 / 0297890 or other known methods, and the amino group at the 1-position can be preferably used as a binding site to the linker structure. Furthermore, exatecan can be released into tumor cells while a part of the linker remains bound thereto. However, even in such a state, this compound exhibits excellent antitumor effects.

[0156] Since exatecan has a camptothecin structure, in an acidic aqueous medium (for example, at about pH 3) the equilibrium is biased towards the structure with a formed lactone ring (closed-ring form), while in a basic aqueous medium ( for example, at about pH 10), the equilibrium is known to be biased towards the structure with an opened lactone ring (opened-ring form). Drugs conjugates into which exatecan residues corresponding to such closed-ring and opened-ring structures are introduced are expected to have equivalent antitumor effects, and it goes without saying that any of them are included in the scope of the present invention.

[0157] As other antitumor compounds, for example, antitumor compounds described in the literature (Pharmacological Revi ews, 68, p3-19, 2016) can be mentioned. As an example thereof, doxorubicin, calicheamicin, dolastatin 10, auristatins such as monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), maytansinoids such as DM1 and DM4, pyrrolobenzodiazepine

[0157] As other antitumor compounds, for example, antitumor compounds described in the literature (Pharmacological Reviews, 68, p3-19, 2016) can be mentioned. As an example thereof, doxorubicin, calicheamicin, dolastatin 10, auristatins such as monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), maytansinoids such as DM1 and DM4, pyrrolobenzodiazepine eamicin), dolastatin 10, auristatins such as monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), such as auristatins ( Auristatins), maytansinoids such as DM1, DM4 (Maytansi noids), pyrrolobenzodiazepine ) The dimer SG2000 (SJG-136), a derivative of camptothecin, SN-38 , duocarmycins such as CC-1065, amanitin (Amanitin), daunorubicin, mitomycin C, bleomycin, cyclocytidine , vincristine, vinblastine, methotrexate, platinum-based antitumor agents (cisplatin tin or its derivatives), taxol or its derivatives, etc. can be mentioned.

[0158] In an antibody-drug conjugate, the number of drug molecules bound to one molecule of the antibody is an important factor affecting its efficacy and safety. The production of an antibody-drug conjugate is carried out by defining reaction conditions such as the amounts of raw materials and reagents used in the reaction so that the number of bound drug molecules becomes a certain number . Different from the chemical reactions of low molecular weight compounds, it is usually obtained as a mixture in which different numbers of drug molecules are bound. The number of drug molecules bound to one molecule of the antibody is specified and expressed as an average value, that is, the average number of bound drug molecules . In the present invention, unless otherwise specified in principle, that is, except when indicating a specific antibody-drug conjugate having a different number of drug molecule binding numbers contained in a mixture of antibody-drug conjugates having different drug molecule binding numbers , the number of bound drug molecules means an average value. The number of exatecan molecules conjugated to the antibody molecule is controllable , and as the average number of drug molecules per antibody, approximately 1 to 10 exatecan molecules can be conjugated . The number of exatecan molecules is preferably 2 to 8, 3 to 8 , 4 to 8, 5 to 8, 6 to 8 or 7 to 8, more preferably 5 to 8, still more preferably 7 to 8, and even more preferably 8. Those skilled in the art can refer to the examples of the present application for the implementation of this application . . . From the description, a reaction for binding the required number of drug molecules to the antibody can be designed, and an antibody-drug conjugate with controlled conjugation number of Exatecan can be obtained.

[0159] (2) Linker structure The linker structure for binding the drug to the anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate of the present invention will be described.

[0160] In the antibody-drug conjugate of the present application, the linker structure that binds the anti-CDH6 antibody and the drug is not particularly limited as long as it can be used as an antibody-drug conjugate. The linker structure can also be appropriately selected and used according to the purpose of use. As an example of the linker structure, linkers described in known literatures (Pharmacol Rev 68:3-19, January 2016, Protein Cell DOI 10.1007 / s13238-016-0323-0, etc.) can be mentioned. More specific examples include VC (valine-citrulline), MC (maleimidocaproyl), SMCC (succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate), SPP (N-succinimidyl 4-(2-pyridyl dithio)pentanoate), SS (disulfide), SPD (N-succinimidyl 4-(2-pyridyl dithio)butyrate). imidyl 4-(2-pyridyldithio)butyrate, SS / hyd Examples include hydrazones, hydrazides, and carbonates.

[0161] As another example, for instance, the linker structure described in US Patent Publication US2016 / 0297890 (as an example, those described in paragraphs

[0260] to

[0289] ) can be mentioned. Any of the following linker structures can be preferably used. Note that the left end of the structure shown below is the binding site with the antibody, and the right end is the binding site with the drug. Also, in the following linker structure, GGFG represents an amino acid sequence connected by a peptide bond consisting of glycine - glycine - phenylalanine - glycine (G GFG). -(succinimid-3-yl-N)-CH2CH2-C(=O)-GGFG-NH-C H2CH2CH2-C(=O)-, -(succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)- GGFG-NH-CH2CH2CH2-C(=O)-, -(succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)- GGFG-NH-CH2-O-CH2-C(=O)-, -(succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)- GGFG-NH-CH2CH2-O-CH2-C(=O)-, -(succinimid-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2 O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2 -C(=O)-, and -(succinimid-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2 O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-G ​ GFG-NH-CH2CH2CH2-C(=O)-.

[0162] More preferably, it is as follows: -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)- GGFG-NH-CH2-O-CH2-C(=O)-, -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)- GGFG-NH-CH2CH2-O-CH2-C(=O)-, and -(Succinimid-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2 O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2 -C(=O)-. Even more preferably, it is as follows: -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)- GGFG-NH-CH2-O-CH2-C(=O)-, and -(Succinimid-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2 O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2 -C(=O)-.

[0163] The antibody binds at the terminal of -(Succinimid-3-yl-N) (for example, at the terminal on the opposite side of the binding of -CH2CH2CH2CH2CH2- (left terminal) in "-(Succ inimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGF G-NH-CH2-O-CH2-C(=O)-"), and the antitumor compound binds at the terminal on the opposite side of -( Succinimid-3-yl-N) (right terminal in the above example, the carbonyl group of CH2 -O-CH2-C(=O)-). "-(Succinimid- -O-CH2-C(=O)- 3-yl-N)-」 has a structure represented by the following formula.

