Combination of antibody-drug conjugates and DNMT inhibitors

Abstract

A pharmaceutical agent for administering an antibody-drug conjugate in combination with a DNA methyltransferase (DNMT) inhibitor is provided. The antibody-drug conjugate is an antibody-drug conjugate in which a drug-linker represented by the following formula (wherein A represents the position of attachment to the antibody) is conjugated to an antibody, particularly an anti-TROP2 antibody, via a thioether bond. Therapeutic uses and methods are also provided in which the antibody-drug conjugate and the DNMT inhibitor are co-administered to a subject: Formula (I): [Formula 1] JPEG2025540063000012.jpg63141

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 428,945, filed November 30, 2022; and U.S. Provisional Application No. 63 / 537,454, filed September 8, 2023. Each of the above-cited applications is incorporated herein by reference in its entirety for all purposes.

[0002] The present disclosure relates to pharmaceutical preparations for the administration of specific antibody-drug conjugates having anti-tumor drugs conjugated via a linker structure to antibodies, particularly anti-TROP2 antibodies, in combination with DNMT inhibitors, as well as therapeutic uses and methods in which the specific antibody-drug conjugates and DNMT inhibitors are co-administered to a subject. [Background technology]

[0003] Increasingly recognized in the field of cancer immunotherapy, DNA methyltransferase (DNMT) inhibitors are agents that inhibit DNA methyltransferase enzymes, inducing DNA hypomethylation and growth inhibition or apoptosis in rapidly dividing cells. For example, decitabine (Dacogen®; 5-aza-2'-deoxycytidine) and azacitidine (Vidiza / Onureg®; 5-aza-cytidine) are nucleoside analogs used in the treatment of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic myelomonocytic leukemia (CMML).

[0004] Antibody-drug conjugates (ADCs), which consist of cytotoxic drugs conjugated to antibodies, can selectively deliver drugs into cancer cells and cancer cells, resulting in cancer cell death (Ducry, L. et al., Bioconjugate Chem. (2010) 21, 5-13; Alley, SC et al., Current Opinion in Chemical Biology (2010) 14, 529-537; Damle NK Expert Opin. Biol. Ther. (2004) 4, 1445-1452; Senter PD et al., Nature Biotechnology (2012) 30, 631-637; Burris HA. et al., J. Clin. Oncol. (2011) 29(4):398-405).

[0005] One such antibody-drug conjugate is datopotamab deruxtecan (Dato-DXd, DS-1062a), which is composed of a TROP2-targeting antibody and a derivative of exatecan. In particular, WO2015 / 098099 and WO2020 / 240467 provide detailed descriptions of exemplary TROP2-targeting antibody-drug conjugates, including datopotamab deruxtecan. Datopotamab deruxtecan has demonstrated clinical efficacy in multiple tumor types, including lung cancer and breast cancer.

[0006] Inactivation of Schlafen 11 (SLFN11) in cancer cells has been shown to confer resistance to anticancer drugs that cause DNA damage and replication stress. Thus, SLFN11 may serve as a determinant of sensitivity to various classes of DNA-damaging agents, including but not limited to topoisomerase I inhibitors (Zoppoli et al., PNAS 2012;109:15030-35; Murai et al., Oncotarget 2016;7:76534-50; Murai et al., Mol. Cell 2018;69:371-84).

[0007] Zhao M et al., AACR Cancer Res 2022;82(12_Suppl):Abstract #1791, report that decitabine (a DNMT inhibitor) upregulates TROP2 and SLFN11 expression and enhances the antitumor efficacy of sacituzumab govitecan (Trodelvy®, a humanized anti-TROP2 antibody conjugated with SN-38) in xenograft cell lines of dysplastic carcinoma origin and mesenchymal subtype breast cancer cell lines.

[0008] There remains a need for improved therapeutic compositions and methods that can enhance the efficacy of existing cancer treatments, increase the durability of the therapeutic response, improve patient tolerance, reduce dose-dependent toxicity, and / or provide alternative treatments for cancers that are resistant or refractory to previous cancer treatments. More specifically, there remains a need to identify additional combinations that partner with antibody-drug conjugates, particularly anti-TROP2 antibody-drug conjugates, to enhance their therapeutic potential. Thus, it is desirable to provide pharmaceuticals and treatments that can achieve superior antitumor effects in cancer treatment, such as enhanced efficacy, increased durability of the therapeutic response, and / or reduced dose-dependent toxicity. Summary of the Invention [Problem to be solved by the invention]

[0009] The present disclosure provides pharmaceuticals that exhibit excellent antitumor effects in the treatment of cancer through the administration of antibody-drug conjugates, particularly anti-TROP2 antibody-drug conjugates, in combination with DNMT inhibitors. The present disclosure also provides therapeutic uses and methods in which the antibody-drug conjugates and DNMT inhibitors are administered in combination to a subject. [Means for solving the problem]

[0010] Specifically, the present disclosure relates to the following [1] to

[27] : [1] A pharmaceutical comprising an antibody-drug conjugate and a DNMT inhibitor for combined administration, wherein the antibody-drug conjugate has the following formula:

[0011] [ka] wherein A represents the attachment position to the antibody, and the drug-linker is conjugated to the anti-TROP2 antibody via a thioether bond; [2] The pharmaceutical agent according to [1], wherein the anti-TROP2 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 4, and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 5, and a light chain comprising CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of the amino acid sequence represented by SEQ ID NO: 7, and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 8; [3] The pharmaceutical agent according to [2], wherein the anti-TROP2 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 9 and a light chain comprising a light chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 10; [4] The pharmaceutical agent according to [2] or [3], wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 12 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 13; [5] The pharmaceutical agent according to [4], wherein the anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain; [6] The pharmaceutical agent according to any one of [1] to [5], wherein the average number of drug-linker bonds per antibody molecule in the antibody-drug conjugate is in the range of 3.5 to 4.5; [7] The pharmaceutical product according to any one of [1] to [5], wherein the antibody-drug conjugate is datopotamab deruxtecan (DS-1062a); [8] The pharmaceutical agent according to any one of [1] to [7], wherein the DNMT inhibitor is decitabine or azacitidine, or a pharmaceutically acceptable salt thereof; [9] The pharmaceutical agent according to [8], wherein the DNMT inhibitor is decitabine or a pharmaceutically acceptable salt thereof;

[10] The pharmaceutical product according to any one of [1] to [9], which is a composition comprising an antibody-drug conjugate and a DNMT inhibitor for simultaneous administration;

[11] The pharmaceutical product according to any one of [1] to [9], which is a combined preparation comprising an antibody-drug conjugate and a DNMT inhibitor for sequential administration or separate simultaneous administration;

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

[11] , wherein the DNMT inhibitor is administered in combination with a cytidine deaminase inhibitor;

[13] The pharmaceutical composition according to

[12] , wherein the cytidine deaminase inhibitor is cedazuridine or a pharmaceutically acceptable salt thereof;

[14] A pharmaceutical product according to any one of [1] to

[13] , which is for the treatment of cancer;

[15] The pharmaceutical product according to

[14] , wherein the cancer is at least one selected from the group consisting of breast cancer, lung cancer, colorectal cancer, gastric cancer, esophageal cancer, head and neck cancer, esophagogastric junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, endometrial cancer, gastrointestinal stromal tumor, gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, endometrial carcinoma, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma, cervical cancer, uterine cancer, testicular cancer, and renal cell carcinoma;

[16] The medicine according to

[15] , wherein the cancer is colorectal cancer;

[17] The medicine according to

[15] , wherein the cancer is lung cancer;

[18] The pharmaceutical agent according to

[17] , wherein the lung cancer is non-small cell lung cancer;

[19] The medicine according to

[15] , wherein the cancer is breast cancer;

[20] The pharmaceutical agent according to any one of

[14] to

[19] , wherein the cancer cells are SLFN11 deficient;

[21] the pharmaceutical agent according to

[20] , in which SLFN11 expression is lower in the patient's cancer cells than in the patient's SLFN11-expressing non-cancerous cells;

[22] An antibody-drug conjugate for use in combination with a DNMT inhibitor in the treatment of cancer, wherein the antibody-drug conjugate and the DNMT inhibitor are as defined in any one of [1] to [9];

[23] The antibody-drug conjugate for use according to

[22] , wherein the cancer is as defined in any one of

[15] to

[21] ;

[24] The antibody-drug conjugate for use according to

[22] or

[23] , wherein the use comprises sequential administration of the antibody-drug conjugate and the DNMT inhibitor;

[25] The antibody-drug conjugate for use according to

[22] or

[23] , wherein the use comprises separate and simultaneous administration of the antibody-drug conjugate and the DNMT inhibitor;

[26] A method for treating cancer, comprising administering to a subject in need thereof an antibody-drug conjugate as defined in any one of [1] to [9] and a DNMT inhibitor; and

[27] The method according to

[26] , wherein the cancer is as defined in any one of

[15] to

[21] . [Effects of the Invention]

