WO2024204679A1 - 抗ＣＤＨ６抗体－薬物コンジュゲートとＨＩＦ－２α阻害剤の組み合わせ - Google Patents

抗ＣＤＨ６抗体－薬物コンジュゲートとＨＩＦ－２α阻害剤の組み合わせ Download PDF

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WO2024204679A1
WO2024204679A1 PCT/JP2024/012972 JP2024012972W WO2024204679A1 WO 2024204679 A1 WO2024204679 A1 WO 2024204679A1 JP 2024012972 W JP2024012972 W JP 2024012972W WO 2024204679 A1 WO2024204679 A1 WO 2024204679A1
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antibody
amino acid
acid sequence
seq
cancer
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PCT/JP2024/012972
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English (en)
French (fr)
Japanese (ja)
Inventor
宏和 鈴木
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Daiichi Sankyo Co Ltd
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Daiichi Sankyo Co Ltd
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Priority to KR1020257036655A priority Critical patent/KR20250173601A/ko
Priority to EP24780774.6A priority patent/EP4691497A1/en
Priority to AU2024248799A priority patent/AU2024248799A1/en
Priority to CN202480022556.2A priority patent/CN120916791A/zh
Priority to MX2025011453A priority patent/MX2025011453A/es
Priority to JP2025511241A priority patent/JPWO2024204679A1/ja
Publication of WO2024204679A1 publication Critical patent/WO2024204679A1/ja
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
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    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
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Definitions

  • the present invention relates to a pharmaceutical composition characterized in that a specific anti-CDH6 antibody-drug conjugate and a HIF-2 ⁇ inhibitor are administered in combination, and/or a treatment method characterized in that a specific anti-CDH6 antibody-drug conjugate and a HIF-2 ⁇ inhibitor are administered in combination to an individual.
  • HIF-2 ⁇ Hydrophila-Inducible Factor 2 ⁇
  • HIF-2 ⁇ one of the hypoxia-inducible factors
  • a transcription factor that plays a central role in the hypoxia response pathway and controls the expression of genes that regulate angiogenesis, cell proliferation, cell survival, extracellular matrix remodeling, pH homeostasis, etc.
  • HIF-2 ⁇ inhibitors are known as drugs that exhibit antitumor effects by, for example, inhibiting the transcriptional activity of HIF-2 ⁇ .
  • Known HIF-2 ⁇ inhibitors include berutifan, PT2385, and PT2399 (Non-Patent Documents 2 and 3).
  • Antibody-drug conjugates which combine a cytotoxic drug with an antibody that binds to an antigen expressed on the surface of cancer cells and can be internalized into the cells, can selectively deliver drugs to cancer cells, allowing the drug to accumulate in the cancer cells and kill them.
  • ADCs Antibody-drug conjugates
  • One known antibody-drug conjugate is one whose components are an anti-CDH6 antibody and a derivative of exatecan, a topoisomerase I inhibitor (Patent Document 1).
  • anti-CDH6 antibody-drug conjugate used in the present invention has been confirmed to exhibit excellent antitumor effects even as a single agent.
  • a treatment method that can comprehensively suppress the proliferation of cancer cells and exert even more excellent antitumor effects can be obtained by using the antibody-drug conjugate in combination with other anticancer drugs that have different mechanisms of action.
  • the present invention aims to provide a pharmaceutical composition characterized by administering a combination of a specific anti-CDH6 antibody-drug conjugate and a HIF-2 ⁇ inhibitor, and/or a treatment method characterized by administering a combination of a specific anti-CDH6 antibody-drug conjugate and a HIF-2 ⁇ inhibitor to an individual.
  • the inventors conducted extensive research to solve the above problems and discovered that administering a specific anti-CDH6 antibody-drug conjugate in combination with a HIF-2 ⁇ inhibitor provides an excellent combined effect (highly safe and significant antitumor effect), leading to the completion of the present invention.
  • a pharmaceutical composition comprising an anti-CDH6 antibody-drug conjugate, the anti-CDH6 antibody-drug conjugate and a HIF-2 ⁇ inhibitor are administered in combination;
  • the anti-CDH6 antibody-drug conjugate has the formula
  • A represents a binding site to an anti-CDH6 antibody or a functional fragment of the antibody.
  • an anti-CDH6 antibody or a functional fragment of the antibody are linked via a thioether bond to a drug linker represented by the formula: [2]
  • the anti-CDH6 antibody or a functional fragment of the antibody is one of the following (1) to (5): (1) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 3, and CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4; (2) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 8, and CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4; (3) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 9, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 10, and CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 11; (4) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 15, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO
  • the anti-CDH6 antibody or a functional fragment of the antibody is selected from the following (1) to (5): (1) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 28; (2) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 31; (3) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 34; (4) an amino acid sequence having at least 95% sequence identity to the framework region sequences other than each CDR sequence in the amino acid sequences of (1) to (3); and (5) an amino acid sequence in which one or several amino acids are deleted, substituted, or added in the framework region sequences other than each CDR sequence in the amino acid sequences of (1) to (4); The following (6) to (9): (6) A light chain variable region consisting of the amino acid sequence set
  • a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 40.
  • the anti-CDH6 antibody or a functional fragment of the antibody is one of the following (1) to (4): (1) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 28 and a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 37; (2) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 31 and a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 37; (3) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 31 and a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 40, or (4) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 34 and a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 37; any one of the heavy
  • the anti-CDH6 antibody or a functional fragment of the antibody is selected from the following (1) to (4): (1) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38; (2) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38; (3) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 41, or (4) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 35 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38;
  • an anti-CDH6 antibody or a functional fragment of the antibody The pharmaceutical composition according to any one of [1] to [11], wherein the heavy chain or light chain is an antibody or a functional fragment of the antibody, which has been modified by one or more selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, isomerization of aspartic acid, oxidation of methionine, addition of a methionine residue to the N-terminus, amidation of proline residues, pyroglutamic oxidation of N-terminal glutamine or N-terminal glutamic acid, and deletion of one or two amino acids at the carboxyl terminus.
  • the heavy chain or light chain is an antibody or a functional fragment of the antibody, which has been modified by one or more selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, isomer
  • cancer selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma,
  • a pharmaceutical composition comprising an anti-CDH6 antibody-drug conjugate, the anti-CDH6 antibody-drug conjugate and a HIF-2 ⁇ inhibitor are administered in combination;
  • the anti-CDH6 antibody-drug conjugate has the formula
  • a pharmaceutical composition comprising an antibody-drug conjugate represented by the formula: [32]
  • cancer selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ova
  • a method for treatment comprising administering an anti-CDH6 antibody-drug conjugate and a HIF-2 ⁇ inhibitor in combination to an individual in need of treatment,
  • the antibody-drug conjugate has the formula
  • A represents a binding site to an anti-CDH6 antibody or a functional fragment of the antibody.
  • an anti-CDH6 antibody or a functional fragment of said antibody are linked via a thioether bond to form an antibody-drug conjugate.
  • the treatment method according to [49], wherein the anti-CDH6 antibody or a functional fragment of the antibody specifically binds to the amino acid sequence set forth in SEQ ID NO: 1 and has the ability to be internalized into cells, or a functional fragment of the antibody.
  • An anti-CDH6 antibody or a functional fragment of the antibody comprising any one of the following (1) to (5): (1) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 3, and CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4; (2) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 8, and CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4; (3) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 9, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 10, and CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 11; (4) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 15, CDRH2 consisting of the amino acid sequence set forth
  • an anti-CDH6 antibody or a functional fragment of the antibody comprising any one of the following (1) to (5): (1) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 28; (2) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 31; (3) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 34; (4) an amino acid sequence having at least 95% sequence identity to the framework region sequences other than each CDR sequence in the amino acid sequences of (1) to (3); and (5) an amino acid sequence in which one or several amino acids are deleted, substituted, or added in the framework region sequences other than each CDR sequence in the amino acid sequences of (1) to (4); The following (6) to (9): (6) A light chain variable region consisting of the amino acid sequence
  • a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 40.
  • An anti-CDH6 antibody or a functional fragment of the antibody comprising any one of the following (1) to (4): (1) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 28 and a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 37; (2) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 31 and a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 37; (3) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 31 and a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 40, or (4) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 34 and a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 37; any one of the heavy chain variable region and the light chain variable region of The therapeutic method according to any one of [49] to [55], wherein the antibody
  • the anti-CDH6 antibody or a functional fragment of the antibody is selected from the following (1) to (4): (1) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38; (2) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38; (3) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 41, or (4) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 35 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38;
  • the therapeutic method according to any one of [49] to [57], wherein the antibody comprises any one of the following: [59] The method of any one of [49] to [58], wherein the anti-CDH6 antibody or
  • an anti-CDH6 antibody or a functional fragment of the antibody The method for treatment according to any one of [49] to [59], wherein the heavy chain or light chain is an antibody or a functional fragment of the antibody which has been modified by one or more selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, isomerization of aspartic acid, oxidation of methionine, addition of a methionine residue to the N-terminus, amidation of proline residues, pyroglutamic oxidation of N-terminal glutamine or N-terminal glutamic acid, and deletion of one or two amino acids at the carboxyl terminus.
  • the heavy chain or light chain is an antibody or a functional fragment of the antibody which has been modified by one or more selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, isomerization
  • [70-2] The method of any one of [49] to [64], wherein the number of bonds per antibody in the drug-linker structure in the anti-CDH6 antibody-drug conjugate is an integer ranging from 1 to 10.
  • [70-3] The method of any one of [49] to [64], wherein the number of bonds per antibody in the drug-linker structure in the anti-CDH6 antibody-drug conjugate is an integer ranging from 2 to 8.
  • [70-4] The method of any one of [49] to [64], wherein the number of drug-linker structures bound per antibody in the anti-CDH6 antibody-drug conjugate is 2, 4, 6, or 8.
  • [70-5] The method for treatment according to any one of [49] to [64], wherein the number of bonds of the drug-linker structure per antibody in the anti-CDH6 antibody-drug conjugate is 8. [71] The method of any one of [49] to [70-5], wherein the HIF-2 ⁇ inhibitor is belstifan, NKT2152, DFF332, AB521, or BPI-452080, or a pharma- ceutical acceptable salt thereof. [72] The method of treatment according to any one of [49] to [70-5], wherein the HIF-2 ⁇ inhibitor is velzutifan or a pharma- ceutical acceptable salt thereof.
  • a method for treatment comprising administering an anti-CDH6 antibody-drug conjugate and a HIF-2 ⁇ inhibitor in combination to an individual in need of treatment,
  • the anti-CDH6 antibody-drug conjugate has the formula
  • the antibody is an anti-CDH6 antibody
  • the drug linker is bound to the antibody via a thioether bond
  • n represents the average number of drug linkers bound per antibody.
  • the therapeutic method comprises administering to the patient an antibody-drug conjugate as defined above.
  • the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38.
  • the treatment method according to [79] or [80] wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.
  • DS-6000a raludotatug deruxtecan
  • A represents a binding site to an anti-CDH6 antibody or a functional fragment of the antibody.