[0164]

Chemical Formula

[0165] The 3-position in this partial structure is the binding site to the anti-CDH6 antibody. The binding of the antibody at this 3-position is characterized by forming a thioether bond. The nitrogen atom at the 1-position of this structural part binds to the carbon atom of the methylene present in the linker containing this structure.

[0166] In the antibody-drug conjugate of the present invention with the drug being exatecan, the following structure of the drug-linker structural part bound to the antibody is preferred. These drug-linker structural parts may have an average number of binding per antibody of 1 to 10, preferably 2 to 8, more preferably 5 to 8, still more preferably 7 to 8 , and even more preferably 8. -(Succinimid-3-yl-N)-CH2CH2-C(=O)-GGFG-NH-C H2CH2CH2-C(=O)-(NH-DX), -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)- GGFG-NH-CH2CH2CH2-C(=O)-(NH-DX), -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)- GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX), -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)- GGFG-NH-CH2CH2-O-CH2-C(=O)-(NH-DX), -(Succinimid-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2 O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2 -C(=O)-(NH-DX), and -(succinimid-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2 O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-G GFG-NH-CH2CH2CH2-C(=O)-(NH-DX).

[0167] More preferably, it is as follows: -(succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)- GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX), -(succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)- GGFG-NH-CH2CH2-O-CH2-C(=O)-(NH-DX), and -(succinimid-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2 O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2 -C(=O)-(NH-DX).

[0168] Even more preferably, it is as follows: -(succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)- GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX), and -(succinimid-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2 O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2 -C(=O)-(NH-DX).

[0169] -(NH-DX) has a structure represented by the following formula:

[0170]

Chemical formula

[0171] It represents a group formed by removing one hydrogen atom from the amino group at the 1-position of exatecan.

[0172] (3) Method for producing antibody-drug conjugate The antibody that can be used in the antibody-drug conjugate of the present invention is the anti-CDH6 antibody having internalization activity described in the above item "2. Production of anti-CDH 6 antibody" and the examples, and there is no particular limitation as long as it is a functional fragment of the antibody.

[0173]

[0173] Next, a typical method for producing the antibody-drug conjugate of the present invention will be described. In the following , in order to indicate compounds, the numbers of the compounds shown in each reaction formula are used. That is , it is referred to as "compound of formula (1)", "compound (1)", etc. The same applies to compounds with other numbers .

[0174] (3)-1 Production method 1 Among the antibody-drug conjugates represented by the following formula (1), those in which the anti-CDH6 antibody and the linker structure are bound via a thioether are obtained by reducing the anti-CDH6 antibody to convert the disulfide bond to a sulfhydryl group, and reacting the resulting antibody with a compound ([[]]END]] (2) (for example, obtainable by the method described in US2016 / 297890 published patent publication (for example, the method described in paragraphs

[0336] to

[0374] )) . This antibody-drug conjugate can be produced, for example, by the following method .

[0175]

[0175]

Number

[0176] In the formula, AB represents an antibody having a sulfhydryl group, L 1 has a structure represented by -(Succinimid-3-yl-N)-, L 1 ’ represents a maleimidyl group represented by the following formula.

[0177]

Chemical formula

[0178] -L 1 -L X has a structure represented by any of the following formulas: -(Succinimid-3-yl-N)-CH2CH2-C(=O)-GGFG-NH-C H2CH2CH2-C(=O)-, -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)- GGFG-NH-CH2CH2CH2-C(=O)-, -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)- GGFG-NH-CH2-O-CH2-C(=O)-, -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)- GGFG-NH-CH2CH2-O-CH2-C(=O)-, -(Succinimid-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2 O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2 -C(=O)-, and -(Succinimid-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2 O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-G GFG-NH-CH2CH2CH2-C(=O)-.

[0179] Among them, more preferable ones are as follows: -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)- GGFG-NH-CH2-O-CH2-C(=O)-, -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)- GGFG-NH-CH2CH2-O-CH2-C(=O)-, and -(Succinimid-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2 O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2 -C(=O)-.

[0180] More preferably, it is as follows: -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)- GGFG-NH-CH2-O-CH2-C(=O)-, and -(Succinimid-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2 O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2 -C(=O)-.

[0181] In the above reaction scheme, the antibody-drug conjugate (1) can be understood to have a structure in which one structural moiety from the drug to the linker terminal is bound to one antibody . However, this explanation is for convenience, and in fact, multiple of the above structural moieties are often linked to one antibody molecule . This situation is the same in the description of the following production method .

[0182] That is, a compound (2) obtainable by a known method (for example, the method described in US2016 / 29 7890 published patent application (for example, the method described in paragraphs

[0336] to

[0374] ​Method) and is available) and is available), and reacting with an antibody (3a) having a sulfhydryl group By doing so, an antibody-drug conjugate (1) can be produced.

[0183] The antibody (3a) having a sulfhydryl group can be obtained by methods well known to those skilled in the art (H ermanson, G.T., Bioconjugate Techniques, pp. 56-136, pp. 456-493, Academic Press (1996)). For example, reacting Traut's reagent with the amino group of the antibody; N-succinimidyl S- acetylthioalkanoates are reacted with the amino group of the antibody, and then hydroxylamine is reacted; N-succinimidyl 3-(pyridyldithio)propionate is reacted and then a reducing agent is reacted; reducing agents such as dithiothreitol, 2-mercaptoethanol, tris(2 -carboxyethyl)phosphine hydrochloride (TCEP) are reacted with the antibody to reduce the interchain disulfide bonds in the antibody to generate sulfhydryl groups; and the like. These can be mentioned, but are not limited thereto.

[0184] Specifically, TCEP is used as a reducing agent at 0.3 to 3 molar equivalents per interchain disulfide bond in the antibody, and reacted with the antibody in a buffer solution containing a chelating agent to obtain an antibody in which the interchain disulfide bonds in the antibody are partially or completely reduced. Examples of the chelating agent include ethylenediaminetetraacetic acid (EDTA) and diethylenetriamine pentaacetic acid (DTPA), etc. These may be used at a concentration of 1 mM to 20 mM. As the buffer solution, sodium phosphate, sodium borate, sodium acetate solution can be used. Examples of the chelating agent include ethylenediaminetetraacetic acid (EDTA) and diethylenetriamine pentaacetic acid (DTPA), etc. These may be used at a concentration of 1 mM to 20 mM. For the buffer solution, sodium phosphate, sodium borate, sodium acetate solution etc. can be used. In a specific example, the antibody is reacted with TCEP at 4°C to 37°C for 1 to 4 hours to obtain an antibody (3a) having partially or fully reduced sulfhydryl groups.

