Wee1 inhibitor combination therapy

Abstract

Disclosed herein is use of a combination of Compound (A), or a pharmaceutically acceptable salt thereof, (also known as azenosertib or ZN-c3) and Compound (B), or a pharmaceutically acceptable salt thereof, or an antibody -drag conjugate comprising Compound (B), or a pharmaceutically acceptable salt thereof, for treating a disease, such as a cancer, wherein Compound (B) can be a topoisomerase I inhibitor (e.g., topotecan, belotecan, irinotecan, SN-38, govitecan, exatecan or deruxtecan).

Description

WEE1 INHIBITOR COMBINATION THERAPYINCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

[0001] Any and all applications for which a foreign or domestic priority7claim is identified, for example, in the Application Data Sheet or Request as filed with the present application, are hereby incorporated by reference under 37 CFR 1.57, and Rules 4.18 and 20.6, including U.S. Provisional Application Nos. 63 / 641,587, filed May 2, 2024 and 63 / 694,334, filed September 13, 2024, each of which is incorporated by reference in their entireties.SEQUENCE STATEMENT

[0002] This application contains a Sequence Listing, which has been submitted electronically and is hereby incorporated by reference in its entirety. The sequence listing, was created on April 11, 2025, is named ZENO181WO_SequenceListing.xml and is 45 kb in size.Field

[0003] The present application relates to the fields of chemistry, biochemistry and medicine. More particularly, disclosed herein are combination therapies, and methods of treating diseases and / or conditions with a combination therapy described herein.Description

[0004] Topoisomerase inhibitors have been widely used as anti-cancer drugs for the past 20 years. Due to their selectivity as topoisomerase I (TOPI) inhibitors that trap TOPI cleavage complexes, camptothecin and its derivatives are promising anti-cancer drugs. Although TOPI inhibitors including camptothecin and its derivatives effectively induce cancer cell death, their potential applicability is limited by: (i) their rapid elimination before achieving therapeutic concentrations in the tumor; and (ii) dose limitations dictated by the inhibition of TOPI in normal cells, which need topoisomerase activity for cell survival.

[0005] Antibody-drug conjugates (ADCs) as targeted therapy has emerged as an approach to address the limitations of TOPI inhibitors. The clinical success of TOPI - ADCs is evidenced by approvals of the U.S. Food and Drug Administration (FDA) grantedof sacituzumab govitecan (brand name Trodelvy) and trastuzumab deruxtecan (brand name Enhertu) for breast cancers with specific genotypes. While the FDA approvals represent milestones in the ongoing development of therapeutic ADCs, there remains a need for improved ADCs and related therapies to help address the long-felt need for additional options to treat different types of cancer and to deliver therapeutic payloads to selected cells and tissues.SUMMARY

[0006] Some embodiments described herein relate to the use of a combination of Compound (A) and (i) Compound (B); or (ii) an antibody-drug conjugate comprising Compound (B) for treating a cancer in a subject. Compound (A) ispharmaceutically acceptable salt thereof.Compound (B) is topotecan, belotecan, irinotecan, SN-38, govitecan, exatecan, or deruxtecan, or a derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing. The antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target selected from the extracellular domain of human receptor tyrosine kinase-like orphan receptor 1 (R0R1), human epidermal growth factor receptor 3 (HER3), folate receptor alpha (FRa), cadherin 6 (CDH6), sodiumdependent phosphate transporter NaPi2b, tissue factor (TF or also known as platelet tissue factor, coagulation factor III (F3) and CD 142), mesothelin (MSLN), mucin 16 (MUC16 or also known as ovarian cancer-related tumor marker CA125), protein tyrosine kinase 7 (PTK7), receptor tyrosine kinase AXL (AXL), antigen CD166 (CD166), ectonucleotide pyrophosphatase / phosphodiesterase family member 3 (ENPP3). T-cell immunoglobulin and mucin domain 1 (TIM-1), cluster of differentiation 70 (CD70, also known as CD27L), B7 homolog 3 (B7-H3, also known as CD276), B7 homolog 4 (B7-H4), trophoblast cell surface antigen 2 (TROP2), Nectin-4, CD22, CD30, CD79b, CD19, B-cell maturation antigen (BCMA), mucin short variant S I (MUC1), Claudin 18.2 (CLDN 18.2), carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5). c-Met tyrosinekinase (c-Met), interleukin-3 receptor (CD123), epidermal growth factor receptor (EFGR) and a combination thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0007] FIGS. 1A and IB show 2D heatmaps of in vitro synergy between Compound (A) (z'.e., azenosertib) and TOPI inhibitors irinotecan (FIG. 1A) and SN-38 (FIG. IB) across a panel of colorectal cancer and breast cancer cell lines.

[0008] FIGS. 2A and 2B illustrate protein biomarker changes in response to Compound (A) monotherapy, TOPI inhibitors monotherapies (irinotecan or SN-38) and a combination of Compound (A) and irinotecan (FIG. 2A) or SN-38 (FIG. 2B) across a panel of colorectal cancer and breast cancer cell lines in cultures in vitro.

[0009] FIGS. 3A and 3B illustrate the mean tumor volumes of mice in response to Compound (A) monotherapy, irinotecan monotherapy (FIG. 3A), topotecan HC1 monotherapy (FIG. 3B), Compound (A) + irinotecan combination therapy (FIG. 3A), and Compound (A) + topotecan HC1 combination therapy (FIG. 3B) in the OV90 model of ovarian cancer. FIG. 3C illustrates the corresponding body weight changes of the mice treated with said monotherapies and combination therapies.

[0010] FIG. 4A illustrates the mean tumor volumes of mice in response to Compound (A) monotherapy, irinotecan monotherapy, and Compound (A) + irinotecan combination therapy in the HCC1569 model of HER2+ breast cancer. FIG. 4B illustrates the corresponding body weight changes of the mice treated with said monotherapies and combination therapies.

[0011] FIG. 5A shows 2D heatmaps of in vitro synergy between Compound (A) and sacituzumab govitecan in MDA-MB-468 and MDA-MB-231 triple negative breast cancer cell lines. FIG. 5B illustrates protein biomarker changes in response to Compound (A) monotherapy, sacituzumab govitecan (SG) monotherapy, and a combination of Compound (A) and sacituzumab govitecan in MDA-MB-468 cells in cultures in vitro.

[0012] FIGS. 6A and 6B illustrate the mean tumor volume of mice in response to Compound (A) monotherapy, sacituzumab govitecan monotherapy (FIG. 3A). datopotomab deruxtecan monotherapy (FIG. 6B), Compound (A) + sacituzumab govitecan combination therapy (FIG. 6A), and Compound (A) + datopotomab deruxtecan combination therapy (FIG. 6B) in the MDA-MB-231 model of triple negative breast cancer. FIG. 6C illustrates the corresponding body weight changes of the mice treated with said monotherapies and combination therapies.DETAILED DESCRIPTIONDefinitions

[0013] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0014] As used herein, an “immunoconjugate’' is a conjugate comprising an immunological substance and a drug moiety that are joined together by a linker. Typically, an immunoconjugate is prepared by reacting the immunological substance with a conjugate as defined herein. An “antibody-drug conjugate” (ADC) is one class of immunoconjugate whereby the immunological substance is an antibody or an antigen-binding fragment thereof.

[0015] As used herein, an “antibody” (Ab) is a protein made by the immune system, or a synthetic or engineered variant thereof, that binds to specific sites on cells or tissues. The term “antibody” herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multi-specific antibodies (e.g.. bispecific antibodies), chimeric antibodies, nanobodies, and antigen-binding fragments so long as they exhibit the desired antigenbinding activity. Monoclonal antibodies are a type of synthetic antibody. In cancer treatment, monoclonal antibodies may kill cancer cells directly, they may block development of tumor blood vessels, and / or they may help the immune system kill cancer cells. Humanized antibodies are antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans. For example, a murine monoclonal antibody, 4D5, directed against the extracellular domain of HER2 and a potent inhibitor of growth of human breast cancer cells overexpressing HER2 in vitro and in xenograft models, was humanized by inserting the complementary determining regions of 4D5 into the framework of a consensus human IgGl. The resulting recombinant humanized anti-HER2 mAb was trastuzumab. An antibody typically is composed of two heavy chains and two light chains; and the heavy chain and the light chain typically each contain three complementarity-determining regions(CDRs) immunoglobulin (Ig) hypervariable domains that determine specific antibody binding.

[0016] An ‘'antigen-binding fragment” refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include but are not limited to Fv, Fab, Fab', Fab'-SH, F(ab’)2. diabodies, linear antibodies, single-chain antibody molecules (e.g.. scFv), and single-domain antibodies.

[0017] As used herein, the term ’‘derivative” when referring to a derivative of Compound (B), or a derivative of topotecan, belotecan, irinotecan, SN-38, govitecan, exatecan, or deruxtecan, refers to a compound that is derived from any one of the aforementioned Compound (B), topotecan, belotecan, irinotecan, SN-38, govitecan, exatecan, or deruxtecan, for example, via one or more chemical reactions such as, but not limited to, hydrolysis, conjugation or esterification. As a non-limiting example, SN-38 is a derivative of irinotecan in that SN-38 is formed via hydrolysis of irinotecan by carboxylesterases and metabolized via glucuronidation by UGT1A1. As another nonlimiting example, deruxtecan is derived from exatecan via conjugation or covalent linking of exatecan to a tetrapeptide-based linker.

[0018] The term “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g. , hydrochloric acid or hydrobromic acid), a sulfuric acid, a nitric acid and a phosphoric acid (such as 2,3-dihydroxypropyl dihydrogen phosphate). Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, trifluoroacetic, benzoic, salicylic, 2-oxopentanedioic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium, a potassium or a lithium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of a carbonate, a salt of a bicarbonate, a salt of organic bases such as dicyclohexylamine, N- methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine and salts with amino acids such asarginine and lysine. Those skilled in the art understand that when a salt is formed by protonation of a nitrogen-based group (for example, NH2). the nitrogen-based group can be associated with a positive charge (for example, NH2 can become NH? ) and the positive charge can be balanced by a negatively charged counterion (such as CT).

[0019] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of ^-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched or a stereoisomeric mixture. In addition, it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included.

[0020] It is to be understood that where compounds disclosed herein have unfilled valencies, then the valencies are to be filled with hydrogens or isotopes thereof, e.g, hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0021] It is understood that the compounds described herein can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as. for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[0022] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent and maybe formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol or the like. Hydrates are formed when the solvent is water or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

[0023] Where a range of values is provided, it is understood that the upper and low er limit, and each intervening value between the upper and low er limit of the range is encompassed within the embodiments.

[0024] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term 'including’ should be read to mean “including, without limitation,” “including but not limited to,” or the like; the term “comprising"’ as used herein is synonymous with “including,” “containing,” or “characterized by,” and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term “having” should be interpreted as “having at least;” the term “includes” should be interpreted as “includes but is not limited to;” the term “example” is used to provide exemplary' instances of the item in discussion, not an exhaustive or limiting list thereof. In addition, the term “comprising” is to be interpreted synonymously with the phrases “having at least” or “including at least.” When used in the context of a compound, composition or device, the term “comprising” means that the compound, composition or device includes at least the recited features or components but may also include additional features or components.

[0025] With respect to the use of substantially any plural and / or singular terms herein, those having skill in the art can translate from the plural to the singular and / or from the singular to the plural as is appropriate to the context and / or application. The various singular / plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.Compounds and Antibody -Drug Conjugates

[0026] Some embodiments described herein relate to the use of a combination of Compound (A) and (i) Compound (B); or (ii) an antibody-drug conjugate comprisingCompound (B) for treating a cancer in a subject. Compound (A) ispharmaceutically acceptable salt thereof.

[0027] In some embodiments, a use described herein comprises use of a combination of Compound (A) and Compound (B). In some embodiments, Compound (B) is a topoisomerase 1 (TOPI) inhibitor.

[0028] In some embodiments, a use described herein comprises use of a combination of Compound (A) and an antibody -drug conjugate comprising Compound (B) for treating a cancer in a subject.

[0029] In some embodiments, Compound (derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0030] In some embodiments, a Compound (B) is topotecan, or a derivative thereof, or a pharmaceutically acceptable salt thereof. In other embodiments, a Compound (B) is belotecan, or a derivative thereof, or a pharmaceutically acceptable salt thereof. In still other embodiments, a Compound (B) is irinotecan, or a derivative thereof, or a pharmaceutically acceptable salt thereof. In yet still other embodiments, a Compound (B) is SN-38, or a derivative thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, a Compound (B) is govitecan, or a derivative thereof, or a pharmaceuticallyacceptable salt thereof. In other embodiments, a Compound (B) is exatecan, or a derivative thereof, or a pharmaceutically acceptable salt thereof. In still other embodiments, a Compound (B) is deruxtecan, or a derivative thereof, or a pharmaceutically acceptable salt thereof.

[0031] The antibody-drug conjugate comprises an antibody or an antigenbinding fragment thereof that specifically binds to a target selected from the extracellular domain of human receptor tyrosine kinase-like orphan receptor 1 (ROR1), human epidermal growth factor receptor 3 (HER3), folate receptor alpha (FRa), cadherin 6 (CDH6), sodium-dependent phosphate transporter NaPi2b, tissue factor (TF or also known as platelet tissue factor, coagulation factor III (F3) and CD 142), mesothelin (MSLN), mucin 16 (MUC16 or also known as ovarian cancer-related tumor marker CA125), protein tyrosine kinase 7 (PTK7), receptor tyrosine kinase AXL (AXL), antigen CD166 (CD166), ectonucleotide pyrophosphatase / phosphodiesterase family member 3 (ENPP3), T-cell immunoglobulin and mucin domain 1 (TIM-1), cluster of differentiation 70 (CD70, also known as CD27L). B7 homolog 3 (B7-H3. also known as CD276), B7 homolog 4 (B7-H4), trophoblast cell surface antigen 2 (TROP2), Nectin-4, CD22, CD30, CD79b, CD19, B-cell maturation antigen (BCMA), mucin short variant SI (MUC 1), Claudin 18.2 (CLDN 18.2), carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), c-Met tyrosine kinase (c-Met). interleukin-3 receptor (CD123), epidermal growth factor receptor (EFGR) and a combination thereof.