  • an anti-CDH6 antibody or a functional fragment of the antibody are linked via a thioether bond.
  • the anti-CDH6 antibody or a functional fragment of the antibody is selected from the following (1) to (5): (1) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 3, and CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4; (2) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 8, and CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4; (3) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 9, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 10, and CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 11; (4) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 15, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO
  • the anti-CDH6 antibody-drug conjugate according to any one of [97] to [101], wherein the anti-CDH6 antibody or a functional fragment of the antibody is a humanized antibody or a functional fragment of the antibody.
  • the anti-CDH6 antibody or a functional fragment of the antibody is selected from the following (1) to (5): (1) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 28; (2) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 31; (3) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 34; (4) an amino acid sequence having at least 95% sequence identity to the framework region sequences other than each CDR sequence in the amino acid sequences of (1) to (3); and (5) an amino acid sequence in which one or several amino acids are deleted, substituted, or added in the framework region sequences other than each CDR sequence in the amino acid sequences of (1) to (4); The following (6) to (9): (6) A light chain variable region consisting
  • a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 40.
  • the anti-CDH6 antibody-drug conjugate according to any one of [97] to [102], which is an antibody or a functional fragment of the antibody comprising: [104]
  • the anti-CDH6 antibody or a functional fragment of the antibody is selected from the following (1) to (4): (1) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 28 and a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 37; (2) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 31 and a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 37; (3) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 31 and a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 40, or (4) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 34 and a light chain variable region consisting of the amino acid sequence set forth in SEQ
  • the anti-CDH6 antibody or a functional fragment of the antibody is selected from the following (1) to (4): (1) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38; (2) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38; (3) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 41, or (4) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 35 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38;
  • the anti-CDH6 antibody-drug conjugate according to any one of [97] to [105], which is an antibody or a functional fragment of the antibody comprising any one of the following: [107]
  • an anti-CDH6 antibody or a functional fragment of the antibody The anti-CDH6 antibody-drug conjugate according to any one of [97] to [107], wherein the heavy chain or light chain is an antibody or a functional fragment of the antibody which has been modified by one or more selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, isomerization of aspartic acid, oxidation of methionine, addition of a methionine residue to the N-terminus, amidation of proline residues, pyroglutamic oxidation of N-terminal glutamine or N-terminal glutamic acid, and deletion of one or two amino acids at the carboxyl terminus.
  • the heavy chain or light chain is an antibody or a functional fragment of the antibody which has been modified by one or more selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, de
  • anti-CDH6 antibody-drug conjugate according to any one of [108] to [111], wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody in which a proline residue at the carboxyl terminus of the heavy chain is further amidated.
  • the anti-CDH6 antibody-drug conjugate according to any one of [97] to [122], for the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, ovarian mucinous tumor, thyroid cancer, cholangiocarcinoma, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, neuroblastoma, colorectal cancer, gastric cancer, endometrial cancer, uterine body cancer, nasopharyngeal cancer, prostate cancer, and cancer associated with von Hippel-Lindau disease.
  • the anti-CDH6 antibody-drug conjugate according to any one of [97] to [122] for the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, ovarian mucinous tumor, thyroid cancer, cholangiocarcinoma, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, and neuroblastoma.
  • the anti-CDH6 antibody-drug conjugate according to any one of [97] to [122], for the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, and papillary renal cell carcinoma.
  • the antibody is an anti-CDH6 antibody
  • the drug linker is bound to the antibody via a thioether bond
  • n represents the average number of drug linkers bound per antibody.
  • the anti-CDH6 antibody-drug conjugate shown in FIG. [128] The anti-CDH6 antibody-drug conjugate according to [127], wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38.
  • the anti-CDH6 antibody-drug conjugate according to any one of [127] to [139], for the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, ovarian mucinous tumor, thyroid cancer, cholangiocarcinoma, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, neuroblastoma, colorectal cancer, gastric cancer, endometrial cancer, uterine body cancer, nasopharyngeal cancer, prostate cancer, and cancer associated with von Hippel-Lindau disease.
  • the anti-CDH6 antibody-drug conjugate according to any one of [127] to [139], for the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, ovarian mucinous tumor, thyroid cancer, cholangiocarcinoma, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, and neuroblastoma.
  • renal cell carcinoma renal clear cell carcinoma
  • papillary renal cell carcinoma ovarian cancer
  • ovarian cancer ovarian serous adenocarcinoma
  • ovarian clear cell carcinoma endometrioid ovarian cancer
  • A represents a binding site to an anti-CDH6 antibody or a functional fragment of the antibody.
  • an anti-CDH6 antibody or a functional fragment of the antibody are linked via a thioether bond.
  • An anti-CDH6 antibody or a functional fragment of the antibody comprising any one of the following (1) to (5): (1) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 3, and CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4; (2) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 8, and CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4; (3) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 9, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 10, and CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 11; (4) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 15, CDRH2 consisting of the amino acid sequence set forth
  • an anti-CDH6 antibody or a functional fragment of the antibody comprising any one of the following (1) to (5): (1) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 28; (2) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 31; (3) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 34; (4) an amino acid sequence having at least 95% sequence identity to the framework region sequences other than each CDR sequence in the amino acid sequences of (1) to (3); and (5) an amino acid sequence in which one or several amino acids are deleted, substituted, or added in the framework region sequences other than each CDR sequence in the amino acid sequences of (1) to (4); The following (6) to (9): (6) A light chain variable region consisting of the amino acid
  • a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 40.
  • the anti-CDH6 antibody or a functional fragment of the antibody is selected from the following (1) to (4): (1) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 28 and a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 37; (2) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 31 and a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 37; (3) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 31 and a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 40, or (4) a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 34 and a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 37; any one of the heavy chain variable region and the light chain variable region of The use according to any one of [145] to [151], wherein the antibody comprises the compound or
  • anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody comprising a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 28 and a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO: 37.
  • An anti-CDH6 antibody or a functional fragment of the antibody comprising any one of the following (1) to (4): (1) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38; (2) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38; (3) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 41, or (4) a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 35 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38;
  • an anti-CDH6 antibody or a functional fragment of the antibody The use according to any one of [145] to [155], wherein the heavy chain or light chain is an antibody or a functional fragment of the antibody which has been modified by one or more selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, isomerization of aspartic acid, oxidation of methionine, addition of a methionine residue to the N-terminus, amidation of proline residues, pyroglutamic oxidation of N-terminal glutamine or N-terminal glutamic acid, and deletion of one or two amino acids at the carboxyl terminus.
  • [160] The use according to any one of [156] to [159], wherein the anti-CDH6 antibody or a functional fragment of the antibody is an antibody or a functional fragment of the antibody in which the proline residue at the carboxyl terminus of the heavy chain is further amidated.
  • [161] The use according to any one of [145] to [160], wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 1 to 10.
  • [162] The use according to any one of [145] to [160], wherein the average number of drug linkers bound per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 2 to 8.
  • [166-4] The use according to any one of [145] to [160], wherein the number of drug-linker structures bound per antibody in the anti-CDH6 antibody-drug conjugate is 2, 4, 6, or 8.
  • [166-5] The use according to any one of [145] to [160], wherein the number of bonds of the drug-linker structure per antibody in the anti-CDH6 antibody-drug conjugate is 8.
  • the HIF-2 ⁇ inhibitor is belstifan, NKT2152, DFF332, AB521, or BPI-452080, or a pharma- ceutical acceptable salt thereof.
  • [172] The use according to any one of [145] to [170] for the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, ovarian mucinous tumor, thyroid cancer, cholangiocarcinoma, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, neuroblastoma, colorectal cancer, gastric cancer, endometrial cancer, uterine cancer, nasopharyngeal cancer, prostate cancer, and cancer associated with von Hippel-Lindau disease.
  • [173] The use described in any one of [145] to [170] for the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, ovarian mucinous tumor, thyroid cancer, cholangiocarcinoma, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, and neuroblastoma.
  • renal cell carcinoma renal clear cell carcinoma
  • papillary renal cell carcinoma ovarian cancer
  • ovarian cancer ovarian serous adenocarcinoma
  • ovarian clear cell carcinoma endometrioid ovarian cancer
  • ovarian mucinous tumor thyroid
  • [174] The use described in any one of [145] to [170] for the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, and papillary renal cell carcinoma.
  • the antibody is an anti-CDH6 antibody
  • the drug linker is bound to the antibody via a thioether bond
  • n represents the average number of drug linkers bound per antibody.
  • [191] The use described in any one of [175] to [187] for the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, and papillary renal cell carcinoma.
  • [192] The use according to any one of [145] to [191], wherein the anti-CDH6 antibody-drug conjugate is raludotatug deruxtecan (DS-6000a).
  • DS-6000a raludotatug deruxtecan
  • [194] The pharmaceutical product according to [193] for the treatment of a disease as defined in any one of [27] to [30] and [44] to [47].
  • [195] The pharmaceutical product according to [193] or [194], characterized in that the anti-CDH6 antibody-drug conjugate and the HIF-2 ⁇ inhibitor are contained (as active ingredients) in separate formulations and are administered simultaneously (almost simultaneously) or at different times.
  • [196] The pharmaceutical product according to [193] or [194], wherein the anti-CDH6 antibody-drug conjugate and the HIF-2 ⁇ inhibitor are contained (as active ingredients) in the same formulation.
  • the combination pharmaceutical according to [197] or [198] characterized in that the anti-CDH6 antibody-drug conjugate and the HIF-2 ⁇ inhibitor are contained (as active ingredients) in different formulations and are administered simultaneously (almost simultaneously) or at different times.
  • a pharmaceutical combination comprising an anti-CDH6 antibody-drug conjugate and a HIF-2 ⁇ inhibitor, wherein the anti-CDH6 antibody-drug conjugate and the HIF-2 ⁇ inhibitor are as defined in any one of [1] to [24], [31] to [41], and [48].
  • [205] Use of an anti-CDH6 antibody-drug conjugate in combination with a HIF-2 ⁇ inhibitor for the treatment of a disease, wherein the anti-CDH6 antibody-drug conjugate and the HIF-2 ⁇ inhibitor are as defined in any one of [1] to [24], [31] to [41], and [48].
  • [206] The use according to [205], wherein the disease is as defined in any one of [27] to [30] and [44] to [47].
  • [207] The use according to [205] or [206], characterized in that the anti-CDH6 antibody-drug conjugate and the HIF-2 ⁇ inhibitor are contained (as active ingredients) in different formulations and are administered simultaneously (almost simultaneously) or at different times.
  • [208] The use according to [205] or [206], wherein the anti-CDH6 antibody-drug conjugate and the HIF-2 ⁇ inhibitor are contained (as active ingredients) in the same formulation.
  • a pharmaceutical comprising an anti-CDH6 antibody-drug conjugate and a HIF-2 ⁇ inhibitor, wherein the anti-CDH6 antibody-drug conjugate and the VEGF inhibitor are administered in combination, and the anti-CDH6 antibody-drug conjugate and the HIF-2 ⁇ inhibitor are as defined in any one of [1] to [24], [31] to [41], and [48].