[0185] Here, the reaction for adding a sulfhydryl group to the drug-linker moiety can be carried out, and the drug-linker moiety can be bonded by a thioether bond.

[0186] Next, 2 to 20 molar equivalents of compound (2) are used per antibody (3a) having a sulfhydryl group, and an antibody-drug conjugate (1) to which 2 to 8 drug molecules are bonded per antibody can be produced. Specifically, a solution in which compound (2) is dissolved is added to a buffer solution containing antibody (3a) having a sulfhydryl group and reacted. Here, as the buffer solution, sodium acetate solution, sodium phosphate, sodium borate, etc. can be used. The pH of the reaction is 5 to 9, and more preferably, the reaction may be carried out around pH 7. As the solvent for dissolving compound (2), organic solvents such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMA), and N-methyl-2-pyridone (NMP) can be used. An organic solvent solution in which compound (2) is dissolved is added to a buffer solution containing antibody (3a) having a sulfhydryl group at 1 to 20% v / v and reacted. The reaction temperature is 0 to 37°C, more preferably 10 to 25°C, and the reaction time is 0.5 to 2 hours. The reaction can be terminated by inactivating the reactivity of unreacted compound (2) with a thiol-containing reagent. Thiol-containing reagent ​​​​​​​​​​​​​For example, it is cysteine or N-acetyl-L-cysteine (NAC). More specifically add 1 to 2 molar equivalents of NAC to the compound (2) used and incubate at room temperature for 10 to 30 minutes to complete the reaction.

[0187] (4) Identification of antibody-drug conjugate The produced antibody-drug conjugate (1) is concentrated, buffer -exchanged, purified, and the antibody concentration and the average number of drug molecules per antibody molecule are measured by the following common operations, and the antibody -drug conjugate (1) can be identified.

[0188] (4)-1 Common operation A: Concentration of aqueous solution of antibody or antibody-drug conjugate Put the antibody or antibody-drug conjugate solution into a container of Amicon Ultra (50,000 MWCO, Millipore Corp oration), and use a centrifuge (Allegra X-15R, Beckman Coulter, Inc.) for centrifugation (centrifuge at 2000G to 3800G for 5 to 20 minutes) to concentrate the antibody or antibody -drug conjugate solution.

[0189] (4)-2 Common operation B: Measurement of antibody concentration Using a UV detector (Nanodrop 1000, Thermo Fisher Scien tific Inc.), the antibody concentration was measured according to the manufacturer's specified method . At that time, different 280 nm extinction coefficients for each antibody (1.3 mL mg -1 cm -1 to 1 .8 mL mg -1 cm -1 ) were used.

[0190] (4)-3 Common operation C: Buffer exchange of antibody NAP-25 column (Cat. No. 17) using Sephadex G-25 support -0852-02,GE Healthcare Japan Corporation ) was diluted with sodium chloride (50 mM) and EDTA (2 mM) according to the method specified by the manufacturer. Phosphate buffer (50 mM, pH 6.0) containing 100 mM EDTA (referred to herein as PBS6.0 / EDTA) The column was equilibrated with 2.5 mL of antibody solution per column. After loading the column, the fraction (3.5 mL) eluted with 3.5 mL of PBS6.0 / EDTA was separated. This fraction was concentrated by common procedure A, and the antibody concentration was measured by common procedure B. After that, the antibody concentration was adjusted to 20 mg / mL using PBS6.0 / EDTA.

[0191] (4)-4 Common Procedure D: Purification of Antibody-Drug Conjugates Commercially available acetate buffer (10 mM, pH 5.5; see below) containing Sorbitol (5%) The NAP-25 column was equilibrated with one of the following buffers: The antibody-drug conjugate reaction solution (approximately 2.5 mL) was placed on the AP-25 column. The antibody fraction was collected by eluting with a specified amount of buffer. The gel filtration purification procedure, in which the product is loaded onto a NAP-25 column and eluted with buffer, is repeated 2 to 3 times. This allows the free drug linker and small molecule (tris(2-carboxyethyl)phosphine) Triglyceride hydrochloride (TCEP), N-acetyl-L-cysteine ​​(NAC), dimethyl sulfoxide The antibody-drug conjugate was obtained by removing the side chain.

[0192] (4)-5 Common Procedure E: Antibody Concentration and Single Antibody Molecule in Antibody-Drug Conjugates Determination of the average number of drug molecules bound per The conjugated drug concentration in the antibody-drug conjugate can be calculated by performing the following calculation after measuring the UV absorbances at two wavelengths of 280 nm and 370 nm of the antibody-drug conjugate aqueous solution. After measuring the UV absorbances at two wavelengths of 280 nm and 370 nm of the following calculation can be performed.

[0193] The total absorbance at a certain wavelength is equal to the sum of the absorbances of all the absorbing chemical species present in the system [additivity of absorbance]. Therefore, assuming that there is no change in the molar extinction coefficients of the antibody and the drug before and after conjugation, the antibody concentration and the drug concentration in the antibody-drug conjugate are represented by the following relational expressions. and the drug concentration in the antibody-drug conjugate are represented by the following relational expressions. If it is assumed that there is no change in the molar extinction coefficients of the antibody and the drug before and after conjugation, the antibody concentration A 280 = A D,280 + A A,280 = ε D,280 C D + ε A,280 C A Equation ([[]] 1)[[]] A 370 = A D,370 + A A,370 = ε D,370 C D + ε A,370 C A Equation ([[]] 2)[[]] Here, A 280 represents the absorbance of the antibody-drug conjugate aqueous solution at 280 nm shows 、 A 370 represents the absorbance of the antibody-drug conjugate aqueous solution at 370 nm, A A,280 represents the absorbance of the antibody at 280 nm, A A,370 represents the absorbance of the antibody at 370 nm shows, A D,280 represents the absorbance of the conjugate precursor at 280 nm shows, A D,370 represents the absorbance of the conjugate precursor at 370 nm, ε A,280 represents the molar extinction coefficient of the antibody at 280 nm, ε A,370 represents the molar extinction coefficient of the antibody at 370 nm shows the molar extinction coefficient of the antibody in, ε D,280 is the conjugate at 280 nm shows the molar extinction coefficient of the precursor, ε D,370 is the conjugate precursor at 370 nm shows the molar extinction coefficient of, C A represents the antibody concentration in the antibody-drug conjugate, C D represents the drug concentration in the antibody-drug conjugate.