[0032] In some embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target selected from human epidermal growth factor receptor 3 (HER3), cadherin 6 (CDH6), trophoblast cell surface antigen 2 (TROP2), B7 homolog 3 (B7-H3. also known as CD276) and combinations thereof. In other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is human receptor tyrosine kinase-like orphan receptor 1 (ROR1). In some embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is human epidermal growth factor receptor 3 (HER3). In other embodiments, an antibody-drug conjugate comprises an antibody or an antigenbinding fragment thereof that specifically binds to a target that is folate receptor alpha (FRa). In still other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is cadherin 6(CDH6). In yet still embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is sodiumdependent phosphate transporter NaPi2b. In some embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is tissue factor (TF or also known as platelet tissue factor, coagulation factor III (F3) and CD142). In other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is mesothelin (MSLN). In still other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is mucin 16 (MUC16 or also known as ovarian cancer-related tumor marker CA125). In yet still other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is protein tyrosine kinase 7 (PTK7). In some embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is receptor tyrosine kinase AXL (AXL). In other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is antigen CD166 (CD166). In still other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is ectonucleotide pyrophosphatase / phosphodi esterase family member 3 (ENPP3). In yet still other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is T- cell immunoglobulin and mucin domain 1 (TIM-1). In some embodiments, an antibodydrug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is cluster of differentiation 70 (CD70, also known as CD27L). In other embodiments, an antibody -drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is B7 homolog 3 (B7-H3, also known as CD276). In still other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is B7 homolog 4 (B7-H4). In yet still other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is trophoblast cell surface antigen 2 (TROP2). In some embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is Nectin-4. In other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specificallybinds to a target that is CD22. In still other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is CD30. In yet still other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is CD79b. In some embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is CD19. In other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is B-cell maturation antigen (BCMA). In still other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is mucin short variant SI (MUC1). In yet still other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is Claudin 18.2 (CLDN 18.2). In some embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5). In other embodiments, an antibody-drug conjugate comprises an antibody or an antigenbinding fragment thereof that specifically binds to a target that is c-Met tyrosine kinase (c- Met). In still other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is interleukin-3 receptor (CD123). In yet still other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is epidermal growth factor receptor (EFGR). In some embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to the extracellular domain of a target described herein.

[0033] One embodiment pertains to the use of a combination of Compound (A) as defined herein, and an antibody-drug conjugate comprising Compound (B) as defined above for treating cancer in a subject, wherein the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target as defined above. In one embodiment, the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target selected from human epidermal growth factor receptor 3 (HER3), cadherin 6 (CDH6), trophoblast cell surface antigen 2 (TROP2), B7 homolog 3 (B7-H3, also known as CD276) and a combination thereof. In one embodiment, the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to trophoblast cell surface antigen2 (TR0P2). In one embodiment, the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to human epidermal growth factor receptor 3 (HER3). In one embodiment, the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to cadherin 6 (CDH6). In one embodiment, the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to B7 homolog 3 (B7-H3, also known as CD276). In some embodiments, a Compound (B) is a topoisomerase 1 (TOPI) inhibitor, or a derivative thereof, or a pharmaceutically acceptable salt thereof (e.g., topotecan, belotecan, irinotecan, SN-38, govitecan, exatecan or deruxtecan, including derivatives and pharmaceutically acceptable salts of any of the foregoing). In some embodiments, a Compound (B) is irinotecan or SN-38, or a derivative thereof, or a pharmaceutically acceptable salt thereof. In other embodiments, a Compound (B) is irinotecan or topotecan, or a derivative of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing. In still other embodiments, a Compound (B) is govitecan or deruxtecan, or a derivative of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing. In yet still other embodiments, a Compound (B) is irinotecan, or a derivative thereof, or a pharmaceutically acceptable salt thereof.

[0034] Another aspect of this disclosure relates to a method of treating a cancer in a subject comprising administering an effective amount of Compound (A) as defined herein, and an effective amount of: (i) Compound (B) as defined herein; or (ii) an antibodydrug conjugate comprising Compound (B), to the subject, wherein the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target as defined above. One embodiment pertains to a method of treating a cancer in a subject comprising administering an effective amount of Compound (A) as defined herein, and an effective amount of an antibody-drug conjugate comprising Compound (B) as defined herein, to the subject, wherein the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target as defined above. In one embodiment, the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target selected from human epidermal grow th factor receptor 3 (HER3), cadherin 6 (CDH6), trophoblast cell surface antigen 2 (TROP2), B7 homolog 3 (B7-H3, also known as CD276) and a combination thereof. In one embodiment, the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to trophoblast cell surface antigen 2 (TROP2). In some embodiments, a Compound (B) is a topoisomerase 1(T0P1) inhibitor, or a derivative thereof, or a pharmaceutically acceptable salt thereof (e.g. , topotecan, belotecan, irinotecan, SN-38, govitecan, exatecan. or deruxtecan, including derivatives and pharmaceutically acceptable salts of any of the foregoing). In some embodiments, a Compound (B) is irinotecan or SN-38, or a derivative thereof, or a pharmaceutically acceptable salt thereof. In other embodiments, a Compound (B) is irinotecan or topotecan, or a derivative of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing. In still other embodiments, a Compound (B) is govitecan or deruxtecan, or a derivative of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing. In yet still other embodiments, a Compound (B) is irinotecan, or a derivative thereof, or a pharmaceutically acceptable salt thereof.

[0035] Yet another aspect of this disclosure relates to a combination of Compound (A) as defined herein, and (i) Compound (B) as defined herein; or (ii) an antibody-drug conjugate comprising Compound (B), for use in treating a cancer, wherein the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target as defined above. One embodiment pertains to a combination of Compound (A) as defined herein, and an antibody-drug conjugate comprising Compound (B) as defined herein, for use in treating a cancer, wherein the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target as defined above. In one embodiment, the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target selected from human epidermal growth factor receptor 3 (HER3), cadherin 6 (CDH6), trophoblast cell surface antigen 2 (TROP2), B7 homolog 3 (B7-H3, also known as CD276) and a combination thereof. In one embodiment, the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to trophoblast cell surface antigen 2 (TROP2). In some embodiments, a Compound (B) is a topoisomerase 1 (TOPI) inhibitor, or a derivative thereof, or a pharmaceutically acceptable salt thereof (e.g., topotecan, belotecan, irinotecan, SN-38, govitecan, exatecan, or deruxtecan, including derivatives and pharmaceutically acceptable salts of any of the foregoing). In some embodiments, a Compound (B) is irinotecan or SN-38. or a derivative of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing. In other embodiments, a Compound (B) is irinotecan or topotecan, or a derivative of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing. In still other embodiments, a Compound (B) is govitecan or deruxtecan, or a derivative of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing. In yet still otherembodiments, a Compound (B) is irinotecan, or a derivative thereof, or a pharmaceutically acceptable salt thereof.

[0036] In one embodiment, the uses and methods described herein exclude the immunoconjugates and compounds described in International Patent Application Publication Nos. WO 2023 / 004266, WO 2024 / 026323 and WO 2024 / 158996, including all U.S. provisional applications to which priority is claimed and all other filed and unfilled applications in all jurisdictions related thereto.

[0037] In some embodiments of the uses and methods provided herein, Compound (B) is topotecan, or a derivative thereof, or a pharmaceutically acceptable salt thereof. In some embodiments of the uses and methods provided herein, Compound (B) is irinotecan, or a derivative thereof, or a pharmaceutically acceptable salt thereof. In some embodiments of the uses and methods provided herein, Compound (B) is SN-38, or a derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of the uses and methods provided herein, Compound (B) is govitecan, or a pharmaceutically acceptable salt thereof. In some embodiments of the uses and methods provided herein. Compound (B) is exatecan or a denvative thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of the uses and methods provided herein, Compound (B) is deruxtecan, or a pharmaceutically acceptable salt thereof.

[0038] In some embodiments of the uses and methods provided herein, the antibody-drug conjugate is represented by the following structural formula:or a pharmaceutically acceptable salt thereof, wherein:Ab is the antibody or an antigen-binding fragment thereof that specifically binds to a target as defined above; and n represents an average number of govitecan compounds conjugated to a single Ab and is in a range of about 1 to about 10. In one embodiment, n is in a range of about 7 to about 8.

[0039] In some embodiments of the uses and methods provided herein, the antibody-drug conjugate is represented by the following structural formula:or a pharmaceutically acceptable salt thereof, wherein:Ab is the antibody or an antigen-binding fragment thereof that specifically binds to a target as defined above; and n represents an average number of deruxtecan compounds conjugated to a single Ab and is in a range of about 1 to about 10. In one embodiment, n is about 4.

[0040] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises:(a) a heavy chain CDRH1 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO: 1; a heavy chain CDRH2 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:2; and a heavy chain CDRH3 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:3; and(b) a light chain CDRL1 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:4; a light chain CDRL2 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:5; and a light chain CDRL3 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:6. In some embodiments, a heavy chain CDRH1 comprises or has at least 95% (e.g., at least 95, 96,97, 98, or 99%) sequence similarity to SEQ ID NO: 1, a heavy chain CDRH2 comprises or has at least 95% (e.g, at least 95, 96. 97. 98, or 99%) sequence similarity to SEQ ID NO:2, and / or a heavy chain CDRH3 comprises or has at least 95% (e.g, at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:3.

[0041] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain CDRH1 comprises or has at least 99% sequence similarity to SEQ ID NO: 1. a heavy chain CDRH2 comprises or has at least 99% sequence similarity to SEQ ID NO: 2, and / or a heavy chain CDRH3 comprises or has at least 99% sequence similarity to SEQ ID NO:3. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain CDRH1 comprises the sequence of SEQ ID NO: 1, a heavy chain CDRH2 comprises the sequence of SEQ ID NO:2, and / or a heavy chain CDRH3 comprises the sequence of SEQ ID NO:3.

[0042] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a light chain CDRL1 comprises or has at least 95% (e.g, at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:4. a light chain CDRL2 comprises or has at least 95% (e.g, at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO: 5, and / or a light chain CDRL3 comprises or has at least 95% (e g, at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:6. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a light chain CDRL1 comprises or has at least 99% sequence similarity to SEQ ID NO:4, a light chain CDRL2 comprises or has at least 99% sequence similarity to SEQ ID NO:5, and / or a light chain CDRL3 comprises or has at least 99% sequence similarity to SEQ ID NO: 6. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a light chain CDRL1 comprises the sequence of SEQ ID NO:4, a light chain CDRL2 comprises the sequence of SEQ ID NO:5, and / or a light chain CDRL3 comprises the sequence of SEQ ID NO:6.

[0043] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 90%, 95%, or 99% sequence similarity to SEQ ID NO:7 and a light chain comprising having at least 90%, 95%, or 99% sequence similarity to SEQ ID NO: 8. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 90% (e.g. at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:7 and a light chaincomprising or having at least 90%. (e.g., at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO: 8. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:7 and a light chain comprising or having at least 95%, (e.g, at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO: 8. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 99% sequence similarity to SEQ ID NO:7 and a light chain comprising or having at least 99%, sequence si mi I an ty to SEQ ID NO: 8. In some embodiments of the uses and methods provided herein, the antibody or an antigenbinding fragment comprises a heavy chain comprising the sequence of SEQ ID NO:7 and a light chain comprising the sequence of SEQ ID NO:8.

[0044] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises:(a) a heavy chain CDRH1 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO: 9; a heavy chain CDRH2 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO: 10; and a heavy chain CDRH3 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:11; and(b) a light chain CDRL 1 comprising or having at least 95% or at least 99% sequence similarity’ to SEQ ID NO: 12; a light chain CDRL2 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO: 13; and a light chain CDRL3 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO: 14.

[0045] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 90%, 95%, or 99% sequence similarity to SEQ ID NO: 15 and a light chain comprising having at least 90%, 95%, or 99% sequence similarity’ to SEQ ID NO: 16. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 90% (e.g.. at least 90. 91. 92, 93, 94, 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO: 15 and a light chain comprising or having at least 90%, (e.g., at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO: 16. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarityto SEQ ID NO: 15 and a light chain comprising or having at least 95%, (e.g.. at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO: 16. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 99% sequence similarity to SEQ ID NO: 15 and a light chain comprising or having at least 99%, sequence similarity to SEQ ID NO: 16. In some embodiments of the uses and methods provided herein, the antibody or an antigenbinding fragment comprises a heavy chain comprising the sequence of SEQ ID NO: 15 and a light chain comprising the sequence of SEQ ID NO: 16.

[0046] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises:(a) a heavy chain CDRH1 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO: 17; a heavy chain CDRH2 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO: 18; and a heavy chain CDRH3 comprising or having at least 95% or at least 99% sequence similarity' to SEQ ID NO: 19; and(b) a light chain CDRL1 comprising or having at least 95% or at least 99% sequence similarity' to SEQ ID NO:20; a light chain CDRL2 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:21; and a light chain CDRL3 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:22.

[0047] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain CDRH1 comprises or has at least 95% (e.g. , at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO: 17, a heavy chain CDRH2 comprises or has at least 95% (e g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO: 18, and / or a heavy chain CDRH3 comprises or has at least 95% (e.g, at least 95, 96, 97, 98, or 99%) sequence similarity’ to SEQ ID NO: 19. In some embodiments of the uses and methods provided herein, the antibody or an antigenbinding fragment comprises a heavy chain CDRH1 comprises or has at least 99% sequence similarity to SEQ ID NO: 17, a heavy chain CDRH2 comprises or has at least 99% sequence similarity to SEQ ID NO: 18, and / or a heavy chain CDRH3 comprises or has at least 99% sequence similarity to SEQ ID NO: 19. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain CDRH1 comprises the sequence of SEQ ID NO: 17, a heavy' chain CDRH2 comprises the sequence of SEQ ID NO: 18, and / or a heavy chain CDRH3 comprises the sequence of SEQ ID NO: 19.

[0048] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a light chain CDRL1 comprises or has at least 95% (e.g, at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:20, a light chain CDRL2 comprises or has at least 95% (e.g, at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:21, and / or a light chain CDRL3 comprises or has at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:22. In some embodiments of the uses and methods provided herein, the antibody or an antigenbinding fragment comprises a light chain CDRL1 comprises or has at least 99% sequence similarity to SEQ ID NO:20, a light chain CDRL2 comprises or has at least 99% sequence similarity to SEQ ID NO:21, and / or a light chain CDRL3 comprises or has at least 99% sequence similarity to SEQ ID NO:22. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a light chain CDRL1 comprises the sequence of SEQ ID NO:20, a light chain CDRL2 comprises the sequence of SEQ ID NO:21, and / or a light chain CDRL3 comprises the sequence of SEQ ID NO:22.

[0049] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain CDRH1 comprises or has at least 95% (e.g. , at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO: 17, a heavy chain CDRH2 comprises or has at least 95% (e.g, at least 95, 96, 97, 98, or 99%) sequence similarity’ to SEQ ID NO: 18, and / or a heavy chain CDRH3 comprises or has at least 95% (e.g, at least 95, 96, 97, 98, or 99%) sequence similarity’ to SEQ ID NO: 19. In some embodiments of the uses and methods provided herein, the antibody or an antigenbinding fragment comprises a heavy chain CDRH1 comprises or has at least 99% sequence similarity to SEQ ID NO: 17, a heavy chain CDRH2 comprises or has at least 99% sequence similarity to SEQ ID NO: 18, and / or a heavy chain CDRH3 comprises or has at least 99% sequence similarity to SEQ ID NO: 19. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain CDRH1 comprises the sequence of SEQ ID NO: 17, a heavy chain CDRH2 comprises the sequence of SEQ ID NO: 18. and / or a heavy chain CDRH3 comprises the sequence of SEQ ID NO: 19

[0050] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a light chain CDRL1 comprises or has at least 95% (e.g, at least 95, 96, 97, 98. or 99%) sequence similarity to SEQ ID NO:20. a light chain CDRL2 comprises or has at least 95% (e.g, at least 95, 96, 97, 98, or 99%)sequence similarity to SEQ ID N0:21, and / or a light chain CDRL3 comprises or has at least 95% (e.g, at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:22. In some embodiments of the uses and methods provided herein, the antibody or an antigenbinding fragment comprises a light chain CDRL1 comprises or has at least 99% sequence similarity to SEQ ID NO:20, a light chain CDRL2 comprises or has at least 99% sequence similarity to SEQ ID NO:21, and / or a light chain CDRL3 comprises or has at least 99% sequence similarity to SEQ ID NO:22. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a light chain CDRL1 comprises the sequence of SEQ ID NO:20, a light chain CDRL2 comprises the sequence of SEQ ID NO:21, and / or a light chain CDRL3 comprises the sequence of SEQ ID NO 22.