[0012] The beneficial effects of disclosure The present disclosure provides pharmaceuticals comprising specific antibody-drug conjugates having an anti-tumor drug conjugated to an antibody (especially an anti-TROP2 antibody) via a linker structure and a DNMT inhibitor for combined administration, as well as therapeutic uses and methods in which the specific antibody-drug conjugates and the DNMT inhibitor are combined and administered to a subject. Thus, the present disclosure provides pharmaceuticals and treatments that can achieve excellent anti-tumor effects in the treatment of cancer. [Brief explanation of the drawings]

[0013] [Anti-TROP2 antibody]: [Figure 1]FIG. 1 shows the amino acid sequence of the heavy chain of an anti-TROP2 antibody (SEQ ID NO: 1). [Figure 2] FIG. 1 shows the amino acid sequence of the light chain of an anti-TROP2 antibody (SEQ ID NO: 2). [Figure 3] FIG. 1 shows the amino acid sequence of heavy chain CDRH1 (SEQ ID NO: 3 [=amino acid residues 50 to 54 of SEQ ID NO: 1]). [Figure 4] FIG. 1 shows the amino acid sequence of heavy chain CDRH2 (SEQ ID NO: 4 [=amino acid residues 69 to 85 of SEQ ID NO: 1]). [Figure 5] FIG. 1 shows the amino acid sequence of heavy chain CDRH3 (SEQ ID NO: 5 [=amino acid residues 118 to 129 of SEQ ID NO: 1]). [Figure 6] FIG. 1 shows the amino acid sequence of light chain CDRL1 (SEQ ID NO: 6 [=amino acid residues 44 to 54 of SEQ ID NO: 2]). [Figure 7] FIG. 1 shows the amino acid sequence of light chain CDRL2 (SEQ ID NO: 7 [=amino acid residues 70 to 76 of SEQ ID NO: 2]). [Figure 8] FIG. 1 shows the amino acid sequence of light chain CDRL3 (SEQ ID NO: 8 [=amino acid residues 109 to 117 of SEQ ID NO: 2]). [Figure 9] FIG. 1 shows the amino acid sequence of the heavy chain variable region (SEQ ID NO: 9 [=amino acid residues 20 to 140 of SEQ ID NO: 1]). [Figure 10] FIG. 1 shows the amino acid sequence of the light chain variable region (SEQ ID NO: 10 [=amino acid residues 21 to 129 of SEQ ID NO: 2]). [Figure 11] FIG. 1 shows the amino acid sequence of the heavy chain (SEQ ID NO: 11 [=amino acid residues 20 to 469 of SEQ ID NO: 1]). [Experiment]: [Figures 12A-12B] FIG. 1 depicts a graph showing the cell growth inhibitory activity of DS-1062a in DLD-1 and HCT-15 cells, respectively, with or without pretreatment with decitabine (DAC). [Figure 13] FIG. 1 depicts a graph showing the antitumor activity of DS-1062a in a DLD-1 xenograft mouse model with or without pretreatment with decitabine (DAC). [Figure 14] FIG. 1 depicts a graph showing the cell growth inhibitory activity of DS-1062a in DLD-1 cells with or without pretreatment with azacytidine (AZA). [Figure 15] FIG. 1 depicts a graph showing the anti-tumor activity of IMMU-132 in a DLD-1 xenograft mouse model with or without pretreatment with decitabine (DAC). DETAILED DESCRIPTION OF THE INVENTION

[0014] In order that this disclosure may be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the detailed description.

[0015] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. For example, Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd Edition, 2002, CRC Press; Dictionary of Cell and Molecular Biology, 3rd Edition, 1999, Academic Press; and Oxford Dictionary of Biochemistry And Molecular Biology, Revised Edition, 2000, Oxford University Press are used by those skilled in the art as general dictionaries for many of the terms used in this disclosure.

[0016] Unless the context otherwise requires, singular terms shall include pluralities and plural terms shall include the singular.

[0017] Units, prefixes, and symbols are denoted in their Systeme International de Unites (SI) recognized form. Numeric ranges are inclusive of the numbers defining the range.

[0018] Wherever embodiments are described herein using the language "comprising," it is understood that otherwise similar embodiments described using the words "consisting of" and / or "consisting essentially of" are also provided.

[0019] The terms "inhibit" and "inhibition" can refer to about a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% decrease in biological activity. Cell proliferation can be assayed using art-recognized techniques (e.g., thymidine incorporation) that measure the rate of cell division and / or the percentage of cells within a cell population undergoing cell division and / or the rate of cell loss from a cell population due to terminal differentiation or cell death.

[0020] The term "subject" refers to any animal (e.g., mammal) that may be the recipient of a particular treatment, including, but not limited to, humans, non-human primates, rodents, etc. Typically, the terms "subject" and "patient" are used interchangeably herein in reference to human subjects.

[0021] The term "pharmaceutical product" refers to a preparation in a form that allows the biological activity of the active ingredients, either as a composition containing all active ingredients (for simultaneous administration) or as a combination of separate compositions (combined preparations) each containing at least one, but not all, of the active ingredients (for sequential or simultaneous administration), and which does not contain additional components that are unacceptably toxic to the subject to which the product is administered. Such a product may be sterile. "Simultaneous administration" means that the active ingredients are administered at the same time. "Sequential administration" means that the active ingredients are administered one after the other, in either order, with a time interval between the individual administrations. The time interval may be, for example, less than 24 hours, preferably less than 6 hours, and more preferably less than 2 hours.

[0022] "Treating" or "treatment" or "to treat" or "alleviating" or "to alleviate" refers to both (1) therapeutic measures that cure, slow, or alleviate the symptoms of a diagnosed pathological condition or disorder and / or halt the progression of the pathological condition or disorder, and (2) prophylactic or preventative measures that prevent and / or delay the onset of the targeted pathological condition or disorder. Thus, those in need of treatment include those already with the disorder; those prone to have the disorder; and those in whom the disorder is to be prevented. In certain embodiments, a subject has been successfully treated for cancer by the methods of the present disclosure if the patient experiences, for example, a complete, partial, or temporary remission of a particular type of cancer.

[0023] The terms "cancer," "tumor," "cancerous," and "malignant" refer to or describe a physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, breast cancer, lung cancer, colorectal cancer, gastric cancer, esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer, bladder cancer, endometrial cancer, gastrointestinal stromal tumor, gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, endometrial carcinoma, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, glioblastoma multiforme, osteosarcoma, sarcoma, melanoma, cervical cancer, uterine cancer, testicular cancer, and renal cell carcinoma. Cancers include hematological malignancies such as acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Burkitt's lymphoma, and follicular lymphoma, as well as solid tumors such as breast cancer, lung cancer, neuroblastoma, and colon cancer.

[0024] As used herein, the term "cytotoxic agent" is broadly defined and refers to a substance that inhibits or prevents the function of cells and / or causes destruction of cells (cell death) and / or exerts an anti-neoplastic / anti-proliferative effect. For example, a cytotoxic agent directly or indirectly prevents the development, maturation, or spread of neoplastic tumor cells. The term also includes those agents that cause only a cytostatic effect and not merely a cytotoxic effect. The term includes chemotherapeutic agents as specified below.

[0025] The term "chemotherapeutic agent" is a subset of the term "cytotoxic drug," which includes natural or synthetic chemical compounds.

[0026] According to the disclosed method or use, the disclosed compound can be administered to a patient to promote a positive therapeutic response for cancer. The term "positive therapeutic response" in the context of cancer treatment refers to an improvement in symptoms associated with the disease. For example, an improvement in disease can be characterized as a complete response. The term "complete response" refers to the normalization of any previous test results and the absence of clinically detectable disease. Alternatively, an improvement in disease can be classified as a partial response. A "positive therapeutic response" encompasses a reduction or inhibition of the progression and / or duration of cancer, a reduction or improvement in the severity of cancer, and / or an improvement in one or more symptoms thereof, resulting from the administration of a disclosed compound. In certain embodiments, such a term refers to one, two, or three or more of the following results after administration of a disclosed compound: (1) Stabilization, reduction, or elimination of cancer cell populations; (2) stabilization or reduction of cancer growth; (3) Impairment of cancer formation; (4) eradication, removal, or control of primary, localized, and / or metastatic cancer; (5) reduced mortality; (6) increased duration or rate of disease-free survival, recurrence-free survival, progression-free survival, and / or overall survival; (7) response rate, durability of response, or increase in the number of patients responding or in remission; (8) reduced hospitalization rates; (9) reduced length of hospital stay; (10) The size of the cancer remains the same, does not increase, or increases by less than 10%, preferably less than 5%, preferably less than 4%, preferably less than 2%; (11) an increase in the number of patients in remission; and (12) A reduction in the number of adjuvant treatments (e.g., chemotherapy or hormone therapy) that would normally be required to treat cancer.

[0027] Clinical responses can be assessed using screening techniques such as PET, magnetic resonance imaging (MRI) scans, X-ray imaging, computed tomography (CT) scans, flow cytometry or fluorescence activated cell sorter (FACS) analysis, histology, gross pathology, and blood chemistries, including, but not limited to, changes detectable by ELISA, RIA, chromatography, etc. In addition to these positive therapeutic responses, treated subjects can experience the beneficial effect of amelioration of disease-related symptoms.