[0194] Here, ε A,280、 ε A,370、 ε D,280、 ε D,370 is a pre-prepared value (calculated estimated value or measured value obtained from UV measurement of the compound) is used. For example , ε A,280 can be estimated from the amino acid sequence of the antibody by a known calculation method (Protein Scie nce, 1995, vol.4, 2411-2423). ε A,370 is usually zero. ε D,280 and ε D,370 are obtained by measuring the absorbance of a solution in which the conjugate precursor used is dissolved at a certain molar concentration, according to the Lambert-Be er's law (absorbance = molar concentration × molar extinction coefficient × cell optical path length). The A and A 280 of the antibody-drug conjugate aqueous solution are measured, and these values are substituted into equations 370 (1) and (2) to solve the simultaneous equations, whereby C and C A and C D can be determined . Furthermore, by dividing C D by C A , the average number of drug molecules bound per antibody can be determined .

[0195] (4)-6 Common Operation F: Drug per Antibody Molecule in Antibody-Drug Conjugate Measurement of Average Number of Molecular Conjugations (2) The average number of drug molecules per antibody molecule in an antibody-drug conjugate can be determined by high performance liquid chromatography ( HPLC) analysis using the following method in addition to the aforementioned “(4)-5 Common Operation E”. The following describes the method for measuring the average number of drug molecules by HPLC when the antibody and the drug linker are linked by a disulfide bond. Those skilled in the art can appropriately measure the average number of drug molecules by HPLC with reference to this method, depending on the binding mode between the antibody and the drug linker.

[0196] F-1. Preparation of Sample for HPLC Analysis (Reduction of Antibody-Drug Conjugate) Mix an antibody-drug conjugate solution (about 1 mg / mL, 60 μL) with an aqueous solution of dithiothreitol ( DTT) (100 mM, 15 μL). Incubate the mixture at 37 °C for 30 minutes to cleave the disulfide bonds between the light and heavy chains of the antibody-drug conjugate. Use the obtained sample for HPLC analysis.

[0197] F-2. HPLC Analysis Perform HPLC analysis under the following measurement conditions.

[0198] HPLC System: Agilent 1290 HPLC System (Agilent Technologies) Detector: Ultraviolet Absorbance Meter (Measurement Wavelength: 280 nm) Column: ACQUITY UPLC BEH Phenyl (2.1 × 50 mm, 1. 7 μm, 130 Å; Waters, P / N 186002884) Column Temperature: 80 °C Mobile Phase A: Water Containing 0.10% Trifluoroacetic Acid (TFA) and 15% 2-Propanol​​ Solution Mobile phase B: Acetonitrile solution containing 0.075% TFA and 15% 2-propanol Gradient program: 14% - 36% (0 min - 15 min), 36% - 80% (15 min -17 min), 80% - 14% (17 min - 17.01 min), 14% (17.01 min - 25 min ) Sample injection volume: 10 μL F-3. Data analysis F-3-1. For the light chain (L0) and heavy chain (H0) of the unbound antibody of the drug, the light chain bound with the drug molecule (the light chain with i drug molecules bound: L i ) and the heavy chain bound with the drug molecule (the heavy chain with i drug molecules bound: H i ) have increasing hydrophobicity and longer retention time in proportion to the number of bound drug molecules. Therefore, these chains elute in the order of, for example, L0 and L1 or H0 , H1, H2, and H3. By comparing the retention times with L0 and H0, the detected peak can be assigned to any of L0, L1, H0, H1, H2, H3. The number of drug molecules bound can be defined by those skilled in the art, but preferably, they are L0, L1, H0, H1, H2, H3 .

[0199] F-3-2. Since the drug linker has UV absorption, according to the number of bound drug linkers, the peak area value is corrected according to the following formula using the molar extinction coefficients of the light chain, heavy chain, and drug linker .

[0200]

Number

[0201]

Number

[0202] ​Here, the molar extinction coefficients (at 280 nm) of the light chain and heavy chain in each antibody can be estimated using known calculation methods (Protein Science, 1995, vol. 4, 2411 - 2423), that is, values estimated from the amino acid sequences of the light chain and heavy chain of each antibody can be used. For H01L02, according to its amino acid sequence, 31710 was used as the estimated value of the molar extinction coefficient of the light chain, and 79990 was used as the estimated value of the molar extinction coefficient of the heavy chain. Also, the molar extinction coefficient (at 280 nm) of the drug linker was determined by reacting each drug linker with mercaptoethanol or N - acetylcysteine to convert the maleimide group to a succinimide thioether, and using the measured molar extinction coefficient (at 280 nm) of the resulting compound. The wavelength at which the absorbance is measured can be appropriately set by those skilled in the art, but preferably, it is a wavelength at which the peak of the antibody can be measured, and more preferably, it is 280 nm.

[0203] F - 3 - 3. Calculate the ratio (%) of the peak area of each chain to the total peak area correction value of the antibody - drug conjugate according to the following formula.

[0204]

[0205] F - 3 - 4. Calculate the average number of drug molecules bound per antibody molecule in the antibody - drug conjugate according to the following formula.

[0206] Average number of drug molecules bound = (Ratio of L0 peak area × 0 + Ratio of L1 peak area × 1 + Ratio of H0 peak area × 0 + Ratio of H1 peak area × 1 + Ratio of H2 peak area × 2 + Ratio of H3 peak area × 3) / 100 × 2 In order to ensure the amount of the antibody - drug conjugate, it is prepared under the same conditions.

[0207]

[0208]

[0209]

Number

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217] A plurality of antibody-drug conjugates having similar average drug molecule binding numbers (for example, about ±1) can be mixed to form a new lot. In that case, the average number of drug molecules falls between the average number of drug molecules before mixing.

[0207] As a specific example of the antibody-drug conjugate of the present invention, those having a structure represented by the following formula can be mentioned.

[0208]

Chemical formula

[0209] Or the following formula:

[0210]

Chemical formula

[0211] Here, AB represents an anti-CDH6 antibody disclosed herein, and is bound to a linking linker via a sulfhydryl group derived from the antibody. Here, n is synonymous with the so-called DAR (Drug-to-Antibody Ratio) and represents the drug-antibody ratio per antibody. That is, it represents the number of drug molecules bound to one molecule of the antibody, which is a numerical value specified and denoted as the average value, that is, the average number of drug molecule binding numbers. In the case of the antibody-drug conjugates represented by [Chemical formula 25] and [Chemical formula 26] of the present invention, in the measurement by the common operation F, n may be from 2 to 8, preferably from 5 to 8, more preferably from 7 to 8, and even more preferably 8.