  • a pharmaceutical composition comprising (i) an anti-CDH6 antibody-drug conjugate and (ii) an HIF-2 ⁇ inhibitor, wherein the anti-CDH6 antibody-drug conjugate and the HIF-2 ⁇ inhibitor are administered in combination, and the anti-CDH6 antibody-drug conjugate and the HIF-2 ⁇ inhibitor are as defined in any one of [1] to [24], [31] to [41], and [48].
  • composition according to [213] or [214] characterized in that the anti-CDH6 antibody-drug conjugate and the HIF-2 ⁇ inhibitor are contained (as active ingredients) in separate formulations and are administered simultaneously (almost simultaneously) or at different times.
  • anti-CDH6 antibody-drug conjugate and the HIF-2 ⁇ inhibitor are contained (as active ingredients) in the same formulation.
  • a kit comprising (i) a first composition comprising an anti-CDH6 antibody-drug conjugate and (ii) a second composition comprising an HIF-2 ⁇ inhibitor, wherein the anti-CDH6 antibody-drug conjugate and the HIF-2 ⁇ inhibitor are administered in combination, and the anti-CDH6 antibody-drug conjugate and the HIF-2 ⁇ inhibitor are as defined in any one of [1] to [24], [31] to [41], and [48].
  • a method for treating cancer comprising administering to an individual in need of treatment an anti-CDH6 antibody-drug conjugate and an HIF-2 ⁇ inhibitor in combination, wherein the anti-CDH6 antibody-drug conjugate and the HIF-2 ⁇ inhibitor are as defined in any one of [1] to [24], [31] to [41], and [48].
  • the present invention can provide a pharmaceutical composition characterized in that a specific anti-CDH6 antibody-drug conjugate and a HIF-2 ⁇ inhibitor are administered in combination, and/or a treatment method characterized in that a specific anti-CDH6 antibody-drug conjugate and a HIF-2 ⁇ inhibitor are administered in combination to an individual.
  • FIG. 1 shows the amino acid sequence of human CDH6 EC3 (sequence number 1).
  • FIG. 1 shows the amino acid sequence of CDRH1 of the anti-CDH6 antibody heavy chain (SEQ ID NO:2).
  • FIG. 1 shows the amino acid sequence of CDRH2 of the anti-CDH6 antibody heavy chain (SEQ ID NO:3).
  • FIG. 1 shows the amino acid sequence of CDRH3 of the anti-CDH6 antibody heavy chain (SEQ ID NO:4).
  • FIG. 1 shows the amino acid sequence of CDRL1 of the anti-CDH6 antibody light chain (SEQ ID NO:5).
  • FIG. 1 shows the amino acid sequence of CDRL2 of the anti-CDH6 antibody light chain (SEQ ID NO:6).
  • FIG. 1 shows the amino acid sequence of CDRL3 of the anti-CDH6 antibody light chain (SEQ ID NO:7).
  • FIG. 2 shows the amino acid sequence of the anti-CDH6 antibody heavy chain (SEQ ID NO:27).
  • FIG. 2 shows the amino acid sequence of the anti-CDH6 antibody heavy chain variable region (SEQ ID NO:28).
  • FIG. 2 shows the amino acid sequence of the anti-CDH6 antibody mature heavy chain (SEQ ID NO:29).
  • FIG. 1 shows the amino acid sequence of the anti-CDH6 antibody light chain (SEQ ID NO:36).
  • FIG. 1 shows the amino acid sequence of the anti-CDH6 antibody light chain variable region (SEQ ID NO:37).
  • FIG. 1 shows the amino acid sequence of the anti-CDH6 antibody mature light chain (SEQ ID NO:38).
  • FIG. 1 shows the tumor growth inhibitory effects of the anti-CDH6 antibody-drug conjugate (1) and Belzutifan single-agent administration group, and the anti-CDH6 antibody-drug conjugate (1) and Belzutifan combined administration group (Combination) in mice subcutaneously implanted with 786-O cells.
  • FIG. 1 shows the rate of change in mean tumor volume on Day 21 from the baseline mean tumor volume on Day 0 in mice subcutaneously implanted with 786-O cells, for groups administered single agents of anti-CDH6 antibody-drug conjugate (1) and Belzutifan, and for a group administered a combination of anti-CDH6 antibody-drug conjugate (1) and Belzutifan (Combination).
  • Cadherins are glycoproteins present on the cell membrane surface, and function as cell adhesion molecules and signal molecules involved in cell-cell interactions by binding to each other via their N-terminal extracellular domains in a calcium ion-dependent manner.
  • cadherin superfamily the group of molecules classified as classic cadherins are single-pass transmembrane proteins that consist of five extracellular domains (EC domains), one transmembrane region, and an intracellular domain.
  • CDH6 (Cadherin-6) is a single-pass transmembrane protein consisting of 790 amino acids, classified into the type II cadherin family, with the N-terminus side extracellular and the C-terminus intracellular.
  • the human CDH6 gene was first cloned in 1995 (Shimoyama Y, et al., Cancer Research, 2206-2211, 55, May 15, 1995), and can be referenced by accession numbers such as NM_004932 and NP_004923 (NCBI).
  • the amino acid sequence described in SEQ ID NO: 1 is the amino acid sequence of the extracellular domain 3 of human CDH6 (also referred to as EC domain 3 or EC3 in this specification).
  • the terms “cancer” and “tumor” are used interchangeably.
  • the term “gene” includes not only DNA but also its mRNA, cDNA and its cRNA.
  • CDH6 may be used interchangeably with CDH6 protein.
  • anti-CDH6 antibody refers to an antibody that specifically binds to CDH6 (Cadherin-6).
  • the anti-CDH6 antibody is preferably an antibody that has the activity of being internalized into CDH6-expressing cells by binding to CDH6.
  • functional fragment of an antibody is also called “antigen-binding fragment of an antibody” and means a partial fragment of an antibody having binding activity to an antigen, and includes Fab, F(ab')2, Fv, scFv, diabody, linear antibody, and multispecific antibody formed from antibody fragments.
  • 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 fragment of an antibody.
  • 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 an appropriate host cell using an antibody gene modified by genetic engineering.
  • CDR means a complementarity determining region (CDR). It is known that there are three CDRs in each of the heavy and light chains of an antibody molecule. CDRs are also called hypervariable regions, and are located in the variable regions of the heavy and light chains of an antibody, and are sites with particularly high variability in the primary structure, and are separated into three locations on the primary structure of the heavy and light chain polypeptide chains.
  • the CDRs of an antibody are represented as CDRH1, CDRH2, and CDRH3 from the amino terminal side of the heavy chain amino acid sequence, and CDRL1, CDRL2, and CDRL3 from the amino terminal side of the light chain amino acid sequence. These sites are adjacent to each other in the three-dimensional structure, and determine the specificity for the antigen to which they bind.
  • Anti-CDH6 antibody-drug conjugate The anti-CDH6 antibody-drug conjugate used in the present invention has the formula
  • A represents a binding site to an anti-CDH6 antibody or a functional fragment of the antibody.
  • an anti-CDH6 antibody or a functional fragment of the antibody are linked via a thioether bond.
  • the partial structure of the antibody-drug conjugate consisting of a linker and a drug is called the "drug linker.”
  • This drug linker is bonded to a thiol group (in other words, the sulfur atom of a cysteine residue) generated at the disulfide bond site between the antibody chains (two sites between the heavy chains and the heavy chains, and two sites between the heavy chains and the light chains).
  • the drug linker of the present invention is composed of the topoisomerase I inhibitor exatecan (IUPAC name: (1S,9S)-1-amino-9-ethyl-5-fluoro-1,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione, (chemical name: (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione)).
  • Exatecan has the formula
  • camptothecin derivative with antitumor effects represented by the formula:
  • anti-CDH6 antibody-drug conjugate used in the present invention can also be represented by the following formula:
  • the antibody is an anti-CDH6 antibody or a functional fragment of the antibody (preferably, an anti-CDH6 antibody), and the drug linker is bound to the antibody via a thioether bond (each drug linker represented by the structure shown in parentheses in the formula is bound to the antibody via a thioether bond).
  • n is synonymous with the so-called average number of drug bonds (DAR; Drug-to-Antibody Ratio) and indicates the average number of drug linkers bound per antibody.
  • the "average number of bound drugs” is also called the drug-to-antibody ratio (DAR), and means the average number of drugs (or drug linkers) bound to one antibody molecule in an antibody-drug conjugate composition.
  • DAR drug-to-antibody ratio
  • the anti-CDH6 antibody-drug conjugate is raludotatug deruxtecan (also referred to as R-DXd or DS-6000a).
  • the anti-CDH6 antibody-drug conjugate used in the present invention is cleaved from the linker after being transferred into cancer cells, and is expressed by the formula
  • compound (A) This releases a compound represented by the formula (hereinafter referred to as compound (A).
  • the above compound is believed to be the main component of the antitumor activity of the anti-CDH6 antibody-drug conjugate used in the present invention, and has been confirmed to have topoisomerase I inhibitory activity (Ogitani Y. et al., Clinical Cancer Research, 2016, Oct 15;22(20):5097-5108, Epub 2016 Mar 29).
  • Topoisomerase I is an enzyme involved in DNA synthesis, which changes the higher-order structure of DNA by breaking and recombining single strands of DNA. Therefore, drugs with topoisomerase I inhibitory activity can inhibit DNA synthesis, thereby stopping cell division at the S phase (DNA synthesis phase) of the cell cycle and inducing cell death by apoptosis, thereby suppressing the proliferation of cancer cells.
  • the antibody-drug conjugate used in the present invention is also known to have a bystander antitumor effect (Suzuki H, et al., Molecular Cancer Therapeutics, (2024) 23(3): 257-271).
  • This bystander antitumor effect is achieved when the antibody-drug conjugate used in the present invention is internalized in target-expressing cancer cells, and the compound is then released to exert an antitumor effect on nearby cancer cells that do not express the target.
  • This bystander antitumor effect is also exhibited as an excellent antitumor effect when the antibody-drug conjugate of the present invention is used in combination with a HIF-2 ⁇ inhibitor.
  • anti-CDH6 antibody-drug conjugates are not particularly limited as long as they are anti-CDH6 antibodies to which anti-tumor compounds are bound via linker structure moieties, but examples include those described in CUSP06, BSI-709, WO 2023/102875, and WO 2023/104188.
  • the anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention may be derived from any species, but is preferably an anti-CDH6 antibody derived from human, rat, mouse, or rabbit. When the anti-CDH6 antibody is derived from a species other than human, it is preferably chimerized or humanized using well-known techniques.
  • the anti-CDH6 antibody of the present invention may be a polyclonal antibody or a monoclonal antibody, but is preferably a monoclonal antibody.
  • the anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention preferably has the property of targeting cancer cells, and preferably has the ability to recognize cancer cells, the ability to bind to cancer cells, the ability to be taken up and internalized within cancer cells, and/or cytocidal activity against cancer cells.
