Combination of anti-CDH6 antibody-drug conjugate and HIF-2alpha inhibitor

Description

117 Combination of antibody-drug conjugate anti-ICDH6 and HIF-2a inhibitor [Technical Field]

[001] The present invention relates to a pharmaceutical composition in which a specific anti-CDH6 antibody-drug conjugate and an HIF-2a inhibitor are administered in combination, and / or to a treatment method comprising administering a specific anti-CDH6 antibody-drug conjugate and an HIF-2a inhibitor in combination to an individual. [Fundamentals of the Technique]

[002] The intratumoral hypoxic environment promotes cancer progression and is closely related to poor patient prognosis and resistance to chemotherapy. Hypoxia-inducible factor 2α (HIF-2α) is a transcription factor that plays a central role in the hypoxic response pathway and controls the expression of genes that regulate angiogenesis, cell growth, cell survival, extracellular matrix modulation, pH homeostasis, and the like (Non-Patent Literature 1).

[003] HIF-2a inhibitors are known as, for example, agents that exhibit an antitumor effect by inhibiting the transcriptional activity of HIF-2a. For example, belzutifan, PT2385 and PT2399 are known HIF2α inhibitors (Non-Patent Literature 2 and 3).

[004] An antibody-drug conjugate (ADC), in which an antibody that binds to an antigen expressed on the surface of cancer cells and can internalize the antigen into the cell is conjugated to a drug with cytotoxic activity, can selectively deliver the drug to cancer cells and thus kill the cancer cells by accumulating the drug in the cancer cells. An antibody-drug conjugate comprising an anti-CDH6 antibody and an exatecan derivative of topoisomerase I inhibitor as components is an antibody-drug conjugate. Petition 870250088320, dated 09 / 29 / 2025, page 11 / 148 / 117 known (Patented Literature 1).

[005] However, the effects are not known when an anti-CDH6 drug conjugate (including the anti-CDH6 antibody-drug conjugate described above) and an HIF-2a inhibitor are used in combination or when an anti-CDH6 antibody and an HIF-2a inhibitor are used in combination. [List of Citations] [Patented Literature]

[006] [Patented Literature 1] International Publication No. WO 2018 / 212136 [Non-Patented Literature]

[007] [Non-Patented Literature 1] Keith et al., Nat. Rev. Cancer. (2011) 12(1): 9 to 22.

[008] [Non-Patented Literature 2] Martinez-Saez et al. Crit Rev Oncol Hematol. (2017) 111: 117 to 123.

[009] [Non-Patented Literature 3] Xu et al., J. Med. Chem. (2019) 62(15): 6876 to 6893. [Summary of the Invention] [Technical Problem]

[0010] The anti-CDH6 antibody-drug conjugate (anti-CDH6 antibody-drug conjugate comprising an exatecan derivative as a component) used in the present invention has demonstrated excellent antitumor effect, even when used alone. However, it has become necessary to obtain a treatment method that can suppress the growth of cancer cells in several ways and exert an even superior antitumor effect, using the antibody-drug conjugate in combination with another anticancer agent with a different mechanism of action.

[0011] One objective of the present invention is to provide a composition Petition 870250088320, dated 09 / 29 / 2025, page 12 / 148 / 117 pharmaceutical in which a specific anti-CDH6 antibody-drug conjugate and an HIF-2a inhibitor are administered in combination, and / or a treatment method comprising administering a specific anti-CDH6 antibody-drug conjugate and an HIF-2a inhibitor in combination to an individual. [Solution to the Problem]

[0012] The present inventors conducted intensive studies aimed at achieving the above-described objective and, consequently, concluded the present invention by finding that a specific anti-CDH6 antibody-drug conjugate and an HIF-2a inhibitor administered in combination exhibit an excellent combinatorial effect (a highly safe and remarkable antitumor effect).

[0013] Thus, the present invention provides the following [1] to

[221] .

[0014] [1] A pharmaceutical composition comprising an anti-CDH6 antibody-drug conjugate, wherein the anti-CDH6 antibody-drug conjugate and an HIF-2a inhibitor are administered in combination, and the anti-CDH6 antibody-drug conjugate is an antibody-drug conjugate in which a drug-ligand is represented by the formula: [Formula 1] where A represents a binding site to an anti-CDH6 antibody or a functional fragment of the antibody, and is conjugated to the anti-CDH6 antibody or the functional fragment of the antibody via a thioether linkage. Petition 870250088320, dated 09 / 29 / 2025, page 13 / 148 / 117

[0015] [2] The pharmaceutical composition according to [1], wherein the anti-CDH6 antibody or functional antibody fragment is an antibody that specifically binds to the amino acid sequence shown in SEQ ID NO: 1 and has an internalization capacity that allows cellular uptake, or a functional antibody fragment.

[0016] [3] The pharmaceutical composition according to [1] or [2], wherein the anti-CDH6 antibody or the functional fragment of the antibody is an antibody comprising CDRH1, CDRH2 and CDRH3 in any combination selected from the group consisting of the following combinations (1) to (5): (1) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 3 and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 4, (2) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 8 and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 4, (3) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 9, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 10, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 11, (4) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 15, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 16, and CDRH3 consisting of the sequence of amino acids shown in SEQ ID NO: 17, and (5) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 21,CDRH2 consisting of an amino acid sequence, Petition 870250088320, dated 09 / 29 / 2025, p. 14 / 148 / 117 shown in SEQ ID NO: 22, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 23; and CDRL1, CDRL2 and CDRL3 in any selected combination from the group consisting of the following combinations (6) to (9): (6) CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 5, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 6 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 7, (7) CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 13 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 14, (8) CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 18, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 19 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 20, and (9) CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 24, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 25, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 26, or a functional fragment of the antibody.

[0017] [4] The pharmaceutical composition according to any of [1] to [3], wherein the anti-CDH6 antibody or the functional antibody fragment is an antibody comprising CDRH1, CDRH2 and CDRH3, and CDRL1, CDRL2 and CDRL3, in any combination selected from the group consisting of the following combinations (1) to (5): (1) CDRH1 consisting of amino acid sequence shown in SEQ ID NO: 2, CDRH2 consisting of amino acid sequence Petition 870250088320, dated 09 / 29 / 2025, page. 15 / 148 / 117 shown in SEQ ID NO: 3, CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 4, CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 5, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 6 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 7, (2) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 8, CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 4, CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 5, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 6 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 7, (3) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 9, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 10,CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 11, CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 13 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 14, (4) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 15, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 16, CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 17, CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 18, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 19 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 20, and (5) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 21, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 22, CDRH3 consisting of the sequence of, Petition 870250088320, dated 09 / 29 / 2025, page 16 / 148 / 117 amino acids shown in SEQ ID NO: 23, CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 24, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 25, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 26, or a functional fragment of the antibody.

[0018] [5] The pharmaceutical composition according to any of [1] to [4], wherein the anti-CDH6 antibody or the functional antibody fragment is an antibody comprising CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 3, CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 4, CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 5, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 6 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 7, or a functional antibody fragment.

[0019] [6] The pharmaceutical composition according to any of [1] to [5], wherein the anti-CDH6 antibody or functional antibody fragment is a humanized antibody or a functional antibody fragment.

[0020] [7] The pharmaceutical composition according to any of [1] to [6], wherein the anti-CDH6 antibody or functional antibody fragment is an antibody comprising any variable region of the heavy chain selected from the group consisting of the following variable regions (1) to (5): (1) a variable region of the heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 28, (2) a variable region of the heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 31, (3) a variable region of the heavy chain consisting of Petition 870250088320, dated 09 / 29 / 2025, p. 17 / 148 / 117 amino acid sequence shown in SEQ ID NO: 34, (4) an amino acid sequence with a sequence identity of at least 95% or more with the sequence of the structural regions, except in each CDR sequence in the amino acid sequences of any one of (1) to (3), and (5) an amino acid sequence comprising a deletion, substitution or addition of one or more amino acids in the sequence of the structural regions, except in each CDR sequence in the amino acid sequences of any one of (1) to (4); and any variable light chain region selected from the group consisting of the following variable regions (6) to (9): (6) a variable region of the light chain consisting of the amino acid sequence shown in SEQ ID NO: 37, (7) a variable region of the light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, (8) an amino acid sequence with a sequence identity of at least 95% or more with the sequence of the structural regions, except in each CDR sequence in the amino acid sequences of any of (6) and (7), and (9) an amino acid sequence comprising a deletion, substitution or addition of one or more amino acids in the sequence of structural regions, except in each CDR sequence in the amino acid sequences of any of (6) to (8), or a functional fragment of the antibody.

[0021] [8] The pharmaceutical composition according to any one of items (1) to [7], wherein the anti-CDH6 antibody or the functional antibody fragment is an antibody comprising a variable heavy chain region and a variable light chain region in any one of the following combinations (1) to (4): Petition 870250088320, dated 09 / 29 / 2025, page. 18 / 148 / 117 (1) a variable region of the heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 28 and a variable region of the light chain consisting of the amino acid sequence shown in SEQ ID NO: 37, (2) a variable region of the heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 31 and a variable region of the light chain consisting of the amino acid sequence shown in SEQ ID NO: 37, (3) a variable region of the heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 31 and a variable region of the light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, and (4) a variable region of the heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34 and a variable region of the light chain consisting of the amino acid sequence shown in SEQ ID NO: 37, or a functional fragment of the antibody.

[0022] [9] The pharmaceutical composition according to any of [1] to [8], wherein the anti-CDH6 antibody or functional antibody fragment is an antibody comprising a variable heavy chain region consisting of the amino acid sequence shown in SEQ ID NO: 28 and a variable light chain region consisting of the amino acid sequence shown in SEQ ID NO: 37, or a functional antibody fragment.

[0023]

[10] The pharmaceutical composition according to any one of [1] to [9], wherein the anti-CDH6 antibody or the functional antibody fragment is an antibody comprising any one of the following combinations (1) to (4): (1) a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 29 and a light chain consisting of Petition 870250088320, dated 09 / 29 / 2025, p. 19 / 148 / 117 amino acid sequence shown in SEQ ID NO: 38, (2) a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 38, (3) a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 41, and (4) a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 35 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 38, or a functional fragment of the antibody.

[0024]

[11] The pharmaceutical composition according to any one of [1] to

[10] , wherein the anti-CDH6 antibody or the functional antibody fragment is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 38, or a functional antibody fragment.

[0025]

[12] The pharmaceutical composition according to any one of [1] to

[11] , wherein the anti-CDH6 antibody or the functional fragment of the antibody is an antibody in which the heavy chain or the light chain has undergone one or two or more selected modifications from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue to the N-terminal, amidation of a proline residue, conversion of N-terminal glutamine or N-terminal glutamic acid to pyroglutamic acid and a deletion of one or two amino acids from the carboxyl terminal, or a functional fragment of the antibody. Petition 870250088320, dated 09 / 29 / 2025, p. 20 / 148 / 117

[0026]

[13] The pharmaceutical composition according to

[12] , wherein the anti-CDH6 antibody or the functional fragment of the antibody is an antibody in which one or two amino acids are deleted from the carboxyl terminal of one of its heavy chains, or a functional fragment of the antibody.

[0027]

[14] The pharmaceutical composition according to

[13] , wherein the anti-CDH6 antibody or the functional fragment of the antibody is an antibody in which an amino acid is deleted from the carboxyl terminal of each of its two heavy chains, or a functional fragment of the antibody.

[0028]

[15] The pharmaceutical composition according to any one of

[12] to

[14] , wherein the deleted amino acid is lysine.

[0029]

[16] The pharmaceutical composition according to any one of

[12] to

[15] , wherein the anti-CDH6 antibody or the functional fragment of the antibody is an antibody in which a proline residue at the carboxyl terminus of one of its heavy chains is further amidated, or a functional fragment of the antibody.

[0030]

[17] The pharmaceutical composition according to any one of [1] to

[16] , wherein the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 1 to 10.

[0031]

[18] The pharmaceutical composition according to any one of [1] to

[16] , wherein the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 2 to 8.

[0032]

[19] The pharmaceutical composition according to any one of [1] to

[16] , wherein the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 5 to 8.

[0033]

[20] The pharmaceutical composition according to any one of [1] to

[16] , where the average number of drug-ligand units Petition 870250088320, dated 09 / 29 / 2025, p. 21 / 148 / 117 antibody conjugate in the anti-CDH6 antibody-drug conjugate. The conjugate is in the range of 7 to 8.

[0034]

[21] The pharmaceutical composition according to any one of [1] to

[16] , wherein the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7.5 to 8.

[0035]

[22] The pharmaceutical composition according to any one of [1] to

[16] , where the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is approximately 8.

[0036] [22-2] The pharmaceutical composition according to any one of [1] to

[16] , wherein the number of antibody-conjugated drug-ligand structures in the anti-CDH6 antibody-drug conjugate is an integer in the range of 1 to 10.

[0037] [22-3] The pharmaceutical composition according to any one of [1] to

[16] , wherein the number of drug-ligand structures conjugated per antibody in the anti-CDH6 antibody-drug conjugate is an integer in the range of 2 to 8.

[0038] [22-4] The pharmaceutical composition according to any one of [1] to

[16] , wherein the number of antibody-conjugated drug-ligand structures in the anti-CDH6 antibody-drug conjugate is 2, 4, 6 or 8.

[0039] [22-5] The pharmaceutical composition according to any one of [1] to

[16] , wherein the number of antibody-conjugated drug-ligand structures in the anti-CDH6 antibody-drug conjugate is 8.

[0040]

[23] The pharmaceutical composition according to any one of [1] to [22-5], wherein the HIF-2a inhibitor is belzutifan, NKT2152, DFF332, AB521, or BPI-452080, or a pharmaceutically acceptable salt thereof.

[0041]

[24] The pharmaceutical composition according to any Petition 870250088320, dated 29 / 09 / 2025, p. 22 / 148 / 117 from [1] to [22-5], wherein the HIF-2a inhibitor is belzutifan or a pharmaceutically acceptable salt thereof.

[0042]

[25] The pharmaceutical composition according to any one of [1] to

[24] , wherein the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained separately (as active components) in different formulations and are administered at the same time (approximately at the same time) or at different times.

[0043]

[26] The pharmaceutical composition according to any one of [1] to

[24] , in which the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained (as active components) in a single formulation for administration.

[0044]

[27] The pharmaceutical composition according to any one of [1] to

[26] , wherein the pharmaceutical composition is for use in the treatment of cancer.

[0045]

[28] The pharmaceutical composition according to any one of [1] to

[26] , wherein the pharmaceutical composition is for use in the treatment of at least one tumor selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, ovarian cancer, serous adenocarcinoma of the ovary, clear cell carcinoma of the ovary, endometrioid ovarian cancer, mucinous tumor of the ovary, 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, stomach cancer, endometrial cancer, uterine body cancer, nasopharyngeal cancer, prostate cancer and cancer related to von Hippel-Lindau disease.

[0046]

[29] The pharmaceutical composition according to anyone Petition 870250088320, dated 09 / 29 / 2025, page 23 / 148 14 / 117 of [1] to

[26] , wherein the pharmaceutical composition is for use in the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, renal papillary 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 and neuroblastoma.

[0047]

[30] The pharmaceutical composition according to any one of [1] to

[26] , wherein the pharmaceutical composition is for use in the treatment of at least one tumor selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma and renal papillary cell carcinoma.

[0048]

[31] A pharmaceutical composition comprising an anti-CDH6 antibody-drug conjugate, wherein the anti-CDH6 antibody-drug conjugate and an HIF-2oc inhibitor are administered in combination, and the anti-CDH6 antibody-drug conjugate is an antibody-drug conjugate represented by the formula: wherein the antibody is an anti-CDH6 antibody, a drug ligand is conjugated to the antibody via a thioether linkage, where represents an average number of drug-ligand units conjugated per antibody.

[0049]

[32] The pharmaceutical composition according to

[31] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 38.

[0050]

[33] The pharmaceutical composition according to

[31] or

[32] , in which a lysine residue is deleted from the carboxyl terminal of an anti-CDH6 antibody heavy chain.

[0051]

[34] The pharmaceutical composition according to any one of

[31] to

[33] , wherein the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 1 to 10.

[0052]

[35] The pharmaceutical composition according to any one of

[31] to

[33] , wherein the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 2 to 8.

[0053]

[36] The pharmaceutical composition according to any one of

[31] to

[33] , wherein the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 5 to 8.

[0054]

[37] The pharmaceutical composition according to any of

[31] to

[33] , wherein the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7 to 8.

[0055]

[38] The pharmaceutical composition according to any one of

[31] to

[33] , wherein the average number of drug-ligand units Petition 870250088320, dated 09 / 29 / 2025, p. 25 / 148 / 117 antibody conjugate in the anti-CDH6 antibody-drug conjugate is in the range of 7.5 to 8.

[0056]

[39] The pharmaceutical composition according to any of

[31] to

[33] , where the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is approximately 8.

[0057]

[40] The pharmaceutical composition according to any one of

[31] to

[39] , wherein the HIF-2a inhibitor is belzutifan, NKT2152, DFF332, AB521 or BPI-452080, or a pharmaceutically acceptable salt thereof.

[0058]

[41] The pharmaceutical composition according to any one of

[31] to

[39] , wherein the HIF-2a inhibitor is belzutifan or a pharmaceutically acceptable salt thereof.

[0059]

[42] The pharmaceutical composition according to any of

[31] to

[41] , wherein the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained separately (as active components) in different formulations and are administered at the same time (approximately at the same time) or at different times.

[0060]

[43] The pharmaceutical composition according to any of

[31] to

[41] , in which the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained (as active components) in a single formulation for administration.

[0061]

[44] The pharmaceutical composition according to any of

[31] to

[43] , wherein the pharmaceutical composition is for use in the treatment of cancer.

[0062]

[45] The pharmaceutical composition according to any one of

[31] to

[43] , wherein the pharmaceutical composition is for use in the treatment of at least one tumor selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, carcinoma Petition 870250088320, dated 09 / 29 / 2025, page 26 / 148 / 117 renal cell papillary carcinoma, ovarian cancer, serous adenocarcinoma of the ovary, clear cell carcinoma of the ovary, endometrioid ovarian cancer, mucinous tumor of the ovary, 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, stomach cancer, endometrial cancer, uterine body cancer, nasopharyngeal cancer, prostate cancer and cancer related to von Hippel-Lindau disease.

[0063]

[46] The pharmaceutical composition according to any one of

[31] to

[43] , wherein the pharmaceutical composition is for use in the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, ovarian cancer, serous adenocarcinoma of the ovary, clear cell carcinoma of the ovary, endometrioid ovarian cancer, mucinous tumor of the ovary, 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 and neuroblastoma.

[0064]

[47] The pharmaceutical composition according to any one of

[31] to

[43] , wherein the pharmaceutical composition is for use in the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma and renal papillary cell carcinoma.

[0065]

[48] The pharmaceutical composition according to any one of [1] to

[47] , wherein the anti-CDH6 antibody-drug conjugate is raludotatug deruxtecan (DS-6000a). Petition 870250088320, dated 09 / 29 / 2025, page 27 / 148 / 117

[0066]

[49] A treatment method comprising administering an anti-CDH6 antibody-drug conjugate and an HIF-2a inhibitor in combination to an individual in need of treatment, wherein the antibody-drug conjugate is an antibody-drug conjugate in which a drug-ligand is represented by the formula: [Formula 3] where A represents a binding site to an anti-CDH6 antibody or a functional fragment of the antibody, and is conjugated to the anti-CDH6 antibody or the functional fragment of the antibody via a thioether linkage.

[0067]

[50] The treatment method according to

[49] , wherein the anti-CDH6 antibody or functional antibody fragment is an antibody that specifically binds to the amino acid sequence shown in SEQ ID NO: 1 and has an internalization capacity that allows cellular uptake, or a functional antibody fragment.

[0068]

[51] The treatment method according to

[49] or

[50] , wherein the anti-CDH6 antibody or the functional antibody fragment is an antibody comprising CDRH1, CDRH2 and CDRH3 in any combination selected from the group consisting of the following combinations (1) to (5): (1) CDRH1 consisting of the amino acid sequence shown Petition 870250088320, dated 09 / 29 / 2025, p. 28 / 148 / 117 in SEQ ID NO: 2, CDRH2 consisting of amino acid sequence shown in SEQ ID NO: 3 and CDRH3 consisting of amino acid sequence shown in SEQ ID NO: 4, (2) CDRH1 consisting of amino acid sequence shown in SEQ ID NO: 2, CDRH2 consisting of amino acid sequence shown in SEQ ID NO: 8 and CDRH3 consisting of amino acid sequence shown in SEQ ID NO: 4, (3) CDRH1 consisting of amino acid sequence shown in SEQ ID NO: 9, CDRH2 consisting of amino acid sequence shown in SEQ ID NO: 10 and CDRH3 consisting of amino acid sequence shown in SEQ ID NO: 11, (4) CDRH1 consisting of amino acid sequence shown in SEQ ID NO: 15, CDRH2 consisting of amino acid sequence shown in SEQ ID NO: 16 and CDRH3 consisting of amino acid sequence shown in SEQ ID NO: 17, and (5) CDRH1 consisting of amino acid sequence shown in SEQ ID NO: 21,CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 22 and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 23; and, CDRL1, CDRL2 and CDRL3 in any combination selected from the group consisting of the following combinations (6) to (9): (6) CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 5, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 6 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 7, (7) CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 13 and CDRL3 consisting of the sequence of Petition 870250088320, dated 09 / 29 / 2025, page 29 / 148 / 117 amino acids shown in SEQ ID NO: 14, (8) CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 18, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 19 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 20, and (9) CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 24, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 25, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 26, or a functional fragment of the antibody.