[0212]

[0212] As an example of the antibody-drug conjugate of the present invention, in the structures represented by the above [Chemical formula 25] and [Chemical formula 26], the antibody represented by AB is selected from the group consisting of the following (a) to (g) and An antibody - drug conjugate or a pharmaceutically acceptable salt thereof, comprising the heavy and light chain antibodies or functional fragments thereof according to any one of the selected items: (a) An antibody consisting of a light chain comprising the amino acid sequence at positions 21 to 233 of the full - length light chain amino acid sequence shown in SEQ ID NO: 61 and a heavy chain comprising the amino acid sequence at positions 20 to 471 of the full - length heavy chain amino acid sequence shown in SEQ ID NO: 69; (b) An antibody consisting of a light chain comprising the amino acid sequence at positions 21 to 233 of the full - length light chain amino acid sequence shown in SEQ ID NO: 61 and a heavy chain comprising the amino acid sequence at positions 20 to 471 of the full - length heavy chain amino acid sequence shown in SEQ ID NO: 73; (c) An antibody consisting of a light chain comprising the amino acid sequence at positions 21 to 233 of the full - length light chain amino acid sequence shown in SEQ ID NO: 61 and a heavy chain comprising the amino acid sequence at positions 20 to 471 of the full - length heavy chain amino acid sequence shown in SEQ ID NO: 77; (d) An antibody consisting of a light chain comprising the amino acid sequence at positions 21 to 233 of the full - length light chain amino acid sequence shown in SEQ ID NO: 65 and a heavy chain comprising the amino acid sequence at positions 20 to 471 of the full - length heavy chain amino acid sequence shown in SEQ ID NO: 69; (e) An antibody consisting of a light chain comprising the amino acid sequence at positions 21 to 233 of the full - length light chain amino acid sequence shown in SEQ ID NO: 65 and a heavy chain comprising the amino acid sequence at positions 20 to 471 of the full - length heavy chain amino acid sequence shown in SEQ ID NO: 73; (f) An antibody consisting of a light chain comprising the amino acid sequence at positions 21 to 233 of the full - length light chain amino acid sequence shown in SEQ ID NO: 65 and a heavy chain comprising the amino acid sequence at positions 20 to 471 of the full - length heavy chain amino acid sequence shown in SEQ ID NO: 77; and (g) An antibody in which the heavy chain or light chain has N - linked glycosylation, O - linked glycosylation, N - terminal processing ​​​​​​​​​​​​Singling, C-terminal processing, deamidation, isomerization of aspartic acid, acidification of methionine, addition of a methionine residue to the N-terminus, amidation of a proline residue, pyroglutaminylation of N-terminal glutamine or N-terminal glutamic acid, and other post-translational modifications, and one or two modifications selected from the group consisting of one or two amino acid deletions at the carboxyl terminus, an antibody according to any one of (a) to (f). such as, and including one or more modifications selected from the group consisting of one or two amino acid deletions at the carboxyl terminus, an antibody according to any one of (a) to (f). Post-translational modifications represented by pyroglutaminylation of N-terminal glutamine or N-terminal glutamic acid, etc., and one or two modifications selected from the group consisting of one or two amino acid deletions at the carboxyl terminus, an antibody according to any one of (a) to (f). including one or two modifications selected from the group consisting of one or two amino acid deletions at the carboxyl terminus, an antibody according to any one of (a) to (f). including one or two modifications selected from the group consisting of one or two amino acid deletions at the carboxyl terminus, an antibody according to any one of (a) to (f).

[0213] 4. Medicine The anti-CDH6 antibody of the present invention described in the above item "2. Production of anti-CDH6 antibody" and the examples, and the functional fragment of the antibody bind to CDH6 on the surface of tumor cells and have internalization activity. Therefore, alone or in combination with other drugs, as a medicine, for the treatment of cancers such as renal cell tumors and ovarian tumors, for example, renal cell carcinoma, clear cell renal carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, thyroid cancer, cholangiocarcinoma, lung cancer (for example, small cell lung cancer or non-small cell lung cancer), glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms tumor or neuroblastoma can be used. The anti-CDH6 antibody of the present invention described in the above item "2. Production of anti-CDH6 antibody" and the examples, and the functional fragment of the antibody bind to CDH6 on the surface of tumor cells and have internalization activity. Therefore, alone or in combination with other drugs, as a medicine, for the treatment of cancers such as renal cell tumors and ovarian tumors, for example, renal cell carcinoma, clear cell renal carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, thyroid cancer, cholangiocarcinoma, lung cancer (for example, small cell lung cancer or non-small cell lung cancer), glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms tumor or neuroblastoma can be used. The anti-CDH6 antibody of the present invention described in the above item "2. Production of anti-CDH6 antibody" and the examples, and the functional fragment of the antibody bind to CDH6 on the surface of tumor cells and have internalization activity. Therefore, alone or in combination with other drugs, as a medicine, for the treatment of cancers such as renal cell tumors and ovarian tumors, for example, renal cell carcinoma, clear cell renal carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, thyroid cancer, cholangiocarcinoma, lung cancer (for example, small cell lung cancer or non-small cell lung cancer), glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms tumor or neuroblastoma can be used. The anti-CDH6 antibody of the present invention described in the above item "2. Production of anti-CDH6 antibody" and the examples, and the functional fragment of the antibody bind to CDH6 on the surface of tumor cells and have internalization activity. Therefore, alone or in combination with other drugs, as a...