  • Binding of antibodies to cancer cells can be confirmed using flow cytometry. Uptake of antibodies into cancer cells can be confirmed using (1) an assay in which a secondary antibody (fluorescently labeled) that binds to the therapeutic antibody is used to visualize the antibody taken up into the cell using a fluorescent microscope (Cell Death and Differentiation (2008) 15, 751-761), (2) an assay in which a secondary antibody (fluorescently labeled) that binds to the therapeutic antibody is used to measure the amount of fluorescence taken up into the cell (Molecular Biology of the Cell Vol.
  • the antitumor activity of an antibody can be confirmed in vitro by measuring its inhibitory activity against cell proliferation.
  • a cancer cell line that overexpresses the antibody's target protein can be cultured, and the antibody can be added to the culture system at various concentrations to measure the inhibitory activity against focus formation, colony formation, and spheroid proliferation.
  • the antitumor activity can be confirmed by administering the antibody to nude mice transplanted with a cancer cell line that highly expresses the target protein, and measuring changes in the cancer cells.
  • the antibody itself has an antitumor effect, but since the antibody-drug conjugate is bound to a compound that exerts an antitumor effect, the antibody itself does not necessarily have an antitumor effect.
  • the antibody For the purpose of exerting the cytotoxicity of the antitumor compound specifically and selectively in cancer cells, it is important and preferable that the antibody has the property of being internalized and transferred into the cancer cell.
  • the anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention can be obtained by known means. For example, it can be obtained by immunizing an animal with an antigenic polypeptide and collecting and purifying the antibody produced in the body using a method commonly used in this field.
  • the origin of the antigen is not limited to humans, and animals can also be immunized with antigens derived from animals other than humans, such as mice and rats.
  • antibodies applicable to human diseases can be selected by testing the cross-reactivity of the obtained antibody that binds to the heterologous antigen with human antigens.
  • hybridomas can be established by fusing antibody-producing cells that produce antibodies against an antigen with myeloma cells, thereby obtaining monoclonal antibodies.
  • Antigens can be obtained by genetically manipulating a gene that codes for an antigen protein to produce it in a host cell. Specifically, a vector capable of expressing an antigen gene is prepared, introduced into a host cell to express the gene, and the expressed antigen is purified. Antibodies can also be obtained by immunizing an animal with the above genetically engineered antigen-expressing cells or a cell line expressing the antigen.
  • the anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is preferably a genetically engineered antibody that has been artificially modified for the purpose of reducing xenoantigenicity to humans, such as a chimeric antibody or a humanized antibody, or is preferably an antibody that has only the genetic sequence of an antibody derived from humans, i.e., a human antibody.
  • a genetically engineered antibody that has been artificially modified for the purpose of reducing xenoantigenicity to humans, such as a chimeric antibody or a humanized antibody, or is preferably an antibody that has only the genetic sequence of an antibody derived from humans, i.e., a human antibody.
  • These antibodies can be produced using known methods.
  • Chimeric antibodies include antibodies whose variable and constant regions are heterologous, such as chimeric antibodies in which the variable region of a mouse or rat antibody is joined to a constant region of human origin (Proc. Natl. Acad. Sci. U.S.A., 81, 6851-6855, (1984)).
  • Humanized antibodies include antibodies in which only the complementarity determining region (CDR) of a heterologous antibody has been incorporated into a human-derived antibody (Nature (1986) 321, p. 522-525), antibodies in which not only the CDR sequence of a heterologous antibody but also some of the amino acid residues in the framework of the heterologous antibody have been grafted onto a human antibody by the CDR grafting method (WO 90/07861), and antibodies humanized using a gene conversion mutagenesis strategy (U.S. Patent No. 5,821,337).
  • CDR complementarity determining region
  • Human antibodies were generated using human antibody-producing mice carrying human chromosomal fragments containing the genes for the heavy and light chains of human antibodies (Tomizuka, K. et al., Nature Genetics (1997) 16, p.133-143; Kuroiwa, Y. et al., Nucl. Acids Res. (1998) 26, p.3447-3448; Yoshida, H. et al., Animal Cell Techn (See, for example, Kitagawa, Y., Matsuda, T. and Iijima, S. eds.), Kluwer Academic Publishers, 1999; Tomizuka, K. et. al., Proc. Natl. Acad. Sci.
  • antibodies obtained by phage display selected from a human antibody library can also be used (see Wormstone, I. M. et. al, Investigative Ophthalmology & Visual Science. (2002) 43 (7), p. 2301-2308; Mé, S. et. al., Briefings in Functional Genomics and Proteomics (2002), 1 (2), p. 189-203; Siriwardena, D. et. al., Ophthalmology (2002) 109 (3), p. 427-431, etc.).
  • the anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention can preferably be an antibody that specifically binds to the amino acid sequence set forth in SEQ ID NO: 1 and has the ability to be internalized into cells.
  • anti-CDH6 antibodies include the antibodies (H01L02, H02L02, H02L03, H04L02, etc.) described in WO 2018/212136.
  • the phrase "an antibody specifically binds to the amino acid sequence set forth in SEQ ID NO: 1" means that the antibody binds more strongly to the EC3 domain of CDH6 compared to other extracellular domains of CDH6.
  • the internalization activity (internalization ability) of an antibody can be evaluated, for example, using a reagent conjugated with a toxin (saporin) that inhibits protein synthesis (e.g., anti-rat IgG reagent Rat-ZAP (ADVANCED TARGETING SYSTEMS), anti-human IgG reagent Hum-ZAP (ADVANCED TARGETING SYSTEMS), etc.) (see International Publication No. WO 2018/212136).
  • a reagent conjugated with a toxin e.g., anti-rat IgG reagent Rat-ZAP (ADVANCED TARGETING SYSTEMS), anti-human IgG reagent Hum-ZAP (ADVANCED TARGETING SYSTEMS), etc.
  • the anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is preferably an antibody that exhibits a viability (expressed as a relative rate assuming that the cell viability in the absence of antibody is 100%) of 80% or less of CDH6-expressing cells administered with the antibody and a saporin-labeled anti-rat IgG antibody or a saporin-labeled anti-human IgG antibody, more preferably an antibody that exhibits a viability of 70% or less, and even more preferably an antibody that exhibits a viability of 60% or less.
  • a viability expressed as a relative rate assuming that the cell viability in the absence of antibody is 100%
  • the anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is preferably any one of the following (1) to (5): (1) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 3, and CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4; (2) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 8, and CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 4; (3) CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 9, CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 10, and CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 11; (3) a CDRH1 having an amino acid sequence set forth in SEQ ID NO: 15, a CDRH2
  • a heavy chain comprising a CDRH1, CDRH2, and CDRH3 selected from the group consisting of a CDRH1 having an amino acid sequence set forth in SEQ ID NO: 21, a CDRH2 having an amino acid sequence set forth in SEQ ID NO: 22, and a CDRH3 having an amino acid sequence set forth in SEQ ID NO: 23; and
  • the antibody comprises a light chain comprising CDRL1, CDRL2, and CDRL3 selected from the group consisting of the following (6) to (9): (6) CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO:5, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO:6, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO:7; (7) CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO:12, CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO:13, and CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO:14; (8) CDRL
  • the anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is more preferably an antibody comprising a heavy chain including a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO:2, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO:3, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO:4, and a light chain including a CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO:5, a CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO:6, and a CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO:7.
  • the anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is more preferably an antibody comprising a heavy chain including a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO:2, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO:8, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO:4, and a light chain including a CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO:5, a CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO:6, and a CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO:7.
  • the anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is more preferably an antibody comprising a heavy chain including a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO:9, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO:10, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO:11, and a light chain including a CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO:12, a CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO:13, and a CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO:14.
  • the anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is more preferably an antibody comprising a heavy chain comprising a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 15, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 16, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 17, and a light chain comprising a CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 18, a CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 19, and a CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 20.
  • the anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is more preferably an antibody comprising a heavy chain comprising a CDRH1 consisting of the amino acid sequence set forth in SEQ ID NO: 21, a CDRH2 consisting of the amino acid sequence set forth in SEQ ID NO: 22, and a CDRH3 consisting of the amino acid sequence set forth in SEQ ID NO: 23, and a light chain comprising a CDRL1 consisting of the amino acid sequence set forth in SEQ ID NO: 24, a CDRL2 consisting of the amino acid sequence set forth in SEQ ID NO: 25, and a CDRL3 consisting of the amino acid sequence set forth in SEQ ID NO: 26.
  • the anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is even more preferably a heavy chain selected from the group consisting of the following (1) to (3): (1) the amino acid sequence set forth in SEQ ID NO: 28, 31 or 34, (2) an amino acid sequence having at least 95% or more identity to the amino acid sequence of (1) above (preferably an amino acid sequence having at least 95% or more 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.
  • antibodies include an antibody that includes a heavy chain containing a chain variable region, and a light chain containing a light chain variable region described in any combination of the following (4) to (6): (4) the amino acid sequence described in SEQ ID NO: 37 or 40, (5) an amino acid sequence having at least 95% or more identity to the amino acid sequence of (4) above (preferably an amino acid sequence having at least 95% or more 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.
  • the anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is an antibody comprising a heavy chain comprising the heavy chain variable region amino acid sequence shown in SEQ ID NO:28, a heavy chain comprising the heavy chain variable region amino acid sequence shown in SEQ ID NO:31, or a heavy chain comprising the heavy chain variable region amino acid sequence shown in SEQ ID NO:34, and a light chain comprising the light chain variable region amino acid sequence shown in SEQ ID NO:37, or a light chain having the light chain variable region amino acid sequence shown in SEQ ID NO:40.
  • the anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is even more preferably an antibody comprising a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO:28 and a light chain comprising a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO:37.
  • the anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is even more preferably an antibody comprising a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO:31 and a light chain comprising a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO:37.
  • the anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is even more preferably an antibody comprising a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO:34 and a light chain comprising a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO:37.
  • the anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is even more preferably an antibody comprising a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence set forth in SEQ ID NO:31 and a light chain comprising a light chain variable region consisting of the amino acid sequence set forth in SEQ ID NO:40.
  • the anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is even more preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO:29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO:38, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain.
  • the anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is even more preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain.
  • the anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is even more preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 35 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 38, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain.
  • the anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is even more preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 41, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain. It is possible to select an antibody having biological activity equivalent to each of the above antibodies by combining sequences that show high identity with the above heavy chain amino acid sequences and light chain amino acid sequences. Such identity is generally 80% or more, preferably 85% or more, more preferably 90% or more, even more preferably 95% or more, and most preferably 99% or more.
  • the identity between two amino acid sequences can be determined by aligning the sequences using the default parameters of ClustalW version 2 (Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H, Valentin F, Wallace 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).
  • the antibody in the anti-CDH6 antibody-drug conjugate used in the present invention also includes modified antibodies.
  • the modified antibody means an antibody according to the present invention that has been chemically or biologically modified. Chemical modifications include those having a chemical moiety bonded to the amino acid backbone, or a chemical moiety bonded to an N- or O-linked carbohydrate chain. Biological modifications include those that have been post-translationally modified (e.g., addition of an N- or O-linked glycan, processing of the N- or C-terminus, deamidation, isomerization of aspartic acid, oxidation of methionine, etc.), and those that have been expressed using a prokaryotic host cell to add a methionine residue to the N-terminus.