[0069]

[52] The treatment method according to any of

[49] to

[51] , wherein the anti-CDH6 antibody or the functional antibody fragment is an antibody comprising CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 in any combination selected from the group consisting of the following combinations (1) to (5): (1) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 3, CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 4, CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 5, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 6 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 7, (2) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 8, CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 4, CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 5, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 6 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 7, Petition 870250088320, dated 09 / 29 / 2025, page. 30 / 148 / 117 (3) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 9, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 10, CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 11, CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 13 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 14, (4) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 15, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 16, CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 17, CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 18, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 19 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 20,and (5) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 21, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 22, CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 23, CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 24, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 25 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 26, or a functional fragment of the antibody.

[0070]

[53] The treatment method according to any of

[49] to

[52] , wherein the anti-CDH6 antibody or the functional antibody fragment is an antibody comprising CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 3, CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 4, CDRL1 consisting Petition 870250088320, dated 09 / 29 / 2025, page 31 / 148 / 117 in the amino acid sequence shown in SEQ ID NO: 5, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 6 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 7, or a functional fragment of the antibody.

[0071]

[54] The treatment method according to any of

[49] to

[53] , wherein the anti-CDH6 antibody or functional antibody fragment is a humanized antibody or functional antibody fragment.

[0072]

[55] The treatment method according to any of

[49] to

[54] , wherein the anti-CDH6 antibody or functional antibody fragment is an antibody comprising any variable region of the heavy chain selected from the group consisting of the following variable regions (1) to (5): (1) a variable region of the heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 28, (2) a variable region of the heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 31, (3) a variable region of the heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34, (4) an amino acid sequence with a sequence identity of at least 95% or more with the sequence of the structural regions, except in each CDR sequence in the amino acid sequences of any of (1) to (3), and (5) an amino acid sequence comprising a deletion, substitution or addition of one or more amino acids in the sequence of the different structural regions of each CDR sequence in the amino acid sequences of any of (1) to (4); and any variable region of the light chain selected from the group consisting of the following variable regions (6) to (9): (6) a variable region of the light chain consisting of Petition 870250088320, dated 09 / 29 / 2025, p. 32 / 148 / 117 amino acid sequence shown in SEQ ID NO: 37, (7) a variable region of the light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, (8) an amino acid sequence with a sequence identity of at least 95% or more with the sequence of the structural regions, except in each CDR sequence in the amino acid sequences of any of (6) and (7), and (9) an amino acid sequence comprising a deletion, substitution or addition of one or more amino acids in the sequence of structural regions, except in each CDR sequence in the amino acid sequences of any of (6) to (8), or a functional fragment of the antibody.

[0073]

[56] The treatment method according to any of

[49] to

[55] , wherein the anti-CDH6 antibody or the functional antibody fragment is an antibody comprising a variable heavy chain region and a variable light chain region in any of the following combinations (1) to (4): (1) a variable heavy chain region consisting of the amino acid sequence shown in SEQ ID NO: 28 and a variable light chain region consisting of the amino acid sequence shown in SEQ ID NO: 37, (2) a variable heavy chain region consisting of the amino acid sequence shown in SEQ ID NO: 31 and a variable light chain region consisting of the amino acid sequence shown in SEQ ID NO: 37, (3) a variable heavy chain region consisting of the amino acid sequence shown in SEQ ID NO: 31 and a variable light chain region consisting of the amino acid sequence shown in SEQ ID NO: 40, and Petition 870250088320, dated 09 / 29 / 2025, page 33 / 148 / 117 (4) a variable heavy chain region consisting of the amino acid sequence shown in SEQ ID NO: 34 and a variable light chain region consisting of the amino acid sequence shown in SEQ ID NO: 37, or a functional antibody fragment.

[0074]

[57] The treatment method according to any of

[49] to

[56] , wherein the anti-CDH6 antibody or the functional antibody fragment is an antibody comprising a variable heavy chain region consisting of the amino acid sequence shown in SEQ ID NO: 28 and a variable light chain region consisting of the amino acid sequence shown in SEQ ID NO: 37, or a functional antibody fragment.

[0075]

[58] The treatment method according to any of

[49] to

[57] , wherein the anti-CDH6 antibody or the functional antibody fragment is an antibody comprising any of the following combinations (1) to (4): (1) a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 38, (2) a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 38, (3) a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 41, and (4) a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 35 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 38, or a functional antibody fragment. Petition 870250088320, dated 09 / 29 / 2025, p. 34 / 148 / 117

[0076]

[59] The treatment method according to any of

[49] to

[58] , wherein the anti-CDH6 antibody or the functional antibody fragment is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 38, or a functional antibody fragment.

[0077]

[60] The treatment method according to any of items

[49] to

[59] , wherein the anti-CDH6 antibody or the functional fragment of the antibody is an antibody in which the heavy chain or the light chain has undergone one or two or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue to the N-terminal, amidation of a proline residue, conversion of N-terminal glutamine or N-terminal glutamic acid to pyroglutamic acid and deletion of one or two amino acids from the carboxylic terminal, or a functional fragment of the antibody.

[0078]

[61] The treatment method according to

[60] , wherein the anti-CDH6 antibody or functional antibody fragment is an antibody in which one or two amino acids are deleted from the carboxyl terminal of one of its heavy chains, or a functional antibody fragment.

[0079]

[62] The treatment method according to

[61] , wherein the anti-CDH6 antibody or functional antibody fragment is an antibody in which an amino acid is deleted from the carboxyl terminal of each of its two heavy chains, or a functional antibody fragment.

[0080]

[63] The treatment method according to any of

[60] to

[62] , where the deleted amino acid is lysine.

[0081]

[64] The treatment method according to any of

[60] to

[63] , in which the anti-CDH6 antibody or the functional fragment of Petition 870250088320, dated 09 / 29 / 2025, p. 35 / 148 / 117 An antibody is an antibody in which a proline residue at the carboxyl terminal of one of its heavy chains is further amidated, or a functional fragment of the antibody.

[0082]

[65] The treatment method according to any of

[49] to

[64] , where the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 1 to 10.

[0083]

[66] The treatment method according to any of

[49] to

[64] , where the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 2 to 8.

[0084]

[67] The treatment method according to any of

[49] to

[64] , where the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 5 to 8.

[0085]

[68] The treatment method according to any of

[49] to

[64] , where the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7 to 8.

[0086]

[69] The treatment method according to any of

[49] to

[64] , where the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7.5 to 8.

[0087]

[70] The treatment method according to any of

[49] to

[64] , where the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is approximately 8.

[0088] [70-2] The treatment method according to any of

[49] to

[64] , wherein the number of drug-ligand conjugated structures Petition 870250088320, dated 09 / 29 / 2025, p. 36 / 148 / 117 per antibody in the anti-CDH6 antibody-drug conjugate is an integer in the range of 1 to 10.

[0089] [70-3] The treatment method according to any of

[49] to

[64] , wherein the number of drug-ligand structures conjugated per antibody in the anti-CDH6 antibody-drug conjugate is an integer in the range of 2 to 8.

[0090] [70-4] The treatment method according to any one of

[49] to

[64] , where the number of drug-ligand structures conjugated per antibody in the anti-CDH6 antibody-drug conjugate is 2, 4, 6 or 8.

[0091] [70-5] The treatment method according to any of

[49] to

[64] , where the number of drug-ligand structures conjugated per antibody in the anti-CDH6 antibody-drug conjugate is 8.

[0092]

[71] The treatment method according to any of

[49] to [70-5], where the HIF-2a inhibitor is belzutifan, NKT2152, DFF332, AB521 or BPI-452080, or a pharmaceutically acceptable salt thereof.

[0093]

[72] The treatment method according to any of

[49] to [70-5], wherein the HIF-2a inhibitor is belzutifan or a pharmaceutically acceptable salt thereof.

[0094]

[73] The treatment method according to any of

[49] to

[72] , in which the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained separately (as active components) in different formulations and are administered at the same time (approximately at the same time) or at different times.

[0095]

[74] The treatment method according to any of

[49] to

[72] , in which the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained (as active components) in a single formulation for administration.

[0096]

[75] The treatment method according to any of

[49] to

[74] , where the treatment method is for treating cancer. Petition 870250088320, dated 09 / 29 / 2025, page 37 / 148 / 117

[0097]

[76] The treatment method according to any of

[49] to

[74] , wherein the treatment method is to treat at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, ovarian cancer, serous adenocarcinoma of the ovary, clear cell carcinoma of the ovary, endometrioid ovarian cancer, mucinous tumor of the ovary, 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, stomach cancer, endometrial cancer, uterine body cancer, nasopharyngeal cancer, prostate cancer and cancer related to von Hippel-Lindau disease.

[0098]

[77] The treatment method according to any of

[49] to

[74] , wherein the treatment method is to treat at least one tumor selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, ovarian cancer, serous adenocarcinoma of the ovary, clear cell carcinoma of the ovary, endometrioid ovarian cancer, mucinous tumor of the ovary, 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 and neuroblastoma.

[0099]

[78] The treatment method according to any of

[49] to

[74] , wherein the treatment method is to treat at least one tumor selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma and renal papillary cell carcinoma. Petition 870250088320, dated 09 / 29 / 2025, page 38 / 148 29 / 117

[00100]

[79] A treatment method comprising administering an anti-CDH6 antibody-drug conjugate and an HIF-2oc inhibitor in combination to an individual in need of treatment, wherein the anti-CDH6 antibody-drug conjugate is an antibody-drug conjugate represented by the formula: [Formula 4] where the antibody is an anti-CDH6 antibody, a drug ligand is conjugated to the antibody via a thioether linkage, and represents an average number of drug-ligand conjugate units per antibody.

[00101]

[80] The treatment method according to

[79] , wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 38.

[00102]

[81] The treatment method according to

[79] or

[80] , in which a lysine residue is deleted from the carboxyl terminal of an anti-CDH6 antibody heavy chain.

[00103]

[82] The treatment method according to any of

[79] to

[81] , where the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 1 to 10.

[00104]

[83] The treatment method according to any of Petition 870250088320, dated 09 / 29 / 2025, p. 39 / 148 / 117

[79] to

[81] , where the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 2 to 8.

[00105]

[84] The treatment method according to any of

[79] to

[81] , where the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 5 to 8.

[00106]

[85] The treatment method according to any of

[79] to

[81] , where the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7 to 8.

[00107]

[86] The treatment method according to any of

[79] to

[81] , where the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7.5 to 8.

[00108]

[87] The treatment method according to any of

[79] to

[81] , where the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is approximately 8.

[00109]

[88] The treatment method according to any of

[79] to

[87] , wherein the HIF-2a inhibitor is belzutifan, NKT2152, DFF332, AB521 or BPI-452080, or a pharmaceutically acceptable salt thereof.

[00110]

[89] The treatment method according to any of

[79] to

[87] , wherein the HIF-2a inhibitor is belzutifan or a pharmaceutically acceptable salt thereof.

[00111]

[90] The treatment method according to any of

[79] to

[89] , in which the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained separately (as active components) in different formulations and are administered at the same time. Petition 870250088320, dated 09 / 29 / 2025, p. 40 / 148 31 / 117 (approximately at the same time) or at different times.

[00112]

[91] The treatment method according to any of

[79] to

[89] , in which the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained (as active components) in a single formulation for administration.

[00113]

[92] The treatment method according to any of

[79] to

[91] , where the treatment method is for treating cancer.

[00114]

[93] The treatment method according to any of

[79] to

[91] , wherein the treatment method is to treat at least one tumor selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, ovarian cancer, serous adenocarcinoma of the ovary, clear cell carcinoma of the ovary, endometrioid ovarian cancer, mucinous tumor of the ovary, 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, stomach cancer, endometrial cancer, uterine body cancer, nasopharyngeal cancer, prostate cancer and cancer related to von Hippel-Lindau disease.

[00115]

[94] The treatment method according to any of

[79] to

[91] , wherein the treatment method is to treat at least one tumor selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, ovarian cancer, serous adenocarcinoma of the ovary, clear cell carcinoma of the ovary, endometrioid ovarian cancer, mucinous tumor of the ovary, 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, Petition 870250088320, dated 09 / 29 / 2025, page 41 / 148 / 117 glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor and neuroblastoma.

[00116]

[95] The treatment method according to any of

[79] to

[91] , wherein the treatment method is to treat at least one tumor selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma and renal papillary cell carcinoma.

[00117]

[96] The treatment method according to any of

[49] to

[95] , wherein the anti-CDH6 antibody-drug conjugate is raludotatug deruxtecan (DS-6000a).

[00118]

[97] An anti-CDH6 antibody-drug conjugate for use in the treatment of a disease by administering the anti-CDH6 antibody-drug conjugate and an HIF-2a inhibitor in combination, wherein in the anti-CDH6 antibody-drug conjugate, a drug-ligand is represented by the formula: [Formula 5] where A represents a binding site to an anti-CDH6 antibody or a functional fragment of the antibody, and is conjugated to the anti-CDH6 antibody or the functional fragment of the antibody via a thioether linkage.

[00119]

[98] The anti-CDH6 antibody-drug conjugate according to

[97] , wherein the anti-CDH6 antibody or functional antibody fragment is an antibody that binds specifically to the sequence of Petition 870250088320, dated 09 / 29 / 2025, p. 42 / 148 / 117 amino acids shown in SEQ ID NO: 1 and has an internalization capacity that allows cellular uptake, or a functional fragment of the antibody.

[00120]

[99] The anti-CDH6 antibody-drug conjugate according to

[97] or

[98] , wherein the anti-CDH6 antibody or the functional fragment of the antibody is an antibody comprising CDRH1, CDRH2 and CDRH3 in any selected combination from the group consisting of the following combinations (1) to (5): (1) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 3 and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 4, (2) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 8 and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 4, (3) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 9, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 10, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 11, (4) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 15, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 16, and CDRH3 consisting of amino acid sequence shown in SEQ ID NO: 17, and (5) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 21,CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 22, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 23; and, Petition 870250088320, dated 09 / 29 / 2025, p. 43 / 148 / 117 CDRL1, CDRL2 and CDRL3 in any selected combination from the group consisting of the following combinations (6) to (9): (6) CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 5, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 6 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 7, (7) CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 13 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 14, (8) CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 18, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 19 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 20, and (9) CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 24, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 25, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 26, or a functional fragment of the antibody.

[00121]

[100] The anti-CDH6 antibody-drug conjugate according to any one of

[97] to

[99] , wherein the anti-CDH6 antibody or functional antibody fragment is an antibody comprising CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 in any combination selected from the group consisting of the following combinations (1) to (5): (1) CDRH1 consisting of amino acid sequence shown in SEQ ID NO: 2, CDRH2 consisting of amino acid sequence shown in SEQ ID NO: 3, CDRH3 consisting of sequence of Petition 870250088320, dated 09 / 29 / 2025, page 44 / 148 / 117 amino acids shown in SEQ ID NO: 4, CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 5, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 6 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 7, (2) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 8, CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 4, CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 5, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 6 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 7.

[00122] (3) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 9, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 10, CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 11, CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 13 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 14.

[00123] (4) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 15, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 16, CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 17, CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 18, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 19 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 20, and (5) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 21, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 22, CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 23, CDRL1 consisting of the sequence Petition 870250088320, dated 09 / 29 / 2025, page 45 / 148 / 117 of amino acids shown in SEQ ID NO: 24, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 25 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 26, or a functional fragment of the antibody.

[00124]

[101] The anti-CDH6 antibody-drug conjugate according to any one of

[97] to

[100] , wherein the anti-CDH6 antibody or the functional antibody fragment is an antibody comprising CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 3, CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 4, CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 5, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 6 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 7, or a functional antibody fragment.

[00125]

[102] The anti-CDH6 antibody-drug conjugate according to any one of

[97] to

[101] , wherein the anti-CDH6 antibody or functional antibody fragment is a humanized antibody or functional antibody fragment.

[00126]

[103] The anti-CDH6 antibody-drug conjugate according to any of

[97] to

[102] , wherein the anti-CDH6 antibody or the functional antibody fragment is an antibody comprising any variable region of the heavy chain selected from the group consisting of the following variable regions (1) to (5): (1) a variable region of the heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 28, (2) a variable region of the heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 31, (3) a variable region of the heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34, Petition 870250088320, dated 09 / 29 / 2025, p. 46 / 148 / 117 (4) an amino acid sequence with a sequence identity of at least 95% or more with the sequence of the structural regions, except in each CDR sequence, in the amino acid sequences of any of (1) to (3), and (5) an amino acid sequence comprising a deletion, substitution or addition of one or more amino acids in the sequence of the structural regions, except in each CDR sequence in the amino acid sequences of any of (1) to (4); and any variable region of the light chain selected from the group consisting of the following variable regions (6) to (9): (6) a variable region of the light chain consisting of the amino acid sequence shown in SEQ ID NO: 37, (7) a variable region of the light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, (8) an amino acid sequence with a sequence identity of at least 95% or more with the sequence of the structural regions, except in each CDR sequence in the amino acid sequences of any of (6) and (7), and (9) an amino acid sequence comprising a deletion, substitution or addition of one or more amino acids in the sequence of structural regions, except in each CDR sequence in the amino acid sequences of any of (6) to (8), or a functional fragment of the antibody.

[00127]

[104] The anti-CDH6 antibody-drug conjugate according to any of items (97] to

[103] , wherein the anti-CDH6 antibody or the functional antibody fragment is an antibody comprising a variable heavy chain region and a variable light chain region in any of the following combinations (1) to (4): (1) a variable region of the heavy chain consisting of Petition 870250088320, dated 09 / 29 / 2025, page 47 / 148 / 117 amino acid sequence shown in SEQ ID NO: 28 and a variable region of the light chain consisting of the amino acid sequence shown in SEQ ID NO: 37, (2) a variable region of the heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 31 and a variable region of the light chain consisting of the amino acid sequence shown in SEQ ID NO: 37, (3) a variable region of the heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 31 and a variable region of the light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, and (4) a variable region of the heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34 and a variable region of the light chain consisting of the amino acid sequence shown in SEQ ID NO: 37, or a functional fragment of the antibody.

[00128]

[105] The anti-CDH6 antibody-drug conjugate according to any one of

[97] to

[104] , wherein the anti-CDH6 antibody or the functional antibody fragment is an antibody comprising a variable heavy chain region consisting of the amino acid sequence shown in SEQ ID NO: 28 and a variable light chain region consisting of the amino acid sequence shown in SEQ ID NO: 37, or a functional antibody fragment.

[00129]

[106] The anti-CDH6 antibody-drug conjugate according to any one of

[97] to

[105] , wherein the anti-CDH6 antibody or the functional antibody fragment is an antibody comprising any one of the following combinations (1) to (4): (1) a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 29 and a light chain consisting of Petition 870250088320, dated 09 / 29 / 2025, p. 48 / 148 / 117 amino acid sequence shown in SEQ ID NO: 38, (2) a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 38, (3) a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 41, and (4) a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 35 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 38, or a functional fragment of the antibody.

[00130]

[107] The anti-CDH6 antibody-drug conjugate according to any one of

[97] to

[106] , wherein the anti-CDH6 antibody or the functional antibody fragment is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 38, or a functional antibody fragment.

[00131]

[108] The anti-CDH6 antibody-drug conjugate according to any one of

[97] to

[107] , wherein the anti-CDH6 antibody or the functional fragment of the antibody is an antibody in which the heavy chain or the light chain has undergone one or two or more selected modifications of the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue to the N-terminal, amidation of a proline residue, conversion of N-terminal glutamine or N-terminal glutamic acid to pyroglutamic acid and a deletion of one or two amino acids from the carboxyl terminal, or a functional fragment of the antibody. Petition 870250088320, dated 09 / 29 / 2025, p. 49 / 148 / 117

[00132]

[109] The anti-CDH6 antibody-drug conjugate according to

[108] , wherein the anti-CDH6 antibody or functional antibody fragment is an antibody in which one or two amino acids are deleted from the carboxyl terminus of one of its heavy chains, or from a functional antibody fragment.

[00133]

[110] The anti-CDH6 antibody-drug conjugate according to

[109] , wherein the anti-CDH6 antibody or functional antibody fragment is an antibody in which an amino acid is deleted from the carboxyl terminus of each of its two heavy chains, or from a functional antibody fragment.

[00134]

[111] The anti-CDH6 antibody-drug conjugate according to any of

[108] to

[110] , wherein the deleted amino acid is lysine.

[00135]

[112] The anti-CDH6 antibody-drug conjugate according to any one of

[108] to

[111] , wherein the anti-CDH6 antibody or the functional fragment of the antibody is an antibody in which a proline residue at the carboxyl terminus of a heavy chain thereof is further amidated, or a functional fragment of the antibody.