[0028] As used herein, the term "SLFN11 expression level" refers to a certain amount, for example, 0%, of cancer cells in a patient's cancer tissue express SLFN11 at the stated amount.Similarly, as used herein, the term "SLFN11 expression level is <" a certain amount, for example, <10%, of cancer cells in a patient's cancer tissue express SLFN11 at less than the stated amount.The expression level of SLFN11 can be, for example, <25%, <20%, <15%, <10%, <9%, <8%, <7%, <6%, <5%, <4%, <3%, <2%, <1%, or 0%.

[0029] As used herein, the term "SLFN11-deficient" refers to an expression level of SLFN11 in a patient, animal, tissue, cell, etc., of interest that is insufficient to exhibit a normal phenotype associated with that gene or insufficient for the protein to exhibit its physiological function. In the context of preclinical models, cells or animals in which the SLFN11 gene has been knocked out (KO) are examples of "SLFN11-deficient."

[0030] As used herein, the term "antibody" refers to a protein capable of recognizing and specifically binding to an antigen. Ordinary or conventional mammalian antibodies are tetramers, typically composed of two identical pairs of polypeptide chains, each pair consisting of one "light" chain (typically having a molecular weight of about 25 kDa) and one "heavy" chain (typically having a molecular weight of about 50-70 kDa). As used herein, the terms "heavy chain" and "light chain" refer to any immunoglobulin polypeptide having sufficient variable domain sequence to confer specificity for a target antigen. The amino-terminal portion of each light and heavy chain typically contains a variable domain of about 100-110 or more amino acids, which is typically responsible for antigen recognition. As used herein, the terms "variable region" or "variable domain" are used interchangeably and are common in the art. The carboxyl terminus of each chain typically defines a constant domain responsible for effector function. Thus, in naturally occurring antibodies, the full-length heavy chain immunoglobulin polypeptide contains a variable domain (V H ) and three constant domains (C H1 , C H2 , and C H3 ) and C H1 and C H2 and a VH domain at the amino terminus of the polypeptide, comprising a hinge region between C H3 The variable domain (V) is located at the carboxyl terminus of the full-length light chain immunoglobulin polypeptide. L ) and constant domains (C L ), including V L The domain is at the amino terminus of the polypeptide and C LThe domain is at the carboxyl terminus. However, those skilled in the art will understand that the position of the domain in a naturally occurring antibody can be altered in a particular antibody-like binding protein without losing antigen binding ability. The classes of human light chains are named kappa light chains and lambda light chains.

[0031] Within full-length light and heavy chains, the variable and constant domains are typically connected by a "J" region of about 12 or more amino acids, with heavy chains also including a "D" region of about 10 or more amino acids. The variable regions of each light / heavy chain pair typically form the antigen-binding site. The variable domains of naturally occurring antibodies typically exhibit the same general structure of relatively conserved framework regions (FR) connected by three hypervariable regions, also called complementarity-determining regions or CDRs. The CDRs from the two chains of each pair are typically aligned by the framework regions, enabling binding to a specific epitope. Both the light and heavy chain variable domains typically include, from the amino terminus to the carboxyl terminus, the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0032] The term "antibody fragment" refers to an intact or full-length chain or portion of an antibody, generally the target binding or variable region. Examples of antibody fragments include F ab , F ab’ , F (ab’)2 , and F v As used herein, the term "functional fragment" is generally synonymous with "antibody fragment" and, with respect to antibodies, refers to a fragment of an antibody that is functionally functional. v , F ab , F (ab’)2 It may refer to an antibody fragment such as:

[0033] Reference to the numbering of amino acid residues described herein is made according to the EU numbering system (also described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD. (1991)).

[0034] A "monoclonal" antibody or antigen-binding fragment thereof refers to a population of homogeneous antibodies or antigen-binding fragments that are involved in highly specific binding of a single antigenic determinant or epitope. This is in contrast to polyclonal antibodies, which typically include different antibodies directed against different antigenic determinants. The term "monoclonal" antibody or antigen-binding fragment thereof encompasses both intact and full-length monoclonal antibodies, as well as antibody fragments (e.g., Fab, Fab', F(ab')2, Fv), single-chain (scFv) variants, fusion proteins containing an antibody portion, and any other modified immunoglobulin molecule containing an antigen recognition site. Furthermore, a "monoclonal" antibody or antigen-binding fragment thereof refers to such antibodies and antigen-binding fragments produced by methods such as, but not limited to, hybridomas, phage selection, recombinant expression, and transgenic animals.

[0035] As used herein, the term "antigen" or "target antigen" refers to a molecule or portion of a molecule that can be recognized and bound by a binding protein of the present disclosure. A target antigen can be used in an animal to produce antibodies capable of binding to an epitope of that antigen. A target antigen can have one or more epitopes.

[0036] As used herein, the term "epitope" refers to a region or structural element of an antigen that is recognized and bound by a binding protein of the present disclosure. More precisely, an epitope is a specific structure bound by a CDR of a binding protein. An epitope may include protein structural elements, carbohydrate chains, or even portions of lipid structures found in membranes. A binding protein is said to specifically bind to an antigen when it preferentially recognizes its antigen target in a complex mixture of proteins and / or macromolecules. The term "specifically binds" refers to a binding protein that specifically binds to a molecule or fragment thereof (e.g., an antigen). A binding protein that specifically binds to a molecule or fragment thereof may bind other molecules with lower affinity, as determined, for example, by immunoassay, BIAcore, or other assays known in the art. In particular, an antibody or fragment that specifically binds to at least one molecule or fragment thereof may compete away from non-specifically binding molecules.

[0037] As used herein, the term "antigen-binding site" refers to a site formed on the surface of a binding protein of the present disclosure to which an antigen or an epitope on an antigen binds. The antigen-binding site of a binding protein is typically described by reference to the loop structures formed by the complementarity-determining regions (CDRs) of the binding protein.

[0038] Description of the embodiment Preferred modes for carrying out the present disclosure are described below. The embodiments described below are provided merely to illustrate one example of a typical embodiment of the present disclosure and are not intended to limit the scope of the present disclosure.

[0039] 1. Antibody-drug conjugates The antibody-drug conjugates used in this disclosure have the following formula:

[0040] [ka] (wherein A represents the attachment position to the antibody) is conjugated to an antibody, particularly an anti-TROP2 antibody, via a thioether bond.

[0041] In the present disclosure, the partial structure consisting of the linker and the drug in the antibody-drug conjugate is referred to as a "drug-linker." The drug-linker is connected to a thiol group (in other words, a sulfur atom of a cysteine ​​residue) formed at the interchain disulfide bond site (two sites between heavy chains and two sites between the heavy chain and the light chain) in the antibody.

[0042] The drug-linker of the present disclosure includes as a component the topoisomerase I inhibitor exatecan (IUPAC name: (1S,9S)-1-amino-9-ethyl-5-fluoro-1,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione (also represented by chemical name: (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione)). Exatecan is a camptothecin derivative with antitumor activity, represented by the following formula:

[0043] [ka]

[0044] The antibody-drug conjugates used in this disclosure may also be represented by the following formula:

[0045] [ka]

[0046] In the formula, the drug-linker is conjugated to an antibody ("antibody-"), particularly an anti-TROP2 antibody, via a thioether bond. The meaning of n is the same as the meaning of the average number of conjugated drug molecules (DAR; drug-antibody ratio), which indicates the average number of drug-linkers bound per antibody molecule.

[0047] After migrating into the cancer cells, the antibody-drug conjugate used in the present disclosure is cleaved at the linker moiety to release a compound represented by the following formula:

[0048] [ka]

[0049] 2. Antibodies in antibody-drug conjugates The antibody in the antibody-drug conjugate used in the present disclosure is an anti-TROP2 antibody and can be derived from any species, preferably human, rat, mouse, or rabbit. If the antibody is derived from a species other than human, it is preferably chimerized or humanized using well-known techniques. The antibody can be a polyclonal antibody or a monoclonal antibody, preferably a monoclonal antibody.

[0050] The antibody in the antibody-drug conjugate used in the present disclosure is preferably an antibody characterized by the ability to target cancer cells, and is preferably an antibody that has, for example, the ability to recognize cancer cells, the ability to bind to cancer cells, the ability to be internalized in cancer cells, and / or cytocidal activity against cancer cells.

[0051] The binding activity of antibodies to cancer cells can be confirmed using flow cytometry. Internalization of antibodies into cancer cells can be confirmed using (1) an assay in which a (fluorescently labeled) secondary antibody that binds to the therapeutic antibody is used to visualize the antibody taken up by the cell under a fluorescence microscope (Cell Death and Differentiation (2008) 15, 751-761); (2) an assay in which a (fluorescently labeled) secondary antibody that binds to the therapeutic antibody is used to measure the intensity of fluorescence taken up by the cell (Molecular Biology of the Cell, Vol. 15, 5268-5282, December 2004); or (3) a Mab-ZAP assay in which an immunotoxin that binds to the therapeutic antibody is released upon cell uptake and inhibits cell growth (BioTechniques 28:162-165, January 2000). A recombinant complex protein of the diphtheria toxin catalytic domain and protein G can be used as the immunotoxin.