  • Chemical modifications include those having a chemical moiety bonded to the amino acid backbone, or a chemical moiety bonded to an N- or O-linked carbohydrate chain.
  • Biological modifications include those that have been post-translationally modified (e.g.
  • modified antibodies are also included in the meaning of such modified antibodies.
  • modified antibodies according to the present invention are useful for improving the stability and blood retention of the antibody, reducing antigenicity, and detecting or isolating the antibody or antigen, etc.
  • antibody-dependent cellular cytotoxicity can be enhanced by regulating the sugar chain modification bound to the antibody of the present invention (glycosylation, defucosylation, etc.)
  • Known techniques for regulating the sugar chain modification of antibodies include those described in International Publication Nos. WO 99/54342, WO 00/61739, WO 02/31140, WO 2007/133855, and WO 2013/120066, but are not limited thereto.
  • the antibodies according to the present invention also include those in which the glycosylation has been regulated.
  • the antibody according to the present invention also includes antibodies and functional fragments of the antibodies that have been modified in this way, and also includes deletion products in which one or two amino acids have been deleted from the carboxyl terminus of the heavy chain, and deletion products that have been amidated (for example, a heavy chain in which the proline residue at the carboxyl terminus is amidated).
  • deletion products in which one or two amino acids have been deleted from the carboxyl terminus of the heavy chain and deletion products that have been amidated (for example, a heavy chain in which the proline residue at the carboxyl terminus is amidated).
  • the carboxyl-terminal deletions of the heavy chains of the antibodies according to the present invention are not limited to the above types.
  • the two heavy chains constituting the antibody of the present invention may be any one of the heavy chains selected from the group consisting of full-length and the above-mentioned deletion forms, or any two of them may be combined.
  • the antibody of the present invention preferably has one amino acid residue deleted at the carboxyl terminus in each of the two heavy chains.
  • the amino acid deleted at the carboxyl terminus of the heavy chain of the antibody according to the present invention is preferably a lysine residue.
  • the isotype of the antibody according to the present invention can be, for example, IgG (IgG1, IgG2, IgG3, IgG4), and preferably IgG1, IgG2 or IgG4.
  • IgG IgG1, IgG2, IgG3, IgG4
  • IgG1, IgG2 or IgG4 In the full-length amino acid sequence of the hH01 heavy chain shown in SEQ ID NO:27, the amino acid sequence consisting of amino acid residues at positions 1 to 19 is a signal sequence, the amino acid sequence consisting of amino acid residues at positions 20 to 141 is a variable region, and the amino acid sequence consisting of amino acid residues at positions 142 to 471 is a constant region.
  • the amino acid sequence consisting of amino acid residues at positions 1 to 19 is a signal sequence
  • the amino acid sequence consisting of amino acid residues at positions 20 to 141 is a variable region
  • the amino acid sequence consisting of amino acid residues at positions 142 to 471 is a constant region.
  • the amino acid sequence consisting of amino acid residues at positions 1 to 19 is a signal sequence
  • the amino acid sequence consisting of amino acid residues at positions 20 to 141 is a variable region
  • the amino acid sequence consisting of amino acid residues at positions 142 to 471 is a constant region.
  • the amino acid sequence consisting of the 1st to 20th amino acid residues is a signal sequence
  • the amino acid sequence consisting of the 21st to 128th amino acid residues is a variable region
  • the amino acid sequence consisting of the 129th to 233rd amino acid residues is a constant region.
  • the amino acid sequence consisting of the 1st to 20th amino acid residues is a signal sequence
  • the amino acid sequence consisting of the 21st to 128th amino acid residues is a variable region
  • the amino acid sequence consisting of the 129th to 233rd amino acid residues is a constant region.
  • the above drug linker intermediate is N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]glycylglycyl-L-phenylalanyl-N-[(2- ⁇ [(1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4': It can be expressed by the chemical name [6,7] indolizino [1,2-b] quinolin-1-yl] amino ⁇ -2-oxoethoxy) methyl] glycinamide, and can be produced with reference to the descriptions in WO 2014/057687, WO 2015/098099, WO 2015/115091, WO 2015/155998, and WO 2019/044947.
  • the anti-CDH6 antibody-drug conjugate used in the present invention can be produced by reacting the aforementioned drug linker intermediate with an anti-CDH6 antibody having a thiol group (also called a sulfhydryl group).
  • An anti-CDH6 antibody having a sulfhydryl group can be obtained by a method well known to those skilled in the art (Hermanson, G. T, Bioconjugate Techniques, pp.56-136, pp.456-493, Academic Press (1996)).
  • a reducing agent such as tris(2-carboxyethyl)phosphine hydrochloride (TCEP) can be used in an amount of 0.3 to 3 molar equivalents per intra-chain disulfide of the antibody, and reacted with the anti-CDH6 antibody in a buffer solution containing a chelating agent such as ethylenediaminetetraacetic acid (EDTA), thereby obtaining an anti-CDH6 antibody having a sulfhydryl group in which the intra-chain disulfides of the antibody have been partially or completely reduced.
  • TCEP tris(2-carboxyethyl)phosphine hydrochloride
  • 2 to 20 molar equivalents of a drug linker intermediate can be used per anti-CDH6 antibody having a sulfhydryl group to produce an anti-CDH6 antibody-drug conjugate in which 2 to 8 drugs are bound per anti-CDH6 antibody.
  • the average number of drugs bound per antibody molecule of the produced anti-CDH6 antibody-drug conjugate can be calculated, for example, by a method in which the UV absorbance of the antibody-drug conjugate and its conjugation precursor are measured at two wavelengths, 280 nm and 370 nm (UV method), or by a method in which the antibody-drug conjugate is treated with a reducing agent, and each of the resulting fragments is quantified by HPLC measurement and calculated (HPLC method).
  • Conjugation of the antibody and the drug linker intermediate, and calculation of the average number of drugs bound per antibody molecule in the antibody-drug conjugate can be carried out with reference to the descriptions in WO 2014/057687, WO 2015/098099, WO 2015/115091, WO 2015/155998, WO 2018/135501, WO 2018/212136, etc.
  • the average number of drug linkers bound per antibody molecule in the anti-CDH6 antibody-drug conjugate used in the present invention is preferably 1 to 10, more preferably 2 to 8, even more preferably 5 to 8, even more preferably 7 to 8, even more preferably 7.5 to 8, and even more preferably about 8.
  • the number of drugs or attached drug linkers per antibody molecule in the anti-CDH6 antibody-drug conjugate used in the present invention is preferably an integer in the range of 2 to 8, more preferably 2, 4, 6 or 8, and even more preferably 8.
  • Anti-CDH6 antibody-drug conjugates can be produced with reference to the descriptions in International Publication No. WO 2018/212136 and the like.
  • hypoxia-inducible factor-2 ⁇ (HIF-2 ⁇ ) Inhibitor in the present invention, the term "HIF-2 ⁇ activity" refers to physiological and/or biological activity mediated by HIF-2 ⁇ , and examples thereof include gene transcription activity mediated by HIF-2 ⁇ .
  • HIF-2 ⁇ inhibitor refers to an agent that slows, reduces, alters, completely eliminates and/or prevents HIF-2 ⁇ activity (eg, the transcriptional activity of HIF-2 ⁇ ).
  • the HIF-2 ⁇ inhibitor in the present invention is not particularly limited as long as it is a drug having the above-mentioned properties, and may be a low molecular weight compound, an antibody, a functional fragment of an antibody, a fusion protein, an immunoadhesin, a nucleic acid, an oligonucleotide, an aptamer or a polypeptide, and is preferably a low molecular weight compound.
  • the low molecular weight compound is preferably an organic compound having a molecular weight of 1000 or less, more preferably a molecular weight of 900 or less, even more preferably a molecular weight of 800 or less, even more preferably a molecular weight of 700 or less, even more preferably a molecular weight of 600 or less, even more preferably a molecular weight of 500 or less, even more preferably a molecular weight of 50 to 500, and even more preferably a molecular weight of 100 to 500.
  • the HIF-2 ⁇ inhibitor in the present invention may preferably be belzutifan (sometimes referred to as Belzutifan, MK-6482, PT2977, or belzutifan), NKT2152 (e.g., see document A below), DFF332 (e.g., see document B below), AB521 (e.g., see document C below), BPI-452080 (e.g., see document D below), PT2385, or PT2399, or a pharma- ceutically acceptable salt thereof. More preferably, the HIF-2 ⁇ inhibitor may be belzutifan, NKT2152, DFF332, or AB521, BPI-452080, or a pharma-ceutically acceptable salt thereof.
  • the HIF-2 ⁇ inhibitor may be belzutifan or NKT2152, or a pharma-ceutically acceptable salt thereof. Even more preferably, the HIF-2 ⁇ inhibitor may be belzutifan or a pharma- ceutical acceptable salt thereof.
  • the "pharmacologically acceptable salt" of the HIF-2 ⁇ inhibitor used in the present invention may be either an acid addition salt or a base addition salt.
  • the acid addition salt include lower alkanesulfonates such as camsylate (camphorsulfonate), mesylate (methanesulfonate), trifluoromethanesulfonate, and ethanesulfonate; arylsulfonates such as tosylate (p-toluenesulfonate) and benzenesulfonate; inorganic acid salts such as phosphate, nitrate, perchlorate, and sulfate; hydrohalide salts such as hydrochloride, hydrobromide, hydroiodide, and hydrofluoride; organic acid salts such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalate, and maleate
  • base addition salts include alkali metal salts such as sodium salts, potassium salts, and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; inorganic salts such as ammonium salts; organic amine salts such as dibenzylamine salts, morpholine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, diethylamine salts, triethylamine salts, cyclohexylamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, diethanolamine salts, N-benzyl-N-(2-phenylethoxy)amine salts, piperazine salts, tetramethylammonium salts, and tris(hydroxymethyl)aminomethane salts; and amino acid salts such as arginine salts.
  • alkali metal salts such as sodium salts, potassium salt
  • HIF-2 ⁇ inhibitors and pharma- ceutically acceptable salts thereof used in the present invention may exist as solvates, and these solvates are also included in the HIF-2 ⁇ inhibitors and pharma-ceutically acceptable salts thereof used in the present invention.
  • the pharmaceutical composition of the present invention may be administered as a pharmaceutical composition containing a pharma- ceutically acceptable carrier, diluent, solubilizer, emulsifier, preservative, adjuvant, etc.
  • the "pharma-ceutically acceptable carrier” etc. may be appropriately selected from a wide range depending on the type of target disease and the administration form of the drug.
  • the "pharma-ceutically acceptable carrier” etc. may be, for example, a sterile liquid.
  • the liquid may include, for example, water and oil (oil of petroleum, animal origin, vegetable origin, or synthetic origin).
  • the oil may be, for example, peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is more typical when the pharmaceutical composition is administered intravenously.
  • Saline solution as well as aqueous dextrose and glycerol solutions may also be used as the liquid, particularly for an injectable solution.
  • Appropriate pharmaceutical excipients may be appropriately selected from those known in the art. Examples of suitable "pharmaceutical acceptable carriers" are described in "Remington's Pharmaceutical Sciences” by E. W. Martin.