[00136]

[113] The anti-CDH6 antibody-drug conjugate according to any of

[97] to

[112] , wherein the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 1 to 10.

[00137]

[114] The anti-CDH6 antibody-drug conjugate according to any of

[97] to

[112] , wherein the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 2 to 8.

[00138]

[115] The anti-CDH6 antibody-drug conjugate according to any of

[97] to

[112] , wherein the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 5 to 8. Petition 870250088320, dated 09 / 29 / 2025, page 50 / 148 / 117

[00139]

[116] The anti-CDH6 antibody-drug conjugate according to any of

[97] to

[112] , wherein the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7 to 8.

[00140]

[117] The anti-CDH6 antibody-drug conjugate according to any of

[97] to

[112] , wherein the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7.5 to 8.

[00141]

[118] The anti-CDH6 antibody-drug conjugate according to any of

[97] to

[112] , wherein the average number of drug-ligand units conjugated per antibody in the anti-CDH6 antibody-drug conjugate is approximately 8.

[00142] [118-2] The anti-CDH6 antibody-drug conjugate according to any of

[97] to

[112] , wherein the number of drug-ligand structures conjugated per antibody in the anti-CDH6 antibody-drug conjugate is an integer in the range of 1 to 10.

[00143] [118-3] The anti-CDH6 antibody-drug conjugate according to any of

[97] to

[112] , wherein the number of drug-ligand structures conjugated per antibody in the anti-CDH6 antibody-drug conjugate is an integer in the range of 2 to 8.

[00144] [118-4] The anti-CDH6 antibody-drug conjugate according to any of

[97] to

[112] , where the number of drug-ligand structures conjugated per antibody in the anti-CDH6 antibody-drug conjugate is 2, 4, 6 or 8.

[00145] [118-5] The anti-CDH6 antibody-drug conjugate according to any of

[97] to

[112] , where the number of drug-ligand structures conjugated per antibody in the anti-CDH6 antibody-drug conjugate is 8.

[00146]

[119] The anti-CDH6 antibody-drug conjugate according Petition 870250088320, dated 09 / 29 / 2025, p. 51 / 148 / 117 with any of

[97] to [118-5], where the HIF-2a inhibitor is belzutifan, NKT2152, DFF332, AB521 or BPI-452080, or a pharmaceutically acceptable salt thereof.

[00147]

[120] The anti-CDH6 antibody-drug conjugate according to any one of

[97] to [118-5], wherein the HIF-2a inhibitor is belzutifan or a pharmaceutically acceptable salt thereof.

[00148]

[121] The anti-CDH6 antibody-drug conjugate according to any of

[97] to

[120] , wherein the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained separately (as active components) in different formulations and are administered at the same time (approximately at the same time) or at different times.

[00149]

[122] The anti-CDH6 antibody-drug conjugate according to any of

[97] to

[120] , wherein the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained (as active components) in a single formulation for administration.

[00150]

[123] The anti-CDH6 antibody-drug conjugate according to any of

[97] to

[122] , wherein the anti-CDH6 antibody-drug conjugate is for use in the treatment of cancer.

[00151]

[124] The anti-CDH6 antibody-drug conjugate according to any one of

[97] to

[122] , wherein the anti-CDH6 antibody-drug conjugate is for use in the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, renal papillary 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, Petition 870250088320, dated 09 / 29 / 2025, page 52 / 148 / 117 mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, neuroblastoma, colorectal cancer, stomach cancer, endometrial cancer, uterine body cancer, nasopharyngeal cancer, prostate cancer and cancer related to von Hippel-Lindau disease.

[00152]

[125] The anti-CDH6 antibody-drug conjugate according to any of

[97] to

[122] , wherein the anti-CDH6 antibody-drug conjugate is for use in the treatment of at least one tumor selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, ovarian cancer, serous adenocarcinoma of the ovary, clear cell carcinoma of the ovary, endometrioid ovarian cancer, mucinous tumor of the ovary, 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 and neuroblastoma.

[00153]

[126] The anti-CDH6 antibody-drug conjugate according to any of

[97] to

[122] , wherein the anti-CDH6 antibody-drug conjugate is for use in the treatment of at least one tumor selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma and renal papillary cell carcinoma.

[00154]

[127] An anti-CDH6 antibody-drug conjugate for use in the treatment of a disease by administering the anti-CDH6 antibody-drug conjugate and an HIF-2a inhibitor in combination, wherein the anti-CDH6 antibody-drug conjugate is represented by the formula: [Formula 6] Petition 870250088320, dated 09 / 29 / 2025, page 53 / 148 44 / 117 where the antibody is an anti-CDH6 antibody, a drug ligand is conjugated to the antibody via a thioether linkage, and represents an average number of drug-ligand units conjugated per antibody.

[00155]

[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 shown in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 38.

[00156]

[129] The anti-CDH6 antibody-drug conjugate according to

[127] or

[128] , in which a lysine residue is deleted from the carboxyl terminal of an anti-CDH6 antibody heavy chain.

[00157]

[130] The anti-CDH6 antibody-drug conjugate according to any of

[127] to

[129] , wherein the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 1 to 10.

[00158]

[131] The anti-CDH6 antibody-drug conjugate according to any of

[127] to

[129] , wherein the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 2 to 8.

[00159]

[132] The anti-CDH6 antibody-drug conjugate according to any of

[127] to

[129] , wherein the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 5 to 8.

[00160]

[133] The anti-CDH6 antibody-drug conjugate according Petition 870250088320, dated 09 / 29 / 2025, page 54 / 148 / 117 with any of

[127] to

[129] , in which the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7 to 8.

[00161]

[134] The anti-CDH6 antibody-drug conjugate according to any of

[127] to

[129] , wherein the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7.5 to 8.

[00162]

[135] Anti-CDH6 antibody-drug conjugate according to any of

[127] to

[129] , where the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is approximately 8.

[00163]

[136] Anti-CDH6 antibody-drug conjugate according to any one of

[127] to

[135] , wherein the HIF-2a inhibitor is belzutifan, NKT2152, DFF332, AB521 or BPI-452080, or a pharmaceutically acceptable salt thereof.

[00164]

[137] The anti-CDH6 antibody-drug conjugate according to any one of

[127] to

[135] , wherein the HIF-2a inhibitor is belzutifan or a pharmaceutically acceptable salt thereof.

[00165]

[138] The anti-CDH6 antibody-drug conjugate according to any of

[127] to

[137] , wherein the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained separately (as active components) in different formulations and are administered at the same time (approximately at the same time) or at different times.

[00166]

[139] The anti-CDH6 antibody-drug conjugate according to any of

[127] to

[137] , wherein the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained (as active components) in a single formulation for administration.

[00167]

[140] The anti-CDH6 antibody-drug conjugate according Petition 870250088320, dated 09 / 29 / 2025, page 55 / 148 / 117 with any of

[127] to

[139] , in which the anti-CDH6 antibody-drug conjugate is for use in the treatment of cancer.

[00168]

[141] The anti-CDH6 antibody-drug conjugate according to any one of

[127] to

[139] , wherein the anti-CDH6 antibody-drug conjugate is for use in the treatment of at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, renal papillary 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, stomach cancer, endometrial cancer, uterine body cancer, nasopharyngeal cancer, prostate cancer and cancer related to von Hippel-Lindau disease.

[00169]

[142] The anti-CDH6 antibody-drug conjugate according to any of

[127] to

[139] , wherein the anti-CDH6 antibody-drug conjugate is for use in the treatment of at least one tumor selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, ovarian cancer, serous adenocarcinoma of the ovary, clear cell carcinoma of the ovary, endometrioid ovarian cancer, mucinous tumor of the ovary, 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 and neuroblastoma.

[00170]

[143] The anti-CDH6 antibody-drug conjugate according Petition 870250088320, dated 09 / 29 / 2025, page 56 / 148 / 117 with any of

[127] to

[139] , wherein the anti-CDH6 antibody-drug conjugate is for use in the treatment of at least one tumor selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma and renal papillary cell carcinoma.

[00171]

[144] The anti-CDH6 antibody-drug conjugate according to any of

[97] to

[143] , wherein the anti-CDH6 antibody-drug conjugate is raludotatug deruxtecan (DS-6000a).

[00172]

[145] Use of an anti-CDH6 antibody-drug conjugate for the manufacture of a medicament for the treatment of a disease, administered in combination with an HIF-2a inhibitor, wherein, in the anti-CDH6 antibody-drug conjugate, a drug-ligand represented by the formula: [Formula 7] where A represents a binding site to an anti-CDH6 antibody or a functional fragment of the antibody, and is conjugated to the anti-CDH6 antibody or the functional fragment of the antibody via a thioether linkage.

[00173]

[146] The use according to

[145] , wherein the anti-CDH6 antibody or functional antibody fragment is an antibody that specifically binds to the amino acid sequence shown in SEQ ID NO: 1 and has an internalization capability that allows cellular uptake, or a functional antibody fragment.

[00174]

[147] Use in accordance with

[145] or

[146] , wherein the anti-CDH6 antibody or the functional fragment of the antibody is an antibody Petition 870250088320, dated 09 / 29 / 2025, page 57 / 148 / 117 comprising CDRH1, CDRH2 and CDRH3 in any combination selected from the group consisting of the following combinations (1) to (5): (1) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 3 and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 4, (2) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 8 and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 4, (3) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 9, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 10, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 11, (4) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 15, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 16, and CDRH3 consisting of the sequence of amino acids shown in SEQ ID NO: 17, and (5) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 21,CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 22, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 23; and, CDRL1, CDRL2 and CDRL3 in any combination selected from the group consisting of the following combinations (6) to (9): (6) CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 5, CDRL2 consisting of the amino acid sequence shown Petition 870250088320, dated 09 / 29 / 2025, page. 58 / 148 / 117 in SEQ ID NO: 6 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 7, (7) CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 13 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 14, (8) CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 18, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 19 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 20, and (9) CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 24, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 25, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 26, or a functional fragment of the antibody.

[00175]

[148] Use in accordance with any of

[145] to

[147] , wherein the anti-CDH6 antibody or functional antibody fragment is an antibody comprising CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 in any combination selected from the group consisting of the following combinations (1) to (5): (1) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 3, CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 4, CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 5, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 6 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 7, (2) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 6 Petition 870250088320, dated 09 / 29 / 2025, page. 59 / 148 / 117 shown in SEQ ID NO: 8, CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 4, CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 5, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 6 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 7, (3) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 9, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 10, CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 11, CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 13 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 14, (4) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 15, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 16,CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 17, CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 18, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 19 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 20, and (5) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 21, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 22, CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 23, CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 24, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 25, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 26, or a functional fragment of the antibody.

[149] Use in accordance with any of

[145] to

[148] , wherein the anti-CDH6 antibody or the functional antibody fragment is a Petition 870250088320, dated 09 / 29 / 2025, page 60 / 148 / 117 antibody comprising CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 3, CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 4, CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 5, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 6 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 7, or a functional fragment of the antibody.

[150] Use in accordance with any of

[145] to

[149] , wherein the anti-CDH6 antibody or functional antibody fragment is a humanized antibody or a functional antibody fragment.

[151] Use in accordance with any of

[145] to

[150] , wherein the anti-CDH6 antibody or functional antibody fragment is an antibody comprising any variable region of the heavy chain selected from the group consisting of the following variable regions (1) to (5): (1) a variable region of the heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 28, (2) a variable region of the heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 31, (3) a variable region of the heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34, (4) an amino acid sequence with a sequence identity of at least 95% or more with the sequence of the structural regions, except in each CDR sequence in the amino acid sequences of any one of (1) to (3), and (5) an amino acid sequence comprising a deletion, substitution or addition of one or more amino acids in the sequence of the structural regions, except in each CDR sequence in the sequences of Petition 870250088320, dated 09 / 29 / 2025, p. 61 / 148 / 117 amino acids from any one of (1) to (4); and any variable region of the light chain selected from the group consisting of the following variable regions (6) to (9): (6) a variable region of the light chain consisting of the amino acid sequence shown in SEQ ID NO: 37, (7) a variable region of the light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, (8) an amino acid sequence with a sequence identity of at least 95% or more with the sequence of the structural regions, except in each CDR sequence in the amino acid sequences of any of (6) and (7), and (9) an amino acid sequence comprising a deletion, substitution or addition of one or more amino acids in the sequence of structural regions, except in each CDR sequence in the amino acid sequences of any of (6) to (8), or a functional fragment of the antibody.

[00176]

[152] Use in accordance with any of

[145] to

[151] , wherein the anti-CDH6 antibody or functional antibody fragment is an antibody comprising a variable heavy chain region and a variable light chain region in any of the following combinations (1) to (4): (1) a variable heavy chain region consisting of the amino acid sequence shown in SEQ ID NO: 28 and a variable light chain region consisting of the amino acid sequence shown in SEQ ID NO: 37, (2) a variable heavy chain region consisting of the amino acid sequence shown in SEQ ID NO: 31 and a variable light chain region consisting of the amino acid sequence shown in SEQ ID NO: 37, (3) a variable heavy chain region consisting of Petition 870250088320, dated 09 / 29 / 2025, page 62 / 148 / 117 amino acid sequence shown in SEQ ID NO: 31 and a variable light chain region consisting of the amino acid sequence shown in SEQ ID NO: 40, and (4) a variable heavy chain region consisting of the amino acid sequence shown in SEQ ID NO: 34 and a variable light chain region consisting of the amino acid sequence shown in SEQ ID NO: 37, or a functional antibody fragment.

[00177]

[153] Use in accordance with any of

[145] to

[152] , wherein the anti-CDH6 antibody or functional antibody fragment is an antibody comprising a variable heavy chain region consisting of the amino acid sequence shown in SEQ ID NO: 28 and a variable light chain region consisting of the amino acid sequence shown in SEQ ID NO: 37, or a functional antibody fragment.

[00178]

[154] Use in accordance with any of

[145] to

[153] , wherein the anti-CDH6 antibody or functional antibody fragment is an antibody comprising any of the following combinations (1) to (4): (1) a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 38, (2) a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 38, (3) a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 41, and (4) a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 35 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 38, Petition 870250088320, dated 09 / 29 / 2025, p. 63 / 148 / 117 or a functional fragment of the antibody.

[00179]

[155] Use in accordance with any of

[145] to

[154] , wherein the anti-CDH6 antibody or functional antibody fragment is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 38, or a functional antibody fragment.

[00180]

[156] The use in accordance with any of

[145] to

[155] , wherein the anti-CDH6 antibody or functional fragment of the antibody is an antibody in which the heavy chain or the light chain has undergone one or two or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue to the N-terminal, amidation of a proline residue, conversion of N-terminal glutamine or N-terminal glutamic acid to pyroglutamic acid and deletion of one or two amino acids from the carboxyl terminal, or a functional fragment of the antibody.

[00181]

[157] The use according to

[156] , wherein the anti-CDH6 antibody or functional antibody fragment is an antibody in which one or two amino acids are deleted from the carboxyl terminal of a heavy chain thereof, or a functional antibody fragment.

[00182]

[158] The use according to

[157] , wherein the anti-CDH6 antibody or functional antibody fragment is an antibody in which an amino acid is deleted from the carboxyl terminal of each of its two heavy chains, or a functional antibody fragment.

[00183]

[159] Use in accordance with any of

[156] to

[158] , wherein the deleted amino acid is lysine. Petition 870250088320, dated 09 / 29 / 2025, page 64 / 148 / 117

[00184]

[160] The use in accordance with any of

[156] to

[159] , wherein the anti-CDH6 antibody or functional antibody fragment is an antibody in which a proline residue at the carboxyl terminus of one of its heavy chains is further amidated, or a functional antibody fragment.

[00185]

[161] Use in accordance with any of

[145] to

[160] , wherein the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 1 to 10.

[00186]

[162] Use in accordance with any of

[145] to

[160] , wherein the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 2 to 8.

[00187]

[163] Use in accordance with any of

[145] to

[160] , wherein the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 5 to 8.

[00188]

[164] Use in accordance with any of

[145] to

[160] , wherein the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7 to 8.

[00189]

[165] Use in accordance with any of

[145] to

[160] , wherein the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7.5 to 8.

[00190]

[166] Use in accordance with any of

[145] to

[160] , wherein the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is approximately 8.

[00191] [166-2] Use in accordance with any of

[145] to

[160] , wherein the number of drug-ligand structures conjugated per antibody in the anti-CDH6 antibody-drug conjugate is an integer in the range of 1 to 10.

[00192] [166-3] Use in accordance with any of

[145] to

[160] , wherein the number of antibody-conjugated drug-ligand structures in the anti-CDH6 antibody-drug conjugate is an integer in the range Petition 870250088320, dated 09 / 29 / 2025, pages 65 / 148 / 117 from 2 to 8.

[00193] [166-4] Use in accordance with any of

[145] to

[160] , wherein the number of antibody-conjugated drug-ligand structures in the anti-CDH6 antibody-drug conjugate is 2, 4, 6 or 8.

[00194] [166-5] Use in accordance with any of

[145] to

[160] , where the number of antibody-conjugated drug-ligand structures in the anti-CDH6 antibody-drug conjugate is 8.

[00195]

[167] Use in accordance with any of

[145] to [166-5], wherein the HIF-2a inhibitor is belzutifan, NKT2152, DFF332, AB521 or BPI-452080, or a pharmaceutically acceptable salt thereof.

[00196]

[168] Use in accordance with any of

[145] to [166-5], wherein the HIF-2a inhibitor is belzutifan or a pharmaceutically acceptable salt thereof.

[00197]

[169] Use in accordance with any of

[145] to

[168] , wherein the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained separately (as active components) in different formulations and are administered at the same time (approximately at the same time) or at different times.

[00198]

[170] Use in accordance with any of

[145] to

[168] , wherein the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained (as active components) in a single formulation for administration.

[00199]

[171] Use in accordance with any of

[145] to

[170] , wherein the use is for the treatment of cancer.

[00200]

[172] Use in accordance with any of

[145] to

[170] , wherein the use is to treat at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, ovarian cancer, serous adenocarcinoma of the ovary, clear cell carcinoma of the ovary, ovarian cancer Petition 870250088320, dated 09 / 29 / 2025, page 66 / 148 / 117 endometrioid, mucinous ovarian 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, stomach cancer, endometrial cancer, uterine body cancer, nasopharyngeal cancer, prostate cancer and cancer related to von Hippel-Lindau disease.

[00201]

[173] Use in accordance with any of

[145] to

[170] , wherein the use is to treat at least one tumor selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, renal papillary 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 and neuroblastoma.

[00202]

[174] Use in accordance with any of

[145] to

[170] , wherein the use is to treat at least one tumor selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma and renal papillary cell carcinoma.

[175] Use of an anti-CDH6 antibody-drug conjugate for the manufacture of a drug for the treatment of a disease, administered in combination with an HIF-2a inhibitor, wherein the anti-CDH6 antibody-drug conjugate is represented by the formula: [Formula 8] Petition 870250088320, dated 09 / 29 / 2025, page 67 / 148 58 / 117 antibody η where the antibody is an anti-CDH6 antibody, a drug ligand is conjugated to the antibody via a thioether linkage. en represents the average number of drug ligand units conjugated per antibody.

[00203]

[176] The use according to

[175] , wherein the antiCDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 38.

[00204]

[177] Use in accordance with

[175] or

[176] , wherein a lysine residue is deleted from the carboxyl terminal of an anti-CDH6 antibody heavy chain.

[00205]

[178] Use in accordance with any of

[175] to

[177] , wherein the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 1 to 10.

[00206]

[179] Use in accordance with any of

[175] to

[177] , wherein the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 2 to 8.

[00207]

[180] Use in accordance with any of

[175] to

[177] , wherein the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 5 to 8.

[00208]

[181] Use in accordance with any of

[175] to

[177] , wherein the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7 to 8.

[00209]

[182] The use in accordance with any of

[175] to

[177] , in Petition 870250088320, dated 09 / 29 / 2025, p. 68 / 148 / 117, states that the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7.5 to 8.

[00210]

[183] ​​Use in accordance with any of

[175] to

[177] , where the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is approximately 8.

[00211]

[184] Use in accordance with any of

[175] to

[183] , wherein the HIF-2a inhibitor is belzutifan, NKT2152, DFF332, AB521 or BPI452080, or a pharmaceutically acceptable salt thereof.

[00212]

[185] Use in accordance with any of

[175] to

[183] , wherein the HIF-2a inhibitor is belzutifan or a pharmaceutically acceptable salt thereof.

[00213]

[186] Use in accordance with any of

[175] to

[185] , wherein the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained separately (as active components) in different formulations and are administered at the same time (approximately at the same time) or at different times.

[00214]

[187] Use in accordance with any of

[175] to

[185] , wherein the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained (as active components) in a single formulation for administration.

[00215]

[188] Use in accordance with any of

[175] to

[187] , wherein the use is for the treatment of cancer.