[0052] The anti-tumor activity of an antibody can be confirmed in vitro by determining its inhibitory activity against cell growth. For example, a cancer cell line that overexpresses the target protein of the antibody is cultured, and the antibody is added to the culture system at various concentrations to determine its inhibitory activity against foci formation, colony formation, and spheroid growth. The anti-tumor activity can be confirmed in vivo, for example, by administering the antibody to nude mice bearing transplanted cancer cell lines that highly express the target protein, and determining changes in the cancer cells.

[0053] Since the conjugated compound in the antibody-drug conjugate exerts an antitumor effect, it is preferable, but not essential, that the antibody itself should produce an antitumor effect. It is important and also preferable that the antibody has the property of being internalized and migrating into cancer cells in order to specifically and selectively exert the cytotoxic activity of the antitumor compound on cancer cells.

[0054] The anti-TROP2 antibody in the antibody-drug conjugate used in the present disclosure can be obtained by procedures known in the art. For example, the antibody of the present disclosure can be obtained using methods commonly used in the art, including immunizing an animal with an antigenic polypeptide in vivo and collecting and purifying the produced antibody. The source of the antigen is not limited to humans; animals can also be immunized with antigens derived from non-human animals such as mice and rats. In this case, the cross-reactivity of the obtained antibody that binds to the heterologous antigen with human antigens can be tested to screen for antibodies applicable to human diseases.

[0055] Alternatively, antibody-producing cells that produce antibodies against an antigen can be fused with myeloma cells according to methods known in the art (e.g., Kohler and Milstein, Nature (1975) 256, pp. 495-497; Kennet, R., ed., Monoclonal Antibodies, pp. 365-367, Plenum Press, NY (1980)) to establish hybridomas, from which monoclonal antibodies can then be obtained.

[0056] Antigens can be obtained by genetically engineering host cells to produce genes encoding antigenic proteins. Specifically, vectors capable of expressing antigen genes are prepared and transfected into host cells, where the genes are expressed. The antigens expressed in this manner can be purified. Antibodies can also be obtained by immunizing animals with the above-mentioned genetically engineered antigen-expressing cells or cell lines expressing the antigen.

[0057] The anti-TROP2 antibody in the antibody-drug conjugate used in the present disclosure is preferably a recombinant antibody obtained by artificial modification to reduce heterologous antigenicity to humans, such as a chimeric antibody or a humanized antibody, or preferably an antibody having only the gene sequence of an antibody derived from a human, i.e., a human antibody. These antibodies can be produced using known methods.

[0058] Examples of chimeric antibodies include antibodies in which the antibody variable region and constant region are derived from different species, for example, chimeric antibodies in which a mouse- or rat-derived antibody variable region is linked to a human-derived antibody constant region (Proc. Natl. Acad. Sci. USA, 81, 6851-6855, (1984)).

[0059] Examples of humanized antibodies include antibodies obtained by incorporating only the complementarity-determining regions of a heterologous antibody into a human-derived antibody (Nature (1986) 321, pp. 522-525), antibodies obtained by grafting a portion of the amino acid residues of the framework of a heterologous antibody, as well as the CDR sequences of that heterologous antibody, into a human antibody using a CDR grafting method (WO90 / 07861), and antibodies humanized using a gene conversion mutagenesis strategy (U.S. Pat. No. 5,821,337).

[0060] Examples of human antibodies include antibodies produced by using a human antibody-producing mouse carrying a human chromosome fragment containing the heavy and light chain genes of a human antibody (see, for example, Tomizuka, K. et al., Nature Genetics (1997) 16, pp. 133-143; Kuroiwa, Y. et al., Nucl. Acids Res. (1998) 26, pp. 3447-3448; Yoshida, H. et al., Animal Cell Technology: Basic and Applied Aspects, Vol. 10, pp. 69-73 (Kitagawa, Y., Matsuda, T., and Iijima, S., eds.), Kluwer Academic Publishers, 1999; Tomizuka, K. et al., Proc. Natl. Acad. Sci. USA (2000) 97, pp. 722-727). Alternatively, examples include antibodies obtained by phage display, in which the antibodies are selected from a human antibody library (see, for example, Wormstone, I. M. et al., Investigative Ophthalmology & Visual Science. (2002) 43(7), pp. 2301-2308; Carmen, S. et al., Briefings in Functional Genomics and Proteomics (2002), 1(2), pp. 189-203; Siriwardena, D. et al., Ophthalmology (2002) 109(3), pp. 427-431).

[0061] The antibody in the antibody-drug conjugate used in the present disclosure also includes modified variants of the antibody. Modified variants refer to variants obtained by subjecting an antibody according to the present disclosure to chemical or biological modification. Examples of chemically modified variants include variants containing a chemical moiety linked to the amino acid backbone, variants containing a chemical moiety linked to an N- or O-linked sugar chain, etc. Examples of biologically modified variants include variants obtained by post-translational modification (e.g., N- or O-linked glycosylation, N- or C-terminal processing, deamidation, aspartic acid isomerization, or methionine oxidation), and variants with an added methionine residue at the N-terminus upon expression in a prokaryotic host cell. Furthermore, antibodies labeled to enable detection or isolation of the antibody or antigen according to the present disclosure, such as enzyme-labeled antibodies, fluorescent-labeled antibodies, and affinity-labeled antibodies, are also included within the meaning of modified variants. Such modified variants of antibodies according to the present disclosure are useful for improving antibody stability and blood retention, reducing their antigenicity, detecting or isolating antibodies or antigens, etc.

[0062] Furthermore, antibody-dependent cellular cytotoxicity can be enhanced by controlling the modification (glycosylation, defucosylation, etc.) of glycans linked to the antibodies of the present disclosure. Techniques for controlling antibody glycan modification are known, including those disclosed in WO99 / 54342, WO00 / 61739, WO02 / 31140, WO2007 / 133855, and WO2013 / 120066. However, the techniques are not limited thereto. Anti-TROP2 antibodies of the present disclosure also include antibodies in which glycan modification is controlled.

[0063] It is known that antibodies produced in cultured mammalian cells lack a lysine residue at the carboxyl terminus of their heavy chains (Journal of Chromatography A, 705:129-134 (1995)). It is also known that antibodies produced in cultured mammalian cells lack two amino acid residues (glycine and lysine) at the carboxyl terminus of their heavy chains and amidate a newly positioned proline residue at the carboxyl terminus (Analytical Biochemistry, 360:75-83 (2007)). However, such deletions and modifications of the heavy chain sequence do not affect the antigen-binding affinity or effector functions (complement activation, antibody-dependent cellular cytotoxicity, etc.) of the antibody. Therefore, the anti-TROP2 antibodies of the present disclosure also include antibodies or functional fragments of antibodies that have been subjected to such modifications, including deletion variants in which one or two amino acids are deleted at the carboxyl terminus of the heavy chain, and variants obtained by amidation of deletion variants (e.g., heavy chains in which the carboxyl-terminal proline residue is amidated). The types of deletion variants with deletions at the carboxyl termini of the heavy chains of antibodies of the present disclosure are not limited to the above variants, as long as the antigen-binding affinity and effector function are preserved. The two heavy chains constituting the antibodies of the present disclosure may be one type selected from the group consisting of full-length heavy chains and the above deletion variants, or a combination of two types selected from the group. The ratio of the amounts of each deletion variant may be affected by the type and culture conditions of cultured mammalian cells producing the antibodies of the present disclosure; however, an antibody of the present disclosure in which one amino acid residue at the carboxyl terminus is deleted in both of its two heavy chains is preferred.

[0064] The isotype of the anti-TROP2 antibody according to the present disclosure can be, for example, IgG (IgG1, IgG2, IgG3, IgG4), with IgG1 being preferred.

[0065] In the present disclosure, the term "anti-TROP2 antibody" refers to an antibody that specifically binds to TROP2 (TACSTD2: tumor-associated calcium signaling transduction factor 2; EGP-1), and preferably has internalization activity by binding to TROP2 in TROP2-expressing cells.

[0066] Examples of anti-TROP2 antibodies include hTINA1-H1L1 (WO2015 / 098099), and datopotamab is a preferred example.

[0067] 3. Preparation of antibody-drug conjugates The drug-linker intermediate used in making the antibody-drug conjugates according to the present disclosure is represented by the following formula:

[0068] [ka]

[0069] The drug-linker intermediate can be expressed as the chemical name N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]glycylglycyl-L-phenylalanyl-N-[(2-{[(1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-1-yl]amino}-2-oxoethoxy)methyl]glycinamide, and can be prepared with reference to descriptions in WO2014 / 057687, WO2015 / 098099, WO2019 / 044947, and the like.

[0070] The antibody-drug conjugates used in the present disclosure can be prepared by reacting the above-described drug-linker intermediate with an anti-TROP2 antibody bearing a thiol group (also called a sulfhydryl group).