  • the formulation corresponds to the mode of administration.
  • the administration method can be appropriately selected, for example, injection administration, and local injection, intraperitoneal injection, selective intravenous injection, intravenous injection, subcutaneous injection, organ perfusion injection, etc. can be adopted. Administration can be, for example, by infusion or bolus injection.
  • the solution for injection can be formulated using a carrier consisting of a salt solution, a glucose solution, or a mixture of a salt solution and a glucose solution, various buffer solutions, etc. Also, it may be formulated in a powder state and mixed with the liquid carrier at the time of use to prepare an injection solution.
  • the administration of the pharmaceutical composition used in the present invention is by injection. Parenteral administration is a preferred administration route.
  • oral liquids powders, pills, capsules, tablets, etc.
  • oral liquid preparations such as suspensions and syrups can be manufactured using water, sugars such as sucrose, sorbitol, fructose, etc., glycols such as polyethylene glycol, oils such as sesame oil and soybean oil, preservatives such as alkyl parahydroxybenzoate, flavors such as strawberry flavor and peppermint, etc.
  • Powders, pills, capsules, and tablets can be formulated using excipients such as lactose, glucose, sucrose, mannitol, etc., disintegrants such as starch and sodium alginate, lubricants such as magnesium stearate and talc, binders such as polyvinyl alcohol, hydroxypropyl cellulose, gelatin, surfactants such as fatty acid esters, plasticizers such as glycerin, etc. Tablets and capsules are preferred unit dosage forms in that they are easy to administer. When making tablets or capsules, solid pharmaceutical carriers are used.
  • compositions comprising anti-CDH6 antibody-drug conjugates used in combination with or administered in combination with a HIF-2 ⁇ inhibitor.
  • the pharmaceutical composition and treatment method of the present invention may be characterized in that the anti-CDH6 antibody-drug conjugate and the HIF-2 ⁇ inhibitor are contained as active ingredients in separate formulations and administered simultaneously (a person skilled in the art will naturally understand that "simultaneously” may or may not mean “almost simultaneously") or at different times, or may be characterized in that the anti-CDH6 antibody-drug conjugate and the HIF-2 ⁇ inhibitor are contained as active ingredients in a single formulation and administered.
  • compositions and treatment method of the present invention can be administered in combination with two or more of the HIF-2 ⁇ inhibitors used in the present invention.
  • the pharmaceutical composition and treatment method of the present invention can be used for the treatment of cancer, and preferably can be used for the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, endometrioid ovarian cancer, ovarian mucinous tumor, thyroid cancer, bile duct cancer, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, neuroblastoma, colorectal cancer, gastric cancer, endometrial cancer, uterine body cancer, nasopharyngeal cancer, prostate cancer, and cancer associated with von Hippel-Lindau disease, and more preferably can be used for the treatment of at least one selected from
  • the cancer associated with von Hippel-Lindau disease is preferably renal cell carcinoma associated with von Hippel-Lindau disease, central nervous system hemangioblastoma associated with von Hippel-Lindau disease, or pancreatic neuroendocrine tumor associated with von Hippel-Lindau disease, and more preferably renal cell carcinoma associated with von Hippel-Lindau disease (the renal cell carcinoma does not require immediate surgery), central nervous system hemangioblastoma associated with von Hippel-Lindau disease (the central nervous system hemangioblastoma does not require immediate surgery), or pancreatic neuroendocrine tumor associated with von Hippel-Lindau disease (the pancreatic neuroendocrine tumor does not require immediate surgery).
  • the pharmaceutical composition and treatment method of the present invention can be used for the treatment of cancer having a mutation in the VHL gene, and can be preferably used for the treatment of renal cell carcinoma, renal clear cell carcinoma or papillary renal cell carcinoma (the renal cell carcinoma, renal clear cell carcinoma or papillary renal cell carcinoma having a mutation in the VHL gene).
  • the pharmaceutical composition and treatment method of the present invention can be used for the treatment of cancer that does not have a VHL gene mutation, and can be preferably used for the treatment of renal cell carcinoma, renal clear cell carcinoma, or papillary renal cell carcinoma (the renal cell carcinoma, renal clear cell carcinoma, or papillary renal cell carcinoma does not have a VHL gene mutation).
  • the VHL gene is the gene that encodes the von Hippel-Lindau tumor suppressor (also called pVHL).
  • the anti-CDH6 antibody-drug conjugate used in the present invention can be suitably used when expression of CDH6 has been confirmed in cancer.
  • the presence or absence of the CDH6 tumor marker can be confirmed, for example, by collecting tumor tissue from a cancer patient, examining the formalin-fixed paraffin-embedded specimen (FFPE) at the gene product (protein) level using immunohistochemistry (IHC), a flow cytometer, western blot, or the like, or by examining the gene transcription level using in situ hybridization (ISH), quantitative PCR (q-PCR), microarray analysis, or the like, or by collecting acellular circulating tumor DNA (ctDNA) from a cancer patient and examining it using a method such as next-generation sequencing (NGS).
  • FFPE formalin-fixed paraffin-embedded specimen
  • IHC immunohistochemistry
  • ISH in situ hybridization
  • q-PCR quantitative PCR
  • ctDNA circulating tumor DNA
  • NGS next-generation sequencing
  • the pharmaceutical composition and treatment method of the present invention can be preferably used in mammals, but more preferably in humans.
  • the antitumor effect of the pharmaceutical composition and treatment method of the present invention can be confirmed, for example, by creating a model in which cancer cells are transplanted into a test animal and measuring the reduction in tumor volume and the life-prolonging effect of administering the pharmaceutical composition and treatment method of the present invention.
  • the combined effect of the antibody-drug conjugate and HIF-2 ⁇ inhibitor used in the present invention can then be confirmed by comparing the antitumor effect with that of the antibody-drug conjugate and HIF-2 ⁇ inhibitor used in the present invention when administered alone.
  • the antitumor effect of the pharmaceutical composition and treatment method of the present invention can be confirmed in clinical trials by the Response Evaluation Criteria in Solid Tumors (RECIST) evaluation method, the WHO evaluation method, the Macdonald evaluation method, weight measurement, and other methods, and a complete response (CR), partial response (Partial response), etc.
  • This can be determined using indicators such as progression (progression rate; PR), progression (progressive disease; PD), objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS).
  • the above-mentioned method makes it possible to confirm the superiority of the antitumor effect of the pharmaceutical composition and treatment method of the present invention over existing pharmaceutical compositions and treatment methods for cancer treatment.
  • the pharmaceutical composition and treatment method of the present invention can slow the growth of cancer cells, inhibit their proliferation, and even destroy them. These actions can relieve cancer patients from symptoms caused by cancer and improve their quality of life, thereby preserving the life of the cancer patient and achieving a therapeutic effect. Even if the cancer cells are not destroyed, the inhibition and control of cancer cell proliferation can enable cancer patients to achieve a higher quality of life and longer survival.
  • the pharmaceutical composition of the present invention can be applied to patients as a systemic therapy, or it can be applied locally to cancer tissue to achieve a therapeutic effect.
  • the pharmaceutical composition of the present invention may be administered containing one or more pharma- ceutical compatible components.
  • the pharma-ceutical compatible components may be appropriately selected from formulation additives and others commonly used in this field depending on the dose and administration concentration of the antibody-drug conjugate and HIF-2 ⁇ inhibitor used in the present invention.
  • the antibody-drug conjugate used in the present invention may be administered as a pharmaceutical composition containing a buffer such as a histidine buffer, an excipient such as sucrose or trehalose, and a surfactant such as polysorbate 80 or 20.
  • a pharmaceutical composition comprising an anti-CDH6 antibody-drug conjugate used in the present invention can be preferably used as an injection, more preferably used as an aqueous injection or a lyophilized injection, and even more preferably used as a lyophilized injection.
  • the pharmaceutical composition containing the anti-CDH6 antibody-drug conjugate used in the present invention is an aqueous injection, it can be preferably administered intravenously by drip infusion after diluting with an appropriate diluent.
  • the diluent include glucose solution and saline solution, and preferably glucose solution, and more preferably 5% glucose solution.
  • the pharmaceutical composition containing the anti-CDH6 antibody-drug conjugate used in the present invention is a lyophilized injection, it can be preferably dissolved in water for injection, diluted with a required amount of an appropriate diluent, and then administered by intravenous drip.
  • the diluent include glucose solution and physiological saline solution, and preferably glucose solution, and more preferably 5% glucose solution.
  • the introduction routes that can be used to administer the pharmaceutical composition of the present invention include, for example, intravenous, intradermal, subcutaneous, intramuscular, and intraperitoneal routes, and preferably, intravenous routes.
  • the anti-CDH6 antibody-drug conjugate used in the present invention can be administered to a human at intervals of once every 1 to 180 days, preferably once every 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks, more preferably once every 3 or 4 weeks, and even more preferably once every 3 weeks. Furthermore, the anti-CDH6 antibody-drug conjugate used in the present invention can be administered at a dose of about 0.001 to 100 mg/kg per administration, preferably about 0.1 to about 15 mg/kg per administration, more preferably about 0.5 to about 12 mg/kg per administration, even more preferably about 1.0 to about 10 mg/kg per administration, even more preferably about 1.6 to about 9.6 mg/kg per administration, and even more preferably about 4.8 to about 8.0 mg/kg per administration.
  • the anti-CDH6 antibody-drug conjugate used in the present invention may be administered at a dose of about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7 , about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about
  • the anti-CDH6 antibody-drug conjugate used in the present invention can be preferably administered at about 1.6 mg/kg, about 3.2 mg/kg, about 4.8 mg/kg, about 5.4 mg/kg, about 5.6 mg/kg, about 6.4 mg/kg, about 8.0 mg/kg, or about 9.6 mg/kg per dose, more preferably at about 3.2 mg/kg, about 4.8 mg/kg, about 5.4 mg/kg, about 5.6 mg/kg, about 6.4 mg/kg, about 8.0 mg/kg, or about 9.6 mg/kg, and even more preferably at about 4.8 mg/kg, about 5.4 mg/kg, about 5.6 mg/kg, about 6.4 mg/kg, or about 8.0 mg/kg.
  • the anti-CDH6 antibody-drug conjugate used in the present invention can be administered at a dose of 0.001 to 100 mg/kg per administration, preferably 0.1 to 15 mg/kg per administration, more preferably 0.5 to 12 mg/kg per administration, even more preferably 1.0 to 10 mg/kg per administration, even more preferably 1.6 to 9.6 mg/kg per administration, and even more preferably 4.8 to 8.0 mg/kg per administration.
  • the anti-CDH6 antibody-drug conjugate used in the present invention may be administered at 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.
  • the anti-CDH6 antibody-drug conjugate used in the present invention can be preferably administered at 1.6 mg/kg, 3.2 mg/kg, 4.8 mg/kg, 5.4 mg/kg, 5.6 mg/kg, 6.4 mg/kg, 8.0 mg/kg or 9.6 mg/kg per dose, more preferably at 3.2 mg/kg, 4.8 mg/kg, 5.4 mg/kg, 5.6 mg/kg, 6.4 mg/kg or 8.0 mg/kg, and even more preferably at 4.8 mg/kg, 5.4 mg/kg, 5.6 mg/kg, 6.4 mg/kg or 8.0 mg/kg.