Claims

1. 1. A pharmaceutical composition comprising an antibody-drug conjugate for use in combination with a platinum-based drug, comprising: The antibody-drug conjugate has the following formula: 【Chemistry 1】 and having a structure represented by (In the formula, AB represents an antibody, n represents the average number of drug-linker structures bound to the antibody per antibody, and the antibody is bound to the linker via a sulfhydryl group derived from the antibody.) The antibody, An anti-CDH6 antibody that specifically binds to the amino acid sequence shown in SEQ ID NO: 4 of the EC3 domain of cadherin-6, The present invention comprises a CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 12, a CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 13, and a CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 14, and a CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 17, a CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 60, and a CDRH3 consisting of the amino acid sequence shown in SEQ ID NO:

19. Pharmaceutical compositions.

2. 1. A pharmaceutical composition comprising a platinum-based drug for use in combination with an antibody-drug conjugate, comprising: The antibody-drug conjugate has the following formula: 【Chemistry 2】 and having a structure represented by (In the formula, A represents an antibody, n represents the average number of drug-linker structures bound to the antibody per antibody, and the antibody is bound to the linker via a sulfhydryl group derived from the antibody.) The antibody, An anti-CDH6 antibody that specifically binds to the amino acid sequence shown in SEQ ID NO: 4 of the EC3 domain of cadherin-6, The present invention comprises a CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 12, a CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 13, and a CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 14, and a CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 17, a CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 60, and a CDRH3 consisting of the amino acid sequence shown in SEQ ID NO:

19. Pharmaceutical compositions.

3. 1. A pharmaceutical composition comprising an antibody-drug conjugate, the antibody-drug conjugate and a platinum-based drug are administered in combination; The antibody-drug conjugate has the following formula: 【Chemistry 3】 and having a structure represented by (In the formula, A represents an antibody, n represents the average number of drug-linker structures bound to the antibody per antibody, and the antibody is bound to the linker via a sulfhydryl group derived from the antibody.) The antibody, An anti-CDH6 antibody that specifically binds to the amino acid sequence shown in SEQ ID NO: 4 of the EC3 domain of cadherin-6, The present invention comprises a CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 12, a CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 13, and a CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 14, and a CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 17, a CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 60, and a CDRH3 consisting of the amino acid sequence shown in SEQ ID NO:

19. Pharmaceutical compositions.

4. The pharmaceutical composition of claim 1, wherein the antibody-drug conjugate and the platinum-based drug are contained separately as active ingredients in different formulations and are administered at the same time or at different times.

5. The pharmaceutical composition according to claim 2, wherein the antibody-drug conjugate and the platinum-based drug are contained separately as active ingredients in different formulations and are administered at the same time or at different times.

6. The pharmaceutical composition according to claim 3, wherein the antibody-drug conjugate and the platinum-based drug are contained separately as active ingredients in different formulations and are administered at the same time or at different times.

7. The pharmaceutical composition of claim 1, wherein the antibody-drug conjugate and the platinum-based drug are contained together as active ingredients in the same formulation and are administered simultaneously.

8. The pharmaceutical composition of claim 2, wherein the antibody-drug conjugate and the platinum-based drug are contained together as active ingredients in the same formulation and are administered simultaneously.

9. The pharmaceutical composition of claim 3, wherein the antibody-drug conjugate and the platinum-based drug are contained together as active ingredients in the same formulation and are administered simultaneously.

10. A pharmaceutical composition in which an antibody-drug conjugate and a platinum-based drug are administered simultaneously, together as active ingredients in the same formulation, The antibody-drug conjugate has the following formula: 【Chemistry 4】 and having a structure represented by (In the formula, A represents the antibody, n represents the average number of drug-linker structures bound to the antibody per antibody, and the antibody is bound to the linker via a sulfhydryl group derived from the antibody.) The antibody, An anti-CDH6 antibody that specifically binds to the amino acid sequence shown in SEQ ID NO: 4 of the EC3 domain of cadherin-6, The present invention comprises a CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 12, a CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 13, and a CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 14, and a CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 17, a CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 60, and a CDRH3 consisting of the amino acid sequence shown in SEQ ID NO:

19. Pharmaceutical compositions.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the antibody comprises a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 63 and a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO:

71.

12. The pharmaceutical composition according to any one of claims 1 to 10, wherein the antibody comprises a light chain consisting of an amino acid sequence of 21 to 233 of SEQ ID NO:61 and a heavy chain consisting of an amino acid sequence of 20 to 471 of SEQ ID NO:

69.

13. The pharmaceutical composition of claim 12, wherein the antibody has a deleted lysine residue at the carboxyl terminus of the heavy chain.

14. The pharmaceutical composition according to any one of claims 1 to 10, wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

15. The pharmaceutical composition according to claim 11, wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

16. The pharmaceutical composition according to claim 12, wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

17. The pharmaceutical composition according to claim 13, wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

18. The pharmaceutical composition according to any one of claims 1 to 10, wherein the platinum-based drug is carboplatin.

19. 16. The pharmaceutical composition of claim 15, wherein the platinum-based drug is carboplatin.

20. 17. The pharmaceutical composition of claim 16, wherein the platinum-based drug is carboplatin.

21. 18. The pharmaceutical composition of claim 17, wherein the platinum-based drug is carboplatin.

22. A pharmaceutical composition according to any one of claims 1 to 10 for the treatment of cancer.

23. A pharmaceutical composition according to any one of claims 1 to 10 for the treatment of ovarian cancer.

24. 20. The pharmaceutical composition of claim 19 for the treatment of ovarian cancer.

25. 21. The pharmaceutical composition according to claim 20 for the treatment of ovarian cancer.

26. 22. The pharmaceutical composition according to claim 21 for the treatment of ovarian cancer.

27. 24. The pharmaceutical composition of claim 23, wherein the ovarian cancer is selected from the group consisting of epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer.

28. 25. The pharmaceutical composition of claim 24, wherein the ovarian cancer is selected from the group consisting of epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer.

29. 26. The pharmaceutical composition of claim 25, wherein the ovarian cancer is selected from the group consisting of epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer.

30. 27. The pharmaceutical composition of claim 26, wherein the ovarian cancer is selected from the group consisting of epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer.

31. The pharmaceutical composition of claim 23, wherein the ovarian cancer is metastatic.

32. The pharmaceutical composition of claim 23, wherein the ovarian cancer is (i) resistant to platinum-based chemotherapy, (ii) resistant to a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, (iii) a recurrent ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, or (iv) an ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug, a taxane, or both a platinum-based drug and a taxane.

33. 25. The pharmaceutical composition of claim 24, wherein the ovarian cancer is (i) resistant to platinum-based chemotherapy, (ii) resistant to a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, (iii) a recurrent ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, or (iv) an ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug, a taxane, or both a platinum-based drug and a taxane.

34. 26. The pharmaceutical composition of claim 25, wherein the ovarian cancer is (i) resistant to platinum-based chemotherapy, (ii) resistant to a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, (iii) a recurrent ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, or (iv) an ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug, a taxane, or both a platinum-based drug and a taxane.