[0071] Anti-TROP2 antibodies bearing sulfhydryl groups can be obtained by methods well known in the art (Hermanson, GT, Bioconjugate Techniques, pp. 56-136, pp. 456-493, Academic Press (1996)). For example, an antibody can be reacted with 0.3 to 3 molar equivalents of a reducing agent such as tris(2-carboxyethyl)phosphine hydrochloride (TCEP) per interchain disulfide in the antibody in a buffer solution containing a chelating agent such as ethylenediaminetetraacetic acid (EDTA) to obtain an anti-TROP2 antibody bearing sulfhydryl groups in which the interchain disulfides in the antibody have been partially or completely reduced.

[0072] Furthermore, by using 2 to 20 molar equivalents of a drug-linker intermediate per anti-TROP2 antibody having a sulfhydryl group, antibody-drug conjugates in which 2 to 8 drug molecules are conjugated per antibody molecule can be prepared.

[0073] The average number of drug molecules conjugated per anti-TROP2 antibody in the antibody-drug conjugate produced can be determined, for example, by a calculation method based on measuring the UV absorbance of the antibody-drug conjugate and its conjugation precursor at two wavelengths, 280 nm and 370 nm (UV method), or by a calculation method based on quantification by HPLC measurement of fragments obtained by treating the antibody-drug conjugate with a reducing agent (HPLC method).

[0074] Conjugation between an anti-TROP2 antibody and a drug-linker intermediate and calculation of the average number of drug molecules conjugated per antibody molecule of an antibody-drug conjugate can be performed with reference to descriptions in WO2014 / 057687, WO2015 / 098099, WO2017 / 002776, WO2022 / 014698, etc.

[0075] In the present disclosure, the term "anti-TROP2 antibody-drug conjugate" refers to an antibody-drug conjugate in which the antibody in the antibody-drug conjugate according to the present disclosure is an anti-TROP2 antibody.

[0076] The anti-TROP2 antibody is preferably an antibody comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence represented by SEQ ID NO:3 (= the amino acid sequence consisting of amino acid residues 50 to 54 of SEQ ID NO:1), CDRH2 consisting of the amino acid sequence represented by SEQ ID NO:4 (= the amino acid sequence consisting of amino acid residues 69 to 85 of SEQ ID NO:1), and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO:5 (= the amino acid sequence consisting of amino acid residues 118 to 129 of SEQ ID NO:1), and a light chain comprising CDRL1 consisting of the amino acid sequence represented by SEQ ID NO:6 (= the amino acid sequence consisting of amino acid residues 44 to 54 of SEQ ID NO:2), CDRL2 consisting of the amino acid sequence represented by SEQ ID NO:7 (= the amino acid sequence consisting of amino acid residues 70 to 76 of SEQ ID NO:2), and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO:8 (= the amino acid sequence consisting of amino acid residues 109 to 117 of SEQ ID NO:2); More preferably, an antibody comprising a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 9 [= the amino acid sequence consisting of amino acid residues 20 to 140 of SEQ ID NO: 1] and a light chain comprising a light chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 10 [= the amino acid sequence consisting of amino acid residues 21 to 129 of SEQ ID NO: 2]; Even more preferred is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 12 [= the amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 1] and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 13 [= the amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 2], or an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 11 [= the amino acid sequence consisting of amino acid residues 20 to 469 of SEQ ID NO: 1] and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 13 [= the amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 2].

[0077] The average number of drug-linker bonds per antibody molecule in the anti-TROP2 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 5, even more preferably 3.5 to 4.5, and even more preferably about 4.

[0078] Anti-TROP2 antibody-drug conjugates can be produced with reference to the descriptions in WO2015 / 098099, WO2017 / 002776, and WO2022 / 014698.

[0079] In a preferred embodiment, the anti-TROP2 antibody-drug conjugate is datopotamab deruxtecan (DS-1062a).

[0080] 4. DNA methyltransferase (DNMT) inhibitors In the present disclosure, the terms "DNA methyltransferase inhibitor" and "DNMT inhibitor" refer to compounds that inhibit DNA methyltransferase enzymes. In some embodiments, the DNMT inhibitor inhibits one or more of human DNA methyltransferase enzymes, such as DNMT1, DNMT2, DNMT3a, and DNMT3b.

[0081] In some embodiments, the DNA methyltransferase inhibitor is selected from decitabine (5-aza-2'-deoxycytidine), azacitidine (5-azacytidine), guadecitabine, 5,6-dihydro-5-azacytidine, fazarabine, 5-fluoro-2'-deoxycytidine, zebularine, hydralizine, procaine, procainamide, epigallocatechin gallate, psammaplin A, (S)-2-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-3-(lH-indol-3-yl)-propionic acid, and pharmaceutically acceptable salts thereof. Preferred DNA methyltransferase inhibitors include decitabine (5-aza-2'-deoxycytidine), azacitidine (5-azacytidine), 5,6-dihydro-5-azacytidine, fazarabine, 5-fluoro-2'-deoxycytidine, zebularine, and pharmaceutically acceptable salts thereof. Preferably, the DNMT inhibitor is decitabine or azacitidine or a pharmaceutically acceptable salt thereof, particularly decitabine or a pharmaceutically acceptable salt thereof.

[0082] 5. Combination of antibody-drug conjugates and DNMT inhibitors In combination embodiments of the present disclosure, the antibody-drug conjugate used in combination with a DNMT inhibitor is an antibody-drug conjugate in which the antibody is an anti-TROP2 antibody.

[0083] In an embodiment of the above combination embodiment, the anti-TROP2 antibody comprises a heavy chain comprising a CDRH1 consisting of the amino acid sequence represented by SEQ ID NO:3 (amino acid residues 50 to 54 of SEQ ID NO:1), a CDRH2 consisting of the amino acid sequence represented by SEQ ID NO:4 (amino acid residues 69 to 85 of SEQ ID NO:1), and a CDRH3 consisting of the amino acid sequence represented by SEQ ID NO:5 (amino acid residues 118 to 129 of SEQ ID NO:1), and a light chain comprising a CDRL1 consisting of the amino acid sequence represented by SEQ ID NO:6 (amino acid residues 44 to 54 of SEQ ID NO:2), a CDRL2 consisting of the amino acid sequence represented by SEQ ID NO:7 (amino acid residues 70 to 76 of SEQ ID NO:2), and a CDRL3 consisting of the amino acid sequence represented by SEQ ID NO:8 (amino acid residues 109 to 117 of SEQ ID NO:2). In another embodiment of the above combination use embodiment, the anti-TROP2 antibody comprises a heavy chain variable region consisting of the amino acid sequence represented by SEQ ID NO:9 (amino acid residues 20-140 of SEQ ID NO:1) and a light chain variable region consisting of the amino acid sequence represented by SEQ ID NO:10 (amino acid residues 21-129 of SEQ ID NO:2). In another embodiment of the above combination use embodiment, the anti-TROP2 antibody comprises a heavy chain consisting of the amino acid sequence represented by SEQ ID NO:12 (amino acid residues 20-470 of SEQ ID NO:1) and a light chain consisting of the amino acid sequence represented by SEQ ID NO:13 (amino acid residues 21-234 of SEQ ID NO:2). In another embodiment of the above combination use embodiment, the anti-TROP2 antibody comprises a heavy chain consisting of the amino acid sequence represented by SEQ ID NO:11 (amino acid residues 20-469 of SEQ ID NO:1) and a light chain consisting of the amino acid sequence represented by SEQ ID NO:13 (amino acid residues 21-234 of SEQ ID NO:2). In another embodiment of the above combination use embodiment, the anti-TROP2 antibody is datopotamab.

[0084] In particularly preferred embodiments of the above combination embodiments, the anti-TROP2 antibody-drug conjugate is datopotamab deruxtecan (DS-1062a) and the DNMT inhibitor is decitabine.

[0085] In another particularly preferred embodiment of the above combination embodiment, the anti-TROP2 antibody-drug conjugate is datopotamab deruxtecan (DS-1062a) and the DNMT inhibitor is azacitidine.

[0086] In some aspects of the above combination embodiments, the antibody-drug conjugate and / or DNMT inhibitor is further administered in combination with one or more chemotherapeutic agents. In some aspects, the DNMT inhibitor is further administered in combination with a cytidine deaminase (CDA) inhibitor, preferably cedazuridine or tetrahydrouridine, particularly cedazuridine, preferably as an oral fixed-dose combination such as oral ASTX727 (Inqovi®: decitabine / cedazuridine).

[0087] 6. Therapeutic Combination Uses and Methods Described below are pharmaceutical agents and therapeutic uses and methods in which an anti-TROP2 antibody-drug conjugate according to the present disclosure and a DNMT inhibitor are administered in combination.

[0088] The pharmaceuticals and therapeutic uses and methods of the present disclosure may be characterized in that the antibody-drug conjugate and the DNMT inhibitor are contained separately as active components in different formulations and administered simultaneously or at different times, or in that the antibody-drug conjugate and the DNMT inhibitor are contained and administered as active components in a single formulation.

[0089] In the pharmaceuticals and treatment methods of the present disclosure, a single DNMT inhibitor used in the present disclosure can be administered in combination with an antibody-drug conjugate, or two or more different DNMT inhibitors can be administered in combination with an antibody-drug conjugate.