  • the anti-CDH6 antibody-drug conjugate used in the present invention can be administered at a dose of about 5 to about 3000 mg per administration, preferably at a dose of about 10 to about 2000 mg, more preferably at a dose of about 100 to about 1500 mg, and even more preferably at a dose of about 200 to about 1000 mg.
  • the anti-CDH6 antibody-drug conjugate used in the present invention is preferably administered in a dose of about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 3 80mg, about 385mg, about 390mg, about 395mg, about 400mg, about 405mg, about 410mg, about 415mg, about 420m
  • the anti-CDH6 antibody-drug conjugate used in the present invention is preferably administered in a dose of 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600
  • the administration regimen of the anti-CDH6 antibody-drug conjugate used in the present invention may be, for example, 0.1 mg/kg (at 3-week intervals, hereinafter referred to as "q3w"), 0.2 mg/kg (q3w), 0.3 mg/kg (q3w), 0.4 mg/kg (q3w), 0.5 mg/kg (q3w), 0.6 mg/kg (q3w), 0.7 mg/kg (q3w), 0.8 mg/kg (q3w), 0.9 mg/kg (q3w), 1.0 mg/kg (q3w), 1.1 mg/kg (q3w), 1.2 mg/kg (q3w), q3w), 1.3mg/kg (q3w), 1.4mg/kg (q3w), 1.5mg/kg (q3w), 1.6mg/kg (q3w), 1.7mg/kg (q3w), 1.8mg/kg (q3w), 1.9mg/kg (q3w), 2.0 mg/kg (q3w), 2.1
  • the administration regimen of the anti-CDH6 antibody-drug conjugate used in the present invention is preferably 1.6 mg/kg (q3w), 3.2 mg/kg (q3w), 4.8 mg/kg (q3w), 5.4 mg/kg (q3w), 5.6 mg/kg (q3w), 6.4 mg/kg (q3w), 8.0 mg/kg (q3w) or 9.6 mg/kg (q3w), and more preferably 3 .
  • the administration regimen of the anti-CDH6 antibody-drug conjugate used in the present invention is preferably 200 mg (q3w), 205 mg (q3w), 210 mg (q3w), 215 mg (q3w), 220 mg (q3w), 225 mg (q3w), 230 mg (q3w), 235 mg (q3w), 240 mg (q3w), 245 mg (q3w), 250 mg (q3w), 255 mg (q3w), 260 mg (q3w), 265 mg (q3w), 270 mg (q3w), 275 mg (q3w), 280 mg (q3w), 290 mg (q3w), 300 mg (q3w), 310 mg (q3w), 320 mg (q3w), 330 mg (q3w), 340 mg (q3w), 350 mg (q3w), 360 mg (q3w), 370 mg (q3w), 380 mg (q3w), 390 mg (q3w), 400 mg (q3w), 410 mg
  • the HIF-2 ⁇ inhibitor of the present invention can be orally administered to humans at intervals of 1 to 7 days, 1 to 2 times per day, preferably once a day or twice a day.
  • the HIF-2 ⁇ inhibitor used in the present invention can be orally administered at a dose of 0.1 mg to 3000 mg per dose, preferably 2.5 mg to 600 mg per dose.
  • the HIF-2 ⁇ inhibitor of the present invention can be intravenously administered to humans at intervals of 1 to 180 days, preferably once a week, 2 weeks, 3 weeks, or 4 weeks.
  • the HIF-2 ⁇ inhibitor used in the present invention can be intravenously administered at a dose of 0.1 mg to 3000 mg per dose, preferably 10 mg to 100 mg per dose.
  • HIF-2 ⁇ inhibitor used in the present invention is belzutifan or a pharma- ceutical acceptable salt thereof
  • examples of administration methods include, but are not limited to, the following dosage and administration methods.
  • belzutifan can be administered at a dose of 5 to 1000 mg per administration at intervals of 1, 2, 3, 4, or 5 times a day.
  • velzutifan As an alternative dosage, 20 to 240 mg of velzutifan can be taken orally once daily.
  • belzutifan preferably 40, 80 or 120 mg
  • belzutifan can be orally administered once a day.
  • belzutifan can be orally administered at a dose of 120 mg once daily.
  • belzutifan can be orally administered at a dose of 80 mg once daily.
  • 40 mg of velzutifan can be orally administered once daily.
  • the pharmaceutical composition and treatment method of the present invention may further comprise a cancer therapeutic agent other than the anti-CDH6 antibody-drug conjugate and HIF-2 ⁇ inhibitor of the present invention.
  • the pharmaceutical composition and treatment method of the present invention can be administered in combination with other cancer therapeutic agents, thereby enhancing the antitumor effect.
  • the other cancer therapeutic agents used for such purposes may be administered to an individual simultaneously (almost simultaneously), separately, or consecutively with the pharmaceutical composition of the present invention, or may be administered at different administration intervals.
  • Such cancer therapeutic agents are not limited as long as they are drugs having antitumor activity, and examples thereof include irinotecan (CPT-11), cisplatin, carboplatin, oxaliplatin, fluorouracil (5-FU), gemcitabine, capecitabine, doxorubicin, epirubicin, cyclophosphamide, and mitomycin C.
  • Tegafur/Gimeracil/Oteracil combination drug Panitumumab, Bevacizumab, Ramucirumab, Regorafenib, Trifluridine/Tipiracil combination drug, Gefitinib, Erlotinib, Afatinib, At least one selected from the group consisting of afatinib, methotrexate, pemetrexed, tamoxifen, toremifene, fulvestrant, leuprorelin, goserelin, letrozole, anastrozole, a progesterone formulation, and lapatinib can be mentioned.
  • the pharmaceutical composition and treatment method of the present invention can also be used in combination with radiation therapy.
  • a cancer patient can receive radiation therapy before and/or after, or simultaneously (almost simultaneously) with, treatment with the pharmaceutical composition of the present invention.
  • the pharmaceutical compositions and treatment methods of the present invention may also be used as adjuvant chemotherapy in combination with surgery.
  • the pharmaceutical compositions of the present invention may be administered prior to surgery to reduce tumor size (referred to as preoperative adjuvant chemotherapy, or neoadjuvant therapy), or after surgery to prevent tumor recurrence (referred to as postoperative adjuvant chemotherapy, or adjuvant therapy).
  • the pharmaceutical compositions and methods of treatment of the present invention can also be used as a maintenance therapy, for example, following an initial chemotherapy treatment to prevent recurrence.
  • the present invention includes a method for treating a disease, comprising administering to an individual in need of treatment a combination of an anti-CDH6 antibody-drug conjugate of the present application and an HIF-2 ⁇ inhibitor.
  • the present invention includes the anti-CDH6 antibody-drug conjugates of the present application for use in combination with HIF-2 ⁇ inhibitors for the treatment of disease.
  • the invention includes the use of an anti-CDH6 antibody-drug conjugate of the present application in combination with a HIF-2 ⁇ inhibitor in the manufacture of a medicament for the treatment of a disease.
  • the present invention includes pharmaceutical products containing the anti-CDH6 antibody-drug conjugates of the present application and HIF-2 ⁇ inhibitors.
  • the present invention includes a combination drug containing the anti-CDH6 antibody-drug conjugate of the present application and a HIF-2 ⁇ inhibitor.
  • the present invention includes a pharmaceutical combination comprising an anti-CDH6 antibody-drug conjugate of the present application and a HIF-2 ⁇ inhibitor.
  • the present invention includes the use of the present anti-CDH6 antibody-drug conjugates in combination with HIF-2 ⁇ inhibitors for the treatment of disease.
  • the present invention includes a pharmaceutical comprising the anti-CDH6 antibody-drug conjugate of the present application and a HIF-2 ⁇ inhibitor.
  • Production Example 1 Production of anti-CDH6 antibody-drug conjugate According to the production method described in WO 2018/212136, a humanized anti-CDH6 antibody (an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO:29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO:38) was used to produce a drug conjugate of the formula:
  • anti-CDH6 antibody-drug conjugate (1) An antibody-drug conjugate (hereinafter referred to as "anti-CDH6 antibody-drug conjugate (1)”) was produced in which the drug linker represented by the formula: was linked to the anti-CDH6 antibody via a thioether bond.
  • the DAR of the anti-CDH6 antibody-drug conjugate (1) was 7.9.
  • Example 1 Antitumor Test (1) Mice: 6-week-old female BALB/c nude mice (Jackson Laboratory Japan, Inc.) were used in the experiment.
  • Measurement and calculation formula The long and short diameters of the tumor were measured twice a week using an electronic digital caliper (CD-15CX, Mitutoyo Corp.), and the tumor volume (mm 3 ) was calculated using the following calculation formula.
  • Anti-CDH6 antibody-drug conjugate (1) was diluted with ABS buffer (10 mM acetate buffer (pH 5.5), 5% sorbitol) and administered into the tail vein at a volume of 10 mL/kg.
  • Belztifan was suspended in 10% dimethyl sulfoxide, 40% polyethylene glycol 300, 5% Tween-80, and 45% saline, and administered orally at a volume of 10 mL/kg.
  • mice 786-O cells a human renal cell line purchased from ATCC (American Type Culture Collection), were suspended in a Matrigel basement membrane matrix, and 4 x 10 6 cells were subcutaneously transplanted into the right flank of female nude mice. 31 days after transplantation, the mice were randomly divided into groups (Day 0).
  • Anti-CDH6 antibody-drug conjugate (1) was administered at a dose of 1 mg/kg on Day 0.
  • Belzutifan was administered once a day, five times a week for three weeks, at a dose of 0.3 mg/kg. Each drug was administered alone or in combination, and an ABS buffer administration group was set as a control group.
  • TGI tumor growth inhibition rate
  • TGI Tumor Growth Inhibition
  • the tumor growth inhibition rate was higher (TGI, 68%) than that of each single-agent administration, indicating that the antitumor effect was enhanced by the combined administration.
  • the rate of change in the average tumor volume on Day 21 from the average tumor volume on Day 0 as the baseline, Change from Baseline (%) was calculated using the following formula and shown in FIG. 15.