35. 27. The pharmaceutical composition of claim 26, wherein the ovarian cancer is (i) resistant to platinum-based chemotherapy, (ii) resistant to a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, (iii) a recurrent ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, or (iv) an ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug, a taxane, or both a platinum-based drug and a taxane.

36. The pharmaceutical composition of claim 28, wherein the ovarian cancer is (i) resistant to platinum-based chemotherapy, (ii) resistant to a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, (iii) a recurrent ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, or (iv) an ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug, a taxane, or both a platinum-based drug and a taxane.

37. 30. The pharmaceutical composition of claim 29, wherein the ovarian cancer is (i) resistant to platinum-based chemotherapy, (ii) resistant to a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, (iii) a recurrent ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, or (iv) an ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug, a taxane, or both a platinum-based drug and a taxane.

38. The pharmaceutical composition of claim 30, wherein the ovarian cancer is (i) resistant to platinum-based chemotherapy, (ii) resistant to a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, (iii) a recurrent ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, or (iv) an ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug, a taxane, or both a platinum-based drug and a taxane.

39. 25. The pharmaceutical composition of claim 24, wherein the ovarian cancer is a recurrent ovarian cancer previously treated with a chemotherapy regimen including a platinum-based drug.

40. 26. The pharmaceutical composition of claim 25, wherein the ovarian cancer is a recurrent ovarian cancer previously treated with a chemotherapy regimen including a platinum-based drug.

41. 27. The pharmaceutical composition of claim 26, wherein the ovarian cancer is a recurrent ovarian cancer previously treated with a chemotherapy regimen including a platinum-based drug.

42. 29. The pharmaceutical composition of claim 28, wherein the ovarian cancer is a recurrent ovarian cancer previously treated with a chemotherapy regimen including a platinum-based drug.

43. 30. The pharmaceutical composition of claim 29, wherein the ovarian cancer is a recurrent ovarian cancer previously treated with a chemotherapy regimen including a platinum-based drug.

44. 31. The pharmaceutical composition of claim 30, wherein the ovarian cancer is a recurrent ovarian cancer previously treated with a chemotherapy regimen including a platinum-based drug.

45. 40. The pharmaceutical composition of claim 39, wherein the recurrence occurs less than or within about 6 months of completion of a chemotherapy regimen that includes a platinum-based drug.

46. 41. The pharmaceutical composition of claim 40, wherein the recurrence occurs less than or within about 6 months of completion of a chemotherapy regimen that includes a platinum-based drug.

47. 42. The pharmaceutical composition of claim 41, wherein the recurrence occurs less than or within about 6 months of completion of a chemotherapy regimen that includes a platinum-based drug.

48. 43. The pharmaceutical composition of claim 42, wherein the recurrence occurs less than or within about 6 months of completion of a chemotherapy regimen that includes a platinum-based drug.

49. 44. The pharmaceutical composition of claim 43, wherein the recurrence occurs less than or within about 6 months of completion of a chemotherapy regimen that includes a platinum-based drug.

50. 45. The pharmaceutical composition of claim 44, wherein the recurrence occurs less than or within about 6 months of completion of a chemotherapy regimen that includes a platinum-based drug.

51. 40. The pharmaceutical composition of claim 39, wherein the recurrence of the cancer occurs at or about 6 months after completion of a chemotherapy regimen that includes a platinum-based drug.

52. 41. The pharmaceutical composition of claim 40, wherein the recurrence of the cancer occurs at or about 6 months after completion of a chemotherapy regimen that includes a platinum-based drug.

53. 42. The pharmaceutical composition of claim 41, wherein the recurrence of the cancer occurs at or about 6 months after completion of a chemotherapy regimen that includes a platinum-based drug.

54. 43. The pharmaceutical composition of claim 42, wherein the recurrence of the cancer occurs at or about 6 months after completion of a chemotherapy regimen that includes a platinum-based drug.

55. 44. The pharmaceutical composition of claim 43, wherein the recurrence of the cancer occurs at or about 6 months after completion of a chemotherapy regimen that includes a platinum-based drug.

56. 45. The pharmaceutical composition of claim 44, wherein the recurrence of the cancer occurs at or about 6 months after completion of a chemotherapy regimen that includes a platinum-based drug.

57. A pharmaceutical combination comprising an antibody-drug conjugate and a platinum-based drug, the antibody-drug conjugate and the platinum-based drug are administered in combination; The antibody-drug conjugate has the following formula: 【Chemistry 5】 and having a structure represented by (In the formula, AB represents the antibody, n represents the average number of drug-linker structures bound to the antibody per antibody, and the antibody is bound to the linker via a sulfhydryl group derived from the antibody.) The antibody, An anti-CDH6 antibody that specifically binds to the amino acid sequence shown in SEQ ID NO: 4 of the EC3 domain of cadherin-6, The present invention comprises a CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 12, a CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 13, and a CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 14, and a CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 17, a CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 60, and a CDRH3 consisting of the amino acid sequence shown in SEQ ID NO:

19. Pharmaceutical combinations.

58. The pharmaceutical combination of claim 57, wherein the antibody-drug conjugate and the platinum-based drug are contained separately as active ingredients in different formulations and are administered at the same time or at different times.

59. 58. The pharmaceutical combination of claim 57, wherein the antibody-drug conjugate and the platinum-based drug are contained together as active ingredients in the same formulation and are administered simultaneously.

60. 60. The pharmaceutical combination of any one of claims 57 to 59, wherein the antibody comprises a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 63 and a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO:

71.

61. The pharmaceutical combination according to any one of claims 57 to 59, wherein the antibody comprises a light chain consisting of an amino acid sequence of 21 to 233 of SEQ ID NO:61 and a heavy chain consisting of an amino acid sequence of 20 to 471 of SEQ ID NO:

69.

62. 62. The pharmaceutical combination of claim 61, wherein the antibody has a deleted lysine residue at the carboxyl terminus of the heavy chain.

63. The pharmaceutical combination according to any one of claims 57 to 59, wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

64. The pharmaceutical combination of claim 60, wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

65. The pharmaceutical combination of claim 61, wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

66. The pharmaceutical combination of claim 62, wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

67. 60. The pharmaceutical combination of any one of claims 57 to 59, wherein the platinum-based drug is carboplatin.

68. 65. The pharmaceutical combination of claim 64, wherein the platinum-based drug is carboplatin.