[00216]

[189] Use in accordance with any of

[175] to

[187] , wherein the use is to treat at least one selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, ovarian cancer, serous adenocarcinoma of the ovary, clear cell carcinoma of the ovary, endometrioid ovarian cancer, mucinous tumor of the ovary, thyroid cancer, bile duct cancer, lung cancer, non-small cell lung cancer, cancer Petition 870250088320, dated 09 / 29 / 2025, page 69 / 148 / 117 cervical, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, neuroblastoma, colorectal cancer, stomach cancer, endometrial cancer, uterine body cancer, nasopharyngeal cancer, prostate cancer and cancer related to von Hippel-Lindau disease.

[00217]

[190] Use in accordance with any of

[175] to

[187] , wherein the use is to treat at least one tumor selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, ovarian cancer, serous adenocarcinoma of the ovary, clear cell carcinoma of the ovary, endometrioid ovarian cancer, mucinous tumor of the ovary, 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 and neuroblastoma.

[00218]

[191] Use in accordance with any of

[175] to

[187] , wherein the use is to treat at least one tumor selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma and renal papillary cell carcinoma.

[00219]

[192] Use in accordance with any of

[145] to

[191] , wherein the anti-CDH6 antibody-drug conjugate is raludotatug deruxtecan (DS6000a).

[00220]

[193] A pharmaceutical product comprising an anti-CDH6 antibody-drug conjugate and an HIF-2a inhibitor for administration in combination, wherein the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are as defined in any of [1] to

[24] ,

[31] to

[41] and

[48] .

[00221]

[194] The pharmaceutical product according to

[193] , in which the Petition 870250088320, dated 09 / 29 / 2025, page 70 / 148 / 117 pharmaceutical product is for use in the treatment of a disease as defined in any of

[27] to

[30] and

[44] to

[47] .

[00222]

[195] The pharmaceutical product according to

[193] or

[194] , in which the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained separately (as active components) in different formulations and are administered at the same time (approximately at the same time) or at different times.

[00223]

[196] The pharmaceutical product according to

[193] or

[194] , in which the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained (as active components) in a single formulation for administration.

[00224]

[197] A combination medicinal product comprising an anti-CDH6 antibody-drug conjugate and an HIF-2a inhibitor, wherein the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are as defined in any of [1] to

[24] ,

[31] to

[41] and

[48] .

[00225]

[198] The combined medicine according to

[197] , wherein the combined medicine is for use in the treatment of a disease as defined in any of items

[27] to

[30] and

[44] to

[47] .

[00226]

[199] The combined medicine according to

[197] or

[198] , in which the anti-CDH6 antibody-drug conjugate and the HIF2α inhibitor are contained separately (as active components) in different formulations and are administered at the same time (approximately at the same time) or at different times.

[00227]

[200] The combined medicine according to

[197] or

[198] , in which the anti-CDH6 antibody-drug conjugate and the HIF2α inhibitor are contained (as active components) in a single formulation for administration.

[00228]

[201] A pharmaceutical combination comprising an anti-CDH6 antibody-drug conjugate and an HIF-2a inhibitor, wherein the Petition 870250088320, dated 09 / 29 / 2025, page 71 / 148 / 117 anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are as defined in any of [1] to

[24] ,

[31] to

[41] and

[48] .

[00229]

[202] The pharmaceutical combination according to

[201] , wherein the pharmaceutical combination is for use in the treatment of a disease as defined in any of

[27] to

[30] and

[44] to

[47] .

[00230]

[203] The pharmaceutical combination according to

[201] or

[202] , in which the anti-CDH6 antibody-drug conjugate and the HIF2α inhibitor are contained separately (as active components) in different formulations and are administered at the same time (approximately at the same time) or at different times.

[00231]

[204] The pharmaceutical combination according to

[201] or

[202] , in which the anti-CDH6 antibody-drug conjugate and the HIF2α inhibitor are contained (as active components) in a single formulation for administration.

[00232]

[205] Use of an anti-CDH6 antibody-drug conjugate combined with an HIF-2a inhibitor for the treatment of a disease, wherein the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are as defined in any of [1] to

[24] ,

[31] to

[41] and

[48] .

[00233]

[206] Use in accordance with

[205] , wherein the disease is as defined in any of items

[27] to

[30] and

[44] to

[47] .

[00234]

[207] Use according to

[205] or

[206] , wherein the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained separately (as active components) in different formulations and are administered at the same time (approximately at the same time) or at different times.

[00235]

[208] Use in accordance with

[205] or

[206] , wherein the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained (as active components) in a single formulation for administration. Petition 870250088320, dated 09 / 29 / 2025, page 72 / 148 / 117

[00236]

[209] A medicinal product comprising an anti-CDH6 antibody-drug conjugate and an HIF-2a inhibitor, wherein the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are as defined in any of [1] to

[24] ,

[31] to

[41] and

[48] .

[00237]

[210] The medicine according to

[209] , wherein the medicine is for use in the treatment of a disease as defined in any of

[27] to

[30] and

[44] to

[47] .

[00238]

[211] The medicine according to

[209] or

[210] , in which the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained separately (as active components) in different formulations and are administered at the same time (approximately at the same time) or at different times.

[00239]

[212] The medicine according to

[209] or

[210] , in which the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained (as active components) in a single formulation for administration.

[00240]

[213] A pharmaceutical composition comprising (i) an anti-CDH6 antibody-drug conjugate and (ii) an HIF-2a inhibitor, wherein the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are administered in combination, wherein the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are as defined in any of [1] to

[24] ,

[31] to

[41] and

[48] .

[00241]

[214] The pharmaceutical composition according to

[213] , wherein the pharmaceutical composition is for use in the treatment of a disease as defined in any of

[27] to

[30] and

[44] to

[47] .

[00242]

[215] The pharmaceutical composition according to

[213] or

[214] , in which the anti-CDH6 antibody-drug conjugate and the HIF2α inhibitor are contained separately (as active components) in different formulations and are administered at the same time (approximately at Petition 870250088320, dated 09 / 29 / 2025, page 73 / 148 / 117 at the same time) or at different times.

[00243]

[216] The pharmaceutical composition according to

[213] or

[214] , in which the anti-CDH6 antibody-drug conjugate and the HIF2α inhibitor are contained (as active components) in a single formulation for administration.

[00244]

[217] A kit comprising (i) a first composition comprising an anti-CDH6 antibody-drug conjugate and (ii) a second composition comprising an HIF-2a inhibitor, wherein the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are administered in combination, wherein the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are as defined in any one of [1] to

[24] ,

[31] to

[41] and

[48] .

[00245]

[218] The kit according to

[217] , wherein the kit is for use in the treatment of a disease as defined in any of items

[27] to

[30] and

[44] to

[47] .

[00246]

[219] The kit according to

[217] or

[218] , in which the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained separately (as active components) in different formulations and are administered at the same time (approximately at the same time) or at different times.

[00247]

[220] The kit according to

[217] or

[218] , in which the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained (as active components) in a single formulation for administration.

[221] A cancer treatment method comprising administering an anti-CDH6 antibody-drug conjugate and an HIF-2a inhibitor in combination to an individual in need of treatment, wherein the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are as defined in any of [1] to

[24] ,

[31] to

[41] and

[48] . [Advantageous Effects of the Invention] Petition 870250088320, dated 09 / 29 / 2025, page 74 / 148 / 117

[00248] The present invention may provide a pharmaceutical composition in which a specific anti-CDH6 antibody-drug conjugate and an HIF-2a inhibitor are administered in combination, and / or a treatment method comprising administering a specific anti-CDH6 antibody-drug conjugate and an HIF-2a inhibitor in combination to an individual. [Brief Description of the Drawings]

[00249] Figure 1 is a diagram showing the amino acid sequence (SEQ ID NO: 1) of human CDH6 EC3.

[00250] Figure 2 is a diagram showing the amino acid sequence (SEQ ID NO: 2) of the CDRH1 heavy chain of an anti-CDH6 antibody.

[00251] Figure 3 is a diagram showing the amino acid sequence (SEQ ID NO: 3) of the CDRH2 heavy chain of an anti-CDH6 antibody.

[00252] Figure 4 is a diagram showing the amino acid sequence (SEQ ID NO: 4) of the CDRH3 heavy chain of an anti-CDH6 antibody.

[00253] Figure 5 is a diagram showing the amino acid sequence (SEQ ID NO: 5) of the CDRL1 light chain of an anti-CDH6 antibody.

[00254] Figure 6 is a diagram showing the amino acid sequence (SEQ ID NO: 6) of the CDRL2 light chain of an anti-CDH6 antibody.

[00255] Figure 7 is a diagram showing the amino acid sequence (SEQ ID NO: 7) of the CDRL3 light chain of an anti-CDH6 antibody.

[00256] Figure 8 is a diagram showing the amino acid sequence (SEQ ID NO: 27) of the heavy chain of an anti-CDH6 antibody. Petition 870250088320, dated 09 / 29 / 2025, p. 75 / 148 / 117

[00257] Figure 9 is a diagram showing the amino acid sequence (SEQ ID NO: 28) of a variable region of the heavy chain of an anti-CDH6 antibody.

[00258] Figure 10 is a diagram showing the amino acid sequence (SEQ ID NO: 29) of a heavy chain of a mature anti-CDH6 antibody.

[00259] Figure 11 is a diagram showing the amino acid sequence (SEQ ID NO: 36) of a light chain of an anti-CDH6 antibody.

[00260] Figure 12 is a diagram showing the amino acid sequence (SEQ ID NO: 37) of a variable region of the light chain of an anti-CDH6 antibody.

[00261] Figure 13 is a diagram showing the amino acid sequence (SEQ ID NO: 38) of a light chain from a mature anti-CDH6 antibody.

[00262] Figure 14 is a diagram showing the tumor growth suppression effects of single administration groups of an anti-CDH6 antibody-drug conjugate (1) and belzutifan (Belzutifan), and a combined administration group of the anti-CDH6 antibody-drug conjugate (1) and belzutifan (Combination), in mice with subcutaneously transplanted 786-O cells.

[00263] Figure 15 is a diagram showing the percent change in mean tumor volume on Day 21, relative to mean tumor volume on Day 0 as baseline, of single administration groups of an anti-CDH6 antibody-drug conjugate (1) and belzutifan (Belzutifan), and of a combined administration group of the anti-CDH6 antibody-drug conjugate (1) and belzutifan (Combination), in mice with subcutaneously transplanted 786-O cells. [Description of the Modalities] Petition 870250088320, dated 09 / 29 / 2025, page 76 / 148 / 117

[00264] Preferred embodiments for carrying out the present invention will be described below. It should be noted that the embodiments described below illustrate only representative embodiments of the present invention, and the scope of the present invention should not be interpreted restrictively because of these examples. 1. Definition

[00265] Cadherins are glycoproteins present on the surface of cell membranes and function as cell-cell adhesion molecules through calcium ion-dependent binding of their N-terminal extracellular domains, or as signaling molecules responsible for cell-cell interactions. Classical cadherins belong to the cadherin superfamily and are single-pass transmembrane proteins composed of five extracellular domains (EC domains), a transmembrane region, and an intracellular domain.

[00266] CDH6 (cadherin-6) is a single-pass transmembrane protein composed of 790 amino acids, classified in the type II cadherin family, and this protein has N-terminal extracellular and C-terminal intracellular domains. The human CDH6 gene was first cloned in 1995 (Shimoyama Y et al., Cancer Research, 2206-2211, 55, May 15, 1995), and its sequence can be consulted, for example, under accession numbers NM_004932 and NP_004923 (NCBI). The amino acid sequence shown in SEQ ID NO: 1 is the amino acid sequence of extracellular domain 3 (in this description, also referred to as EC3 domain or EC3) of human CDH6.

[00267] In this description, the term cancer is used with the same meaning as the term tumor.

[00268] In the present description, the term gene is used to include not only DNA, but also its mRNA and cDNA, and its cRNA.

[00269] In the present description, the term CDH6 may be used Petition 870250088320, dated 09 / 29 / 2025, p. 77 / 148 / 117 with the same meaning as the CDH6 protein.

[00270] In the present description, the term 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 cells expressing CDH6 by binding to CDH6.

[00271] In the present description, the term functional fragment of an antibody, also called antigen-binding fragment of an antibody, is used to designate a partial fragment of the antibody with binding activity against an antigen, and includes Fab, F(ab')2, Fv, scFv, a diabody, a linear antibody and a multispecific antibody formed from antibody fragments, and the like. Fab', which is a monovalent fragment of variable antibody regions obtained by treating F(ab')2 under reducing conditions, is also included in the antigen-binding fragment of an antibody. However, the antigen-binding fragment of an antibody is not limited to these molecules, provided that the antigen-binding fragment has antigen-binding capability.These antigen-binding fragments include not only those obtained by treating a complete antibody protein molecule with an appropriate enzyme, but also proteins produced in appropriate host cells using a genetically modified antibody gene.

[00272] In the present description, the term CDR is used to designate a complementarity-determining region. It is known that the heavy chain and the light chain of an antibody molecule each have three CDRs. This CDR is also called a hypervariable region and is located in the variable regions of the heavy chain and the light chain of an antibody. These regions have a particularly variable primary structure and are separated into three sites in the primary structure of the polypeptide chain, Petition 870250088320, dated 09 / 29 / 2025, p. 78 / 148 / 117, both in the heavy chain and in the light chain. In the present description, with respect to the CDR of an antibody, the CDRs of a heavy chain are designated CDRH1, CDRH2, and CDRH3, respectively, from the amino-terminal end of the amino acid sequence of the heavy chain, while the CDRs of a light chain are designated CDRL1, CDRL2, and CDRL3, respectively, from the amino-terminal end of the amino acid sequence of the light chain. These sites are located close to each other in the three-dimensional structure and determine the specificity of the antibody for an antigen to which the antibody binds.

[00273] In the present description, the term approximately refers to a value that may vary by up to plus or minus 10%, 8%, 6%, 5%, 4%, 3%, 2% or 1% relative to the reference value. Preferably, the term approximately refers to the range of plus or minus 10%, 5% or 1% relative to the reference value. 2. Anti-CDH6 antibody-drug conjugate

[00274] The anti-CDH6 antibody-drug conjugate used in the present invention is an antibody-drug conjugate in which a drug ligand is represented by the formula: [Formula 9] where A represents a binding site to an anti-CDH6 antibody or a functional fragment of the antibody, and is conjugated to the anti-CDH6 antibody or the functional fragment of the antibody via a thioether linkage. Petition 870250088320, dated 09 / 29 / 2025, p. 79 / 148 70 / 117

[00275] In the present invention, the partial structure consisting of a ligand and a drug in the antibody-drug conjugate is called the drug-ligand. This drug-ligand is linked to a thiol group (i.e., the sulfur atom of a cysteine ​​residue) formed at an interchain disulfide binding site (two sites between heavy chains and two sites between a heavy chain and a light chain) in the antibody.

[00276] The drug-ligand of the present invention comprises an exatecan topoisomerase I inhibitor (IUPAC name: (lS,9S)-l-amino-9-ethyl-5-fluoro-l,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-10,13-dione, (also expressed as a chemical name: (lS,9S)-l-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-lH,12H-benzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-10,13(9H,15H)-dione)) as a component. The formula for exactano is: [Formula 10] It is a camptothecin derivative with antitumor effects.

[00277] The anti-CDH6 antibody-drug conjugate used in the present invention can also be represented by the following formula: [Formula 11]

[00278] In this context, the antibody is an anti-CDH6 antibody or a Petition 870250088320, dated 09 / 29 / 2025, p. 80 / 148 / 117 functional fragment of the antibody (preferably an anti-CDH6 antibody), and the drug-ligand is conjugated to the antibody via a thioether linkage (each of the drug-ligands represented by the structure shown in parentheses in the formula is conjugated to the antibody via a thioether linkage). n has the same meaning as the so-called average number of drug-conjugated molecules (DAR; drug-antibody ratio) and represents the average number of drug-ligand units conjugated per antibody.

[00279] In some embodiments, the anti-CDH6 antibody-drug conjugate is raludotatug deruxtecan (also known as R-DXd or DS-6000a).

[00280] After migrating to cancer cells, the antibody-drug conjugate used in the present invention is cleaved at the binding portion to release a compound represented by the formula: [Formula 12] (hereinafter referred to as compound (A)).

[00281] The compound mentioned is considered the original source of the antitumor activity of the anti-CDH6 antibody-drug conjugate used in the present invention and has been confirmed to have an inhibitory effect on topoisomerase I (Ogitani Y. et al., Clinical Cancer Research, 2016, October 15; 22 (20): 5097 to 5108, Epub 2016, March 29).

[00282] Topoisomerase I is an enzyme that cleaves and reassembles a single strand of DNA, thus transforming the DNA conformation to participate in DNA synthesis. Therefore, agents with an inhibitory effect on topoisomerase I Petition 870250088320, dated 09 / 29 / 2025, page 81 / 148 / 117 can inhibit DNA synthesis, thus interrupting cell division in the S phase (DNA synthesis phase) of the cell cycle and inducing cell death by apoptosis, thereby suppressing the growth of cancerous cells.

[00283] The antibody-drug conjugate used in the present invention is also known to have an indirect antitumor effect (Suzuki H, et al., Molecular Cancer Therapeutics, (2024) 23(3): 257 to 271).

[00284] This indirect antitumor effect is exerted by means of a process in which the antibody-drug conjugate used in the present invention is internalized into cancer cells that express the target, where the compound is then released, so as to also exert an antitumor effect on cancer cells that do not express the target present around it.

[00285] This indirect antitumor effect is also exerted as an excellent antitumor effect when the antibody-drug conjugate according to the present invention is used in combination with an HIF2α inhibitor.

[00286] Other examples of anti-CDH6 antibody-drug conjugates are not particularly limited, provided that an antitumor compound is conjugated to an anti-CDH6 antibody via a linker structure fraction. Examples of these may include those described in CUSP06, BSI709 and in International Publications No. WO 2023 / 102875 and WO 2023 / 104188. 3. Antibody in anti-CDH6 antibody-drug conjugate

[00287] The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention may be derived from any species and, preferably, is an anti-CDH6 antibody derived from a human, rat, mouse, or rabbit. When the anti-CDH6 antibody is derived from a species other than humans, it is preferable to chimerize or humanize the anti-CDH6 antibody by a well-known technique. Petition 870250088320, dated 09 / 29 / 2025, p. 82 / 148 / 117 The anti-CDH6 antibody of the present invention may be a polyclonal or monoclonal antibody, with a monoclonal antibody being preferred.

[00288] The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention preferably has the property of being able to target cancer cells and is preferably an antibody that has, for example, the property of being able to recognize cancer cells, the property of being able to bind to cancer cells, the property of being internalized into cancer cells by cellular uptake and / or cytocidal activity against cancer cells.

[00289] The binding activity of an antibody against cancer cells can be confirmed by flow cytometry. The uptake of an antibody into cancer cells can be confirmed by (1) an assay that visualizes a cell-taken antibody under a fluorescence microscope using a secondary antibody (fluorescently labeled) binding to the antibody (Cell Death and Differentiation (2008) 15, 751 to 761), (2) an assay that measures the amount of cell-taken fluorescence using a secondary antibody (fluorescently labeled) binding to the antibody (Molecular Biology of the Cell Volume 15, 5268 to 5282, December 2004) or (3) a Mab-ZAP assay using an immunotoxin binding to the antibody, in which the toxin is released after cell uptake in order to suppress cell growth (Bio Techniques 28: 162 to 165, January 2000).A recombinant protein conjugate of a catalytic region of diphtheria toxin and a G protein can be used as an immunotoxin.

[00290] The antitumor activity of the antibody can be confirmed in vitro by measuring the inhibitory activity against cell growth. For example, a cancer cell line that overexpresses the antibody's target protein is cultured, and the antibody is added in concentrations Petition 870250088320, dated 09 / 29 / 2025, page 83 / 148 / 117 varied to the culture system to measure inhibitory activity against foci formation, colony formation, and spheroid growth. Antitumor activity can be confirmed in vivo, for example, by administering the antibody to a skinless mouse in which a tumor cell line strongly expressing the target protein has been inoculated, and then measuring the change in the cancer cells.

[00291] Since the conjugated compound in the antibody-drug conjugate exerts an antitumor effect, it is preferable, but not essential, that the antibody itself have an antitumor effect. For the purpose of specifically and / or selectively exerting the cytotoxicity of the antitumor compound against cancer cells, it is important and preferable that the antibody have the property of being internalized and transferred to cancer cells. The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention can be obtained by procedures known in the art. For example, the anti-CDH6 antibody can be obtained using a method commonly used in the art, which involves immunizing an animal with an antigenic polypeptide and then collecting and purifying an antibody produced in vivo.The origin of the antigen is not limited to a human being, and therefore an animal can also be immunized with an antigen derived from a non-human animal, such as a mouse, rat, or similar. In this case, the cross-reactivity of antibodies that bind to the heterologous antigen obtained with human antigens can be tested to identify an antibody applicable to a human disease.