  • SEQ ID NO:1 Amino acid sequence of human CDH6 EC3
  • SEQ ID NO:2 Amino acid sequence of CDRH1 of chG019
  • SEQ ID NO:3 Amino acid sequence of CDRH2 of chG019
  • SEQ ID NO:4 Amino acid sequence of CDRH3 of chG019
  • SEQ ID NO:5 Amino acid sequence of CDRL1 of chG019
  • SEQ ID NO:6 Amino acid sequence of CDRL2 of chG019
  • SEQ ID NO:7 Amino acid sequence of CDRL3 of chG019
  • SEQ ID NO:8 Amino acid sequence of CDRH2 of rG019
  • SEQ ID NO:9 Amino acid sequence of CDRH1 of rG055
  • SEQ ID NO:11 Amino acid sequence of CDRH3 of rG055
  • SEQ ID NO:12 Amino acid sequence of CDRH1 of rG

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Citations (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990007861A1 (en) 1988-12-28 1990-07-26 Protein Design Labs, Inc. CHIMERIC IMMUNOGLOBULINS SPECIFIC FOR p55 TAC PROTEIN OF THE IL-2 RECEPTOR
US5821337A (en) 1991-06-14 1998-10-13 Genentech, Inc. Immunoglobulin variants
WO1999054342A1 (en) 1998-04-20 1999-10-28 Pablo Umana Glycosylation engineering of antibodies for improving antibody-dependent cellular cytotoxicity
WO2000061739A1 (fr) 1999-04-09 2000-10-19 Kyowa Hakko Kogyo Co., Ltd. Methode de regulation de l'activite d'une molecule immunologiquement fonctionnelle
WO2002031140A1 (en) 2000-10-06 2002-04-18 Kyowa Hakko Kogyo Co., Ltd. Cells producing antibody compositions
WO2007133855A2 (en) 2006-03-27 2007-11-22 University Of Maryland Biotechnology Institute Glycoprotein synthesis and remodeling by enzymatic transglycosylation
WO2013120066A1 (en) 2012-02-10 2013-08-15 University Of Maryland, Baltimore Chemoenzymatic glycoengineering of antibodies and fc fragments thereof
WO2014057687A1 (ja) 2012-10-11 2014-04-17 第一三共株式会社 抗体－薬物コンジュゲート
WO2015098099A1 (ja) 2013-12-25 2015-07-02 第一三共株式会社 抗ｔｒｏｐ２抗体－薬物コンジュゲート
WO2015115091A1 (ja) 2014-01-31 2015-08-06 第一三共株式会社 抗ｈｅｒ２抗体－薬物コンジュゲート
WO2015155998A1 (en) 2014-04-10 2015-10-15 Daiichi Sankyo Company, Limited Anti-her3 antibody-drug conjugate
WO2018135501A1 (ja) 2017-01-17 2018-07-26 第一三共株式会社 抗ｇｐｒ２０抗体及び抗ｇｐｒ２０抗体－薬物コンジュゲート
WO2018212136A1 (ja) 2017-05-15 2018-11-22 第一三共株式会社 抗ｃｄｈ６抗体及び抗ｃｄｈ６抗体－薬物コンジュゲート
WO2019044947A1 (ja) 2017-08-31 2019-03-07 第一三共株式会社 抗体－薬物コンジュゲートの改良製造方法
WO2020031936A1 (ja) * 2018-08-06 2020-02-13 第一三共株式会社 抗体－薬物コンジュゲートとチューブリン阻害剤の組み合わせ
WO2020097336A1 (en) * 2018-11-09 2020-05-14 Beth Israel Deaconess Medical Center Cdcp1-targeted therapies
WO2020122034A1 (ja) * 2018-12-11 2020-06-18 第一三共株式会社 抗体－薬物コンジュゲートとｐａｒｐ阻害剤の組み合わせ
WO2020130125A1 (ja) * 2018-12-21 2020-06-25 第一三共株式会社 抗体－薬物コンジュゲートとキナーゼ阻害剤の組み合わせ
WO2021262563A1 (en) * 2020-06-22 2021-12-30 Merck Sharp & Dohme Corp. Methods for treating cancer or von-hippel lindau disease using a combination of a hif-2 alpha inhibitor and lenvatinib
WO2023102875A1 (en) 2021-12-10 2023-06-15 Multitude Therapeutics Inc. Anti-cdh6 antibody drug conjugate
WO2023104188A1 (en) 2021-12-10 2023-06-15 Multitude Therapeutics Inc. Anti-cdh6 antibodies and antibody-drug conjugates thereof

Patent Citations (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990007861A1 (en) 1988-12-28 1990-07-26 Protein Design Labs, Inc. CHIMERIC IMMUNOGLOBULINS SPECIFIC FOR p55 TAC PROTEIN OF THE IL-2 RECEPTOR
US5821337A (en) 1991-06-14 1998-10-13 Genentech, Inc. Immunoglobulin variants
WO1999054342A1 (en) 1998-04-20 1999-10-28 Pablo Umana Glycosylation engineering of antibodies for improving antibody-dependent cellular cytotoxicity
WO2000061739A1 (fr) 1999-04-09 2000-10-19 Kyowa Hakko Kogyo Co., Ltd. Methode de regulation de l'activite d'une molecule immunologiquement fonctionnelle
WO2002031140A1 (en) 2000-10-06 2002-04-18 Kyowa Hakko Kogyo Co., Ltd. Cells producing antibody compositions
WO2007133855A2 (en) 2006-03-27 2007-11-22 University Of Maryland Biotechnology Institute Glycoprotein synthesis and remodeling by enzymatic transglycosylation
WO2013120066A1 (en) 2012-02-10 2013-08-15 University Of Maryland, Baltimore Chemoenzymatic glycoengineering of antibodies and fc fragments thereof
WO2014057687A1 (ja) 2012-10-11 2014-04-17 第一三共株式会社 抗体－薬物コンジュゲート
WO2015098099A1 (ja) 2013-12-25 2015-07-02 第一三共株式会社 抗ｔｒｏｐ２抗体－薬物コンジュゲート
WO2015115091A1 (ja) 2014-01-31 2015-08-06 第一三共株式会社 抗ｈｅｒ２抗体－薬物コンジュゲート
WO2015155998A1 (en) 2014-04-10 2015-10-15 Daiichi Sankyo Company, Limited Anti-her3 antibody-drug conjugate
WO2018135501A1 (ja) 2017-01-17 2018-07-26 第一三共株式会社 抗ｇｐｒ２０抗体及び抗ｇｐｒ２０抗体－薬物コンジュゲート
WO2018212136A1 (ja) 2017-05-15 2018-11-22 第一三共株式会社 抗ｃｄｈ６抗体及び抗ｃｄｈ６抗体－薬物コンジュゲート
WO2019044947A1 (ja) 2017-08-31 2019-03-07 第一三共株式会社 抗体－薬物コンジュゲートの改良製造方法
WO2020031936A1 (ja) * 2018-08-06 2020-02-13 第一三共株式会社 抗体－薬物コンジュゲートとチューブリン阻害剤の組み合わせ
WO2020097336A1 (en) * 2018-11-09 2020-05-14 Beth Israel Deaconess Medical Center Cdcp1-targeted therapies
WO2020122034A1 (ja) * 2018-12-11 2020-06-18 第一三共株式会社 抗体－薬物コンジュゲートとｐａｒｐ阻害剤の組み合わせ
WO2020130125A1 (ja) * 2018-12-21 2020-06-25 第一三共株式会社 抗体－薬物コンジュゲートとキナーゼ阻害剤の組み合わせ
WO2021262563A1 (en) * 2020-06-22 2021-12-30 Merck Sharp & Dohme Corp. Methods for treating cancer or von-hippel lindau disease using a combination of a hif-2 alpha inhibitor and lenvatinib
WO2023102875A1 (en) 2021-12-10 2023-06-15 Multitude Therapeutics Inc. Anti-cdh6 antibody drug conjugate
WO2023104188A1 (en) 2021-12-10 2023-06-15 Multitude Therapeutics Inc. Anti-cdh6 antibodies and antibody-drug conjugates thereof

Non-Patent Citations (27)

* Cited by examiner, † Cited by third party
Title
"Advanced Clear Cell Renal Cell Carcinoma", 15 November 2021, NATIONAL LIBRARY OF MEDICINE
ANALYTICAL BIOCHEMISTRY, vol. 360, 2007, pages 75 - 83
BIO TECHNIQUES, vol. 28, January 2000 (2000-01-01), pages 162 - 165
C: A PHASE 1 STUDY OF AB521 IN RENAL CELL CARCINOMA AND OTHER SOLID TUMORS (ARC-20, 10 September 2022 (2022-09-10)
CARMEN, S. ET AL., BRIEFINGS IN FUNCTIONAL GENOMICS AND PROTEOMICS, vol. 1, no. 2, 2002, pages 189 - 203
CELL DEATH AND DIFFERENTIATION, vol. 15, 2008, pages 751 - 761
D: WANG ET AL., CANCER RES, vol. 83, 2023, pages 494
HERMANSON, G.T: "Bioconjugate Techniques", 1996, ACADEMIC PRESS, pages: 56 - 493
JOURNAL OF CHROMATOGRAPHY A, vol. 705, 1995, pages 129 - 134
KEITH ET AL., NAT. REV. CANCER., vol. 12, no. 1, 2011, pages 9 - 22
KOHLERMILSTEIN, NATURE, vol. 256, 1975, pages 495 - 497
KUROIWA, Y. ET AL., NUCL. ACIDS RES., vol. 26, 1998, pages 3447 - 3448
LARKIN MABLACKSHIELDS GBROWN NPCHENNA RMCGETTIGAN PAMCWILLIAM HVALENTIN FWALLACE IMWILM ALOPEZ R: "Clustal W and Clustal X version 2.0", BIOINFORMATICS, vol. 23, no. 21, 2007, pages 2947 - 2948
MARTINEZ-SAEZ ET AL., CRIT REV ONCOL HEMATOL., vol. 111, 2017, pages 117 - 123
MOLECULAR BIOLOGY OF THE CELL, vol. 15, December 2004 (2004-12-01), pages 5268 - 5282
NATURE, vol. 321, 1986, pages 522 - 525
OGITANI Y. ET AL., CLINICAL CANCER RESEARCH, vol. 22, no. 20, 29 March 2016 (2016-03-29), pages 5097 - 5108
PROC. NATL. ACAD. SCI. U.S.A., vol. 81, 1984, pages 6851 - 6855
SHIMOYAMA Y ET AL., CANCER RESEARCH, vol. 55, 15 May 1995 (1995-05-15), pages 2206 - 2211
SINGLE AGENT AND IN COMBINATION WITH EVEROLIMUS & IMMUNO-ONCOLOGY AGENTS IN ADVANCED/RELAPSED RENAL CANCER & OTHER MALIGNANCIES, 20 May 2021 (2021-05-20)
SIRIWARDENA, D. ET AL., OPHTHALMOLOGY, vol. 109, no. 3, 2002, pages 427 - 431
SUZUKI H ET AL., MOLECULAR CANCER THERAPEUTICS, vol. 23, no. 3, 2024, pages 257 - 271
TOMIZUKA, K. ET AL., NATURE GENETICS, vol. 16, 1997, pages 133 - 143
TOMIZUKA, K. ET AL., PROC. NATL. ACAD. SCI. USA, vol. 97, 2000, pages 722 - 727
WORMSTONE, I. M. ET AL., INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, vol. 43, no. 7, 2002, pages 2301 - 2308
XU ET AL., J. MED. CHEM., vol. 62, no. 15, 2019, pages 6876 - 6893
YOSHIDA, H. ET AL.: "Animal Cell Technology: Basic and Applied Aspects", vol. 10, 1999, KLUWER ACADEMIC PUBLISHERS, pages: 69 - 73

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