69. 66. The pharmaceutical combination of claim 65, wherein the platinum-based drug is carboplatin.

70. 67. The pharmaceutical combination of claim 66, wherein the platinum-based drug is carboplatin.

71. 60. A pharmaceutical combination according to any one of claims 57 to 59 for the treatment of cancer.

72. 60. A pharmaceutical combination according to any one of claims 57 to 59 for the treatment of ovarian cancer.

73. 69. The pharmaceutical combination of claim 68 for the treatment of ovarian cancer.

74. 70. The pharmaceutical combination of claim 69 for the treatment of ovarian cancer.

75. 71. The pharmaceutical combination of claim 70 for the treatment of ovarian cancer.

76. 73. The pharmaceutical combination of claim 72, wherein the ovarian cancer is selected from the group consisting of epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer.

77. 74. The pharmaceutical combination of claim 73, wherein the ovarian cancer is selected from the group consisting of epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer.

78. 75. The pharmaceutical combination of claim 74, wherein the ovarian cancer is selected from the group consisting of epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer.

79. 76. The pharmaceutical combination of claim 75, wherein the ovarian cancer is selected from the group consisting of epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer.

80. The pharmaceutical combination of claim 72, wherein the ovarian cancer is metastatic.

81. 73. The pharmaceutical combination of claim 72, wherein the ovarian cancer is (i) resistant to platinum-based chemotherapy, (ii) resistant to a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, (iii) a recurrence of ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, or (iv) an ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug, a taxane, or both a platinum-based drug and a taxane.

82. The pharmaceutical combination of claim 73, wherein the ovarian cancer is (i) resistant to platinum-based chemotherapy, (ii) resistant to a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, (iii) a recurrence of ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, or (iv) an ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug, a taxane, or both a platinum-based drug and a taxane.

83. The pharmaceutical combination of claim 74, wherein the ovarian cancer is (i) resistant to platinum-based chemotherapy, (ii) resistant to a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, (iii) a recurrence of ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, or (iv) an ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug, a taxane, or both a platinum-based drug and a taxane.

84. 76. The pharmaceutical combination of claim 75, wherein the ovarian cancer is (i) resistant to platinum-based chemotherapy, (ii) resistant to a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, (iii) a recurrence of ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, or (iv) an ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug, a taxane, or both a platinum-based drug and a taxane.

85. 78. The pharmaceutical combination of claim 77, wherein the ovarian cancer is (i) resistant to platinum-based chemotherapy, (ii) resistant to a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, (iii) a recurrence of ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, or (iv) an ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug, a taxane, or both a platinum-based drug and a taxane.

86. The pharmaceutical combination of claim 78, wherein the ovarian cancer is (i) resistant to platinum-based chemotherapy, (ii) resistant to a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, (iii) a recurrence of ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, or (iv) an ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug, a taxane, or both a platinum-based drug and a taxane.

87. The pharmaceutical combination of claim 79, wherein the ovarian cancer is (i) resistant to platinum-based chemotherapy, (ii) resistant to a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, (iii) a recurrent ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug alone or in combination with a taxane, or (iv) an ovarian cancer previously treated with a chemotherapy regimen comprising a platinum-based drug, a taxane, or both a platinum-based drug and a taxane.

88. 74. The pharmaceutical combination of claim 73, wherein the ovarian cancer is a recurrent ovarian cancer previously treated with a chemotherapy regimen including a platinum-based drug.

89. 75. The pharmaceutical combination of claim 74, wherein the ovarian cancer is a recurrent ovarian cancer previously treated with a chemotherapy regimen including a platinum-based drug.

90. 76. The pharmaceutical combination of claim 75, wherein the ovarian cancer is a recurrent ovarian cancer previously treated with a chemotherapy regimen including a platinum-based drug.

91. 78. The pharmaceutical combination of claim 77, wherein the ovarian cancer is a recurrent ovarian cancer previously treated with a chemotherapy regimen including a platinum-based drug.

92. 79. The pharmaceutical combination of claim 78, wherein the ovarian cancer is a recurrent ovarian cancer previously treated with a chemotherapy regimen including a platinum-based drug.

93. 80. The pharmaceutical combination of claim 79, wherein the ovarian cancer is a recurrent ovarian cancer previously treated with a chemotherapy regimen including a platinum-based drug.

94. 90. The pharmaceutical combination of claim 88, wherein the recurrence occurs less than or within about 6 months of completion of a chemotherapy regimen that includes a platinum-based drug.

95. 90. The pharmaceutical combination of claim 89, wherein the recurrence occurs less than or within about 6 months of completion of a chemotherapy regimen that includes a platinum-based drug.

96. 91. The pharmaceutical combination of claim 90, wherein the recurrence occurs less than or within about 6 months of completion of a chemotherapy regimen that includes a platinum-based drug.

97. 92. The pharmaceutical combination of claim 91, wherein the recurrence occurs less than or within about 6 months of completion of a chemotherapy regimen that includes a platinum-based drug.

98. 93. The pharmaceutical combination of claim 92, wherein the recurrence occurs less than or within about 6 months of completion of a chemotherapy regimen that includes a platinum-based drug.

99. 94. The pharmaceutical combination of claim 93, wherein the recurrence occurs less than or within about 6 months of completion of a chemotherapy regimen that includes a platinum-based drug.

100. 91. The pharmaceutical combination of claim 90, wherein said recurrence of said cancer occurs at or about 6 months after completion of a chemotherapy regimen that includes a platinum-based drug.

101. 92. The pharmaceutical combination of claim 91, wherein said recurrence of said cancer occurs at or about 6 months after completion of a chemotherapy regimen that includes a platinum-based drug.

102. 93. The pharmaceutical combination of claim 92, wherein said recurrence of said cancer occurs at or about 6 months after completion of a chemotherapy regimen that includes a platinum-based drug.

103. 94. The pharmaceutical combination of claim 93, wherein said recurrence of said cancer occurs at or about 6 months after completion of a chemotherapy regimen that includes a platinum-based drug.

104. 95. The pharmaceutical combination of claim 94, wherein said recurrence of said cancer occurs at or about 6 months after completion of a chemotherapy regimen that includes a platinum-based drug.

105. 96. The pharmaceutical combination of claim 95, wherein said recurrence of said cancer occurs at or about 6 months after completion of a chemotherapy regimen that includes a platinum-based drug.

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