[00292] Alternatively, antibody-producing cells that produce an antibody against the antigen can be fused with myeloma cells according to a method known in the field (e.g., Kohler and Milstein, Nature (1975) 256, 495 to 497; and Kennet, R. ed., Monoclonal Antibodies, 365 to 367, Plenum Press, NY (1980)) to establish hybridomas in order to obtain a monoclonal antibody. Petition 870250088320, dated 09 / 29 / 2025, p. 84 / 148 / 117

[00293] The antigen can be obtained by enabling host cells to produce a gene that encodes the antigen protein according to genetic manipulation. Specifically, a vector capable of expressing the antigen gene is produced, and the vector is then introduced into host cells so that the gene is expressed in them and, subsequently, the expressed antigen can be purified. The antibody can also be obtained by a method of immunizing an animal with cells expressing the antigen, based on the genetic manipulation described above, or with a cell line that expresses the antigen.

[00294] The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is preferably a genetically recombinant antibody that has been artificially modified with the aim of reducing heterogenetic antigenicity to humans, such as a chimeric antibody or a humanized antibody, or preferably an antibody containing only the genetic sequence of a human-derived antibody, i.e., a human antibody. These antibodies can be produced by known methods.

[00295] An example of a chimeric antibody might include antibodies in which a variable region and a constant region are heterologous to each other, such as a chimeric antibody formed by conjugating the variable region of a mouse- or rat-derived antibody with a human-derived constant region (Proc. Natl. Acad. Sci. USA, 81, 6851 to 6855, (1984)). Examples of humanized antibodies might include an antibody formed by incorporating only complementarity-determining regions (CDRs) of a heterologous antibody into a human-derived antibody (Nature (1986) 321, pages 522 to 525), an antibody formed by incorporating amino acid residues from some structures of a heterologous antibody, as well as CDR sequences from the heterologous antibody, into a human antibody, according to a grafting method. Petition 870250088320, dated 09 / 29 / 2025, page 85 / 148 / 117 of CDR (International Publication No. WO90 / 07861), and a humanized antibody using a gene conversion mutagenesis strategy (U.S. Patent No. 5821337).

[00296] Examples of human antibodies may include an antibody prepared using a human antibody-producing mouse having a human chromosomal fragment comprising the heavy chain and light chain genes of a human antibody (see Tomizuka, K. et al., Nature Genetics (1997) 16, pages 133 to 143; Kuroiwa, Y. et al., Nucl. Acids Res. (1998) 26, pages 3447 to 3448; Yoshida, H. et al., Animal Cell Technology: Basic and Applied Aspects volume 10, pages 69 to 73 (Kitagawa, Y., Matsuda, T. and Iijima, S. eds.), Kluwer Academic Publishers, 1999; 97, pages 722 to 727; etc.). Another example might include a phage display-derived antibody that was selected from a human antibody library (see Wormstone, IM et al., Investigative Ophthalmology & Visual Science. (2002) 43 (7), pages 2301 to 2308; Carmen, S. et al., Briefings in Functional Genomics and Proteomics (2002), 1 (2), pages 189 to 203; Siriwardena, D. et al., Ophthalmology (2002) 109 (3), pages 427 to 431; etc.).

[00297] The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is preferably an antibody that specifically binds to the amino acid sequence shown in SEQ ID NO: 1 and has an internalization capacity that allows cellular uptake. Examples of anti-CDH6 antibodies may include the antibodies described in International Publication No. WO 2018 / 212136 (H01L02, H02L02, H02L03, H04L02, etc.).

[00298] The phrase specifically links to the amino acid sequence shown in SEQ ID NO: 1, applied to the antibody, is used to indicate that the antibody binds strongly to the EC3 domain of CDH6 compared to other extracellular domains of CDH6. Petition 870250088320, dated 09 / 29 / 2025, p. 86 / 148 / 117

[00299] The internalization activity (internalization capacity) of the antibody can be evaluated using, for example, a reagent conjugated with a toxin (saporin) that inhibits protein synthesis (for example, the Rat-ZAP (Advanced Targeting Systems) anti-mouse IgG reagent and the Hum-ZAP (Advanced Targeting Systems) anti-human IgG reagent) (see International Publication No. WO 2018 / 212136).

[00300] The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is preferably an antibody whose survival rate (indicated by a ratio relative to the cell survival rate without the addition of the antibody defined as 100%) of CDH6-expressing cells to which the aforementioned antibody and a saporin-labeled anti-mouse IgG antibody or a saporin-labeled anti-human IgG antibody have been administered is 80% or less, more preferably 70% or less, and even more preferably 60% or less.

[00301] The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is preferably an antibody comprising a heavy chain comprising CDRH1, CDRH2 and CDRH3 in any combination selected from the group consisting of the following combinations (1) to (5): (1) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 3 and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 4, (2) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 8 and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 4, (3) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 9, CDRH2 consisting of the amino acid sequence shown in SEQ Petition 870250088320, dated 09 / 29 / 2025, p. 87 / 148 / 117 ID NO: 10, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 11, (4) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 15, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 16, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 17, and (5) CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 21, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 22, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 23, and a light chain comprising CDRL1, CDRL2 and CDRL3 in any combination selected from the group consisting of the following combinations (6) to (9): (6) CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 5, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 6, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 7, (7) CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 12,CDRL2 consisting of amino acid sequence shown in SEQ ID NO: 13 and CDRL3 consisting of amino acid sequence shown in SEQ ID NO: 14, (8) CDRL1 consisting of amino acid sequence shown in SEQ ID NO: 18, CDRL2 consisting of amino acid sequence shown in SEQ ID NO: 19 and CDRL3 consisting of amino acid sequence shown in SEQ ID NO: 20 and (9) CDRL1 consisting of amino acid sequence shown in SEQ ID NO: 24, CDRL2 consisting of amino acid sequence shown in SEQ ID NO: 25 and CDRL3 consisting of amino acid sequence shown in SEQ ID NO: 26.,

[00302] 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 CDRH1, which consists of the amino acid sequence shown in SEQ ID NO: 2, CDRH2, Petition 870250088320, dated 09 / 29 / 2025, p. 88 / 148 / 117, which consists of the amino acid sequence shown in SEQ ID NO: 3, and CDRH3, which consists of the amino acid sequence shown in SEQ ID NO: 4, and a light chain comprising CDRL1, which consists of the amino acid sequence shown in SEQ ID NO: 5, CDRL2, which consists of the amino acid sequence shown in SEQ ID NO: 6, and CDRL3, which consists of the amino acid sequence shown in SEQ ID NO: 7.

[00303] 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 CDRH1, consisting of the amino acid sequence shown in SEQ ID NO: 2, CDRH2, consisting of the amino acid sequence shown in SEQ ID NO: 8, and CDRH3, consisting of the amino acid sequence shown in SEQ ID NO: 4 and a light chain comprising CDRL1, consisting of the amino acid sequence shown in SEQ ID NO: 5, CDRL2, consisting of the amino acid sequence shown in SEQ ID NO: 6, and CDRL3, consisting of the amino acid sequence shown in SEQ ID NO: 7.

[00304] 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 CDRH1, consisting of the amino acid sequence shown in SEQ ID NO: 9, CDRH2, consisting of the amino acid sequence shown in SEQ ID NO: 10, and CDRH3, consisting of the amino acid sequence shown in SEQ ID NO: 11, and a light chain comprising CDRL1, consisting of the amino acid sequence shown in SEQ ID NO: 12, CDRL2, consisting of the amino acid sequence shown in SEQ ID NO: 13, and CDRL3, consisting of the amino acid sequence shown in SEQ ID NO: 14.

[00305] 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 CDRH1, which Petition 870250088320, dated 09 / 29 / 2025, p. 89 / 148 / 117 consists of the amino acid sequence shown in SEQ ID NO: 15, CDRH2, which consists of the amino acid sequence shown in SEQ ID NO: 16, and CDRH3, which consists of the amino acid sequence shown in SEQ ID NO: 17, and a light chain comprising CDRL1, which consists of the amino acid sequence shown in SEQ ID NO: 18, CDRL2, which consists of the amino acid sequence shown in SEQ ID NO: 19, and CDRL3, which consists of the amino acid sequence shown in SEQ ID NO: 20.

[00306] 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 CDRH1, consisting of the amino acid sequence shown in SEQ ID NO: 21, CDRH2, consisting of the amino acid sequence shown in SEQ ID NO: 22, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 23 and a light chain comprising CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 24, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 25 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 26.

[00307] The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention may more preferably be an antibody comprising a given combination of a heavy chain comprising any variable region of the heavy chain selected from the group consisting of the following variable regions (1) to (3): (1) the amino acid sequence shown in SEQ ID NO: 28, 31 or 34, (2) an amino acid sequence having at least 95% or more identity with the amino acid sequence (1) (preferably an amino acid sequence having at least 95% or more sequence identity with the sequence of the different structure regions of each CDR sequence), and (3) an amino acid sequence comprising a deletion, substitution or addition of one or more amino acids in the sequence of Petition 870250088320, dated 09 / 29 / 2025, p. 90 / 148 / 117 amino acids (1), and a light chain comprising any variable region of the light chain selected from the group consisting of the following variable regions (4) to (6): (4) the amino acid sequence shown in SEQ ID NO: 37 or 40, (5) an amino acid sequence having at least 95% or more identity with the amino acid sequence (4) (preferably an amino acid sequence having at least 95% or more sequence identity with the sequence of structural regions, except in each CDR sequence), and (6) an amino acid sequence comprising a deletion, substitution or addition of one or more amino acids in the amino acid sequence (4).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 the amino acid sequence of the variable region of the heavy chain shown in SEQ ID NO: 28, a heavy chain comprising the amino acid sequence of the variable region of the heavy chain shown in SEQ ID NO: 31, or a heavy chain comprising the amino acid sequence of the variable region of the heavy chain shown in SEQ ID NO: 34, and a light chain comprising the amino acid sequence of the variable region of the light chain shown in SEQ ID NO: 37 or the light chain with an amino acid sequence of the variable region of the light chain shown in SEQ ID NO: 40.

[00308] 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 variable region of the heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 28 and a light chain comprising a variable region of the light chain consisting of the amino acid sequence shown in SEQ ID NO: 37.

[00309] The anti-CDH6 antibody the antibody in the antibody conjugate Petition 870250088320, dated 09 / 29 / 2025, page 91 / 148 / 117 The anti-CDH6 drug used in the present invention is, more preferably, an antibody comprising a heavy chain comprising a variable region of the heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 31 and a light chain comprising a variable region of the light chain consisting of the amino acid sequence shown in SEQ ID NO: 37.

[00310] 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 variable region of the heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34 and a light chain comprising a variable region of the light chain consisting of the amino acid sequence shown in SEQ ID NO: 37.

[00311] 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 variable region of the heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 31 and a light chain comprising a variable region of the light chain consisting of the amino acid sequence shown in SEQ ID NO: 40.

[00312] 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 consisting of the amino acid sequence shown in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 38, or an antibody in which a lysine residue is deleted from the carboxyl terminus of a heavy chain of the antibody.

[00313] The anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate used in the present invention is even more preferably a Petition 870250088320, dated 09 / 29 / 2025, p. 92 / 148 / 117 antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 38, or an antibody in which a lysine residue is deleted from the carboxyl terminus of a heavy chain of the antibody.

[00314] 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 consisting of the amino acid sequence shown in SEQ ID NO: 35 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 38, or an antibody in which a lysine residue is deleted from the carboxyl terminus of a heavy chain of the antibody.

[00315] 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 consisting of the amino acid sequence shown in SEQ ID NO: 32 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 41, or an antibody in which a lysine residue is deleted from the carboxyl terminus of a heavy chain of the antibody.

[00316] By combining sequences that exhibit high identity with the heavy chain and light chain amino acid sequences described above, it is possible to select an antibody with biological activity equivalent to that of each of the antibodies described above. Such identity is generally 80% or more, preferably 85% or more, more preferably 90% or more, even more preferably 95% or more, and even more preferably 99% or more.

[00317] The identity between two types of amino acid sequences can be determined by aligning the sequences using the standard parameters of Clustal W version 2 (Larkin MA, Blackshields G, Brown NP, Chenna R, Petition 870250088320, dated 09 / 29 / 2025, p. 93 / 148 / 117 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).

[00318] The antibody in the anti-CDH6 antibody-drug conjugate used in the present invention also includes a modification of an antibody. The modification refers to the antibody, according to the present invention, which is chemically or biologically modified. Examples of such chemical modification include chemical modifications such as the attachment of a chemical moiety to an amino acid backbone or the attachment of a chemical moiety to an N- or O-linked carbohydrate chain. Examples of such biological modification include antibodies that have undergone post-translational modification (e.g., N-linked or O-linked glycosylation, N-terminal or C-terminal processing, deamidation, aspartic acid isomerization, and methionine oxidation) and antibodies to the N-terminal to which a methionine residue is added as a result of having been allowed to be expressed using prokaryotic host cells.Furthermore, such modification is also intended to include labeled antibodies to allow the detection or isolation of the antibody according to the present invention or of an antigen, for example, an enzymatically labeled antibody, a fluorescently labeled antibody, and an affinity-labeled antibody. Such modification of the antibody according to the present invention is useful for improving the stability and retention in blood of an antibody; a reduction in antigenicity; detection or isolation of an antibody or antigen; etc.

[00319] Furthermore, by regulating a modification of the sugar chain (glycosylation, defucosylation, etc.) that binds to the antibody according to the present invention, the antibody-dependent cellular cytotoxic activity can be increased. Techniques for regulating the modification of the sugar chain of an antibody are those described in International Publications Nos. WO 99 / 54342, WO 00 / 61739, WO 02 / 31140, Petition 870250088320, dated 09 / 29 / 2025, pp. 94 / 148 / 117 WO 2007 / 133855 and WO 2013 / 120066, etc., although the techniques are not limited to them. The antibody according to the present invention also includes antibodies for which the aforementioned sugar chain modification has been regulated.

[00320] It is known that the lysine residue at the carboxyl terminal of the heavy chain of an antibody produced in cultured mammalian cells is deleted (Journal of Chromatography A, 705: 129-134 (1995)), and it is also known that the two amino acid residues at the carboxyl terminal of the heavy chain, glycine and lysine, are deleted, and that the newly positioned proline residue at the carboxyl terminal is amidated (Analytical Biochemistry, 360: 75-83 (2007)). However, such deletion and modification of these heavy chain sequences do not influence the antigen-binding activity and effector function (complement activation, antibody-dependent cellular cytotoxicity, etc.) of an antibody.Thus, the antibody according to the present invention also includes an antibody that has undergone the aforementioned modification and a functional fragment of the antibody, and specific examples of such an antibody include a deletion mutant comprising a deletion of 1 or 2 amino acids at the carboxyl terminus of the heavy chain and a deletion mutant formed by the amidation of the aforementioned deletion mutant (for example, a heavy chain in which the proline residue at the carboxyl terminus site is amidated). However, deletion mutants involving a deletion at the carboxyl terminus of the heavy chain of the antibody according to the present invention are not limited to the deletion mutants described above, provided they retain antigen-binding activity and effector function.The two heavy chains that constitute the antibody according to the present invention can be any type of heavy chain selected from the group consisting of a full-length antibody and the deletion mutants described above, or they can be a combination of any two types selected from the group. Petition 870250088320, dated 09 / 29 / 2025, p. 95 / 148 / 117 mentioned above. The proportion of individual deletion mutants may be influenced by the types of cultured mammalian cells that produce the antibody according to the present invention and by the culture conditions. Examples of the antibody according to the present invention may preferably include antibodies in which an amino acid residue is deleted at the carboxyl terminus of each of the two heavy chains. The amino acid deleted at the carboxyl terminus of the heavy chain in the antibody according to the present invention is preferably a lysine residue.

[00321] Examples of antibody isotypes according to the present invention may include IgG (IgG1, IgG2, IgG3 and IgG4). Among others, IgG1, IgG2 and IgG4 are preferred.

[00322] In the complete amino acid sequence of the hH01 heavy chain shown in SEQ ID NO: 27, the amino acid sequence composed of amino acid residues at positions 1 to 19 is the signal sequence, the amino acid sequence composed of amino acid residues at positions 20 to 141 is the variable region, and the amino acid sequence composed of amino acid residues at positions 142 to 471 is the constant region.

[00323] In the complete amino acid sequence of the hH02 heavy chain shown in SEQ ID NO: 30, the amino acid sequence composed of amino acid residues at positions 1 to 19 is the signal sequence, the amino acid sequence composed of amino acid residues at positions 20 to 141 is the variable region, and the amino acid sequence composed of amino acid residues at positions 142 to 471 is the constant region.

[00324] In the complete amino acid sequence of the hL04 heavy chain shown in SEQ ID NO: 33, the amino acid sequence composed of amino acid residues at positions 1 to 19 is the signal sequence, the amino acid sequence composed of amino acid residues at positions 20 to 141 is the variable region, and the amino acid sequence composed of amino acid residues at positions 142 to 471 is the constant region. Petition 870250088320, dated 09 / 29 / 2025, pp. 96 / 148 / 117

[00325] In the complete amino acid sequence of the hL02 light chain shown in SEQ ID NO: 36, the amino acid sequence composed of amino acid residues at positions 1 to 20 is the signal sequence, the amino acid sequence composed of amino acid residues at positions 21 to 128 is the variable region, and the amino acid sequence composed of amino acid residues at positions 129 to 233 is the constant region.

[00326] In the complete amino acid sequence of the hL03 light chain shown in SEQ ID NO: 39, the amino acid sequence composed of amino acid residues at positions 1 to 20 is the signal sequence, the amino acid sequence composed of amino acid residues at positions 21 to 128 is the variable region, and the amino acid sequence composed of amino acid residues at positions 129 to 233 is the constant region. 4. Production of the anti-CDH6 antibody-drug conjugate

[00327] The drug-ligand intermediate for use in the production of the anti-CDH6 antibody-drug conjugate according to the present invention is represented by the following formula: [Formula 13]

[00328] The drug-ligand intermediate described above may be represented by the chemical name N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]glycylglycyl-L-phenylalanine-N-[(2-{[(1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl]amino}-2-oxoethoxy)methyl]glycinamide and may be produced with reference to the description in International Publications Nos. Petition 870250088320, dated 09 / 29 / 2025, pp. 97 / 148 / 117 WO 2014 / 057687, WO 2015 / 098099, WO 2015 / 115091, WO 2015 / 155998 and WO 2019 / 044947, etc.

[00329] The anti-CDH6 antibody-drug conjugate used in the present invention can be produced by reacting the drug-ligand intermediate described above with an anti-CDH6 antibody with a thiol group (also known as a sulfhydryl group).

[00330] The anti-CDH6 antibody with a sulfhydryl group can be obtained by a method well known to a person skilled in the art (Hermanson, GT, Bioconjugate Techniques, pages 56 to 136, pages 456 to 493, Academic Press (1996)). For example, using 0.3 to 3 molar equivalents of a reducing agent, such as tris(2-carboxyethyl)phosphine hydrochloride (TCEP), per interchain disulfide in the antibody and reacting with the anti-CDH6 antibody in a buffer solution containing a chelating agent, such as ethylenediaminetetraacetic acid (EDTA), it is possible to obtain an anti-CDH6 antibody with a sulfhydryl group with partially or completely reduced interchain disulfides in the antibody.

[00331] Furthermore, using 2 to 20 molar equivalents of the drug-ligand intermediate per anti-CDH6 antibody with a sulfhydryl group, it is possible to produce the anti-CDH6 antibody-drug conjugate, in which 2 to 8 drug molecules are conjugated per anti-CDH6 antibody.

[00332] The average number of drug molecules conjugated per antibody molecule in the produced anti-CDH6 antibody-drug conjugate can be calculated, for example, by a calculation method comprising measuring the UV absorbance of the antibody-drug conjugate and a conjugation precursor thereof at two wavelengths of 280 nm and 370 nm (UV method), or a calculation method comprising treating the antibody-drug conjugate with a reducing agent and quantifying each resulting fragment by HPLC measurement (HPLC method). The conjugation between the antibody and the drug-ligand intermediate Petition 870250088320, dated 09 / 29 / 2025, p. 98 / 148 / 117 and the calculation of the average number of drug molecules conjugated per antibody molecule in the antibody-drug conjugate can be performed with reference to the description in International Publications Nos. WO 2014 / 057687, WO 2015 / 098099, WO 2015 / 115091, WO 2015 / 155998, WO 2018 / 135501 and WO 2018 / 212136, etc.

[00333] In some embodiments, the average number of drug-ligand units conjugated per antibody molecule in the anti-CDH6 antibody-drug conjugate, according to the present invention, is preferably from 1 to 10, more preferably from 2 to 8, even more preferably from 5 to 8, even more preferably from 7 to 8, even more preferably from 7.5 to 8, and even more preferably from approximately 8.

[00334] In other embodiments, the number of the drug or drug ligand conjugated per antibody molecule in the anti-CDH6 antibody-drug conjugate, according to the present invention, is an integer in the range of, preferably, 2 to 8, more preferably selected from 2, 4, 6 or 8, and even more preferably 8.

[00335] The anti-CDH6 antibody-drug conjugate can be produced with reference to the description in International Publication No. WO 2018 / 212136, etc. 5. Hypoxia-inducible factor-2a (HIF-2a) inhibitor

[00336] In the present invention, the term HIF-2a activity refers to physiological and / or biological activity mediated by HIF-2a. Examples of this may include HIF-2a-mediated gene transcription activity.

[00337] In the present invention, the term HIF-2a inhibitor refers to an agent that slows down, reduces, alters, completely eliminates and / or prevents the activity of HIF-2a (for example, the transcriptional activity of HIF-2a).