[0051] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 90%, 95%, or 99% sequence similarity to SEQ ID NO:23 and alight chain comprising having at least 90%, 95%, or 99% sequence similarity to SEQ ID NO:24. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 90% (e.g., at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:23 and a light chain comprising or having at least 90%. (e.g.. at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:24. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:23 and a light chain comprising or having at least 95%, (e.g.. at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:24. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 99% sequence similarity to SEQ ID NO: 23 and a light chain comprising or having at least 99%, sequence similarity to SEQ ID NO:24. In some embodiments of the uses and methods provided herein, the antibody or an antigenbinding fragment comprises a heavy chain comprising the sequence of SEQ ID NO:23 and a light chain comprising the sequence of SEQ ID NO:24.

[0052] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises:(a) a heavy chain CDRH1 comprising or having at least 95% or at least 99% sequence similarity’ to SEQ ID NO:25; a heavy chain CDRH2 comprising or having at least95% or at least 99% sequence similarity to SEQ ID NO:26; and a heavy chain CDRH3 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:27; and(b) a light chain CDRL1 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:28; a light chain CDRL2 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:29; and a light chain CDRL3 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:30.

[0053] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain CDRH1 comprises or has at least 95% (e.g. , at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:25, a heavy chain CDRH2 comprises or has at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:26, and / or a heavy chain CDRH3 comprises or has at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:27. In some embodiments of the uses and methods provided herein, the antibody or an antigenbinding fragment comprises a heavy chain CDRH1 comprises or has at least 99% sequence similarity to SEQ ID NO:25. a heavy chain CDRH2 comprises or has at least 99% sequence similarity to SEQ ID NO:26, and / or a heavy chain CDRH3 comprises or has at least 99% sequence similarity to SEQ ID NO:27. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain CDRH1 comprises the sequence of SEQ ID NO:25, a heavy chain CDRH2 comprises the sequence of SEQ ID NO:26, and / or a heavy chain CDRH3 comprises or comprises the sequence of SEQ ID NO:27.

[0054] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a light chain CDRL1 comprises or has at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:28, a light chain CDRL2 comprises or has at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:29, and / or a light chain CDRL3 comprises or has at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:30. In some embodiments of the uses and methods provided herein, the antibody or an antigenbinding fragment comprises a light chain CDRL1 comprises or has at least 99% sequence similarity to SEQ ID NO:28, a light chain CDRL2 comprises or has at least 99% sequence similarity to SEQ ID NO:29, and / or a light chain CDRL3 comprises or has at least 99% sequence similarity to SEQ ID NO: 30. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a light chainCDRL1 comprises the sequence of SEQ ID NO:28, a light chain CDRL2 comprises the sequence of SEQ ID NO:29. and / or a light chain CDRL3 comprises the sequence of SEQ ID NO:30.

[0055] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 90%, 95%, or 99% sequence similarity to SEQ ID NO:31 and alight chain comprising having at least 90%, 95%. or 99% sequence similarity to SEQ ID NO:32. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 90% (e.g., at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:31 and a light chain comprising or having at least 90%. (e.g.. at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO: 32. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:31 and a light chain comprising or having at least 95%, (e.g.. at least 95, 96, 97. 98. or 99%) sequence similarity to SEQ ID NO: 32. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 99% sequence similarity' to SEQ ID NO: 31 and a light chain comprising or having at least 99%, sequence similarity to SEQ ID NO:32. In some embodiments of the uses and methods provided herein, the antibody or an antigenbinding fragment comprises a heavy chain comprising the sequence of SEQ ID NO:31 and a light chain comprising the sequence of SEQ ID NO:32.

[0056] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises:(a) a heavy chain CDRH1 comprising or having at least 95% or at least 99% sequence similarity' to SEQ ID NO:33; a heavy chain CDRH2 comprising or having at least 95% or at least 99% sequence similarity' to SEQ ID NO: 34; and a heavy chain CDRH3 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:35; and(b) a light chain CDRL1 comprising or having at least 95% or at least 99% sequence similarity' to SEQ ID NO: 36; a light chain CDRL2 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:37; and a light chain CDRL3 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:38.

[0057] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain CDRH1 comprises or has at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:33, a heavy chain CDRH2 comprises or has at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:34, and / or a heavy chain CDRH3 comprises or has at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:35. In some embodiments of the uses and methods provided herein, the antibody or an antigenbinding fragment comprises a heavy chain CDRH1 comprises or has at least 99% sequence similarity' to SEQ ID NO:33, a heavy chain CDRH2 comprises or has at least 99% sequence similarity to SEQ ID NO:34, and / or a heavy chain CDRH3 comprises or has at least 99% sequence similarity to SEQ ID NO:35. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain CDRH1 comprises the sequence of SEQ ID NO:33, a heavy chain CDRH2 comprises the sequence of SEQ ID NO:34, and / or a heavy chain CDRH3 comprises the sequence of SEQ ID NO:35.

[0058] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a light chain CDRL1 comprises or has at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:36, a light chain CDRL2 comprises or has at least 95% (e.g, at least 95, 96, 97, 98. or 99%) sequence similarity to SEQ ID NO:37, and / or a light chain CDRL3 comprises or has at least 95% (e.g, at least 95, 96, 97, 98, or 99%) sequence similarity’ to SEQ ID NO:38. In some embodiments of the uses and methods provided herein, the antibody or an antigenbinding fragment comprises a light chain CDRL1 comprises or has at least 99% sequence similarity to SEQ ID NO: 36. a light chain CDRL2 comprises or has at least 99% sequence similarity to SEQ ID NO:37, and / or a light chain CDRL3 comprises or has at least 99% sequence similarity to SEQ ID NO:38. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a light chain CDRL1 comprises the sequence of SEQ ID NO:36, a light chain CDRL2 comprises the sequence of SEQ ID NO:37. and / or a light chain CDRL3 comprises the sequence of SEQ ID NO:38

[0059] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 90%, 95%, or 99% sequence similarity to SEQ ID NO:39 and alight chain comprising having at least 90%, 95%, or 99% sequence similarity to SEQ ID NO:40. In someembodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 90% (e.g., at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:39 and a light chain comprising or having at least 90%, (e.g., at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:40. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 95% (e.g., at least 95, 96, 97, 98. or 99%) sequence similarity to SEQ ID NO:39 and a light chain comprising or having at least 95%, (e.g. , at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:40. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 99% sequence similarity to SEQ ID NO: 39 and a light chain comprising or having at least 99%, sequence similarity to SEQ ID NO:40. In some embodiments of the uses and methods provided herein, the antibody or an antigenbinding fragment comprises a heavy chain comprising the sequence of SEQ ID NO: 39 and a light chain comprising the sequence of SEQ ID NO:40.

[0060] In one embodiment, this disclosure relates to the use of a combination of Compound (A) as defined herein, and an antibody-drug conjugate for treating a cancer in a subject. The antibody-drug conjugate is represented by the following structural formula:or a pharmaceutically acceptable salt thereof, wherein:Ab is an antibody or an antigen-binding fragment thereof that comprises:(a) a heavy chain CDRH1 comprising SEQ ID NO:1; a heavy chain CDRH2 comprising SEQ ID NO:2; and a heavy chain CDRH3 comprising SEQ ID NO:3; and(b) a light chain CDRL1 comprising SEQ ID NO:4; a light chain CDRL2 comprising SEQ ID NO:5; and a light chain CDRL3 comprising SEQ ID NO:6; and n is in a range of about 1 to about 10 (e.g, about 7 to about 8)

[0061] In one embodiment, this disclosure relates to the use of a combination of Compound (A) as defined herein, and an antibody-drug conjugate for treating a cancer in a subject. The antibody-drug conjugate is represented by the following structural formula:or a pharmaceutically acceptable salt thereof, wherein:Ab is an antibody or an antigen-binding fragment thereof that comprises:(a) a heavy chain CDRH1 comprising SEQ ID NO:9; a heavy chain CDRH2 comprising SEQ ID NOTO; and a heavy chain CDRH3 comprising SEQ ID NO: 11 ; and(b) a light chain CDRL1 comprising SEQ ID NO: 12; a light chain CDRL2 comprising SEQ ID NO: 13; and a light chain CDRL3 comprising SEQ ID NO: 14; and n is in a range of about 1 to about 10 (e.g.. about 4).

[0062] The uses and methods of the present disclosure include uses and methods of treating a cancer selected from a brain cancer, a cervicocerebral cancer, an esophageal cancer, a thyroid cancer, a small cell cancer, a non-small cell cancer, a breast cancer, a lung cancer (e.g.. non-small cell lung cancer and small cell lung cancer), a stomach cancer, a urothelial cancer, a gallbladder / bile duct cancer, a kidney cancer (e.g, renal cell carcinoma), a liver cancer, a pancreatic cancer, a colon cancer, a rectal cancer, a colorectal cancer, an ovarian cancer (e.g., epithelial ovarian cancer), a fallopian tube cancer, a prima y- peritoneal cancer, an uterine cancer, a choriocarcinoma, an uterus body cancer, an uterocervical cancer, a renal pelvis / ureter cancer, a bladder cancer, a prostate cancer, a penis cancer, a testicular cancer, a fetal cancer, Wilms' cancer, a skin cancer,malignant melanoma, a neuroblastoma, an osteosarcoma, an Ewing's tumor, a soft part sarcoma, an acute leukemia, a chronic lymphatic leukemia, a chronic myelocytic leukemia, polycythemia vera, a malignant lymphoma, multiple myeloma, a Hodgkin's lymphoma and a non-Hodgkin’s lymphoma.

[0063] In one embodiment, the cancer is a breast cancer. In one embodiment, the breast cancer has a hormone receptor (HR)-positive (HR+) status. In one embodiment, the breast cancer has a hormone receptor (HR)-low (HRlow) status. In one embodiment, the breast cancer has a hormone receptor (HR)-positive (HR+) status. In one embodiment, the breast cancer has a HER2 -negative (HER-) status. In one embodiment, the breast cancer has a HER2-positive (HER+) status. In one embodiment, the breast cancer has a TROP2- low (TROP2low) status. In one embodiment, the breast cancer has a TROP2-high (TROP2hlgh) status. This disclosure contemplates breast cancers with any non-contradictory combination of the biomarkers mentioned above. In one embodiment, the breast cancer is triple negative breast cancer. In some embodiments, a cancer is selected from colorectal cancer, breast cancer and ovarian cancer.

[0064] In one embodiment, the cancer is urothelial cancer. In one embodiment, the cancer is non-small cell lung cancer (NSCLC). In one embodiment, the cancer is a neuroblastoma. In one embodiment, the cancer is a colorectal cancer. In one embodiment, the cancer is a renal cell carcinoma.

[0065] In one embodiment, the cancer is an ovarian cancer. In one embodiment, the ovarian cancer is high-grade serous ovarian cancer or high-grade serous ovarian carcinoma (HGSOC). In one embodiment, the ovarian cancer has a Cyclin Ellowstatus.

[0066] The status of the protein biomarkers described above, such as HER2, HR, TROP2 and Cyclin El, may be determined from the respective receptor or protein levels, or mRNA or transcript levels thereof, in a tumor sample obtained from a subject; and a H-score, an immunochemistry (IHC) staining intensity score (e.g., 1+, 2+, 3+) may be derived or calculated. The expression of each protein is assessed using a 0 to 3+ intensity score by a trained and qualified observer with categorization of ambiguous cases confirmed by a pathologist and the percentage of tumor cells having an IHC 1+, 2+, or 3+ intensity staining score (z.e., score 1 and above, score 2 and above, score 3 and above) is obtained and used to determine protein expression level.

[0067] In some embodiments, the cancer treated in the uses and methods provided herein has one or more mutations (e.g., deletion, nucleotide / amino acidsubstitution, altered expression or function, etc.) in a gene selected from TP53, PIK3CA, BRAE. BRCAL BRCA2. PTEN, KRAS and RBI.

[0068] In some embodiments, the subject with the cancer has received at least one prior systemic treatment regimens. In one embodiment, the subject has received one to three prior systemic treatment regimens. Such first-line standard therapies include immunotherapy, such as an immune checkpoint inhibitor, alone or in combination with chemotherapy, such as platinum-based chemotherapy. Non-limiting examples of platinumbased chemotherapy include cisplatin, carboplatin and oxaliplatin (including pharmaceutically acceptable salts of any of the foregoing).

[0069] In some embodiments, the cancer treated in the uses and methods provided herein is a “platinum-sensitive cancer,” which as used herein and per Response Evaluation Criteria in Solid Tumors (RECIST) vl.l refers to a cancer or tumor that is sensitive to platinum-based chemotherapy (e.g., cisplatin, carboplatin, oxaliplatin and pharmaceutically acceptable salts thereof) that is defined as (1) > 30% decrease from baseline, confirmed at 4 weeks, (2) no > 20% increase over smallest sum observed or (3) no new lesions.

[0070] In some embodiments, the cancer treated in the uses and methods of provided herein is a “platinum-resistant cancer,” which as used herein and per Response Evaluation Criteria in Solid Tumors (RECIST) v l. l refers to a cancer or tumor that may have previously responded to. but no longer responds, to platinum-based chemotherapy that is defined as (1) > 30% decrease from baseline or (2) no > 20% increase over smallest sum observed and no new lesions at 4 weeks. In one embodiment, the cancer acquires resistance, for example, via prior exposure to platinum-based therapy, either as monotherapy or in combination with other compounds (such as other chemotherapy, immune checkpoint inhibitors, etc.).

[0071] In some embodiments, the cancer treated in the uses and methods of provided herein is a “platinum-refractory cancer,” which as used herein and per Response Evaluation Criteria in Solid Tumors (RECIST) vl. l refers to a cancer or tumor which never responded to platinum-based chemotherapy that is defined as (1) > 30% decrease from baseline or (2) no > 20% increase over smallest sum observed and no new lesions at 4 weeks. In one embodiment, the cancer is inherently resistant.

[0072] Non-limiting examples of immune checkpoint inhibitors include PD-1 inhibitors, PD-L1 inhibitors. CTLA-4 inhibitors and LAG-3 inhibitors (including pharmaceutically acceptable salts of any of the foregoing). In some embodiments, animmune checkpoint inhibitor may be bi- or multi-specific and may target at least two proteins, including, but not limited to. two proteins selected from PD-1, PD-L1. CTLA-4 and LAG-3. Non-limiting examples of PD-1 inhibitors include retifanlimab, pucotenlimab, cadonilimab, serplulimab, nivolumab (relatimab), zimberelimab, penpulimab, dostarlimab (dostarlimab-gxly), prolgolimab, tislelizumab, camrelizumab, sintilimab, toripalimab, cemiplimab (cemiplimab-RWLC). pembrolizumab, nivolumab. balstilimab, finotonlimab, iparomlimab. ivonescimab, tuvonralimab / iparomlimab, cetrelimab. favezelimab / pembrolizumab, genolimzumab, nofazinlimab, pembrolizumab / hyaluronidase, pembrolizumab / quavonlimab, pembrolizumab / vibostolimab, pembrolizumab / quavonlimab, rilvegostomig, sasanlimab, spartalizumab, tebotelimab and volrustomig (including pharmaceutically acceptable salts of any of the foregoing).