[0090] The medicaments and treatment methods of the present disclosure can be used to treat cancer, and preferably can be used to treat at least one cancer selected from the group consisting of breast cancer, lung cancer, colorectal cancer, gastric cancer, esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, endometrial cancer, gastrointestinal stromal tumor, gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, endometrial carcinoma, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, melanoma, cervical cancer, uterine cancer, testicular cancer, and renal cell carcinoma.

[0091] The presence or absence of a tumor marker, such as the TROP2 tumor marker, can be determined, for example, by collecting tumor tissue from a cancer patient, preparing a formalin-fixed, paraffin-embedded (FFPE) specimen, and subjecting the specimen to testing for gene products (proteins), for example, by immunohistochemistry (IHC) methods, flow cytometry, or Western blotting, or for gene transcription, for example, by in situ hybridization (ISH) methods, quantitative PCR methods (q-PCR), or microarray analysis, or by collecting cell-free circulating tumor DNA (ctDNA) from a cancer patient and subjecting the ctDNA to testing by methods such as next-generation sequencing (NGS).

[0092] The pharmaceutical agents and treatment methods of the present disclosure are preferably used in mammals, and more preferably in humans.

[0093] The antitumor effects of the pharmaceuticals and treatment methods of the present disclosure can be confirmed by transplanting cancer cells into a test animal to prepare a model and measuring the reduction in tumor volume or survival effect of the pharmaceuticals and treatment methods of the present disclosure.The effect of the combined use of an antibody-drug conjugate used in the present disclosure and a DNMT inhibitor can then be confirmed by comparing the antitumor effects of the antibody-drug conjugate used in the present disclosure administered alone with those of the DNMT inhibitor administered alone.

[0094] The anti-tumor efficacy of the pharmaceutical agents and treatment methods disclosed herein can be confirmed in clinical trials using any of the Response Evaluation Criteria in Solid Tumors (RECIST) assessment methods, WHO assessment methods, Macdonald assessment methods, body weight measurements, and other approaches, and can be determined based on indicators such as complete response (CR), partial response (PR); progressive disease (PD), objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS).

[0095] By using the above method, it is possible to confirm the superiority of the pharmaceutical agents and therapeutic methods of the present disclosure in terms of anti-tumor effects over existing pharmaceutical agents and therapeutic methods for cancer treatment.

[0096] The pharmaceuticals and treatment methods disclosed herein can delay the onset of cancer cells, inhibit their growth, and even kill cancer cells. These effects can relieve cancer patients from symptoms caused by cancer or improve their quality of life (QOL), achieving a therapeutic effect by sustaining the life of cancer patients. Even if the pharmaceuticals and treatment methods disclosed herein do not kill cancer cells, they can achieve a longer survival period and a higher QOL for cancer patients by inhibiting or controlling the growth of cancer cells.

[0097] The pharmaceutical agent of the present disclosure is expected to exert a therapeutic effect when applied to a patient as a systemic treatment, and additionally when applied locally to cancer tissue.

[0098] In another aspect, the pharmaceutical agent and treatment method of the present disclosure provide for use as an adjunct in cancer treatment with ionizing radiation or other chemotherapeutic agents. For example, in the treatment of cancer, the treatment may include administering a therapeutically effective amount of the pharmaceutical agent to a subject in need of treatment, simultaneously or sequentially with ionizing radiation or other chemotherapeutic agents.

[0099] The pharmaceuticals and treatment methods of the present disclosure can be used as adjuvant chemotherapy in conjunction with surgery. The pharmaceuticals of the present disclosure can be administered before surgery to reduce tumor size (also called preoperative adjuvant chemotherapy or neoadjuvant therapy), or can be administered after surgery to prevent tumor recurrence (also called postoperative adjuvant chemotherapy or adjuvant therapy).

[0100] In some embodiments, cancer cells may have a BRCA1 and / or BRCA2-deficient phenotype, i.e., BRCA1 and / or BRCA2 activity is reduced or absent in the cancer cells. Cancer cells with this phenotype may be BRCA1 and / or BRCA2-deficient, i.e., BRCA1 and / or BRCA2 expression and / or activity may be reduced or absent in the cancer cells, for example, due to mutations or polymorphisms in the encoding nucleic acids, or amplifications, mutations, or polymorphisms in genes encoding regulators, such as the EMSY gene encoding the BRCA2 regulator (Hughes-Davies et al., Cell, 115, 523-535). BRCA1 and BRCA2 are known tumor suppressors whose wild-type alleles are frequently lost in tumors of heterozygous carriers (Jasin M., Oncogene, 21(58), 8981-93(2002); Tutt et al., Trends Mol Med., 8(12), 571-6, (2002)). The association of BRCA1 and / or BRCA2 mutations with breast cancer has been well characterized in the art (Radice, PJ, Exp Clin Cancer Res., 21(3 Suppl), 9-12(2002)). Amplification of the EMSY gene, which encodes a BRCA2 binding factor, is also known to be associated with breast and ovarian cancer. Carriers of mutations in BRCA1 and / or BRCA2 are also at increased risk of certain cancers, including breast, ovarian, pancreatic, prostate, hematologic, gastrointestinal, and lung cancers. In some embodiments, the individual is heterozygous for one or more variations, such as mutations and polymorphisms, in BRCA1 and / or BRCA2 or regulators thereof.Detection of variations in BRCA1 and BRCA2 is well known in the art and is described, for example, in EP699754, EP705903, Neuhausen, SL and Ostrander, EA, Genet. Test, 1, 75-83 (1992); Chappnis, PO and Foulkes, WO, Cancer Treat Res, 107, 29-59 (2002); Janatova M. et al., Neoplasma, 50(4), 246-505 (2003); Jancarkova, N., Ceska Gynekol., 68(1), 11-6 (2003). Determination of amplification of the BRCA2 binding factor EMSY is described in Hughes-Davies et al., Cell, 115, 523-535).

[0101] Cancer-associated mutations and polymorphisms can be detected at the nucleic acid level by detecting the presence of variant nucleic acid sequences, or at the protein level by detecting the presence of variant (i.e., mutant or allelic variant) polypeptides.

[0102] The pharmaceutical preparations of the present disclosure may be administered containing at least one pharmaceutically suitable ingredient. The pharmaceutically suitable ingredient may be appropriately selected and applied from formulation additives commonly used in the art according to the dosage, administration concentration, etc., of the antibody-drug conjugate and DNMT inhibitor used in the present disclosure. The antibody-drug conjugate used in the present disclosure may be administered as a pharmaceutical preparation containing, for example, a buffer such as a histidine buffer, a medium such as sucrose and trehalose, and a surfactant such as polysorbate 80 or 20. The antibody-drug conjugate used in the pharmaceutical preparations of the present disclosure may preferably be used as an injection, more preferably as an aqueous injection or a lyophilized injection, and even more preferably as a lyophilized injection. When the pharmaceutical preparation containing the antibody-drug conjugate used in the present disclosure is an aqueous injection, the aqueous injection may preferably be diluted with an appropriate diluent and then administered as an intravenous infusion. Examples of diluents include dextrose solution and physiological saline, with dextrose solution being preferred and 5% dextrose solution being more preferred. When the pharmaceutical product of the present disclosure is a freeze-dried injection, the required amount of the freeze-dried injection, which is dissolved in water beforehand for injection, can be preferably diluted with a suitable diluent, and then administered as intravenous infusion.Examples of the diluent include dextrose solution and physiological saline, and preferably dextrose solution, more preferably 5% dextrose solution.

[0103] Examples of administration routes applicable for administering the pharmaceutical agents of the present disclosure include intravenous, intradermal, subcutaneous, intramuscular, and intraperitoneal routes, with the intravenous route being preferred.

[0104] The size of the dose required for the therapeutic treatment of a particular disease state necessarily varies depending on the subject being treated, the route of administration, and the severity of the disease being treated.For further information on the route of administration and dosage regimen, refer to Chapter 25.3 of Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of the Editorial Board), Pergamon Press 1990.

[0105] The anti-TROP2 antibody-drug conjugates used in the present disclosure can be administered to humans once every 1 to 180 days, preferably once per week, once per 2 weeks, once per 3 weeks, or once per 4 weeks, and even more preferably once per 3 weeks. The antibody-drug conjugates used in the present disclosure can be administered at a dose of approximately 0.001 to 100 mg / kg, preferably 0.8 to 12.4 mg / kg. For example, the anti-TROP2 antibody-drug conjugates can be administered at a dose of 0.27 mg / kg, 0.5 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 4.0 mg / kg, 6.0 mg / kg, or 8.0 mg / kg once per 3 weeks, preferably 4.0 or 6.0 mg / kg once per 3 weeks.

[0106] The DNMT inhibitor may be administered in a suitable dose by any suitable route of administration.