[00338] The HIF-2a inhibitor according to the present invention is not particularly limited, provided that the agent exhibits the properties Petition 870250088320, dated 09 / 29 / 2025, p. 99 / 148 / 117 described above. The HIF-2a inhibitor may be a low molecular weight compound, an antibody, a functional antibody fragment, a fusion protein, an immunoadhesin, a nucleic acid, an oligonucleotide, an aptamer or a polypeptide, and is preferably a low molecular weight compound. In the present invention, the low molecular weight compound is an organic compound with a molecular weight of 1,000 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.

[00339] The HIF-2a inhibitor according to the present invention may preferably be belzutifan (also referred to as MK-6482 or PT2977), NKT2152 (see, for example, the following literature A), DFF332 (see, for example, the following literature B), AB521 (see, for example, the following literature C), BPI-452080 (see, for example, the following literature D), PT2385 or PT2399, or a pharmaceutically acceptable salt thereof. More preferably, the HIF-2a inhibitor may be belzutifan, NKT2152, DFF332, AB521 or BPI-452080, or a pharmaceutically acceptable salt thereof. Even more preferably, the HIF-2a inhibitor may be belzutifan or NKT2152, or a pharmaceutically acceptable salt thereof. Even more preferably, the HIF-2a inhibitor may be belzutifan or a pharmaceutically acceptable salt thereof.

[00340] A: A Study with NKT2152, a HIF2a Inhibitor, in Patients with Advanced Clear Cell Renal Carcinoma, [online], November 15, 2021 (First Publication), National Library of Medicine (National Institutes of Health), [accessed February 10, 2023], Petition 870250088320, dated 09 / 29 / 2025, pages 100 / 148 / 117 internet<URL: clinicaltrials.gov / ct2 / show / NCT05119335>

[00341] B: DFF332 as a Single Agent and in Combination with Everolimus and Immuno-oncology Agents in Advanced / Recurrent Renal Cancer and Other Malignancies, [online], May 20, 2021 (First Publication), National Library of Medicine (National Institutes of Health), [accessed February 10, 2023], internet<URL: clinicaltrials.gov / ct2 / show / NCT04895748>

[00342] C: A Phase 1 Study of AB521 in Renal Cell Carcinoma and Other Solid Tumors (ARC-20), [online], September 10, 2022 (First Publication), National Library of Medicine (National Institutes of Health), [retrieved February 10, 2023], Internet<URL: clinicaltrials.gov / ct2 / show / NCT05536141 >

[00343] D: Wang et al., Cancer Res (2023) 83 (7_Supplement): 494.

[00344] Belzutifan refers to a compound represented by the following formula: [Formula 14] (Non-Patented Literature 3).

[00345] The pharmaceutically acceptable salt of the HIF-2oc inhibitor used in the present invention may be an acid addition salt or a base addition salt. Examples of acid addition salts may include lower alkanesulfonates such as camsylate (camphorsulfonate), mesylate (methanesulfonate), trifluoromethanesulfonate and ethanesulfonate; arylsulfonates such as tosylate (p-toluenesulfonate) and benzenesulfonate; salts of inorganic acids such as phosphate, nitrate, perchlorate and sulfate; salts of Petition 870250088320, dated 09 / 29 / 2025, page 101 / 148 / 117 hydrogen halide, such as hydrochloride, hydrobromide, iodide and fluoride; salts of organic acids, such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalate and maleate; and salts of amino acids, such as ornithinate, glutamate and aspartate.Examples of base addition salts may include alkali metal salts, such as sodium salt, potassium salt, and lithium salt; alkaline earth metal salts, such as calcium salt and magnesium salt; inorganic salts, such as ammonium salt; organic amine salts, such as dibenzylamine salt, morpholine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, diethanolamine salt, N-benzyl-N-(2-phenylethoxy)amine salt, piperazine salt, tetramethylammonium salt, and tris(hydroxymethyl)aminomethane salt; and amino acid salts, such as alginate.

[00346] The HIF-2a inhibitor and its pharmaceutically acceptable salt used in the present invention may be present as solvates. These solvates are also included in the HIF-2a inhibitor and its pharmaceutically acceptable salt used in the present invention.

[00347] The pharmaceutical composition of the present invention can be administered as a pharmaceutical composition containing a pharmaceutically acceptable vehicle, diluent, solubilizer, emulsifier, preservative, adjuvant and the like. The pharmaceutically acceptable vehicle and the like can be suitably selected from a wide range, depending on the type of target disease or the pharmaceutical form of the agent. The pharmaceutically acceptable vehicle and the like include, for example, sterile liquid. In this case, the liquid includes, for example, water and oil (petroleum and oil of animal, vegetable or synthetic origin). The oil can be, for example, peanut oil, soybean oil, mineral oil or sesame oil. Water is a more typical liquid when the above pharmaceutical composition is administered intravenously. Saline solution, an aqueous solution Petition 870250088320, dated 09 / 29 / 2025, pp. 102 / 148 / 117. Dextrose and an aqueous glycerol solution can also be used as the liquid, in particular for an injectable solution. A suitable pharmaceutical vehicle can be selected from those known in the art. Examples of suitable pharmaceutically acceptable vehicles are described in Remington's Pharmaceutical Sciences, by E.W. Martin. The formulations correspond to the route of administration.

[00348] A method of administration may be appropriately selected. For example, administration by injection may be performed, and local, intraperitoneal, selective intravenous, intravenous, subcutaneous, organ perfusate or similar injections may be adopted. Administration may be by injection or bolus injection, for example. An injectable solution may be formulated using a vehicle formed from a saline solution, a glucose solution or a mixture of saline and a glucose solution, various buffer solutions and the like. Alternatively, the injectable solution may be prepared by mixing a powder formulation with the liquid vehicle at the time of use. According to a specific preferred embodiment, the administration of the pharmaceutical composition used in the present invention is performed by injection. Parenteral administration is a preferred route of administration.

[00349] Other methods of administration may also be appropriately selected along with the development of a formulation. In the case of oral administration, for example, an oral solution, a powder, a tablet, a capsule, and a lozenge are applicable. The oral solution may be produced as a liquid oral preparation, such as a suspension and a syrup, using, for example: water; sugars such as sucrose, sorbitol, and fructose; glycols such as polyethylene glycol; oils such as sesame oil and soybean oil; antiseptics such as alkyl p-hydroxybenzoate; and flavorings such as strawberry and peppermint. The powder, tablet, capsule, and lozenge may be formulated using, for example: a Petition 870250088320, dated 09 / 29 / 2025, p. 103 / 148 / 117 excipient such as lactose, glucose, sucrose or mannitol; a disintegrant such as starch or sodium alginate; a lubricant such as magnesium stearate or talc; a binder such as polyvinyl alcohol, hydroxypropylcellulose or gelatin; a surfactant such as a fatty acid ester; and / or a plasticizer such as glycerin. Tablets and capsules are preferred unit pharmaceutical forms due to their ease of administration. A solid pharmaceutical vehicle is used in the production of the tablet or capsule. 6. Medication

[00350] The pharmaceutical composition and treatment method according to the present invention will be described below, in which an anti-CDH6 antibody-drug conjugate and an HIF-2a inhibitor are administered in combination. The present invention includes a pharmaceutical composition comprising an anti-CDH6 antibody-drug conjugate for use in combination with an HIF-2a inhibitor or administered in combination with an HIF-2a inhibitor.

[00351] In the pharmaceutical composition and treatment method of the present invention, the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor may be contained separately as active components in different formulations and administered at the same time (a person skilled in the art would naturally understand that at the same time may or may not be approximately at the same time) or at different times, or the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor may be contained as active components in a single formulation for administration.

[00352] In the pharmaceutical composition and treatment method of the present invention, two or more types of HIF-2a inhibitors used in the present invention can be combined for administration. The pharmaceutical composition and treatment method of the present invention can be used to treat cancer, and can preferably be used to treat cancer. Petition 870250088320, dated 09 / 29 / 2025, page 104 / 148 / 117 at least one selected from the group consisting of renal cell carcinoma, clear cell renal carcinoma, papillary renal cell carcinoma, ovarian cancer, serous ovarian adenocarcinoma, clear cell ovarian carcinoma, endometrioid ovarian cancer, mucinous ovarian 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, stomach cancer, endometrial cancer, uterine body cancer, nasopharyngeal cancer, prostate cancer and cancer related to von Hippel-Lindau disease,These drugs may be used in a more preferred manner to treat 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, renal 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, and neuroblastoma; they may also be used in a more preferred manner to treat at least one cancer 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, and ovarian mucinous tumor, and may even be used more preferably to treat at least one cancer selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, and papillary renal cell carcinoma. Petition 870250088320, dated 09 / 29 / 2025, pp. 105 / 148 / 117

[00353] Cancer related to Von Hippel-Lindau disease is preferably renal cell carcinoma related to Von Hippel-Lindau disease, central nervous system hemangioblastoma related to Von Hippel-Lindau disease, or pancreatic neuroendocrine tumor related to Von Hippel-Lindau disease, and more preferably renal cell carcinoma related to Von Hippel-Lindau disease (renal cell carcinoma does not require immediate surgery), central nervous system hemangioblastoma related to Von Hippel-Lindau disease (central nervous system hemangioblastoma does not require immediate surgery), or pancreatic neuroendocrine tumor related to Von Hippel-Lindau disease (pancreatic neuroendocrine tumor does not require immediate surgery).

[00354] The pharmaceutical composition and treatment method of the present invention can be used to treat cancer with a mutation in the VHL gene and, preferably, to treat renal cell carcinoma, renal clear cell carcinoma or papillary renal cell carcinoma (renal cell carcinoma, renal clear cell carcinoma or papillary renal cell carcinoma has a mutation in the VHL gene).

[00355] The pharmaceutical composition and treatment method of the present invention can be used to treat cancer without a mutation in the VHL gene and, preferably, to treat renal cell carcinoma, renal clear cell carcinoma or papillary renal cell carcinoma (renal cell carcinoma, renal clear cell carcinoma or papillary renal cell carcinoma does not have a mutation in the VHL gene).

[00356] The VHL gene is a gene that encodes a von Hippel-Lindau tumor suppressor (also called pVHL).

[00357] The anti-CDH6 antibody-drug conjugate used in the present invention can be used in a preferred manner when CDH6 expression is confirmed in cancer. Petition 870250088320, dated 09 / 29 / 2025, pp. 106 / 148 / 117

[00358] The presence or absence of a CDH6 tumor marker can be confirmed, for example, by collecting tumor tissue from a cancer patient, preparing formalin-fixed paraffin-embedded (FFPE) samples, and performing a gene product (protein) level test by immunohistochemistry (IHC), flow cytometry, Western blot, or similar methods, or a gene transcription level test by in situ hybridization (ISH), quantitative PCR (q-PCR), microarray analysis, or similar methods, or it can also be confirmed by collecting circulating cell-free tumor DNA (ctDNA) from a cancer patient and performing a test using a next-generation sequencer (NGS) or similar devices.

[00359] The pharmaceutical composition and treatment method of the present invention can preferably be used in mammals and, more preferably, in humans.

[00360] The antitumor effect of the pharmaceutical composition and treatment method of the present invention can be confirmed, for example, by generating a model in which cancer cells are transplanted into a test animal and measuring the reduction in tumor volume or the life-prolonging effects due to the application of the pharmaceutical composition and treatment method of the present invention. Furthermore, comparison with the antitumor effect of single administrations of each of the antibody-drug conjugates and HIF-2a inhibitor used in the present invention can confirm the combined effect of the antibody-drug conjugate and the HIF-2a inhibitor used in the present invention.

[00361] Furthermore, the antitumor effect of the pharmaceutical composition and treatment method of the present invention can be confirmed in a clinical study using the WHO Response Evaluation Criteria in Solid Tumors (RECIST) assessment methods, the MacDonald method, body weight measurement, and other methods; and can be determined by indicators such as Complete Response (CR), Partial Response (PR), Disease Petition 870250088320, dated 09 / 29 / 2025, pages 107 / 148 / 117 Progressive Matrices (PM), Objective Response Rate (ORR), Duration of Response (DDR), Progression-Free Survival (PFS), and Overall Survival (OS).

[00362] The above methods can confirm the superiority in terms of the antitumor effect of the pharmaceutical composition and treatment method of the present invention compared with existing pharmaceutical compositions and treatment methods for cancer therapy.

[00363] The pharmaceutical composition and treatment method of the present invention can retard the growth of cancer cells, suppress their proliferation, and even kill cancer cells. These effects can allow cancer patients to get rid of cancer symptoms or achieve an improvement in the quality of life of cancer patients and obtain a therapeutic effect, prolonging their lives. Even if the pharmaceutical composition or treatment method does not manage to kill cancer cells, it can provide a higher quality of life for cancer patients while achieving longer survival by inhibiting or controlling the growth of cancer cells.

[00364] The pharmaceutical composition of the present invention can acquire a therapeutic effect through application as systemic therapy in patients and, additionally, through local application in cancerous tissues.

[00365] The pharmaceutical composition of the present invention can be administered as a composition comprising one or more pharmaceutically compatible components. The pharmaceutically compatible components can be suitably selected for use from pharmaceutical additives and the like commonly used in the art, depending on the doses, administration concentrations, etc., of the antibody-drug conjugate and the HIF-2a inhibitor used in the present invention. For example, the antibody-drug conjugate used in the present Petition 870250088320, dated 09 / 29 / 2025, pp. 108 / 148 / 117. The invention can 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. The pharmaceutical composition comprising the anti-CDH6 antibody-drug conjugate used in the present invention can preferably be used as an injection, more preferably as an aqueous injection or a lyophilized injection, and even more preferably as a lyophilized injection.

[00366] In the case of an aqueous injection, the pharmaceutical composition comprising the anti-CDH6 antibody-drug conjugate used in the present invention may preferably be diluted with an appropriate diluent and then administered by intravenous drip. Examples of diluents may include glucose and saline solutions, may preferably include glucose solutions, and more preferably, 5% glucose solutions.

[00367] In the case of a lyophilized injection, the pharmaceutical composition comprising the anti-CDH6 antibody-drug conjugate used in the present invention may preferably be dissolved in water for injection, diluted to the required amount with an appropriate diluent, and then administered by intravenous drip. Examples of diluents may include glucose and saline solutions, may preferably include glucose solutions, and more preferably, 5% glucose solutions.

[00368] Examples of routes of administration that can be used to administer the pharmaceutical composition of the present invention may include intravenous, intradermal, subcutaneous, intramuscular and intraperitoneal routes, and may preferably include intravenous routes.

[00369] The anti-CDH6 antibody-drug conjugate used in the present invention can be administered to a human being once in Petition 870250088320, dated 09 / 29 / 2025, pp. 109 / 148 100 / 117 intervals of 1 to 180 days, may be administered in a preferred manner once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks or once every 10 weeks, and may be administered in a more preferred manner once every 3 weeks or once every 4 weeks, and may be administered in a still more preferred manner once every 3 weeks.The anti-CDH6 antibody-drug conjugate used in the present invention can be administered at a dose of approximately 0.001 to 100 mg / kg per administration, and can be administered in a preferred manner at approximately 0.1 to approximately 15 mg / kg, in a more preferred manner at approximately 0.5 to approximately 12 mg / kg, in a still more preferred manner at approximately 1.0 to approximately 10 mg / kg, in a still more preferred manner at approximately 1.6 to approximately 9.6 mg / kg, and in a still more preferred manner at approximately 4.8 to approximately 8.0 mg / kg per administration.

[00370] The anti-CDH6 antibody-drug conjugate used in the present invention can be administered in approximately 0.1, approximately 0.2, approximately 0.3, approximately 0.4, approximately 0.5, approximately 0.6, approximately 0.7, approximately 0.8, approximately 0.9, approximately 1.0, approximately 1.1, approximately 1.2, approximately 1.3, approximately 1.4, approximately 1.5, approximately 1.6, approximately 1.7, approximately 1.8, approximately 1.9, approximately 2.0, approximately 2.1, approximately 2.2, approximately 2.3, approximately 2.4, approximately 2.5, approximately 2.6, approximately 2.7, approximately 2.8, approximately 2.9, approximately 3.0, approximately 3.1, approximately 3.2, approximately 3.3, approximately 3.4, approximately 3.5, Petition 870250088320, dated 09 / 29 / 2025, pp. 110 / 148 101 / 117 approximately 3.6, approximately 3.7, approximately 3.8, approximately 3.9, approximately 4.0, approximately 4.1, approximately 4.2, approximately 4.3, approximately 4.4, approximately 4.5, approximately 4.6, approximately 4.7, approximately 4.8, approximately 4.9, approximately 5.0, approximately 5.1, approximately 5.2, approximately 5.3, approximately 5.4, approximately 5.5, approximately 5.6, approximately 5.7, approximately 5.8, approximately 5.9, approximately 6.0, approximately 6.1, approximately 6.2, approximately 6.3, approximately 6.4, approximately 6.5, approximately 6.6, approximately 6.7, approximately 6.8, approximately 6.9, approximately 7.0, approximately 7.1, approximately 7.2, approximately 7.3, approximately 7.4, approximately 7.5, approximately 7.6 approximately 7.7, approximately 7.8, approximately 7.9, approximately 8.0, approximately 8.1, approximately 8.2,approximately 8.3, approximately 8.4, approximately 8.5, approximately 8.6, approximately 8.7, approximately 8.8, approximately 8.9, approximately 9.0, approximately 9.1, approximately 9.2, approximately 9.3, approximately 9.4, approximately 9.5, approximately 9.6, approximately 9.7, approximately 9.8, approximately 9.9, approximately 10.0, approximately 10.1, approximately 10.2, approximately 10.3, approximately 10.4, approximately 10.5, approximately 10.6, approximately 10.7, approximately 10.8, approximately 10.9, approximately 11.0, approximately 11.1, approximately 11.2, approximately 11.3, approximately 11.4, approximately 11.5, approximately 11.6, approximately 11.7, approximately 11.8, approximately 11.9 or, approximately 12.0 mg / kg or more per administration. Petition 870250088320, dated 09 / 29 / 2025, pp. 111 / 148 102 / 117

[00371] The anti-CDH6 antibody-drug conjugate used in the present invention can preferably be administered at approximately 1.6 mg / kg, approximately 3.2 mg / kg, approximately 4.8 mg / kg, approximately 5.4 mg / kg, approximately 5.6 mg / kg, approximately 6.4 mg / kg, approximately 8.0 mg / kg or approximately 9.6 mg / kg per administration, can more preferably be administered at approximately 3.2 mg / kg, approximately 4.8 mg / kg, approximately 5.4 mg / kg, approximately 5.6 mg / kg, approximately 6.4 mg / kg, approximately 8.0 mg / kg or approximately 9.6 mg / kg, and can still more preferably be administered at approximately 4.8 mg / kg, approximately 5.4 mg / kg, approximately 5.6 mg / kg, approximately 6.4 mg / kg or approximately 8.0 mg / kg.

[00372] 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 at a dose of 0.1 to 15 mg / kg, more preferably at a dose of 0.5 to 12 mg / kg, even more preferably at a dose of 1.0 to 10 mg / kg, even more preferably at a dose of 1.6 to 9.6 mg / kg, and even more preferably at a dose of 4.8 to 8.0 mg / kg per administration. The anti-CDH6 antibody-drug conjugate used in the present invention can be administered in 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, 2,6, 2,7, 2,8, 2,9, 3,0, 3,1, 3,2, 3,3, 3,4, 3,5,3,6, 3,7, 3,8, 3,9, 4,0, 4,1, 4,2, 4,3, 4,4, 4,5, 4,6, 4,7, 4,8, 4,9, 5,0, 5,1, 5,2, 5,3,5,4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2 7,3, 7,4, 7,5, 7,6, 7,7, 7,8, 7,9, 8,0, 8,1, 8,2, 8,3, 8,4, 8,5, 8,6, 8,7, 8,8, 8,9,9,0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9 or 12.0 mg / kg or more per administration.

[00373] The anti-CDH6 antibody-drug conjugate used in Petition 870250088320, dated 09 / 29 / 2025, pp. 112 / 148 103 / 117 The present invention can preferably be administered in doses of 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 administration, more preferably in doses of 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 in doses of 4.8 mg, 5.4 mg / kg, 5.6 mg / kg, 6.4 mg / kg or 8.0 mg / kg.

[00374] The anti-CDH6 antibody-drug conjugate used in the present invention can be administered at a dose of approximately 5 to approximately 3,000 mg per administration, can preferably be administered at a dose of approximately 10 to approximately 2,000 mg, can more preferably be administered at a dose of approximately 100 to approximately 1,500 mg, and can still more preferably be administered at a dose of approximately 200 to approximately 1,000 mg.