[0073] Non-limiting examples of PD-L1 inhibitors include socazolimab, adebrelimab, sugemalimab, envafolimab, durvalumab, avelumab, atezolizumab, benmelstobart, tagitanlimab. bintrafusp alfa, erfonrilimab and retlirafusp alfa (including pharmaceutically acceptable salts of any of the foregoing).

[0074] Non-limiting examples of CTLA-4 inhibitors include tremelimumab, cadonilimab, ipilimumab, tuvonralimab / paromlimab, erfonrilimab, gotistobart, pembrolizumab / quavonlimab, pembrolizumab / quavonlimab, quavonlimab and volrustomig (including pharmaceutically acceptable salts of any of the foregoing).

[0075] Non-limiting examples of LAG-3 inhibitors include nivolumab / relatlimab, favezelimab / pembrolizumab, fianlimab, relatlimab, tebotelimab, eftilagimod alpha and favezelimab (including pharmaceutically acceptable salts of any of the foregoing).

[0076] When the treatment is a combination of compounds, the order of administration or use of the combination of Compound (A) and Compound (B) or an antibody-drug conjugate comprising Compound (B) described herein can vary'. In some embodiments, Compound (A) and Compound (B) or an antibody-drug conjugate comprising Compound (B) are administered or used sequentially. In some embodiments. Compound (A) can be administered prior to Compound (B) or an antibody-drug conjugate comprising Compound (B). In other embodiments, Compound (A) can be administered subsequent to or after Compound (B) or an antibody-drug conjugate comprising Compound (B). In still other embodiments, Compound (A) can be administered concomitantly orconcurrently with Compound (B) or an antibody-drug conjugate comprising Compound (B)

[0077] In some embodiments, Compound (A) is provided on an intermittent dosing schedule. In some embodiments, Compound (A) the intermittent dosing schedule comprises 5 days on, 2 days off; 4 days on, 3 days off; 3 days on , 4 days off; or 6 days on, 1 day off on in one or more dosing weeks.

[0078] In some embodiments, the use of a combination of Compound (A) and Compound (B) or an antibody-drug conjugate comprising Compound (B) for treating a cancer or methods of treatment with a combination of Compound (A) and Compound (B) or an antibody-drug conjugate comprising Compound (B), provided herein can decrease the number and / or severity of side effects that can be attributed to monotherapy of Compound (B) or an antibody-drug conjugate comprising Compound (B).

[0079] Using a combination of Compound (A) and Compound (B) or an antibody-drug conjugate comprising Compound (B) as described herein can result in additive, synergistic or strongly synergistic effect. A combination of compounds described herein can result in an effect that is not antagonistic.

[0080] As used herein, the term “antagonistic” means that the activity of the combination of compounds is less compared to the sum of the activities of the compounds in combination when the activity of each compound is determined individually (i.e., as a single compound). As used herein, the term “synergistic effect” means that the activity of the combination of compounds is greater than the sum of the individual activities of the compounds in the combination when the activity of each compound is determined individually. As used herein, the term “additive effect” means that the activity of the combination of compounds is about equal to the sum of the individual activities of the compounds in the combination when the activity of each compound is determined individually.

[0081] A potential advantage of utilizing a combination as described herein may be a reduction in the required amount(s) of the compound(s) that is effective in treating a disease condition disclosed herein compared to when Compound (B) or an antibody-drug conjugate comprising Compound (B) is administered as a monotherapy and / or wherein Compound (A) is administered as a monotherapy. For example, the amount of Compound (A) and Compound (B) or an antibody-drug conjugate comprising Compound (B) used in a combination described herein can be less compared to the amount of Compound (A) and Compound (B) or an antibody-drug conjugate comprising Compound (B) needed toachieve the same reduction in a disease marker (for example, tumor size) when each is administered as a monotherapy. Another potential advantage of utilizing a combination as described herein is that the use of two or more compounds having different mechanisms of action can create a higher barrier to the development of resistance compared to when Compound (A) and Compound (B) or an antibody-drug conjugate comprising Compound (B) are each administered as monotherapy. Additional advantages of utilizing a combination as described herein may include little to no cross resistance between the compounds of a combination described herein; different routes for elimination of the compounds of a combination described herein; and / or little to no overlapping toxicities between the compounds of a combination described herein.Pharmaceutical Compositions

[0082] Compound (A) can be provided in a pharmaceutical composition. Likewise, Compound (B) or an antibody-drug conjugate comprising Compound (B) can be provided in a pharmaceutical composition.

[0083] The term “pharmaceutical composition” refers to a mixture of one or more compounds and / or salts disclosed herein with other chemical components, such as diluents, carriers and / or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutical compositions will generally be tailored to the specific intended route of administration.

[0084] As used herein, a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

[0085] As used herein, a “diluent” refers to an ingredient in a pharmaceutical composition that lacks appreciable pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and / or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as. without limitation, phosphate buffered saline that mimics the pH and isotonicity of human blood.

[0086] As used herein, an “excipient’' refers to an essentially inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. For example, stabilizers such as anti-oxidants and metal-chelating agents are excipients. In an embodiment, the pharmaceutical composition comprises an anti-oxidant and / or a metal-chelating agent. A “diluent” is a type of excipient.

[0087] In some embodiments. Compound (B) or an antibody-drug conjugate comprising Compound (B) can be provided in a pharmaceutical composition that includes Compound (A). In other embodiments, Compound (B) or an antibody-drug conjugate comprising Compound (B) can be administered in a pharmaceutical composition that is separate from a pharmaceutical composition that includes Compound (A).

[0088] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are know n to those skilled in the art.

[0089] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g.. by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.

[0090] Multiple techniques of administering a compound, salt and / or composition exist in the art including, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection, infusion and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections. In some embodiments, Compound (A) can be administered orally. In some embodiments. Compound (A) can be provided to a subject by the same route of administration as Compound (B) or an antibody-drug conjugate comprising Compound (B). In other embodiments, Compound (A) can be provided to a subject by a different route of administration as Compound (B) or an antibody-drug conjugate comprising Compound (B).

[0091] One may also administer the compound, salt and / or composition in a local rather than systemic manner, for example, via injection or implantation of the compound directly into the affected area, often in a depot or sustained release formulation. Furthermore, one may administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the organ. For example, intranasal or pulmonary delivery to target a respiratory disease or condition may be desirable.

[0092] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions that can include a compound and / or salt described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.Uses and Methods of Treatment

[0093] As provided herein, in some embodiments, a combination of compounds that includes an effective amount of Compound (A) and an effective amount of Compound (B) or an antibody -drug conjugate comprising Compound (B) can be used to treat a cancer.

[0094] In some cases, following cancer treatment, a subject can relapse or have reoccurrence of the cancer. As used herein, the terms “relapse” and “recurrence” are used in their normal sense as understood by those skilled in the art. Thus, the cancer can be a recurrent cancer.

[0095] As used herein, a “subject” refers to an animal that is the object of treatment, observation or experiment. “Animal” includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and, in particular, humans. In some embodiments, the subject can be human. In some embodiments, thesubject can be a child (z.e., > 1 year and < 18 years old) and / or an infant (z.e., < 1 year old). In other embodiments, the subject can be an adult (>18 years of age).

[0096] As used herein, the terms '‘treat,” “treating,” “treatment,” “therapeutic,” and “therapy” do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of the disease or condition, to any extent can be considered treatment and / or therapy. Furthermore, treatment may include acts that may worsen the subject's overall feeling of well-being or appearance.

[0097] The term “effective amount” is used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. For example, an effective amount of compound, salt or composition can be the amount needed to prevent, alleviate or ameliorate symptoms of the disease or condition, or prolong the survival of the subject being treated. This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease or condition being treated. Determination of an effective amount is well within the capability’ of those skilled in the art, in view of the disclosure provided herein. The effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.

[0098] For example, an effective amount of a compound, or radiation, is the amount that results in: (a) the reduction, alleviation or disappearance of one or more symptoms caused by the cancer, (b) the reduction of tumor size, (c) the elimination of the tumor, and / or (d) long-term disease stabilization (growth arrest) of the tumor.

[0099] The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials, in vivo studies and in vitro studies. For example, useful dosages of Compounds (A) and Compound (B) or an antibody-drug conjugate comprising Compound (B), can be determined by comparing their in vitro activity, and in vivo activity in animal models. Such comparison can be done by comparison against an established drug, such as cisplatin and / or gemcitabine, or against monotherapy with Compound (A) or Compound (B).

[0100] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects,or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vivo and / or in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, such as between 30-90% and between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration. A dosing regimen may comprise an “intermittent” dosing, during which one or more dosing parameters such as dosage amount and / or dosage interval are varied or changed. For example, an intermittent dosing phase may comprise a period of continuous administration (e.g., 6 days, 5 days, 4 days in a week) followed by a “rest” phase (e.g., 1 day, 2 days, 3 days in the same week) during which Compound (A) is not administered or is administered at a reduced dosage amount and / or less frequently. A dosing regimen may further comprise one or more repeated cycles of intermittent dosing regimens.

[0101] It should be noted that the attending physician would know how to and when to terminate, interrupt or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response was not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the disease or condition to be treated and to the route of administration. The severity of the disease or condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.

[0102] Compounds, conjugates, salts and compositions disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties, may be established by determining in vitro toxicity towards a cell line, such as a human cell line. The results of such studies are often predictive of toxicity. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, dogs or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilledartisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and / or regime.EXAMPLES

[0103] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims. In these examples and in the accompanying figures. Compound (A) is azenosertib and is also referred to as the same.Example 1 : Azenosertib and topoisomerase I (TOPI) inhibitors exhibit synergy in vitro

[0104] HT-29 (ATCC) was cultured in McCoy's 5 A medium (ATCC) supplemented with 10% FBS (Gibco) and 1% penicillin-streptomycin (Gibco). HCC1569 was cultured in RPMI 1640 medium (ATCC modification) (Gibco) supplemented with 10% FBS (Gibco) and 1% penicillin-streptomycin (Gibco). MDA-MB-231 and MDA-MB- 468 were cultured in DMEM / F12 medium (Gibco) supplemented with 10% FBS (Gibco) and 1% penicillin-streptomycin (Gibco). Cells were maintained at 37°C in an atmosphere containing 5% CO2.

[0105] Colorectal cancer (HT-29) and breast cancer (HCC1569, MDA-MB- 231, and MDA-MB-468) cells were seeded at optimal density in 96-well plates for evaluation of combination treatments on cell viability. Treatments were performed the following day with azenosertib, irinotecan, and SN-38 as monotherapies or in a matrix combination format. Specifically, HT-29 was treated with azenosertib (0-500 nM) and irinotecan (0-10 pM); HCC1569 was treated with azenosertib (1-150 nM) and irinotecan (0-100 nM); MDA-MB-231 was treated with azenosertib (0-850 nM) and SN-38 (0-350 nM); MDA-MB-468 was treated with azenosertib (0-650 nM) and SN-38 (0-4 nM). Cell viability was then measured 3-, 4- or 6-days following treatment by CellTiter-Glo 2.0 assay. Synergies between azenosertib and Irinotecan and between azenosertib and SN-38 were then calculated using ZIP synergy score from SynergyFinder tool (http: / / www.synergyfmderplus.org / ).

[0106] As shown in FIGS. 1A-1B, azenosertib demonstrates synergy in combination with irinotecan or SN-38 in vitro. All tested cell lines demonstrated clear synergy' (ZIP synergy' score > 10) at depicted dose ranges. Overall, the results showed that azenosertib and topoisomerase I (TOPI) inhibitors exhibited synergy in vitro.Example 2: Azenosertib in combination with topoisomerase I (TOPI) inhibitors increases DNA damage and apoptosis in vitro

[0107] Colorectal cancer (HT-29) and breast cancer (HCC1569, and MDA- MB-468) cells were seeded at optimal density in 6-well plates for the evaluation of combination treatments on biomarker changes. Treatment doses were determined from combination CellTiter-Glo assays and treatments were performed the following day with azenosertib, irinotecan, and SN-38 as monotherapies or as combination therapies. Specifically, HT-29 was treated with azenosertib (350 nM) and / or irinotecan (5 pM); HCC1569 was treated with azenosertib (150 nM) and / or irinotecan (30 nM); MDA-MB- 468 was treated with azenosertib (650 nM) and / or SN-38 (2 nM). After indicated time of drug exposure, cells were harvested, rinsed with PBS, lysed in cold RIP A buffer (Sigma) containing protease and phosphatase inhibitors for 15 minutes, and centrifuged at 4°C, 15,000 rpm for 15 minutes. Protein concentrations were measured using the Pierce BCA Protein Assay kit (Thermo Fisher). JESS plates were loaded and run according to the manufacturer’s instructions. Primary antibodies anti-Cyclin El was purchased from Abeam, anti-GAPDH was purchased from Invitrogen, anti-yH2AX, anti-phospho-CDKl, anti-phsopho-Chkl, anti-cleaved caspase 3, anti-Weel, and anti-CDKl were purchased from Cell Signaling Technology.