[0107] In some embodiments, the DNMT inhibitor is administered at a dose of about 0.1 to 10,000 mg / m 2 The subject is administered a dose of 15-75 mg / m body surface area per dose. 2 and even more preferably at a dose of 15 or 20 mg / m 2 can be administered at a dose of

[0108] In some embodiments, the dose of the DNMT inhibitor is administered to a subject daily for 2-7 days every 3-6 weeks, preferably daily for 3 or 5 days every 6 or 4 weeks, and even more preferably at 20 mg / m daily for 5 days every 4 weeks. 2 It can be administered at .

[0109] In some embodiments, the DNMT inhibitor is administered in combination with one or more other chemotherapeutic agents. In some embodiments, the other chemotherapeutic agent is cedazuridine. In some embodiments, the chemotherapeutic agent is pemetrexed.

[0110] In some embodiments, the DNMT inhibitors disclosed herein can be formulated as pharmaceutical compositions with pharmaceutically acceptable carriers, excipients, or stabilizers. In certain embodiments, such pharmaceutical compositions are suitable for administration to humans or non-humans via any one or more routes of administration using methods known in the art. The term "pharmaceutically acceptable carrier" refers to one or more non-toxic materials that do not interfere with the effectiveness of the biological activity of the active ingredient. Such preparations may routinely contain salts, buffers, preservatives, compatible carriers, and optionally other therapeutic agents. Such pharmaceutically acceptable preparations may also contain compatible solid or liquid fillers, diluents, or encapsulating materials suitable for human administration. Other contemplated carriers, excipients, and / or additives that may be utilized in the formulations described herein include, for example, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic agents, lipids, protein excipients such as serum albumin, gelatin, casein, and the like, salt-forming counterions such as sodium, and the like. These and other known pharmaceutical carriers, excipients, and / or additives suitable for use in the formulations described herein are known in the art, for example, as listed in "Remington: The Science & Practice of Pharmacy," 21st Edition, Lippincott Williams & Wilkins (2005), and "Physician's Desk Reference," 60th Edition, Medical Economics, Montvale, NJ (2005). Pharmaceutically acceptable carriers can be selected that are suitable for the desired or required mode of administration, solubility, and / or stability.

[0111] In some embodiments, therapeutic compositions can be formulated for specific routes of administration, such as oral, nasal, pulmonary, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. As used herein, the terms "parenteral administration" and "administered parenterally" refer to modes of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion. Formulations of the present disclosure suitable for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. Antibodies and other active agents may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required (see, e.g., U.S. Pat. Nos. 7,378,110; 7,258,873; and 7,135,180; U.S. Patent Application Publication Nos. 2004 / 0042972 and 2004 / 0042971).

[0112] The formulations can be provided in unit dosage form and can be prepared by any method known in the art of pharmacy. The actual dosage level of the active ingredient in the pharmaceutical compositions of the present disclosure can be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration (e.g., a "therapeutically effective amount") without being toxic to the patient. The selected dosage level depends on various pharmacokinetic factors, including the activity of the particular composition used, the route of administration, the time of administration, the excretion rate of the particular compound being used, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular composition being used, the age, sex, weight, condition, overall health, and past medical history of the patient being treated, and similar factors well known in the medical field. These dosages can be administered daily, weekly, biweekly, monthly, or less frequently, for example, semi-annually, depending on the dosage, the method of administration, the disorder or symptom being treated, and the characteristics of the individual subject. Dosages can also be administered by continuous infusion (e.g., via a pump). The administered dose can also depend on the route of administration. For example, subcutaneous administration may require a higher dosage than intravenous administration. As mentioned above, any commonly used dosing regimen (e.g., 1-10 mg / kg administered daily or twice weekly by injection or infusion) may be applicable and appropriate in methods for treating human cancer patients. [Example]

[0113] The present disclosure is specifically described in terms of the examples shown below. However, the present disclosure is not limited thereto, and should not be construed as limiting in any way.

[0114] Example 1A Preparation of anti-TROP2 antibody-drug conjugate (1) According to the production methods described in WO2015 / 098099, WO2017 / 002776, and WO2022 / 014698, an antibody having a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 12 [= amino acid residues 20 to 470 of SEQ ID NO: 1] and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 13 [= amino acid residues 21 to 234 of SEQ ID NO: 2] was prepared using an anti-TROP2 antibody (an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 12 [= amino acid residues 20 to 470 of SEQ ID NO: 1] and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 13 [= amino acid residues 21 to 234 of SEQ ID NO: 2]).

[0115] [ka] An anti-TROP2 antibody-drug conjugate (DS-1062a: datopotamab deruxtecan) was prepared in which a drug-linker represented by the formula (wherein A represents the attachment position to the antibody) is conjugated to the anti-TROP2 antibody via a thioether bond. The DAR of the antibody-drug conjugate (1) is 4.0.

[0116] Example 1B Preparation of anti-TROP2 antibody-drug conjugate (2) Sacituzumab govitecan (IMMU-132) was prepared according to the production method described in Example 12 of US Pat. No. 7,999,083 using the hRS7 antibody (an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 14 and a light chain comprising the amino acid sequence represented by SEQ ID NO: 15). The DAR of the antibody-drug conjugate (2) is 7.5.

[0117] [Example 2] Cell growth inhibition studies Antibody-drug conjugate DS-1062a in combination with decitabine Human colorectal cancer cell lines DLD-1 and HCT-15 (obtained from the American Type Culture Collection (ATCC)) were incubated in RPMI 1640 medium supplemented with 10% (v / v) heat-inactivated FBS, 1% (v / v) penicillin-streptomycin solution, and 1 mM sodium pyruvate with or without 1 μM, 0.3, or 0.1 μM decitabine (DAC) (Tokyo Chemical Industry Co., Ltd.) at 37°C and 5% CO2 for 3 days. Cells were harvested and replated at 1,000 cells / 80 μL / well into 96-well black clear-bottom plates and incubated overnight at 37°C and 5% CO2. Then, 20 μL of DS-1062a diluted in medium at concentrations ranging from 500 nM to 0.5 nM was added to the wells and incubated for 6 days for DLD-1 cells and 8 days for HCT-15 cells. The final concentrations of DS-1062a were 100, 10, 1, and 0.1 nM. After incubation, cellular ATP levels were measured using the CellTiter-Glo luminescent cell viability assay (Promega) and a microplate reader.

[0118] In each group treated with or without DAC, cell viability, defined as the relative percentage to the value of cells not treated with DS-1062a, was assessed (N=1 (triplicate), mean ± SD).

[0119] Individual cell viability (%) was calculated by the following equation: Cell viability (%)=100×T / C T: Individual luminescence intensity of wells treated with each concentration of DS-1062a C: Mean luminescence intensity of wells treated without DS-1062a

[0120] result: As shown in Figures 12A and 12B, the cell growth inhibitory activity of DS-1062a was enhanced in DAC-treated cells compared to untreated cells in both DLD-1 and HCT-15 cell lines.

[0121] [Example 3] Antitumor Testing Antibody-drug conjugate DS-1062a in combination with decitabine Female BALB / c-nu mice (Jackson Laboratory Japan, Inc.), aged 5 to 6 weeks, were used after 4 days of acclimation before entering the study.

[0122] 3 x 10 suspended in saline 6 DLD-1 cells were implanted subcutaneously into the flank of mice. The major and minor diameters of the tumor were measured twice a week with an electronic digital caliper, and the tumor volume was calculated by the following equation: Tumor volume (mm 3 )= 1 / 2 x major axis (mm) x [minor axis (mm)] 2 Tumor volume is approximately 100-150mm 3 When tumor-bearing mice reached 0 days, they were randomly assigned to treatment groups as shown in Table 1 (day 0):

[0123] [Table 1]

[0124] Decitabine (Tokyo Chemical Industry Co., Ltd.) was dissolved and diluted with phosphate-buffered saline (PBS) and administered subcutaneously to mice. DS-1062a solution was diluted with ABS buffer (10 mM acetate buffer [pH 5.5], 5% sorbitol) and administered intravenously to the tail vein of mice. The compound dose for each mouse was calculated based on the individual body weight on the day of administration. Decitabine was administered subcutaneously at 0.5 mg / kg once daily from day 0 to day 4 (a total of five doses). DS-1062a was administered intravenously to the tail vein at 10 mg / kg in a volume of 10 mL / kg on day 7 (a single dose).

[0125] Statistical significance between the "DS-1062a" group and the "decitabine + DS-1062a" group was evaluated using Welch's t-test for tumor volume on the day of final measurement (day 28).

[0126] result: As shown in FIG. 13, the antitumor activity of DS-1062a was significantly enhanced in the group pretreated with DAC compared with the untreated group (P<0.05).

[0127] [Example 4] Cell growth inhibition studies Antibody-drug conjugate DS-1062a in combination with azacitidine Human colorectal cancer cell line DLD-1 was incubated in RPMI 1640 medium supplemented with 10% (v / v) heat-inactivated FBS with or without 10, 3.3, or 1.1 μM azacytidine (AZA) at 37°C and 5% CO2 for 3 days. Cells were harvested and replated at 1000 cells / 90 μL / well into a 96-well black clear-bottom plate and incubated overnight at 37°C and 5% CO2. Subsequently, 10 μL of DS-1062a diluted in medium at concentrations ranging from 1000 nM to 1 nM was added to the wells and incubated for 6 days. The final concentrations of DS-1062a were 100, 10, 1, and 0.1 nM. After incubation, cellular ATP levels were measured using a CellTiter-Glo luminescent cell viability assay (Promega Corporation) and a microplate reader.