[00375] The anti-CDH6 antibody-drug conjugate used in the present invention can preferably be administered in a dose of approximately 200 mg, approximately 205 mg, approximately 210 mg, approximately 215 mg, approximately 220 mg, approximately 225 mg, approximately 230 mg, approximately 235 mg, approximately 240 mg, approximately 245 mg, approximately 250 mg, approximately 255 mg, approximately 260 mg, approximately 265 mg, approximately 270 mg, approximately 275 mg, approximately 280 mg, approximately 285 mg, approximately 290 mg, approximately 295 mg, approximately 300 mg, approximately 305 mg, approximately 310 mg, approximately 315 mg, approximately 320 mg, approximately 325 mg, approximately 330 mg, approximately 335 mg, approximately 340 mg, approximately 345 mg, approximately 350 mg, approximately 355 mg, approximately 360 mg, approximately 365 mg, approximately 370 Petition 870250088320, dated 09 / 29 / 2025, pp. 113 / 148 104 / 117 mg, approximately 375 mg, approximately 380 mg, approximately 385 mg, approximately 390 mg, approximately 395 mg, approximately 400 mg, approximately 405 mg, approximately 410 mg, approximately 415 mg, approximately 420 mg, approximately 425 mg, approximately 430 mg, approximately 435 mg, approximately 440 mg, approximately 445 mg, approximately 450 mg, approximately 455 mg, approximately 460 mg, approximately 465 mg, approximately 470 mg, approximately 475 mg, approximately 480 mg, approximately 485 mg, approximately 490 mg, approximately 495 mg, approximately 500 mg, approximately 505 mg, approximately 510 mg, approximately 515 mg, approximately 520 mg, approximately 525 mg, approximately 530 mg, approximately 535 mg, approximately 540 mg, approximately 545 mg, approximately 550 mg, approximately 555 mg, approximately 560 mg, approximately 565 mg, approximately 570 mg, approximately 575 mg,approximately 580 mg, approximately 585 mg, approximately 590 mg, approximately 595 mg, approximately 600 mg, approximately 605 mg, approximately 610 mg, approximately 615 mg, approximately 620 mg, approximately 625 mg, approximately 630 mg, approximately 635 mg, approximately 640 mg, approximately 645 mg, approximately 650 mg, approximately 655 mg, approximately 660 mg, approximately 665 mg, approximately 670 mg, approximately 675 mg, approximately 680 mg, approximately 685 mg, approximately 690 mg, approximately 695 mg, approximately 700 mg, approximately 705 mg, approximately 710 mg, approximately 715 mg, approximately 720 mg, approximately 725 mg, approximately 730 mg, approximately 735 mg, approximately 740 mg, approximately 745 mg, approximately 750 mg, approximately 755 mg Petition 870250088320, dated 09 / 29 / 2025, pp. 114 / 148 105 / 117 approximately 760 mg, approximately 765 mg, approximately 770 mg, approximately 775 mg, approximately 780 mg, approximately 785 mg, approximately 790 mg, approximately 795 mg, approximately 800 mg, approximately 805 mg, approximately 810 mg, approximately 815 mg, approximately 820 mg, approximately 825 mg, approximately 830 mg, approximately 835 mg, approximately 840 mg, approximately 845 mg, approximately 850 mg, approximately 855 mg, approximately 860 mg, approximately 865 mg, approximately 870 mg, approximately 875 mg, approximately 880 mg, approximately 885 mg, approximately 890 mg, approximately 895 mg, approximately 900 mg, approximately 905 mg, approximately 910 mg, approximately 915 mg, approximately 920 mg, approximately 925 mg, approximately 930 mg, approximately 935 mg, approximately 940 mg, approximately 945 mg, approximately 950 mg, approximately 955 mg, approximately 960 mg,Approximately 965 mg, approximately 970 mg, approximately 975 mg, approximately 980 mg, approximately 985 mg, approximately 990 mg, approximately 995 mg, or approximately 1,000 mg per administration.

[00376] The anti-CDH6 antibody-drug conjugate used in the present invention can preferably be administered in doses of 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg,285mg, 290mg, 295mg, 300mg, 305mg, 310mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg,370mg, 375mg, 380mg, 385mg, 390mg, 395mg, 400mg, 405mg, 410mg, 415mg, 420mg, 425mg, 430mg, 435mg, 440mg, 445mg, 450mg,455mg, 460mg, 465mg, 470mg, 475mg, 480mg, 485mg, 490mg, 495mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg,540 Petição 870250088320, de 29 / 09 / 2025, pág. 115 / 148 106 / 117 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg, 605 mg, 610 mg, 615 mg, 620 mg, 625 mg, 630 mg, 635 mg, 640 mg, 645 mg, 650 mg, 655 mg, 660 mg, 665 mg, 670 mg, 675 mg, 680 mg, 685 mg, 690 mg, 695 mg, 700 mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg, 750 mg, 755 mg, 760 mg, 765 mg, 770 mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 mg, 800 mg, 805 mg, 810 mg, 815 mg, 820 mg, 825 mg, 830 mg, 835mg, 840 mg, 845 mg, 850 mg, 855 mg, 860 mg, 865 mg, 870 mg, 875 mg,880 mg, 885 mg, 890 mg, 895 mg, 900 mg, 905 mg, 910 mg, 915 mg, 920mg, 925 mg, 930 mg, 935 mg, 940 mg, 945 mg, 950 mg, 955 mg, 960 mg,965 mg, 970 mg, 975 mg, 980 mg, 985 mg, 990 mg, 995 mg ou 1.000 mg por administração.

[00377] The dosage 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), 1.3 mg / kg (q3w), 1.6 mg / kg (q3w), 1.7 mg / kg (q3w), 2.0 mg / kg (q3w), 2.1 mg / kg (q3w) mg / kg (q3w), 4.4 mg / kg (q3w), 4.5 mg / kg (q3w), 4.8 mg / kg (q3w), 4.9 mg / kg (q3w), 5.2 mg / kg (q3w), 5.3 mg / kg (q3w), 5.6 mg / kg (q3w), 5.7 mg / kg (q3w), 1.4 mg / kg (q3w), 1.5 mg / kg (q3w), 1.8 mg / kg (q3w), 1.9 mg / kg (q3w), 2.2 mg / kg (q3w), 2.3 mg / kg (q3w), 2.6 mg / kg (q3w), 2.7 mg / kg (q3w), 3.0 mg / kg (q3w), 3.1 mg / kg (q3w), 3.4 mg / kg (q3w), 3.5 mg / kg (q3w), 3.8 mg / kg (q3w), 3.9 mg / kg (q3w),4.2 mg / kg (q3w), 4.3 mg / kg (q3w), 4.6 mg / kg (q3w), 4.7 mg / kg (q3w), 5.0 mg / kg (q3w), 5.1 mg / kg (q3w), 5.4 mg / kg (q3w), 5.5 mg / kg (q3w), 5.8 mg / kg (q3w), 5.9 mg / kg, Petition 870250088320, dated 09 / 29 / 2025, pp. 116 / 148 107 / 117 (q3w), 6,0 mg / kg (q3w), 6,4 mg / kg (q3w), 6,8 mg / kg (q3w), 7,2 mg / kg (q3w), 7,6 mg / kg (q3w), 8,0 mg / kg (q3w), 8,4 mg / kg (q3w), 8,8 mg / kg (q3w), 9,2 mg / kg (q3w), 9,6 mg / kg (q3w), 6,1 mg / kg (q3w), 6,5 mg / kg (q3w), 6,9 mg / kg (q3w), 7,3 mg / kg (q3w), 7,7 mg / kg (q3w), 8,1 mg / kg (q3w), 8,5 mg / kg (q3w), 8,9 mg / kg (q3w), 9,3 mg / kg (q3w), 9,7 mg / kg (q3w), 6,2 mg / kg (q3w), 6,6 mg / kg (q3w), 7,0 mg / kg (q3w), 7,4 mg / kg (q3w), 7,8 mg / kg (q3w), 8,2 mg / kg (q3w), 8,6 mg / kg (q3w), 9,0 mg / kg (q3w), 9,4 mg / kg (q3w), 9,8 mg / kg (q3w), 6,3 mg / kg (q3w), 6,7 mg / kg (q3w), 7,1 mg / kg (q3w), 7,5 mg / kg (q3w), 7,9 mg / kg (q3w), 8,3 mg / kg (q3w), 8,7 mg / kg (q3w), 9,1 mg / kg (q3w), 9,5 mg / kg (q3w), 9,9 mg / kg (q3w), 10,0 mg / kg (q3w), 10,1 mg / kg (q3w), 10,2 mg / kg (q3w), 10,3 mg / kg (q3w), 10,4 mg / kg (q3w), 10,5 mg / kg (q3w), 10,6 mg / kg (q3w), 10,7 mg / kg (q3w), 10,8 mg / kg (q3w), 10,9 mg / kg (q3w), 11,0 mg / kg (q3w), 11,1 mg / kg (q3w), 11,2 mg / kg (q3w), 11,3 mg / kg (q3w), 11,4 mg / kg (q3w), 11,5 mg / kg (q3w), 11,6 mg / kg (q3w), 11.7 mg / kg (q3w), 11.8 mg / kg (q3w), 11.9 mg / kg (q3w) or 12.0 mg / kg (q3w). The dosage 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), more preferably 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) or 8.0 mg / kg (q3w), and even more preferably 4.8 mg / kg (q3w), 5.4 mg / kg (q3w), 5.6 mg / kg (q3w), 6.4 mg / kg (q3w) or 8.0 mg / kg (q3w). The dosage 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), 285 mg (q3w), 290 mg (q3w), 295 mg (q3w), 300 mg (q3w),305 mg (q3w), 310 mg (q3w), 315 mg (q3w), 320 mg (q3w), 325, Petition 870250088320, dated 09 / 29 / 2025, pp. 117 / 148 108 / 117 mg (q3w), 330 mg (q3w), 335 mg (q3w), 340 mg (q3w), 345 mg (q3w),350 mg (q3w), 355 mg (q3w), 360 mg (q3w), 365 mg (q3w), 370 mg (q3w),375 mg (q3w), 380 mg (q3w), 385 mg (q3w), 390 mg (q3w), 395 mg (q3w),400 mg (q3w), 405 mg (q3w), 410 mg (q3w), 415 mg (q3w), 420 mg (q3w),425 mg (q3w), 430 mg (q3w), 435 mg (q3w), 440 mg (q3w), 445 mg (q3w),450 mg (q3w), 455 mg (q3w), 460 mg (q3w), 465 mg (q3w), 470 mg (q3w),475 mg (q3w), 480 mg (q3w), 485 mg (q3w), 490 mg (q3w), 495 mg (q3w),500 mg (q3w), 505 mg (q3w), 510 mg (q3w), 515 mg (q3w), 520 mg (q3w),525 mg (q3w), 530 mg (q3w), 535 mg (q3w), 540 mg (q3w), 545 mg (q3w),550 mg (q3w), 555 mg (q3w), 560 mg (q3w), 565 mg (q3w), 570 mg (q3w),575 mg (q3w), 580 mg (q3w), 585 mg (q3w), 590 mg (q3w), 595 mg (q3w),600 mg (q3w), 605 mg (q3w), 610 mg (q3w), 615 mg (q3w), 620 mg (q3w),625 mg (q3w), 630 mg (q3w), 635 mg (q3w), 640 mg (q3w), 645 mg (q3w),650 mg (q3w), 655 mg (q3w), 660 mg (q3w), 665 mg (q3w), 670 mg (q3w),675 mg (q3w), 680 mg (q3w),685 mg (q3w), 690 mg (q3w), 695 mg (q3w),700 mg (q3w), 705 mg (q3w), 710 mg (q3w), 715 mg (q3w), 720 mg (q3w),725 mg (q3w), 730 mg (q3w), 735 mg (q3w), 740 mg (q3w), 745 mg (q3w),750 mg (q3w), 755 mg (q3w), 760 mg (q3w), 765 mg (q3w), 770 mg (q3w),775 mg (q3w), 780 mg (q3w), 785 mg (q3w), 790 mg (q3w), 795 mg (q3w),800 mg (q3w), 805 mg (q3w), 810 mg (q3w), 815 mg (q3w), 820 mg (q3w),825 mg (q3w), 830 mg (q3w), 835 mg (q3w), 840 mg (q3w), 845 mg (q3w),850 mg (q3w), 855 mg (q3w), 860 mg (q3w), 865 mg (q3w), 870 mg (q3w),875 mg (q3w), 880 mg (q3w), 885 mg (q3w), 890 mg (q3w), 895 mg (q3w),900 mg (q3w), 905 mg (q3w), 910 mg (q3w), 915 mg (q3w), 920 mg (q3w),925 mg (q3w), 930 mg (q3w), 935 mg (q3w), 940 mg (q3w), 945 mg (q3w),950 mg (q3w), 955 mg (q3w), 960 mg (q3w), 965 mg (q3w), 970 mg (q3w),975 mg (q3w), 980 mg (q3w), 985 mg (q3w), 990 mg (q3w), 995 mg (q3w) ou 1.000 mg (q3w). O inibidor de HIF-2a, de acordo com a presente invenção,It can be administered orally to humans at intervals of one or two doses. Petition 870250088320, dated 09 / 29 / 2025, pp. 118 / 148 109 / 117 times a day up to once or twice every 7 days, and may preferably be administered at once or twice-daily intervals. The HIF-2a inhibitor used in the present invention may be administered orally at a dose of 0.1 mg to 3,000 mg per administration, and may preferably be administered at a dose of 2.5 mg to 600 mg per administration. The HIF-2a inhibitor, according to the present invention, may be administered to humans intravenously at intervals of 1 to 180 days, and may preferably be administered intravenously once a week, once every 2 weeks, once every 3 weeks, or once every 4 weeks. The HIF-2a inhibitor used in the present invention can be administered intravenously (drip) at a dose of 0.1 mg to 3,000 mg per administration, and preferably intravenously (drip) at a dose of 10 mg to 100 mg per administration.

[00378] When the HIF-2a inhibitor used in this invention is belzutifan or a pharmaceutically acceptable salt thereof, examples of the method of administration include, but are not limited to, the following dosages and administrations. For example, belzutifan can be administered at a dose of 5 to 1,000 mg per administration, at intervals of one, two, three, four, or five times a day.

[00379] As for other dosage and administration, belzutifan can be administered orally at a dose of 20 to 240 mg per administration, at once-daily intervals.

[00380] As for other dosage and administration, belzutifan can be administered orally at a dose of 20, 40, 80, 120, 160 or 240 mg (preferably 40, 80 or 120 mg) per administration, at once-daily intervals.

[00381] As for other dosage and administration, belzutifan can be administered orally at a dose of 120 mg per administration, at once-daily intervals. Petition 870250088320, dated 09 / 29 / 2025, pp. 119 / 148 110 / 117

[00382] As for other dosage and administration, belzutifan can be administered orally at a dose of 80 mg per administration, at once-daily intervals.

[00383] As for other dosage and administration, belzutifan can be administered orally at a dose of 40 mg per administration, at once-daily intervals.

[00384] 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 according to the present invention and the HIF-2a inhibitor. The pharmaceutical composition and treatment method of the present invention may also be administered in combination with an additional cancer therapeutic agent, thereby enhancing the antitumor effect. The additional cancer therapeutic agent used for this purpose may be administered to an individual simultaneously (approximately at the same time), separately, or continuously, together with the pharmaceutical composition of the present invention. Alternatively, the additional therapeutic agent and the pharmaceutical composition may be administered to the individual at different administration intervals. Such a cancer therapeutic agent is not limited, provided it has antitumor activity.Examples of these may include at least one selected from the group consisting of irinotecan (CPT-11), cisplatin, carboplatin, oxaliplatin, fluorouracil (5FU), gemcitabine, capecitabine, doxorubicin, epirubicin, cyclophosphamide, mitomycin C, tegafur / gimeracil / oteracil, panitumumab, bevacizumab, ramucirumab, regorafenib, trifluridine / tipiracil, gefitinib, erlotinib, afatinib, methotrexate, pemetrexed, tamoxifen, toremifene, fulvestrant, leuprorelin, goserelin, letrozole, anastrozole, progesterone formulations, and lapatinib.

[00385] The pharmaceutical composition and method of treatment of Petition 870250088320, dated 09 / 29 / 2025, pages 120 / 148 111 / 117 The present invention can be used in combination with radiotherapy. For example, a cancer patient receives radiotherapy before and / or after, or at the same time (approximately at the same time) as treatment with the pharmaceutical composition of the present invention.

[00386] The pharmaceutical composition and treatment method of the present invention can be used as adjuvant chemotherapy combined with surgery. The pharmaceutical composition of the present invention can be administered with the aim of reducing tumor size before surgery (neoadjuvant chemotherapy) or it can be administered with the aim of preventing tumor recurrence after surgery (adjuvant chemotherapy).

[00387] The pharmaceutical composition and treatment method of the present invention can be used as maintenance therapy. For example, after initial chemotherapy, treatment is continued with the aim of preventing recurrence.

[00388] The present invention includes a method of treating a disease, comprising administering the anti-CDH6 antibody-drug conjugate of the present application and an HIF-2a inhibitor in combination to an individual in need of treatment. The present invention includes the anti-CDH6 antibody-drug conjugate of the present application for use in combination with an HIF-2a inhibitor for the treatment of a disease. The present invention includes the use of the anti-CDH6 antibody-drug conjugate of the present application combined with an HIF-2a inhibitor for the manufacture of a medicament for the treatment of a disease. The present invention includes a pharmaceutical product comprising the anti-CDH6 antibody-drug conjugate of the present application and an HIF-2a inhibitor. The present invention includes a combination medicament comprising the anti-CDH6 antibody-drug conjugate of the present application and an HIF-2a inhibitor. The present invention includes a pharmaceutical combination comprising the Petition 870250088320, dated 09 / 29 / 2025, pp. 121 / 148 112 / 117 anti-CDH6 antibody-drug conjugate of the present application and an HIF-2a inhibitor. The present invention includes the use of the anti-CDH6 antibody-drug conjugate of the present application combined with an HIF-2a inhibitor for the treatment of a disease. The present invention includes a medicament comprising the anti-CDH6 antibody-drug conjugate of the present application and an HIF-2a inhibitor. [Examples]

[00389] The present invention will now be described specifically in the following examples. However, these examples are not intended to limit the scope of the present invention. Furthermore, these examples should not be interpreted in a limiting manner in any way. Production Example 1: Production of anti-CDH6 antibody-drug conjugate

[00390] According to the production method described in International Publication No. WO 2018 / 212136, using a humanized anti-CDH6 antibody (antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 38), an antibody-drug conjugate was produced in which a drug-ligand represented by the formula: [Formula 15] where A represents a binding site for an antibody, it is conjugated to the anti-CDH6 antibody via a linkage. Petition 870250088320, dated 09 / 29 / 2025, pp. 122 / 148 113 / 117 thioether (hereinafter referred to as the anti-CDH6 antibody-drug conjugate (1)). The DAR of the anti-CDH6 antibody-drug conjugate (1) was 7.9. Production Example 2: Preparation of compound (B)

[00391] A compound (B) represented by the formula: [Formula 16] (belzutifan) was produced according to the production method described in the literature J. Med. Chem. 2019, 62, 6876 to 6893. Example 7: Antitumor test (1)

[00392] Mouse: Six-week-old female naked BALB / c mice (The Jackson Laboratory Japan, Inc.) were subjected to an experiment.

[00393] Measurement and calculation expression: The long and short diameters of each tumor were measured twice a week using electronic digital calipers (CD-15CX, Mitutoyo Corp.), and the tumor volume was then calculated. The following expression was used in the calculation. Tumor volume (mm3) = 1 / 2 x Long diameter (mm) x [Short diameter (mm)]2

[00394] The anti-CDH6 antibody-drug conjugate (1) was diluted with ABS buffer (10 mM acetate buffer (pH 5.5), 5% sorbitol) and the dilution was administered intravenously at a dose of 10 mL / kg into the tail of each mouse. Belzutifan was suspended in 10% dimethyl sulfoxide, 40% polyethylene glycol 300, 5% Tween-80 and 45% physiological saline solution, and the suspension was administered orally at a dose of 10 mL / kg.

[00395] Human renal cancer cell line 786-0 Petition 870250088320, dated 09 / 29 / 2025, pp. 123 / 148 114 / 117 cells acquired from the ATCC (American Type Culture Collection) were suspended in a Matrigel matrix, and the cell suspension was subcutaneously inoculated at a dose of 4 x 10⁶ cells in the right flank region of each naked female mouse. Thirty-one days after inoculation, the mice were randomly grouped (Day 0). The anti-CDH6 antibody-drug conjugate (1) was administered at a dose of 1 mg / kg on Day 0. Belzutifan was administered at a dose of 0.3 mg / kg once daily, five times a week for 3 weeks. Their respective single-dose and combined-dose groups, and an ABS-buffered-dose group as a control group, were established.

[00396] The result of the combined use of the anti-CDH6 antibody-drug conjugate (1) and belzutifan is shown in Figure 14. In Figure 14, the abscissa represents the number of days after the start of administration and the ordinate represents the tumor volume.