[0108] As shown in FIGS. 2A-2B, azenosertib in combination with irinotecan or SN-38 increases DNA damage and apoptosis in vitro. Colorectal (HT-29) and breast (HCC1569 and MDA-MB-468) cell lines were treated with monotherapies or combination therapies for indicated time points. DNA damage and apoptosis levels were increased as indicated by yH2AX and cleaved caspase 3 respectively, when cells were treated with combination doses compared to monotherapies. The results showed that azenosertib in combination with topoisomerase I (TOPI) inhibitors increased DNA damage and apoptosis in vitro.Example 3: Azenosertib in combination with topoisomerase I (TOPI) inhibitors improves efficacy in ovarian cancer model in vivo

[0109] The anti-tumor activity of azenosertib, irinotecan, and topotecan hydrochloride, as monotherapy or as combination therapies, was evaluated in an ovarian cancer model OV90. Table 1 summarizes the groups and treatments. Tumor measurements and animal body weights were monitored twice weekly throughout the study. As shown in FIGS. 3A-3B, the combinations of azenosertib / irinotecan or azenosertib / topotecan bothresulted in greater tumor growth inhibition (z'.e., 89% TGI for azenosertib / irinotecan combination. 72% TGI for azenosertib / topotecan combination) than their respective monotherapies (i.e., 53% TGI for azenosertib monotherapy, 60% TGI for irinotecan monotherapy, 9.5% TGI for topotecan monotherapy) on Day 25 of treatment. In FIGS. 3A- 3B, the top lines are Vehicle, the middle lines are monotherapies and the bottom lines are combination therapies. Azenosertib in combination with irinotecan or topotecan led to significant tumor growth inhibition of 89% and 72%. respectively. Treatment with single agents azenosertib, irinotecan or topotecan resulted in tumor growth inhibition of 53%, 60% and 9.5%, respectively. The results showed that combination therapy resulted in greater tumor growth inhibition than monotherapy in an ovarian cancer model in vivo. Furthermore, the body weight changes shown in FIG. 3C indicated that the combination therapies were well-tolerated by the mice.Table 1. OV90-xenografted mice treatment groups and dosing regimensExample 4: Azenosertib in combination with irinotecan improves efficacy in breast cancer model in vivo

[0110] The anti -tumor activity of azenosertib and irinotecan, as monotherapy or as combination therapies, was evaluated in a breast cancer model HCC1569. Table 2 summarizes the groups and treatments. Tumor measurements and animal body weights were monitored twice weekly throughout the study. As shown in FIG. 4A, the combination of azenosertib / irinotecan resulted in greater tumor grow th inhibition than their respective monotherapies on Day 25 of treatment. In FIG. 4A, the top line is Vehicle, the middle lines are monotherapies and the bottom line is combination therapy. Azenosertib in combinationwith irinotecan led to significant tumor growth inhibitions of 99% (azenosertib 60 mg / kg QD 5:2) and 100% (azenosertib 80 mg / kg QD 5:2). Treatment with single agents azenosertib or irinotecan resulted in tumor growth inhibitions of 42% (azenosertib 60 mg / kg QD 5:2), 69% (azenosertib 80 mg / kg QD 5:2), and 80% (irinotecan 30 mg / kg QW), respectively. As shown in FIG. 4B, the combination treatments of azenosertib and irinotecan were well-tolerated. The results showed that azenosertib in combination with irinotecan led to increased tumor growth inhibition and showed improved efficacy in a breast cancer model in vivo.Table 2. HCC1569-xenografted mice treatment groups and dosing regimensExample 5: Azenosertib and sacituzumab govitecan exhibit synergy in vitro

[0111] Culturing of cancer cells, maintenance of cell cultures, setting up of in vitro monotherapy and combination treatment of MDA-MB-468 and MDA-MB-431 breast cancer cells, in vitro synergy studies, and immunoblotting are as described in Examples 1 and 2, with azenosertib and the TROP2-directed antibody-drug conjugate sacituzumab govitecan as the therapeutic agents. Compared to MDA-MB-468, MDA-MB-231 breast cancer cells have a TROP2-low (TROP2low) status and are less sensitive to sacituzumab govitecan.

[0112] As shown in FIG. 5A, azenosertib and sacituzumab govitecan exhibit synergy' in vitro. Azenosertib in combination with sacituzumab govitecan showed significant synergy' in TROP2-high (TROP2hlgh) MDA-MB-468 tiple negative breast cancer cell line with increased DNA damage and apoptosis as indicated by phospho-Chkl / yH2AX and cleaved caspase 3, respectively (see FIG. 5B). The results showed that azenosertib and sacituzumab govitecan exhibited synergy in vitro.Example 6: Azenosertib in combination with TROP2-directed antibody-drug conjugates improves efficacy in breast cancer model in vivo

[0113] The anti-tumor activity of azenosertib and a TROP2-directed antibodydrug conjugate (i.e., either sacituzumab govitecan or datopotamab deruxtecan or Dato- DXd), as monotherapy or as combination therapies, was evaluated in the triple negative breast cancer model MDA-MB-231 that expresses low levels of TROP2 and is also known to be less sensitive to TROP2-directed antibody -drug conjugates. Table 3 summarizes the groups and treatments. Tumor measurements and animal body weights were monitored twice weekly throughout the study. As shown in FIGS. 6A-6B, the combinations of azenosertib / sacituzumab govitecan or azenosertib / datopotamab deruxtecan both resulted in greater tumor growth inhibition than their respective monotherapies on Day 46 of treatment. In FIGS. 6A-6B. the top lines are vehicle, the middle lines are monotherapies and the bottom lines are combination therapies. Azenosertib in combination with sacituzumab govitecan led to significant tumor growth inhibition of 91%, whereas treatment with single agent azenosertib or single agent sacituzumab govitecan resulted in tumor growth inhibitions of 28% and 71%. respectively. Although treatment with single agent datopotamab deruxtecan already resulted in 98% tumor growth inhibition, its combination with azenosertib led to 103% tumor growth inhibition. The results showed that azenosertib in combination with TROP2-directed antibody-drug conjugates improved efficacy in a breast cancer model in vivo. Furthermore, the body weight changes shown in FIG. 6C indicated that the combination therapies were well-tolerated by the mice.Table 3. MDA-MB-231 -xenografted mice treatment groups and dosing regimens

[0114] Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather to also cover all modification and alternatives coming with the true scope and spirit of the present disclosure.SEQUENCE LISTINGSSEQ ID NO:1 - Sacituzumab CDRH1GYFMNSEQ ID N0:2 - Sacituzumab CDRH2RIHPYDGDTFYNQKFQGSEQ ID N0:3 - Sacituzumab CDRH3YDGSRAMDYSEQ ID N0:4 - Sacituzumab CDRL1KASQSVSFAGTSLMHSEQ ID N0:5 - Sacituzumab CDRL2RASNLEASEQ ID N0:6 - Sacituzumab CDRL3QQSREYPYTSEQ ID N0:7 - Sacituzumab heavy chainQVQLQQSGSELKKPGASVKVSCKASGYTFTNYGMNWVKQAPGQGLKWMGWINTYTGEPTYTDDFKGRFAFSLDTSVSTAYLQISSLKADDTAVYFCARGGFGSSYWYFDVWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSEQ ID NO: 8 - Sacituzumab light chainDIQLTQSPSSLSASVGDRVSITCKASQDVSIAVAWYQQKPGKAPKLLIYSASYRYTGVPDRFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYITPLTFGAGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 9 - Datopotamab CDRH1TAGMQSEQ ID NO: 10 - Datopotamab CDRH2WINTHSGVPKYAEDFKGSEQ ID NO: 11 Datopotamab CDRH3SGFGSSYWYFDVSEQ ID NO: 12 - Datopotamab CDRL1 KASQDVSTAVASEQ ID NO: 13 - Datopotamab CDRL2 SASYRYTSEQ ID NO: 14 - Datopotamab CDRL3QQHYITPLTSEQ ID NO: 15 - Datopotamab heavy chainQVQLVQSGAEVKKPGASVKVSCKASGYTFTTAGMQWVRQAPGQGLEWMGWINTHSGVPKYAEDFKGRVTISADTSTSTAYLQLSSLKSEDTAVYYCARSGFGSSYWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSEQ ID NO: 16 - Datopotamab light chainDIQMTQSPSSLSASVGDRVTITCKASQDVSTAVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYITPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 17 - Patritumab CDRH1GGSFSGYYWSSEQ ID NO: 18 - Patritumab CDRH2EINHSGSTNYNPSLKSSEQ ID NO: 19 - Patritumab CDRH3DKWTWYFDLSEQ ID NO:20 - Patritumab CDRL1RSSQSVLYSSSNRNYLSEQ ID NO:21 - Patritumab CDRL2WASTRESSEQ ID NO:22 - Patritumab CDRL3QQYYSTPRTSEQ ID NO:23 - Patritumab heavy chainQVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVETSKNQFSLKLSSVTAADTAVYYCARDKWTWYFDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPGKSEQ ID NO:24 - Patritumab light chainDIEMTQSPDSLAVSLGERATINCRSSQSVLYSSSNRNYLAWYQQNPGQPPKLLIY WASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPRTFGQGTKV EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO:25 - Ifinatamab CDRH1NYVMHSEQ ID NO:26 - Ifinatamab CDRH2YINPYNDDVKYNEKFKGSEQ ID NO: 27 - Ifinatamab CDRH3WGYYGSPLYYFDYSEQ ID NO:28 - Ifinatamab CDRL1RASSRLIYMHSEQ ID NO: 29 - Ifinatamab CDRL2ATSNLASSEQ ID NO:30 - Ifinatamab CDRL3QQWNSNPPTSEQ ID NO:31 - Ifinatamab heavy chainQVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYVMHWVRQAPGQGLEWMGYIN PYNDDVKYNEKFKGRVTITADESTSTAYMELSSLRSEDTAVYYCARWGYYGSPL YYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV DKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGKSEQ ID NO:32 - Ifinatamab light chainEIVLTQSPATLSLSPGERATLSCRASSRLIYMHWYQQKPGQAPRPLIYATSNLASG IPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQWNSNPPTFGQGTKVEIKRTVAAP SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO 33 - Raludotatug CDRH1GYTFTRNFMHSEQ ID NO: 34 - Raludotatug CDRH2WIYPGDGETESEQ ID NO:35 - Raludotatug CDRH3 GVYGGFAGGYFDFSEQ ID NO:36 - Raludotatug CDRL1KASQNIYKNLASEQ ID NO:37 - Raludotatug CDRL2DANTLQTSEQ ID NO: 38 - Raludotatug CDRL3QQYYSGWASEQ ID NO:39 - Raludotatug heavy chainEVQLVQSGAEVKKPGASVKVSCKASGYTFTRNFMHWVRQAPGQGLEWMGWIYPGDGETEYAQKFQGRVTITADTSTSTAYMELSSLRSEDTAVYYCARGVYGGFAGGYFDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSEQ ID NO:40 - Raludotatug light chainDIQMTQSPSSLSASVGDRVTITCKASQNIYKNLAWYQQKPGKAPKLLIYDANTLQTGVPSRFSGSGSGSDFTLTISSLQPEDFATYFCQQYYSGWAFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECZENO. 181 WO PATENTWEE1 INHIBITOR COMBINATION THERAPYINCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

[0001] Any and all applications for which a foreign or domestic priority7claim is identified, for example, in the Application Data Sheet or Request as filed with the present application, are hereby incorporated by reference under 37 CFR 1.57, and Rules 4.18 and 20.6, including U.S. Provisional Application Nos. 63 / 641,587, filed May 2, 2024 and 63 / 694,334, filed September 13, 2024, each of which is incorporated by reference in their entireties.SEQUENCE STATEMENT

[0002] This application contains a Sequence Listing, which has been submitted electronically and is hereby incorporated by reference in its entirety. The sequence listing, was created on April 11, 2025, is named ZENO181WO_SequenceListing.xml and is 45 kb in size.Field

[0003] The present application relates to the fields of chemistry, biochemistry and medicine. More particularly, disclosed herein are combination therapies, and methods of treating diseases and / or conditions with a combination therapy described herein.Description

[0004] Topoisomerase inhibitors have been widely used as anti-cancer drugs for the past 20 years. Due to their selectivity as topoisomerase I (TOPI) inhibitors that trap TOPI cleavage complexes, camptothecin and its derivatives are promising anti-cancer drugs. Although TOPI inhibitors including camptothecin and its derivatives effectively induce cancer cell death, their potential applicability is limited by: (i) their rapid elimination before achieving therapeutic concentrations in the tumor; and (ii) dose limitations dictated by the inhibition of TOPI in normal cells, which need topoisomerase activity for cell survival.

[0005] Antibody-drug conjugates (ADCs) as targeted therapy has emerged as an approach to address the limitations of TOPI inhibitors. The clinical success of TOPI - ADCs is evidenced by approvals of the U.S. Food and Drug Administration (FDA) granted-1-of sacituzumab govitecan (brand name Trodelvy) and trastuzumab deruxtecan (brand name Enhertu) for breast cancers with specific genotypes. While the FDA approvals represent milestones in the ongoing development of therapeutic ADCs, there remains a need for improved ADCs and related therapies to help address the long-felt need for additional options to treat different types of cancer and to deliver therapeutic payloads to selected cells and tissues.SUMMARY

[0006] Some embodiments described herein relate to the use of a combination of Compound (A) and (i) Compound (B); or (ii) an antibody-drug conjugate comprising Compound (B) for treating a cancer in a subject. Compound (A) ispharmaceutically acceptable salt thereof.Compound (B) is topotecan, belotecan, irinotecan, SN-38, govitecan, exatecan, or deruxtecan, or a derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing. The antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target selected from the extracellular domain of human receptor tyrosine kinase-like orphan receptor 1 (R0R1), human epidermal growth factor receptor 3 (HER3), folate receptor alpha (FRa), cadherin 6 (CDH6), sodiumdependent phosphate transporter NaPi2b, tissue factor (TF or also known as platelet tissue factor, coagulation factor III (F3) and CD 142), mesothelin (MSLN), mucin 16 (MUC16 or also known as ovarian cancer-related tumor marker CA125), protein tyrosine kinase 7 (PTK7), receptor tyrosine kinase AXL (AXL), antigen CD166 (CD166), ectonucleotide pyrophosphatase / phosphodiesterase family member 3 (ENPP3). T-cell immunoglobulin and mucin domain 1 (TIM-1), cluster of differentiation 70 (CD70, also known as CD27L), B7 homolog 3 (B7-H3, also known as CD276), B7 homolog 4 (B7-H4), trophoblast cell surface antigen 2 (TROP2), Nectin-4, CD22, CD30, CD79b, CD19, B-cell maturation antigen (BCMA), mucin short variant S I (MUC1), Claudin 18.2 (CLDN 18.2), carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5). c-Met tyrosinekinase (c-Met), interleukin-3 receptor (CD123), epidermal growth factor receptor (EFGR) and a combination thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0007] FIGS. 1A and IB show 2D heatmaps of in vitro synergy between Compound (A) (z'.e., azenosertib) and TOPI inhibitors irinotecan (FIG. 1A) and SN-38 (FIG. IB) across a panel of colorectal cancer and breast cancer cell lines.

[0008] FIGS. 2A and 2B illustrate protein biomarker changes in response to Compound (A) monotherapy, TOPI inhibitors monotherapies (irinotecan or SN-38) and a combination of Compound (A) and irinotecan (FIG. 2A) or SN-38 (FIG. 2B) across a panel of colorectal cancer and breast cancer cell lines in cultures in vitro.

[0009] FIGS. 3A and 3B illustrate the mean tumor volumes of mice in response to Compound (A) monotherapy, irinotecan monotherapy (FIG. 3A), topotecan HC1 monotherapy (FIG. 3B), Compound (A) + irinotecan combination therapy (FIG. 3A), and Compound (A) + topotecan HC1 combination therapy (FIG. 3B) in the OV90 model of ovarian cancer. FIG. 3C illustrates the corresponding body weight changes of the mice treated with said monotherapies and combination therapies.

[0010] FIG. 4A illustrates the mean tumor volumes of mice in response to Compound (A) monotherapy, irinotecan monotherapy, and Compound (A) + irinotecan combination therapy in the HCC1569 model of HER2+ breast cancer. FIG. 4B illustrates the corresponding body weight changes of the mice treated with said monotherapies and combination therapies.

[0011] FIG. 5A shows 2D heatmaps of in vitro synergy between Compound (A) and sacituzumab govitecan in MDA-MB-468 and MDA-MB-231 triple negative breast cancer cell lines. FIG. 5B illustrates protein biomarker changes in response to Compound (A) monotherapy, sacituzumab govitecan (SG) monotherapy, and a combination of Compound (A) and sacituzumab govitecan in MDA-MB-468 cells in cultures in vitro.