[0128] Cell viability, defined as the relative percentage to the value of cells not treated with DS-1062a, was assessed in each group treated with or without AZA (N=1 in triplicate, mean ± SD).

[0129] Individual cell viability (%) was calculated by the following equation: Cell viability (%)=100×T / C T: Individual luminescence intensity of wells treated with each concentration of DS-1062a C: Mean luminescence intensity of wells treated without DS-1062a

[0130] result: As shown in Figure 14, the cell growth inhibitory activity of DS-1062a was enhanced in cells treated with AZA compared to cells not treated with AZA.

[0131] [Example 5] Antitumor Testing Antibody-drug conjugate IMMU-132 in combination with decitabine Five-week-old female BALB / c-nu mice (Jackson Laboratory Japan) were used after 5 days of acclimation before entering the study.

[0132] 3 x 10 suspended in saline 6 DLD-1 cells were implanted subcutaneously into the flank of mice. The major and minor diameters of the tumor were measured twice a week with an electronic digital caliper, and the tumor volume was calculated by the following equation: Tumor volume (mm 3 )= 1 / 2 x major axis (mm) x [minor axis (mm)] 2 Tumor volume is approximately 100-150mm 3 When tumor-bearing mice reached 0 days, they were randomly assigned to treatment groups as shown in Table 2 (Day 0):

[0133] Statistical significance between the IMMU-132 group and the decitabine + IMMU-132 group was assessed using Welch's t-test for tumor volume on the day of final measurement (day 28).

[0134] [Table 2]

[0135] Decitabine (DAC) was dissolved in phosphate-buffered saline (PBS) and administered subcutaneously to mice. IMMU-132 was dissolved in ABS buffer (10 mM acetate buffer [pH 5.5], 5% sorbitol) and administered intravenously to the tail vein of mice. The compound dose volume for each mouse was calculated based on the most recent individual body weight within 2 days prior to dosing. DAC was administered subcutaneously at 0.5 mg / kg once daily from day 0 to day 4 (a total of 5 doses). IMMU-132 was administered intravenously to the tail vein at 10 mg / kg on days 7 and 14 (2 weekly doses).

[0136] result: DS-1062a showed significantly enhanced antitumor activity with DAC pretreatment (Example 3), as shown in Figure 13, whereas the antitumor activity of IMMU-132 with DAC pretreatment was not significantly different from that of IMMU-132 without DAC pretreatment, as shown in Figure 15.

[0137] The foregoing specification is believed to be sufficient to enable one skilled in the art to practice the present embodiments. The foregoing description and examples detail certain particular embodiments and set forth the best mode contemplated by the inventors. However, no matter how detailed the foregoing appears in text, it will be understood that the present embodiments can be variously practiced, and the appended claims encompass any equivalents thereof.

[0138] Free text in the sequence listing SEQ ID NO: 1 - Amino acid sequence of the heavy chain of the anti-TROP2 antibody SEQ ID NO: 2 - Amino acid sequence of the light chain of the anti-TROP2 antibody SEQ ID NO:3 - amino acid sequence of heavy chain CDRH1 [= amino acid residues 50 to 54 of SEQ ID NO:1] SEQ ID NO: 4 - amino acid sequence of heavy chain CDRH2 [= amino acid residues 69 to 85 of SEQ ID NO: 1] SEQ ID NO:5 - amino acid sequence of heavy chain CDRH3 [= amino acid residues 118 to 129 of SEQ ID NO:1] SEQ ID NO:6 - Amino acid sequence of light chain CDRL1 [=amino acid residues 44 to 54 of SEQ ID NO:2] SEQ ID NO:7 - Amino acid sequence of light chain CDRL2 [=amino acid residues 70-76 of SEQ ID NO:2] SEQ ID NO:8 - Amino acid sequence of light chain CDRL3 [=amino acid residues 109-117 of SEQ ID NO:2] SEQ ID NO: 9 - amino acid sequence of the heavy chain variable region [= amino acid residues 20 to 140 of SEQ ID NO: 1] SEQ ID NO: 10 - Amino acid sequence of the light chain variable region [= amino acid residues 21 to 129 of SEQ ID NO: 2] SEQ ID NO:11 - amino acid sequence of the heavy chain [= amino acid residues 20 to 469 of SEQ ID NO:1] SEQ ID NO:12 - amino acid sequence of the heavy chain [= amino acid residues 20 to 470 of SEQ ID NO:1] SEQ ID NO: 13 - light chain amino acid sequence [= amino acid residues 21 to 234 of SEQ ID NO: 2] SEQ ID NO: 14 - Amino acid sequence of the heavy chain of the hRS7 antibody SEQ ID NO: 15 - Amino acid sequence of the light chain of the hRS7 antibody

Claims

1. A pharmaceutical comprising an antibody-drug conjugate and a DNMT inhibitor for combined administration, wherein the antibody-drug conjugate has the following formula: 【Chemistry 1】 wherein A represents the attachment position to the antibody, and is conjugated to the anti-TROP2 antibody via a thioether bond.

2. The pharmaceutical product of claim 1, wherein the anti-TROP2 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 4, and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 5, and a light chain comprising CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of the amino acid sequence represented by SEQ ID NO: 7, and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO:

8.

3. The pharmaceutical product according to claim 2, wherein the anti-TROP2 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 9 and a light chain comprising a light chain variable region consisting of the amino acid sequence represented by SEQ ID NO:

10.

4. The pharmaceutical product according to claim 2 or 3, wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 12 and a light chain consisting of the amino acid sequence represented by SEQ ID NO:

13.

5. The pharmaceutical product of claim 4, wherein the antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

6. The pharmaceutical product according to any one of claims 1 to 5, wherein the average number of drug-linker bonds per antibody molecule in the antibody-drug conjugate is in the range of 3.5 to 4.

5.

7. The pharmaceutical product of any one of claims 1 to 5, wherein the antibody-drug conjugate is datopotamab deruxtecan (DS-1062a).

8. The pharmaceutical product according to any one of claims 1 to 7, wherein the DNMT inhibitor is decitabine or azacitidine or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical product of claim 8, wherein the DNMT inhibitor is decitabine or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical product according to any one of claims 1 to 9, which is a composition comprising an antibody-drug conjugate and a DNMT inhibitor for simultaneous administration.

11. The pharmaceutical product according to any one of claims 1 to 9, which is a combined preparation comprising the antibody-drug conjugate and the DNMT inhibitor for sequential administration or separate simultaneous administration.

12. The pharmaceutical product of any one of claims 1 to 11, wherein the DNMT inhibitor is administered in combination with a cytidine deaminase inhibitor.

13. 13. The pharmaceutical product of claim 12, wherein the cytidine deaminase inhibitor is cedazuridine or a pharmaceutically acceptable salt thereof.

14. The pharmaceutical product according to any one of claims 1 to 13, which is for the treatment of cancer.

15. 15. The pharmaceutical product of claim 14, wherein the cancer is at least one selected from the group consisting of breast cancer, lung cancer, colorectal cancer, gastric cancer, esophageal cancer, head and neck cancer, esophagogastric junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, endometrial cancer, gastrointestinal stromal tumor, gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, endometrial carcinoma, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma, cervical cancer, uterine cancer, testicular cancer, and renal cell carcinoma.

16. The pharmaceutical product of claim 15, wherein the cancer is colorectal cancer.

17. The pharmaceutical product of claim 15, wherein the cancer is lung cancer.

18. The pharmaceutical product of claim 17, wherein the lung cancer is non-small cell lung cancer.

19. The pharmaceutical product of claim 15, wherein the cancer is breast cancer.

20. The pharmaceutical product of any one of claims 14 to 19, wherein the cancer cells of the cancer are SLFN11 deficient.

21. The pharmaceutical product of claim 20, wherein SLFN11 expression is lower in the patient's cancer cells compared to the patient's SLFN11-expressing non-cancer cells.

22. 10. An antibody-drug conjugate for use in combination with a DNMT inhibitor in the treatment of cancer, wherein the antibody-drug conjugate and the DNMT inhibitor are as defined in any one of claims 1 to 9.

23. The antibody-drug conjugate for use according to claim 21, wherein the cancer is as defined in any one of claims 15 to 21.

24. 24. The antibody-drug conjugate for use according to claim 22 or 23, wherein the use comprises sequential administration of the antibody-drug conjugate and the DNMT inhibitor.

25. 24. The antibody-drug conjugate for use according to claim 22 or 23, wherein the use comprises separate and simultaneous administration of the antibody-drug conjugate and the DNMT inhibitor.

26. A method of treating cancer, comprising co-administering an antibody-drug conjugate as defined in any one of claims 1 to 9 and a DNMT inhibitor to a subject in need thereof.

27. The method of claim 26, wherein the cancer is as defined in any one of claims 15 to 21.

Images