[00397] Tumor growth inhibition (TGI) is calculated according to the following expression. [Expression 2] TGI (%) = [1 - (Average tumor volume of the drug administration group / Average tumor volume of the control group)] x 100

[00398] The inhibition of tumor growth (TGI) at the response assessment date of single belzutifan administration (Day 21) was 29%. The TGI of single administration of the anti-CDH6 antibody-drug conjugate (1) was 43%. On the other hand, the combined administration of the anti-CDH6 antibody-drug conjugate (1) and belzutifan showed a significantly greater tumor growth suppression effect than single administration of the anti-CDH6 antibody-drug conjugate (1) and single administration of belzutifan (P = 0.0325 and P = 0.0028, respectively; calculated by Dunnett's test using a value obtained from tumor volume by common logarithmic transformation). The TGI of the combined administration Petition 870250088320, dated 09 / 29 / 2025, pages 124 / 148 115 / 117 (68%) was superior to that of the respective single administrations, demonstrating that combined use potentiates the antitumor effect. The change from baseline (%) (percentage change in mean tumor volume on Day 21 relative to mean tumor volume on Day 0 as baseline) was calculated according to the following expression and is shown in Figure 15. [Expression 3] Change from baseline (%) = (Mean tumor volume on Day 21 - Mean tumor volume on Day 0) / (Mean tumor volume on Day 0) x 100

[00399] Furthermore, the change from baseline (%) for each group is described in Table 1. As shown in Figure 15 and Table 1, the change from baseline (%) was a negative value in the combined administration group, demonstrating a strong combinatorial effect with regression. [Table 1] Compound Change from baseline (%) Anti-CDH6 antibody-drug conjugate (1) 25 Belzutifan 53 Anti-CDH6 antibody-drug conjugate (1) + belzutifan -31

[00400] Neither the single-dose groups nor the combined-dose group showed any particularly noteworthy findings, such as severe weight loss. Therefore, the combination of the anti-CDH6 antibody-drug conjugate (1) and belzutifan increased efficacy without increasing toxicity. [Industrial Applicability]

[00401] Based on the experimental results described above, it has been verified that the antibody-drug conjugate, according to the present invention, exhibits an excellent antitumor effect when administering the antibody-drug conjugate and an HIF-2a inhibitor in combination. [Free Text from the Sequence Listing]

[00402] SEQ ID NO: 1: Amino acid sequence of human CDH6 EC3 Petition 870250088320, dated 09 / 29 / 2025, pp. 125 / 148 116 / 117 SEQ ID NO: 2: Amino acid sequence of chG019 CDRH1 SEQ ID NO: 3: Amino acid sequence of chG019 CDRH2 SEQ ID NO: 4: Amino acid sequence of chG019 CDRH3 SEQ ID NO: 5: Amino acid sequence of chG019 CDRL1 SEQ ID NO: 6: Amino acid sequence of chG019 CDRL2 SEQ ID NO: 7: Amino acid sequence of chG019 CDRL3 SEQ ID NO: 8: Amino acid sequence of rG019 CDRH2 SEQ ID NO: 9: Amino acid sequence of rG055 CDRH1 SEQ ID NO: 10: Amino acid sequence of rG055 CDRH2 SEQ ID NO: 11: Amino acid sequence of rG055 CDRH3 SEQ ID NO: 12: Amino acid sequence of rG055 CDRL1 SEQ ID NO: 13: Amino acid sequence of rG055 CDRL2 SEQ ID NO: 14: Amino acid sequence of rG055 CDRL3 SEQ ID NO: 15: Amino acid sequence of rG056 CDRH1 SEQ ID NO: 16: Amino acid sequence of rG056 CDRH2 SEQ ID NO: 17: Amino acid sequence of rG056 CDRH3 SEQ ID NO: 18: Amino acid sequence of rG056 CDRL1 SEQ ID NO: 19: Amino acid sequence of rG056 CDRL2 SEQ ID NO:20: Amino acid sequence of rG056 CDRL3 SEQ ID NO: 21: Amino acid sequence of rG061 CDRH1 SEQ ID NO: 22: Amino acid sequence of rG061 CDRH2 SEQ ID NO: 23: Amino acid sequence of rG061 CDRH3 SEQ ID NO: 24: Amino acid sequence of rG061 CDRL1 SEQ ID NO: 25: Amino acid sequence of rG061 CDRL2 SEQ ID NO: 26: Amino acid sequence of rG061 CDRL3 SEQ ID NO: 27: Complete amino acid sequence of the heavy chain of hH01 SEQ ID NO: 28: Amino acid sequence of the variable region of the hH01 heavy chain Petition 870250088320, dated 09 / 29 / 2025, pp. 126 / 148 117 / 117 SEQ ID NO: 29: Complete amino acid sequence of the hH01 heavy chain, except for a signal sequence. SEQ ID NO: 30: Complete amino acid sequence of the hH02 heavy chain SEQ ID NO: 31: Amino acid sequence of the variable region of the hH02 heavy chain SEQ ID NO: 32: Complete amino acid sequence of the hH02 heavy chain, except for a signal sequence. SEQ ID NO: 33: Complete amino acid sequence of the hH04 heavy chain SEQ ID NO: 34: Amino acid sequence of the variable region of the hH04 heavy chain SEQ ID NO: 35: Complete amino acid sequence of the hH04 heavy chain, except for a signal sequence. SEQ ID NO: 36: Total length Amino acid sequence of a light chain of hL02 SEQ ID NO: 37: Amino acid sequence of a variable region of the hL02 light chain SEQ ID NO: 38: Complete amino acid sequence of the hL02 light chain, except for a signal sequence. SEQ ID NO: 39: Complete amino acid sequence of an hL03 light chain SEQ ID NO: 40: Amino acid sequence of a variable region of the hL03 light chain SEQ ID NO: 41: Complete amino acid sequence of the hL03 light chain, except for a signal sequence. Petition 870250088320, dated 09 / 29 / 2025, pp. 127 / 148

Claims

1 / 13 CLAIMS 1. Pharmaceutical composition, characterized in that it comprises an anti-CDH6 antibody-drug conjugate, wherein the anti-CDH6 antibody-drug conjugate and an HIF-2a inhibitor are administered in combination, and the anti-CDH6 antibody-drug conjugate is an antibody-drug conjugate in which a drug-ligand represented by the formula: [Formula 1] wherein A represents a binding site to an anti-CDH6 antibody or to a functional fragment of the antibody, is conjugated to the anti-CDH6 antibody or to the functional fragment of the antibody by means of a thioether linkage.

2. Pharmaceutical composition according to claim 1, characterized in that the anti-CDH6 antibody or the functional fragment of the antibody is an antibody that specifically binds to the amino acid sequence shown in SEQ ID NO: 1 and has an internalization capacity that allows cellular uptake, or to a functional fragment of the antibody.

3. Pharmaceutical composition according to claim 1 or 2, characterized in that the anti-CDH6 antibody or the functional fragment of the antibody is an antibody comprising CDRH1, consisting of the amino acid sequence shown in SEQ ID NO: 2, CDRH2, consisting of the amino acid sequence shown in SEQ ID NO: 3, CDRH3, consisting of the amino acid sequence shown in SEQ ID NO: 4, Petition 870250088320, dated 09 / 29 / 2025, page 128 / 148 2 / 13 CDRL1, consisting of the amino acid sequence shown in SEQ ID NO: 5, CDRL2, consisting of the amino acid sequence shown in SEQ ID NO: 6, and CDRL3, consisting of the amino acid sequence shown in SEQ ID NO: 7, or a functional fragment of the antibody.

4. Pharmaceutical composition according to any one of claims 1 to 3, characterized in that the anti-CDH6 antibody or the functional fragment of the antibody is an antibody comprising a variable region of the heavy chain, consisting of the amino acid sequence shown in SEQ ID NO: 28, and a variable region of the light chain, consisting of the amino acid sequence shown in SEQ ID NO: 37, or a functional fragment of the antibody.

5. Pharmaceutical composition according to any one of claims 1 to 4, characterized in that the anti-CDH6 antibody or the functional fragment of the antibody is an antibody comprising a heavy chain, consisting of the amino acid sequence shown in SEQ ID NO: 29, and a light chain, consisting of the amino acid sequence shown in SEQ ID NO: 38, or a functional fragment of the antibody.

6. Pharmaceutical composition according to any one of claims 1 to 5, characterized in that the anti-CDH6 antibody or the functional fragment of the antibody is an antibody in which the heavy chain or the light chain has undergone one or two or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue to the N-terminal, amidation of a proline residue, conversion of N-terminal glutamine or N-terminal glutamic acid to pyroglutamic acid and a deletion of one or two amino acids from the carboxylic terminal, or a functional fragment of the antibody.

7. Pharmaceutical composition according to claim 6, Petition 870250088320, dated 09 / 29 / 2025, page 129 / 148 3 / 13 characterized in that the anti-CDH6 antibody or the functional fragment of the antibody is an antibody in which one or two amino acids are deleted from the carboxyl terminal of one of its heavy chains, or a functional fragment of the antibody.

8. Pharmaceutical composition according to claim 7, characterized in that the anti-CDH6 antibody or the functional fragment of the antibody is an antibody in which an amino acid is deleted from the carboxyl terminal of each of its two heavy chains, or a functional fragment of the antibody.

9. Pharmaceutical composition according to any one of claims 6 to 8, characterized in that the deleted amino acid is lysine.

10. Pharmaceutical composition according to any one of claims 6 to 9, characterized in that the anti-CDH6 antibody or the functional fragment of the antibody is an antibody in which a proline residue at the carboxyl terminus of one of its heavy chains is further amidated, or a functional fragment of the antibody.

11. Pharmaceutical composition according to any one of claims 1 to 10, characterized in that the average number of drug-ligand structure units conjugated per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 1 to 10.

12. Pharmaceutical composition according to any one of claims 1 to 10, characterized in that the average number of drug-ligand structure units conjugated per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7 to 8.

13. Pharmaceutical composition according to any one of claims 1 to 12, characterized in that the HIF-2a inhibitor is belzutifan, NKT2152, DFF332, AB521 or BPI-452080, or a pharmaceutically acceptable salt thereof. Petition 870250088320, dated 09 / 29 / 2025, pp. 130 / 148 4 / 13 14. Pharmaceutical composition according to any one of claims 1 to 12, characterized in that the HIF-2a inhibitor is belzutifan or a pharmaceutically acceptable salt thereof.

15. Pharmaceutical composition according to any one of claims 1 to 14, characterized in that the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained separately in different formulations and are administered simultaneously or at different times.

16. Pharmaceutical composition according to any one of claims 1 to 14, characterized in that the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained in a single formulation for administration.

17. Pharmaceutical composition according to any one of claims 1 to 16, characterized in that the pharmaceutical composition is for use in the treatment of cancer.

18. Pharmaceutical composition according to any one of claims 1 to 16, characterized in that the pharmaceutical composition is for use in the treatment of at least one tumor selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, ovarian cancer, serous adenocarcinoma of the ovary, clear cell carcinoma of the ovary, endometrioid ovarian cancer, mucinous tumor of the ovary, 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, stomach cancer, endometrial cancer, uterine body cancer, nasopharyngeal cancer, prostate cancer and cancer related to von Hippel-Lindau disease.Petition 870250088320, dated 09 / 29 / 2025, pp. 131 / 148 5 / 13.

19. Pharmaceutical composition according to any one of claims 1 to 16, characterized in that the pharmaceutical composition is for use in the treatment of at least one renal cell carcinoma selected from the group consisting of renal cell carcinoma, clear cell renal carcinoma and papillary renal cell carcinoma.

20. Pharmaceutical composition, characterized in that it comprises an anti-CDH6 antibody-drug conjugate, wherein the anti-CDH6 antibody-drug conjugate and an HIF-2oc inhibitor are administered in combination, and the anti-CDH6 antibody-drug conjugate is an antibody-drug conjugate represented by the formula: [Formula 2] wherein the antibody is an anti-CDH6 antibody, a drug ligand is conjugated to the antibody via a thioether linkage, and en represents an average number of drug-ligand units conjugated per antibody.

21. Pharmaceutical composition according to claim 20, characterized in that the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence shown in SEQ ID NO:

38.

22. Pharmaceutical composition according to claim 20 or 21, characterized in that a lysine residue is deleted from the carboxyl terminal of a heavy chain of the anti-CDH6 antibody. Petition 870250088320, dated 09 / 29 / 2025, pp. 132 / 148 6 / 13 23. Pharmaceutical composition according to any one of claims 20 to 22, characterized in that the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7 to 8.

24. Pharmaceutical composition according to any one of claims 20 to 23, characterized in that the HIF2α inhibitor is belzutifan, NKT2152, DFF332, AB521 or BPI-452080, or a pharmaceutically acceptable salt thereof.

25. Pharmaceutical composition according to any one of claims 20 to 23, characterized in that the HIF2α inhibitor is belzutifan or a pharmaceutically acceptable salt thereof.

26. Pharmaceutical composition according to any one of claims 20 to 25, characterized in that the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained separately in different formulations and are administered simultaneously or at different times.

27. Pharmaceutical composition according to any one of claims 20 to 25, characterized in that the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained in a single formulation for administration.

28. Pharmaceutical composition according to any one of claims 20 to 27, characterized in that the pharmaceutical composition is for use in the treatment of cancer.

29. Pharmaceutical composition according to any one of claims 20 to 27, characterized in that the pharmaceutical composition is for use in the treatment of at least one tumor selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, serous adenocarcinoma of the ovary, clear cell carcinoma of the ovary, Petition 870250088320, dated 09 / 29 / 2025, p.133 / 148 7 / 13 endometrioid ovarian cancer, mucinous ovarian 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, stomach cancer, endometrial cancer, uterine body cancer, nasopharyngeal cancer, prostate cancer and cancer related to von Hippel-Lindau disease.

30. Pharmaceutical composition according to any one of claims 20 to 27, characterized in that the pharmaceutical composition is for use in the treatment of at least one renal cell carcinoma selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma and renal papillary cell carcinoma.

31. Pharmaceutical composition according to any one of claims 1 to 30, characterized in that the anti-CDH6 antibody-drug conjugate is raludotatug deruxtecan (DS-6000a).

32. Treatment method, characterized in that it comprises administering an anti-CDH6 antibody-drug conjugate and an HIF-2a inhibitor in combination to an individual in need of treatment, wherein the antibody-drug conjugate is an antibody-drug conjugate in which a drug-ligand represented by the formula: [Formula 3] wherein A represents a binding site to an anti-CDH6 antibody or to a functional fragment of the antibody, Petition 870250088320, dated 29 / 09 / 2025, p. 134 / 148 8 / 13 is conjugated to the anti-CDH6 antibody or to the functional fragment of the antibody by means of a thioether linkage.

33. Treatment method according to claim 32, characterized in that the anti-CDH6 antibody or the functional fragment of the antibody is an antibody that specifically binds to the amino acid sequence shown in SEQ ID NO: 1 and has an internalization capacity that allows cellular uptake, or a functional fragment of the antibody.

34. Treatment method according to claim 32 or 33, characterized in that the anti-CDH6 antibody or the functional fragment of the antibody is an antibody comprising CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 2, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 3, CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 4, CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 5, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 6 and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 7, or a functional fragment of the antibody.

35. Treatment method according to any one of claims 32 to 34, characterized in that the anti-CDH6 antibody or the functional fragment of the antibody is an antibody comprising a variable region of the heavy chain, consisting of the amino acid sequence shown in SEQ ID NO: 28, and a variable region of the light chain, consisting of the amino acid sequence shown in SEQ ID NO: 37, or a functional fragment of the antibody.

36. Treatment method according to any one of claims 32 to 35, characterized in that the anti-CDH6 antibody or the functional fragment of the antibody is an antibody comprising a heavy chain, consisting of the amino acid sequence shown in SEQ ID Petition 870250088320, dated 09 / 29 / 2025, page 135 / 148 9 / 13 NO: 29, and a light chain, consisting of the amino acid sequence shown in SEQ ID NO: 38, or a functional fragment of the antibody.

37. A treatment method according to any one of claims 32 to 36, characterized in that the anti-CDH6 antibody or the functional fragment of the antibody is an antibody in which the heavy chain or the light chain has undergone one or two or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, addition of a methionine residue to the N-terminal, amidation of a proline residue, conversion of N-terminal glutamine or N-terminal glutamic acid to pyroglutamic acid and deletion of one or two amino acids from the carboxylic terminal, or a functional fragment of the antibody.

38. Treatment method according to claim 37, characterized in that the anti-CDH6 antibody or the functional fragment of the antibody is an antibody in which one or two amino acids are deleted from the carboxyl terminal of one of its heavy chains, or a functional fragment of the antibody.

39. Treatment method according to claim 38, characterized in that the anti-CDH6 antibody or the functional fragment of the antibody is an antibody in which an amino acid is deleted from the carboxyl terminus of each of its two heavy chains, or from a functional fragment of the antibody.

40. Treatment method according to any one of claims 37 to 39, characterized in that the deleted amino acid is lysine.

41. Treatment method according to any one of claims 37 to 40, characterized in that the anti-CDH6 antibody or the functional fragment of the antibody is an antibody in which a proline residue at the carboxyl terminus of one of its heavy chains is further amidated, or a functional fragment of the antibody.

42. Treatment method according to any one of claims 32 to 41, characterized in that the average number of drug-ligand structure units conjugated per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 1 to 10.

43. Treatment method according to any one of claims 32 to 41, characterized in that the average number of drug-ligand structure units conjugated per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7 to 8.

44. Treatment method according to any one of claims 32 to 43, characterized in that the HIF-2a inhibitor is belzutifan, NKT2152, DFF332, AB521 or BPI-452080, or a pharmaceutically acceptable salt thereof.

45. Treatment method according to any one of claims 32 to 43, characterized in that the HIF-2a inhibitor is belzutifan or a pharmaceutically acceptable salt thereof.

46. ​​Treatment method according to any one of claims 32 to 45, characterized in that the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained separately in different formulations and are administered simultaneously or at different times.

47. Treatment method according to any one of claims 32 to 45, characterized in that the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained in a single formulation for administration.

48. Treatment method according to any one of claims 32 to 47, characterized in that the treatment method is for treating cancer. Petition 870250088320, dated 09 / 29 / 2025, pp. 137 / 148 11 / 13 49. Treatment method according to any one of claims 32 to 47, characterized in that the treatment method is for treating at least one tumor selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, ovarian cancer, serous adenocarcinoma of the ovary, clear cell carcinoma of the ovary, endometrioid ovarian cancer, mucinous tumor of the ovary, 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, stomach cancer, endometrial cancer, uterine body cancer, nasopharyngeal cancer, prostate cancer and cancer related to von Hippel-Lindau disease.

50. Treatment method according to any one of claims 32 to 47, characterized in that the treatment method is for treating at least one renal cell carcinoma selected from the group consisting of renal cell carcinoma, clear cell renal carcinoma and papillary renal cell carcinoma.

51. Treatment method, characterized in that it comprises administering an anti-CDH6 antibody-drug conjugate and an HIF-2oc inhibitor in combination to an individual in need of treatment, wherein the anti-CDH6 antibody-drug conjugate is an antibody-drug conjugate represented by the formula: [Formula 4] Petition 870250088320, dated 29 / 09 / 2025, p. 138 / 148 12 / 13 wherein the antibody is an anti-CDH6 antibody, a drug ligand is conjugated to the antibody via a thioether linkage, and n represents an average number of drug-ligand units conjugated per antibody.

52. Treatment method according to claim 51, characterized in that the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 29 and a light chain consisting of the amino acid sequence shown in SEQ ID NO:

38.

53. Treatment method according to claim 51 or 52, characterized in that a lysine residue is deleted from the carboxyl terminal of a heavy chain of the anti-CDH6 antibody.

54. Treatment method according to any one of claims 51 to 53, characterized in that the average number of drug-ligand conjugate units per antibody in the anti-CDH6 antibody-drug conjugate is in the range of 7 to 8.

55. Treatment method according to any one of claims 51 to 54, characterized in that the HIF-2a inhibitor is belzutifan, NKT2152, DFF332, AB521 or BPI-452080, or a pharmaceutically acceptable salt thereof.

56. Treatment method according to any one of claims 51 to 54, characterized in that the HIF-2a inhibitor is belzutifan or a pharmaceutically acceptable salt thereof.

57. Treatment method according to any one of claims 51 to 56, characterized in that the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained separately in different formulations and are administered simultaneously or at different times.

58. Treatment method according to any of claims 51 to 56, characterized in that the anti-CDH6 antibody-drug conjugate and the HIF-2a inhibitor are contained in a single formulation for administration.

59. Treatment method according to any one of claims 51 to 58, characterized in that the treatment method is for treating cancer.

60. Treatment method according to any one of claims 51 to 58, characterized in that the treatment method is for treating at least one tumor selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, ovarian cancer, serous adenocarcinoma of the ovary, clear cell carcinoma of the ovary, endometrioid ovarian cancer, mucinous ovarian 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, stomach cancer, endometrial cancer, uterine body cancer, nasopharyngeal cancer, prostate cancer, and cancer related to von Hippel-Lindau disease.

61. Treatment method according to any one of claims 51 to 58, characterized in that the treatment method is for treating at least one tumor selected from the group consisting of renal cell carcinoma, renal clear cell carcinoma and renal papillary cell carcinoma.

62. Treatment method according to any one of claims 32 to 61, characterized in that the anti-CDH6 antibody-drug conjugate is raludotatug deruxtecan (DS-6000a). Petition 870250088320, dated 09 / 29 / 2025, pp. 140 / 148

Images