[0012] FIGS. 6A and 6B illustrate the mean tumor volume of mice in response to Compound (A) monotherapy, sacituzumab govitecan monotherapy (FIG. 3A). datopotomab deruxtecan monotherapy (FIG. 6B), Compound (A) + sacituzumab govitecan combination therapy (FIG. 6A), and Compound (A) + datopotomab deruxtecan combination therapy (FIG. 6B) in the MDA-MB-231 model of triple negative breast cancer. FIG. 6C illustrates the corresponding body weight changes of the mice treated with said monotherapies and combination therapies.DETAILED DESCRIPTIONDefinitions

[0013] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0014] As used herein, an “immunoconjugate’' is a conjugate comprising an immunological substance and a drug moiety that are joined together by a linker. Typically, an immunoconjugate is prepared by reacting the immunological substance with a conjugate as defined herein. An “antibody-drug conjugate” (ADC) is one class of immunoconjugate whereby the immunological substance is an antibody or an antigen-binding fragment thereof.

[0015] As used herein, an “antibody” (Ab) is a protein made by the immune system, or a synthetic or engineered variant thereof, that binds to specific sites on cells or tissues. The term “antibody” herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multi-specific antibodies (e.g.. bispecific antibodies), chimeric antibodies, nanobodies, and antigen-binding fragments so long as they exhibit the desired antigenbinding activity. Monoclonal antibodies are a type of synthetic antibody. In cancer treatment, monoclonal antibodies may kill cancer cells directly, they may block development of tumor blood vessels, and / or they may help the immune system kill cancer cells. Humanized antibodies are antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans. For example, a murine monoclonal antibody, 4D5, directed against the extracellular domain of HER2 and a potent inhibitor of growth of human breast cancer cells overexpressing HER2 in vitro and in xenograft models, was humanized by inserting the complementary determining regions of 4D5 into the framework of a consensus human IgGl. The resulting recombinant humanized anti-HER2 mAb was trastuzumab. An antibody typically is composed of two heavy chains and two light chains; and the heavy chain and the light chain typically each contain three complementarity-determining regions(CDRs) immunoglobulin (Ig) hypervariable domains that determine specific antibody binding.

[0016] An ‘'antigen-binding fragment” refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include but are not limited to Fv, Fab, Fab', Fab'-SH, F(ab’)2. diabodies, linear antibodies, single-chain antibody molecules (e.g.. scFv), and single-domain antibodies.

[0017] As used herein, the term ’‘derivative” when referring to a derivative of Compound (B), or a derivative of topotecan, belotecan, irinotecan, SN-38, govitecan, exatecan, or deruxtecan, refers to a compound that is derived from any one of the aforementioned Compound (B), topotecan, belotecan, irinotecan, SN-38, govitecan, exatecan, or deruxtecan, for example, via one or more chemical reactions such as, but not limited to, hydrolysis, conjugation or esterification. As a non-limiting example, SN-38 is a derivative of irinotecan in that SN-38 is formed via hydrolysis of irinotecan by carboxylesterases and metabolized via glucuronidation by UGT1A1. As another nonlimiting example, deruxtecan is derived from exatecan via conjugation or covalent linking of exatecan to a tetrapeptide-based linker.

[0018] The term “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g. , hydrochloric acid or hydrobromic acid), a sulfuric acid, a nitric acid and a phosphoric acid (such as 2,3-dihydroxypropyl dihydrogen phosphate). Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, trifluoroacetic, benzoic, salicylic, 2-oxopentanedioic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium, a potassium or a lithium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of a carbonate, a salt of a bicarbonate, a salt of organic bases such as dicyclohexylamine, N- methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine and salts with amino acids such as-5-arginine and lysine. Those skilled in the art understand that when a salt is formed by protonation of a nitrogen-based group (for example, NH2). the nitrogen-based group can be associated with a positive charge (for example, NH2 can become NH? ) and the positive charge can be balanced by a negatively charged counterion (such as CT).

[0019] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of ^-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched or a stereoisomeric mixture. In addition, it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included.

[0020] It is to be understood that where compounds disclosed herein have unfilled valencies, then the valencies are to be filled with hydrogens or isotopes thereof, e.g, hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0021] It is understood that the compounds described herein can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as. for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[0022] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent and may-6-be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol or the like. Hydrates are formed when the solvent is water or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

[0023] Where a range of values is provided, it is understood that the upper and low er limit, and each intervening value between the upper and low er limit of the range is encompassed within the embodiments.

[0024] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term 'including’ should be read to mean “including, without limitation,” “including but not limited to,” or the like; the term “comprising"’ as used herein is synonymous with “including,” “containing,” or “characterized by,” and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term “having” should be interpreted as “having at least;” the term “includes” should be interpreted as “includes but is not limited to;” the term “example” is used to provide exemplary' instances of the item in discussion, not an exhaustive or limiting list thereof. In addition, the term “comprising” is to be interpreted synonymously with the phrases “having at least” or “including at least.” When used in the context of a compound, composition or device, the term “comprising” means that the compound, composition or device includes at least the recited features or components but may also include additional features or components.

[0025] With respect to the use of substantially any plural and / or singular terms herein, those having skill in the art can translate from the plural to the singular and / or from the singular to the plural as is appropriate to the context and / or application. The various singular / plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.-7-Compounds and Antibody -Drug Conjugates

[0026] Some embodiments described herein relate to the use of a combination of Compound (A) and (i) Compound (B); or (ii) an antibody-drug conjugate comprisingCompound (B) for treating a cancer in a subject. Compound (A) ispharmaceutically acceptable salt thereof.

[0027] In some embodiments, a use described herein comprises use of a combination of Compound (A) and Compound (B). In some embodiments, Compound (B) is a topoisomerase 1 (TOPI) inhibitor.

[0028] In some embodiments, a use described herein comprises use of a combination of Compound (A) and an antibody -drug conjugate comprising Compound (B) for treating a cancer in a subject.

[0029] In some embodiments, Compound (derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0030] In some embodiments, a Compound (B) is topotecan, or a derivative thereof, or a pharmaceutically acceptable salt thereof. In other embodiments, a Compound (B) is belotecan, or a derivative thereof, or a pharmaceutically acceptable salt thereof. In still other embodiments, a Compound (B) is irinotecan, or a derivative thereof, or a pharmaceutically acceptable salt thereof. In yet still other embodiments, a Compound (B) is SN-38, or a derivative thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, a Compound (B) is govitecan, or a derivative thereof, or a pharmaceutically-9-acceptable salt thereof. In other embodiments, a Compound (B) is exatecan, or a derivative thereof, or a pharmaceutically acceptable salt thereof. In still other embodiments, a Compound (B) is deruxtecan, or a derivative thereof, or a pharmaceutically acceptable salt thereof.

[0031] The antibody-drug conjugate comprises an antibody or an antigenbinding fragment thereof that specifically binds to a target selected from the extracellular domain of human receptor tyrosine kinase-like orphan receptor 1 (ROR1), human epidermal growth factor receptor 3 (HER3), folate receptor alpha (FRa), cadherin 6 (CDH6), sodium-dependent phosphate transporter NaPi2b, tissue factor (TF or also known as platelet tissue factor, coagulation factor III (F3) and CD 142), mesothelin (MSLN), mucin 16 (MUC16 or also known as ovarian cancer-related tumor marker CA125), protein tyrosine kinase 7 (PTK7), receptor tyrosine kinase AXL (AXL), antigen CD166 (CD166), ectonucleotide pyrophosphatase / phosphodiesterase family member 3 (ENPP3), T-cell immunoglobulin and mucin domain 1 (TIM-1), cluster of differentiation 70 (CD70, also known as CD27L). B7 homolog 3 (B7-H3. also known as CD276), B7 homolog 4 (B7-H4), trophoblast cell surface antigen 2 (TROP2), Nectin-4, CD22, CD30, CD79b, CD19, B-cell maturation antigen (BCMA), mucin short variant SI (MUC 1), Claudin 18.2 (CLDN 18.2), carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), c-Met tyrosine kinase (c-Met). interleukin-3 receptor (CD123), epidermal growth factor receptor (EFGR) and a combination thereof.

[0032] In some embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target selected from human epidermal growth factor receptor 3 (HER3), cadherin 6 (CDH6), trophoblast cell surface antigen 2 (TROP2), B7 homolog 3 (B7-H3. also known as CD276) and combinations thereof. In other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is human receptor tyrosine kinase-like orphan receptor 1 (ROR1). In some embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is human epidermal growth factor receptor 3 (HER3). In other embodiments, an antibody-drug conjugate comprises an antibody or an antigenbinding fragment thereof that specifically binds to a target that is folate receptor alpha (FRa). In still other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is cadherin 6-10-(CDH6). In yet still embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is sodiumdependent phosphate transporter NaPi2b. In some embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is tissue factor (TF or also known as platelet tissue factor, coagulation factor III (F3) and CD142). In other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is mesothelin (MSLN). In still other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is mucin 16 (MUC16 or also known as ovarian cancer-related tumor marker CA125). In yet still other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is protein tyrosine kinase 7 (PTK7). In some embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is receptor tyrosine kinase AXL (AXL). In other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is antigen CD166 (CD166). In still other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is ectonucleotide pyrophosphatase / phosphodi esterase family member 3 (ENPP3). In yet still other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is T- cell immunoglobulin and mucin domain 1 (TIM-1). In some embodiments, an antibodydrug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is cluster of differentiation 70 (CD70, also known as CD27L). In other embodiments, an antibody -drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is B7 homolog 3 (B7-H3, also known as CD276). In still other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is B7 homolog 4 (B7-H4). In yet still other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is trophoblast cell surface antigen 2 (TROP2). In some embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is Nectin-4. In other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically-11-binds to a target that is CD22. In still other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is CD30. In yet still other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is CD79b. In some embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is CD19. In other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is B-cell maturation antigen (BCMA). In still other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is mucin short variant SI (MUC1). In yet still other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is Claudin 18.2 (CLDN 18.2). In some embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5). In other embodiments, an antibody-drug conjugate comprises an antibody or an antigenbinding fragment thereof that specifically binds to a target that is c-Met tyrosine kinase (c- Met). In still other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is interleukin-3 receptor (CD123). In yet still other embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target that is epidermal growth factor receptor (EFGR). In some embodiments, an antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to the extracellular domain of a target described herein.

[0033] One embodiment pertains to the use of a combination of Compound (A) as defined herein, and an antibody-drug conjugate comprising Compound (B) as defined above for treating cancer in a subject, wherein the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target as defined above. In one embodiment, the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target selected from human epidermal growth factor receptor 3 (HER3), cadherin 6 (CDH6), trophoblast cell surface antigen 2 (TROP2), B7 homolog 3 (B7-H3, also known as CD276) and a combination thereof. In one embodiment, the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to trophoblast cell surface antigen-12-2 (TR0P2). In one embodiment, the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to human epidermal growth factor receptor 3 (HER3). In one embodiment, the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to cadherin 6 (CDH6). In one embodiment, the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to B7 homolog 3 (B7-H3, also known as CD276). In some embodiments, a Compound (B) is a topoisomerase 1 (TOPI) inhibitor, or a derivative thereof, or a pharmaceutically acceptable salt thereof (e.g., topotecan, belotecan, irinotecan, SN-38, govitecan, exatecan or deruxtecan, including derivatives and pharmaceutically acceptable salts of any of the foregoing). In some embodiments, a Compound (B) is irinotecan or SN-38, or a derivative thereof, or a pharmaceutically acceptable salt thereof. In other embodiments, a Compound (B) is irinotecan or topotecan, or a derivative of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing. In still other embodiments, a Compound (B) is govitecan or deruxtecan, or a derivative of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing. In yet still other embodiments, a Compound (B) is irinotecan, or a derivative thereof, or a pharmaceutically acceptable salt thereof.

[0034] Another aspect of this disclosure relates to a method of treating a cancer in a subject comprising administering an effective amount of Compound (A) as defined herein, and an effective amount of: (i) Compound (B) as defined herein; or (ii) an antibodydrug conjugate comprising Compound (B), to the subject, wherein the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target as defined above. One embodiment pertains to a method of treating a cancer in a subject comprising administering an effective amount of Compound (A) as defined herein, and an effective amount of an antibody-drug conjugate comprising Compound (B) as defined herein, to the subject, wherein the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target as defined above. In one embodiment, the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target selected from human epidermal grow th factor receptor 3 (HER3), cadherin 6 (CDH6), trophoblast cell surface antigen 2 (TROP2), B7 homolog 3 (B7-H3, also known as CD276) and a combination thereof. In one embodiment, the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to trophoblast cell surface antigen 2 (TROP2). In some embodiments, a Compound (B) is a topoisomerase 1-13-(T0P1) inhibitor, or a derivative thereof, or a pharmaceutically acceptable salt thereof (e.g. , topotecan, belotecan, irinotecan, SN-38, govitecan, exatecan. or deruxtecan, including derivatives and pharmaceutically acceptable salts of any of the foregoing). In some embodiments, a Compound (B) is irinotecan or SN-38, or a derivative thereof, or a pharmaceutically acceptable salt thereof. In other embodiments, a Compound (B) is irinotecan or topotecan, or a derivative of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing. In still other embodiments, a Compound (B) is govitecan or deruxtecan, or a derivative of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing. In yet still other embodiments, a Compound (B) is irinotecan, or a derivative thereof, or a pharmaceutically acceptable salt thereof.

[0035] Yet another aspect of this disclosure relates to a combination of Compound (A) as defined herein, and (i) Compound (B) as defined herein; or (ii) an antibody-drug conjugate comprising Compound (B), for use in treating a cancer, wherein the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target as defined above. One embodiment pertains to a combination of Compound (A) as defined herein, and an antibody-drug conjugate comprising Compound (B) as defined herein, for use in treating a cancer, wherein the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target as defined above. In one embodiment, the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target selected from human epidermal growth factor receptor 3 (HER3), cadherin 6 (CDH6), trophoblast cell surface antigen 2 (TROP2), B7 homolog 3 (B7-H3, also known as CD276) and a combination thereof. In one embodiment, the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to trophoblast cell surface antigen 2 (TROP2). In some embodiments, a Compound (B) is a topoisomerase 1 (TOPI) inhibitor, or a derivative thereof, or a pharmaceutically acceptable salt thereof (e.g., topotecan, belotecan, irinotecan, SN-38, govitecan, exatecan, or deruxtecan, including derivatives and pharmaceutically acceptable salts of any of the foregoing). In some embodiments, a Compound (B) is irinotecan or SN-38. or a derivative of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing. In other embodiments, a Compound (B) is irinotecan or topotecan, or a derivative of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing. In still other embodiments, a Compound (B) is govitecan or deruxtecan, or a derivative of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing. In yet still other-14-embodiments, a Compound (B) is irinotecan, or a derivative thereof, or a pharmaceutically acceptable salt thereof.

[0036] In one embodiment, the uses and methods described herein exclude the immunoconjugates and compounds described in International Patent Application Publication Nos. WO 2023 / 004266, WO 2024 / 026323 and WO 2024 / 158996, including all U.S. provisional applications to which priority is claimed and all other filed and unfilled applications in all jurisdictions related thereto.

[0037] In some embodiments of the uses and methods provided herein, Compound (B) is topotecan, or a derivative thereof, or a pharmaceutically acceptable salt thereof. In some embodiments of the uses and methods provided herein, Compound (B) is irinotecan, or a derivative thereof, or a pharmaceutically acceptable salt thereof. In some embodiments of the uses and methods provided herein, Compound (B) is SN-38, or a derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of the uses and methods provided herein, Compound (B) is govitecan, or a pharmaceutically acceptable salt thereof. In some embodiments of the uses and methods provided herein. Compound (B) is exatecan or a denvative thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of the uses and methods provided herein, Compound (B) is deruxtecan, or a pharmaceutically acceptable salt thereof.

[0038] In some embodiments of the uses and methods provided herein, the antibody-drug conjugate is represented by the following structural formula:or a pharmaceutically acceptable salt thereof, wherein:-15-Ab is the antibody or an antigen-binding fragment thereof that specifically binds to a target as defined above; and n represents an average number of govitecan compounds conjugated to a single Ab and is in a range of about 1 to about 10. In one embodiment, n is in a range of about 7 to about 8.

[0039] In some embodiments of the uses and methods provided herein, the antibody-drug conjugate is represented by the following structural formula:or a pharmaceutically acceptable salt thereof, wherein:Ab is the antibody or an antigen-binding fragment thereof that specifically binds to a target as defined above; and n represents an average number of deruxtecan compounds conjugated to a single Ab and is in a range of about 1 to about 10. In one embodiment, n is about 4.

[0040] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises:(a) a heavy chain CDRH1 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO: 1; a heavy chain CDRH2 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:2; and a heavy chain CDRH3 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:3; and(b) a light chain CDRL1 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:4; a light chain CDRL2 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:5; and a light chain CDRL3 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:6. In some embodiments, a heavy chain CDRH1 comprises or has at least 95% (e.g., at least 95, 96,97, 98, or 99%) sequence similarity to SEQ ID NO: 1, a heavy chain CDRH2 comprises or has at least 95% (e.g, at least 95, 96. 97. 98, or 99%) sequence similarity to SEQ ID NO:2, and / or a heavy chain CDRH3 comprises or has at least 95% (e.g, at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:3.

[0041] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain CDRH1 comprises or has at least 99% sequence similarity to SEQ ID NO: 1. a heavy chain CDRH2 comprises or has at least 99% sequence similarity to SEQ ID NO: 2, and / or a heavy chain CDRH3 comprises or has at least 99% sequence similarity to SEQ ID NO:3. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain CDRH1 comprises the sequence of SEQ ID NO: 1, a heavy chain CDRH2 comprises the sequence of SEQ ID NO:2, and / or a heavy chain CDRH3 comprises the sequence of SEQ ID NO:3.

[0042] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a light chain CDRL1 comprises or has at least 95% (e.g, at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:4. a light chain CDRL2 comprises or has at least 95% (e.g, at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO: 5, and / or a light chain CDRL3 comprises or has at least 95% (e g, at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:6. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a light chain CDRL1 comprises or has at least 99% sequence similarity to SEQ ID NO:4, a light chain CDRL2 comprises or has at least 99% sequence similarity to SEQ ID NO:5, and / or a light chain CDRL3 comprises or has at least 99% sequence similarity to SEQ ID NO: 6. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a light chain CDRL1 comprises the sequence of SEQ ID NO:4, a light chain CDRL2 comprises the sequence of SEQ ID NO:5, and / or a light chain CDRL3 comprises the sequence of SEQ ID NO:6.

[0043] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 90%, 95%, or 99% sequence similarity to SEQ ID NO:7 and a light chain comprising having at least 90%, 95%, or 99% sequence similarity to SEQ ID NO: 8. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 90% (e.g. at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:7 and a light chain-17-comprising or having at least 90%. (e.g., at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO: 8. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:7 and a light chain comprising or having at least 95%, (e.g, at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO: 8. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 99% sequence similarity to SEQ ID NO:7 and a light chain comprising or having at least 99%, sequence si mi I an ty to SEQ ID NO: 8. In some embodiments of the uses and methods provided herein, the antibody or an antigenbinding fragment comprises a heavy chain comprising the sequence of SEQ ID NO:7 and a light chain comprising the sequence of SEQ ID NO:8.

[0044] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises:(a) a heavy chain CDRH1 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO: 9; a heavy chain CDRH2 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO: 10; and a heavy chain CDRH3 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:11; and(b) a light chain CDRL 1 comprising or having at least 95% or at least 99% sequence similarity’ to SEQ ID NO: 12; a light chain CDRL2 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO: 13; and a light chain CDRL3 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO: 14.

[0045] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 90%, 95%, or 99% sequence similarity to SEQ ID NO: 15 and a light chain comprising having at least 90%, 95%, or 99% sequence similarity’ to SEQ ID NO: 16. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 90% (e.g.. at least 90. 91. 92, 93, 94, 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO: 15 and a light chain comprising or having at least 90%, (e.g., at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO: 16. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarity-18-to SEQ ID NO: 15 and a light chain comprising or having at least 95%, (e.g.. at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO: 16. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 99% sequence similarity to SEQ ID NO: 15 and a light chain comprising or having at least 99%, sequence similarity to SEQ ID NO: 16. In some embodiments of the uses and methods provided herein, the antibody or an antigenbinding fragment comprises a heavy chain comprising the sequence of SEQ ID NO: 15 and a light chain comprising the sequence of SEQ ID NO: 16.

[0046] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises:(a) a heavy chain CDRH1 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO: 17; a heavy chain CDRH2 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO: 18; and a heavy chain CDRH3 comprising or having at least 95% or at least 99% sequence similarity' to SEQ ID NO: 19; and(b) a light chain CDRL1 comprising or having at least 95% or at least 99% sequence similarity' to SEQ ID NO:20; a light chain CDRL2 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:21; and a light chain CDRL3 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:22.

[0047] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain CDRH1 comprises or has at least 95% (e.g. , at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO: 17, a heavy chain CDRH2 comprises or has at least 95% (e g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO: 18, and / or a heavy chain CDRH3 comprises or has at least 95% (e.g, at least 95, 96, 97, 98, or 99%) sequence similarity’ to SEQ ID NO: 19. In some embodiments of the uses and methods provided herein, the antibody or an antigenbinding fragment comprises a heavy chain CDRH1 comprises or has at least 99% sequence similarity to SEQ ID NO: 17, a heavy chain CDRH2 comprises or has at least 99% sequence similarity to SEQ ID NO: 18, and / or a heavy chain CDRH3 comprises or has at least 99% sequence similarity to SEQ ID NO: 19. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain CDRH1 comprises the sequence of SEQ ID NO: 17, a heavy' chain CDRH2 comprises the sequence of SEQ ID NO: 18, and / or a heavy chain CDRH3 comprises the sequence of SEQ ID NO: 19.-19-

[0048] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a light chain CDRL1 comprises or has at least 95% (e.g, at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:20, a light chain CDRL2 comprises or has at least 95% (e.g, at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:21, and / or a light chain CDRL3 comprises or has at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:22. In some embodiments of the uses and methods provided herein, the antibody or an antigenbinding fragment comprises a light chain CDRL1 comprises or has at least 99% sequence similarity to SEQ ID NO:20, a light chain CDRL2 comprises or has at least 99% sequence similarity to SEQ ID NO:21, and / or a light chain CDRL3 comprises or has at least 99% sequence similarity to SEQ ID NO:22. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a light chain CDRL1 comprises the sequence of SEQ ID NO:20, a light chain CDRL2 comprises the sequence of SEQ ID NO:21, and / or a light chain CDRL3 comprises the sequence of SEQ ID NO:22.

[0049] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain CDRH1 comprises or has at least 95% (e.g. , at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO: 17, a heavy chain CDRH2 comprises or has at least 95% (e.g, at least 95, 96, 97, 98, or 99%) sequence similarity’ to SEQ ID NO: 18, and / or a heavy chain CDRH3 comprises or has at least 95% (e.g, at least 95, 96, 97, 98, or 99%) sequence similarity’ to SEQ ID NO: 19. In some embodiments of the uses and methods provided herein, the antibody or an antigenbinding fragment comprises a heavy chain CDRH1 comprises or has at least 99% sequence similarity to SEQ ID NO: 17, a heavy chain CDRH2 comprises or has at least 99% sequence similarity to SEQ ID NO: 18, and / or a heavy chain CDRH3 comprises or has at least 99% sequence similarity to SEQ ID NO: 19. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain CDRH1 comprises the sequence of SEQ ID NO: 17, a heavy chain CDRH2 comprises the sequence of SEQ ID NO: 18. and / or a heavy chain CDRH3 comprises the sequence of SEQ ID NO: 19

[0050] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a light chain CDRL1 comprises or has at least 95% (e.g, at least 95, 96, 97, 98. or 99%) sequence similarity to SEQ ID NO:20. a light chain CDRL2 comprises or has at least 95% (e.g, at least 95, 96, 97, 98, or 99%)-20-sequence similarity to SEQ ID N0:21, and / or a light chain CDRL3 comprises or has at least 95% (e.g, at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:22. In some embodiments of the uses and methods provided herein, the antibody or an antigenbinding fragment comprises a light chain CDRL1 comprises or has at least 99% sequence similarity to SEQ ID NO:20, a light chain CDRL2 comprises or has at least 99% sequence similarity to SEQ ID NO:21, and / or a light chain CDRL3 comprises or has at least 99% sequence similarity to SEQ ID NO:22. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a light chain CDRL1 comprises the sequence of SEQ ID NO:20, a light chain CDRL2 comprises the sequence of SEQ ID NO:21, and / or a light chain CDRL3 comprises the sequence of SEQ ID NO 22.

[0051] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 90%, 95%, or 99% sequence similarity to SEQ ID NO:23 and alight chain comprising having at least 90%, 95%, or 99% sequence similarity to SEQ ID NO:24. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 90% (e.g., at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:23 and a light chain comprising or having at least 90%. (e.g.. at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:24. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:23 and a light chain comprising or having at least 95%, (e.g.. at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:24. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 99% sequence similarity to SEQ ID NO: 23 and a light chain comprising or having at least 99%, sequence similarity to SEQ ID NO:24. In some embodiments of the uses and methods provided herein, the antibody or an antigenbinding fragment comprises a heavy chain comprising the sequence of SEQ ID NO:23 and a light chain comprising the sequence of SEQ ID NO:24.

[0052] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises:(a) a heavy chain CDRH1 comprising or having at least 95% or at least 99% sequence similarity’ to SEQ ID NO:25; a heavy chain CDRH2 comprising or having at least-21-95% or at least 99% sequence similarity to SEQ ID NO:26; and a heavy chain CDRH3 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:27; and(b) a light chain CDRL1 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:28; a light chain CDRL2 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:29; and a light chain CDRL3 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:30.

[0053] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain CDRH1 comprises or has at least 95% (e.g. , at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:25, a heavy chain CDRH2 comprises or has at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:26, and / or a heavy chain CDRH3 comprises or has at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:27. In some embodiments of the uses and methods provided herein, the antibody or an antigenbinding fragment comprises a heavy chain CDRH1 comprises or has at least 99% sequence similarity to SEQ ID NO:25. a heavy chain CDRH2 comprises or has at least 99% sequence similarity to SEQ ID NO:26, and / or a heavy chain CDRH3 comprises or has at least 99% sequence similarity to SEQ ID NO:27. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain CDRH1 comprises the sequence of SEQ ID NO:25, a heavy chain CDRH2 comprises the sequence of SEQ ID NO:26, and / or a heavy chain CDRH3 comprises or comprises the sequence of SEQ ID NO:27.

[0054] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a light chain CDRL1 comprises or has at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:28, a light chain CDRL2 comprises or has at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:29, and / or a light chain CDRL3 comprises or has at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:30. In some embodiments of the uses and methods provided herein, the antibody or an antigenbinding fragment comprises a light chain CDRL1 comprises or has at least 99% sequence similarity to SEQ ID NO:28, a light chain CDRL2 comprises or has at least 99% sequence similarity to SEQ ID NO:29, and / or a light chain CDRL3 comprises or has at least 99% sequence similarity to SEQ ID NO: 30. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a light chain-22-CDRL1 comprises the sequence of SEQ ID NO:28, a light chain CDRL2 comprises the sequence of SEQ ID NO:29. and / or a light chain CDRL3 comprises the sequence of SEQ ID NO:30.

[0055] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 90%, 95%, or 99% sequence similarity to SEQ ID NO:31 and alight chain comprising having at least 90%, 95%. or 99% sequence similarity to SEQ ID NO:32. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 90% (e.g., at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:31 and a light chain comprising or having at least 90%. (e.g.. at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO: 32. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:31 and a light chain comprising or having at least 95%, (e.g.. at least 95, 96, 97. 98. or 99%) sequence similarity to SEQ ID NO: 32. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 99% sequence similarity' to SEQ ID NO: 31 and a light chain comprising or having at least 99%, sequence similarity to SEQ ID NO:32. In some embodiments of the uses and methods provided herein, the antibody or an antigenbinding fragment comprises a heavy chain comprising the sequence of SEQ ID NO:31 and a light chain comprising the sequence of SEQ ID NO:32.

[0056] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises:(a) a heavy chain CDRH1 comprising or having at least 95% or at least 99% sequence similarity' to SEQ ID NO:33; a heavy chain CDRH2 comprising or having at least 95% or at least 99% sequence similarity' to SEQ ID NO: 34; and a heavy chain CDRH3 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:35; and(b) a light chain CDRL1 comprising or having at least 95% or at least 99% sequence similarity' to SEQ ID NO: 36; a light chain CDRL2 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:37; and a light chain CDRL3 comprising or having at least 95% or at least 99% sequence similarity to SEQ ID NO:38.-23-

[0057] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain CDRH1 comprises or has at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:33, a heavy chain CDRH2 comprises or has at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:34, and / or a heavy chain CDRH3 comprises or has at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:35. In some embodiments of the uses and methods provided herein, the antibody or an antigenbinding fragment comprises a heavy chain CDRH1 comprises or has at least 99% sequence similarity' to SEQ ID NO:33, a heavy chain CDRH2 comprises or has at least 99% sequence similarity to SEQ ID NO:34, and / or a heavy chain CDRH3 comprises or has at least 99% sequence similarity to SEQ ID NO:35. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain CDRH1 comprises the sequence of SEQ ID NO:33, a heavy chain CDRH2 comprises the sequence of SEQ ID NO:34, and / or a heavy chain CDRH3 comprises the sequence of SEQ ID NO:35.

[0058] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a light chain CDRL1 comprises or has at least 95% (e.g., at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:36, a light chain CDRL2 comprises or has at least 95% (e.g, at least 95, 96, 97, 98. or 99%) sequence similarity to SEQ ID NO:37, and / or a light chain CDRL3 comprises or has at least 95% (e.g, at least 95, 96, 97, 98, or 99%) sequence similarity’ to SEQ ID NO:38. In some embodiments of the uses and methods provided herein, the antibody or an antigenbinding fragment comprises a light chain CDRL1 comprises or has at least 99% sequence similarity to SEQ ID NO: 36. a light chain CDRL2 comprises or has at least 99% sequence similarity to SEQ ID NO:37, and / or a light chain CDRL3 comprises or has at least 99% sequence similarity to SEQ ID NO:38. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a light chain CDRL1 comprises the sequence of SEQ ID NO:36, a light chain CDRL2 comprises the sequence of SEQ ID NO:37. and / or a light chain CDRL3 comprises the sequence of SEQ ID NO:38

[0059] In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 90%, 95%, or 99% sequence similarity to SEQ ID NO:39 and alight chain comprising having at least 90%, 95%, or 99% sequence similarity to SEQ ID NO:40. In some-24-embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 90% (e.g., at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:39 and a light chain comprising or having at least 90%, (e.g., at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:40. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 95% (e.g., at least 95, 96, 97, 98. or 99%) sequence similarity to SEQ ID NO:39 and a light chain comprising or having at least 95%, (e.g. , at least 95, 96, 97, 98, or 99%) sequence similarity to SEQ ID NO:40. In some embodiments of the uses and methods provided herein, the antibody or an antigen-binding fragment comprises a heavy chain comprising or having at least 99% sequence similarity to SEQ ID NO: 39 and a light chain comprising or having at least 99%, sequence similarity to SEQ ID NO:40. In some embodiments of the uses and methods provided herein, the antibody or an antigenbinding fragment comprises a heavy chain comprising the sequence of SEQ ID NO: 39 and a light chain comprising the sequence of SEQ ID NO:40.

[0060] In one embodiment, this disclosure relates to the use of a combination of Compound (A) as defined herein, and an antibody-drug conjugate for treating a cancer in a subject. The antibody-drug conjugate is represented by the following structural formula:or a pharmaceutically acceptable salt thereof, wherein:Ab is an antibody or an antigen-binding fragment thereof that comprises:(a) a heavy chain CDRH1 comprising SEQ ID NO:1; a heavy chain CDRH2 comprising SEQ ID NO:2; and a heavy chain CDRH3 comprising SEQ ID NO:3; and(b) a light chain CDRL1 comprising SEQ ID NO:4; a light chain CDRL2 comprising SEQ ID NO:5; and a light chain CDRL3 comprising SEQ ID NO:6; and n is in a range of about 1 to about 10 (e.g, about 7 to about 8)

[0061] In one embodiment, this disclosure relates to the use of a combination of Compound (A) as defined herein, and an antibody-drug conjugate for treating a cancer in a subject. The antibody-drug conjugate is represented by the following structural formula:or a pharmaceutically acceptable salt thereof, wherein:Ab is an antibody or an antigen-binding fragment thereof that comprises:(a) a heavy chain CDRH1 comprising SEQ ID NO:9; a heavy chain CDRH2 comprising SEQ ID NOTO; and a heavy chain CDRH3 comprising SEQ ID NO: 11 ; and(b) a light chain CDRL1 comprising SEQ ID NO: 12; a light chain CDRL2 comprising SEQ ID NO: 13; and a light chain CDRL3 comprising SEQ ID NO: 14; and n is in a range of about 1 to about 10 (e.g.. about 4).

[0062] The uses and methods of the present disclosure include uses and methods of treating a cancer selected from a brain cancer, a cervicocerebral cancer, an esophageal cancer, a thyroid cancer, a small cell cancer, a non-small cell cancer, a breast cancer, a lung cancer (e.g.. non-small cell lung cancer and small cell lung cancer), a stomach cancer, a urothelial cancer, a gallbladder / bile duct cancer, a kidney cancer (e.g, renal cell carcinoma), a liver cancer, a pancreatic cancer, a colon cancer, a rectal cancer, a colorectal cancer, an ovarian cancer (e.g., epithelial ovarian cancer), a fallopian tube cancer, a prima y- peritoneal cancer, an uterine cancer, a choriocarcinoma, an uterus body cancer, an uterocervical cancer, a renal pelvis / ureter cancer, a bladder cancer, a prostate cancer, a penis cancer, a testicular cancer, a fetal cancer, Wilms' cancer, a skin cancer,malignant melanoma, a neuroblastoma, an osteosarcoma, an Ewing's tumor, a soft part sarcoma, an acute leukemia, a chronic lymphatic leukemia, a chronic myelocytic leukemia, polycythemia vera, a malignant lymphoma, multiple myeloma, a Hodgkin's lymphoma and a non-Hodgkin’s lymphoma.

[0063] In one embodiment, the cancer is a breast cancer. In one embodiment, the breast cancer has a hormone receptor (HR)-positive (HR+) status. In one embodiment, the breast cancer has a hormone receptor (HR)-low (HRlow) status. In one embodiment, the breast cancer has a hormone receptor (HR)-positive (HR+) status. In one embodiment, the breast cancer has a HER2 -negative (HER-) status. In one embodiment, the breast cancer has a HER2-positive (HER+) status. In one embodiment, the breast cancer has a TROP2- low (TROP2low) status. In one embodiment, the breast cancer has a TROP2-high (TROP2hlgh) status. This disclosure contemplates breast cancers with any non-contradictory combination of the biomarkers mentioned above. In one embodiment, the breast cancer is triple negative breast cancer. In some embodiments, a cancer is selected from colorectal cancer, breast cancer and ovarian cancer.

[0064] In one embodiment, the cancer is urothelial cancer. In one embodiment, the cancer is non-small cell lung cancer (NSCLC). In one embodiment, the cancer is a neuroblastoma. In one embodiment, the cancer is a colorectal cancer. In one embodiment, the cancer is a renal cell carcinoma.

[0065] In one embodiment, the cancer is an ovarian cancer. In one embodiment, the ovarian cancer is high-grade serous ovarian cancer or high-grade serous ovarian carcinoma (HGSOC). In one embodiment, the ovarian cancer has a Cyclin Ellowstatus.

[0066] The status of the protein biomarkers described above, such as HER2, HR, TROP2 and Cyclin El, may be determined from the respective receptor or protein levels, or mRNA or transcript levels thereof, in a tumor sample obtained from a subject; and a H-score, an immunochemistry (IHC) staining intensity score (e.g., 1+, 2+, 3+) may be derived or calculated. The expression of each protein is assessed using a 0 to 3+ intensity score by a trained and qualified observer with categorization of ambiguous cases confirmed by a pathologist and the percentage of tumor cells having an IHC 1+, 2+, or 3+ intensity staining score (z.e., score 1 and above, score 2 and above, score 3 and above) is obtained and used to determine protein expression level.

[0067] In some embodiments, the cancer treated in the uses and methods provided herein has one or more mutations (e.g., deletion, nucleotide / amino acid-27-substitution, altered expression or function, etc.) in a gene selected from TP53, PIK3CA, BRAE. BRCAL BRCA2. PTEN, KRAS and RBI.

[0068] In some embodiments, the subject with the cancer has received at least one prior systemic treatment regimens. In one embodiment, the subject has received one to three prior systemic treatment regimens. Such first-line standard therapies include immunotherapy, such as an immune checkpoint inhibitor, alone or in combination with chemotherapy, such as platinum-based chemotherapy. Non-limiting examples of platinumbased chemotherapy include cisplatin, carboplatin and oxaliplatin (including pharmaceutically acceptable salts of any of the foregoing).

[0069] In some embodiments, the cancer treated in the uses and methods provided herein is a “platinum-sensitive cancer,” which as used herein and per Response Evaluation Criteria in Solid Tumors (RECIST) vl.l refers to a cancer or tumor that is sensitive to platinum-based chemotherapy (e.g., cisplatin, carboplatin, oxaliplatin and pharmaceutically acceptable salts thereof) that is defined as (1) > 30% decrease from baseline, confirmed at 4 weeks, (2) no > 20% increase over smallest sum observed or (3) no new lesions.

[0070] In some embodiments, the cancer treated in the uses and methods of provided herein is a “platinum-resistant cancer,” which as used herein and per Response Evaluation Criteria in Solid Tumors (RECIST) v l. l refers to a cancer or tumor that may have previously responded to. but no longer responds, to platinum-based chemotherapy that is defined as (1) > 30% decrease from baseline or (2) no > 20% increase over smallest sum observed and no new lesions at 4 weeks. In one embodiment, the cancer acquires resistance, for example, via prior exposure to platinum-based therapy, either as monotherapy or in combination with other compounds (such as other chemotherapy, immune checkpoint inhibitors, etc.).

[0071] In some embodiments, the cancer treated in the uses and methods of provided herein is a “platinum-refractory cancer,” which as used herein and per Response Evaluation Criteria in Solid Tumors (RECIST) vl. l refers to a cancer or tumor which never responded to platinum-based chemotherapy that is defined as (1) > 30% decrease from baseline or (2) no > 20% increase over smallest sum observed and no new lesions at 4 weeks. In one embodiment, the cancer is inherently resistant.

[0072] Non-limiting examples of immune checkpoint inhibitors include PD-1 inhibitors, PD-L1 inhibitors. CTLA-4 inhibitors and LAG-3 inhibitors (including pharmaceutically acceptable salts of any of the foregoing). In some embodiments, an-28-immune checkpoint inhibitor may be bi- or multi-specific and may target at least two proteins, including, but not limited to. two proteins selected from PD-1, PD-L1. CTLA-4 and LAG-3. Non-limiting examples of PD-1 inhibitors include retifanlimab, pucotenlimab, cadonilimab, serplulimab, nivolumab (relatimab), zimberelimab, penpulimab, dostarlimab (dostarlimab-gxly), prolgolimab, tislelizumab, camrelizumab, sintilimab, toripalimab, cemiplimab (cemiplimab-RWLC). pembrolizumab, nivolumab. balstilimab, finotonlimab, iparomlimab. ivonescimab, tuvonralimab / iparomlimab, cetrelimab. favezelimab / pembrolizumab, genolimzumab, nofazinlimab, pembrolizumab / hyaluronidase, pembrolizumab / quavonlimab, pembrolizumab / vibostolimab, pembrolizumab / quavonlimab, rilvegostomig, sasanlimab, spartalizumab, tebotelimab and volrustomig (including pharmaceutically acceptable salts of any of the foregoing).

[0073] Non-limiting examples of PD-L1 inhibitors include socazolimab, adebrelimab, sugemalimab, envafolimab, durvalumab, avelumab, atezolizumab, benmelstobart, tagitanlimab. bintrafusp alfa, erfonrilimab and retlirafusp alfa (including pharmaceutically acceptable salts of any of the foregoing).

[0074] Non-limiting examples of CTLA-4 inhibitors include tremelimumab, cadonilimab, ipilimumab, tuvonralimab / paromlimab, erfonrilimab, gotistobart, pembrolizumab / quavonlimab, pembrolizumab / quavonlimab, quavonlimab and volrustomig (including pharmaceutically acceptable salts of any of the foregoing).

[0075] Non-limiting examples of LAG-3 inhibitors include nivolumab / relatlimab, favezelimab / pembrolizumab, fianlimab, relatlimab, tebotelimab, eftilagimod alpha and favezelimab (including pharmaceutically acceptable salts of any of the foregoing).

[0076] When the treatment is a combination of compounds, the order of administration or use of the combination of Compound (A) and Compound (B) or an antibody-drug conjugate comprising Compound (B) described herein can vary'. In some embodiments, Compound (A) and Compound (B) or an antibody-drug conjugate comprising Compound (B) are administered or used sequentially. In some embodiments. Compound (A) can be administered prior to Compound (B) or an antibody-drug conjugate comprising Compound (B). In other embodiments, Compound (A) can be administered subsequent to or after Compound (B) or an antibody-drug conjugate comprising Compound (B). In still other embodiments, Compound (A) can be administered concomitantly or-29-concurrently with Compound (B) or an antibody-drug conjugate comprising Compound (B)

[0077] In some embodiments, Compound (A) is provided on an intermittent dosing schedule. In some embodiments, Compound (A) the intermittent dosing schedule comprises 5 days on, 2 days off; 4 days on, 3 days off; 3 days on , 4 days off; or 6 days on, 1 day off on in one or more dosing weeks.

[0078] In some embodiments, the use of a combination of Compound (A) and Compound (B) or an antibody-drug conjugate comprising Compound (B) for treating a cancer or methods of treatment with a combination of Compound (A) and Compound (B) or an antibody-drug conjugate comprising Compound (B), provided herein can decrease the number and / or severity of side effects that can be attributed to monotherapy of Compound (B) or an antibody-drug conjugate comprising Compound (B).

[0079] Using a combination of Compound (A) and Compound (B) or an antibody-drug conjugate comprising Compound (B) as described herein can result in additive, synergistic or strongly synergistic effect. A combination of compounds described herein can result in an effect that is not antagonistic.

[0080] As used herein, the term “antagonistic” means that the activity of the combination of compounds is less compared to the sum of the activities of the compounds in combination when the activity of each compound is determined individually (i.e., as a single compound). As used herein, the term “synergistic effect” means that the activity of the combination of compounds is greater than the sum of the individual activities of the compounds in the combination when the activity of each compound is determined individually. As used herein, the term “additive effect” means that the activity of the combination of compounds is about equal to the sum of the individual activities of the compounds in the combination when the activity of each compound is determined individually.

[0081] A potential advantage of utilizing a combination as described herein may be a reduction in the required amount(s) of the compound(s) that is effective in treating a disease condition disclosed herein compared to when Compound (B) or an antibody-drug conjugate comprising Compound (B) is administered as a monotherapy and / or wherein Compound (A) is administered as a monotherapy. For example, the amount of Compound (A) and Compound (B) or an antibody-drug conjugate comprising Compound (B) used in a combination described herein can be less compared to the amount of Compound (A) and Compound (B) or an antibody-drug conjugate comprising Compound (B) needed to-30-achieve the same reduction in a disease marker (for example, tumor size) when each is administered as a monotherapy. Another potential advantage of utilizing a combination as described herein is that the use of two or more compounds having different mechanisms of action can create a higher barrier to the development of resistance compared to when Compound (A) and Compound (B) or an antibody-drug conjugate comprising Compound (B) are each administered as monotherapy. Additional advantages of utilizing a combination as described herein may include little to no cross resistance between the compounds of a combination described herein; different routes for elimination of the compounds of a combination described herein; and / or little to no overlapping toxicities between the compounds of a combination described herein.Pharmaceutical Compositions

[0082] Compound (A) can be provided in a pharmaceutical composition. Likewise, Compound (B) or an antibody-drug conjugate comprising Compound (B) can be provided in a pharmaceutical composition.

[0083] The term “pharmaceutical composition” refers to a mixture of one or more compounds and / or salts disclosed herein with other chemical components, such as diluents, carriers and / or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutical compositions will generally be tailored to the specific intended route of administration.

[0084] As used herein, a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

[0085] As used herein, a “diluent” refers to an ingredient in a pharmaceutical composition that lacks appreciable pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and / or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as. without limitation, phosphate buffered saline that mimics the pH and isotonicity of human blood.-31-

[0086] As used herein, an “excipient’' refers to an essentially inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. For example, stabilizers such as anti-oxidants and metal-chelating agents are excipients. In an embodiment, the pharmaceutical composition comprises an anti-oxidant and / or a metal-chelating agent. A “diluent” is a type of excipient.

[0087] In some embodiments. Compound (B) or an antibody-drug conjugate comprising Compound (B) can be provided in a pharmaceutical composition that includes Compound (A). In other embodiments, Compound (B) or an antibody-drug conjugate comprising Compound (B) can be administered in a pharmaceutical composition that is separate from a pharmaceutical composition that includes Compound (A).

[0088] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are know n to those skilled in the art.

[0089] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g.. by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.

[0090] Multiple techniques of administering a compound, salt and / or composition exist in the art including, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection, infusion and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections. In some embodiments, Compound (A) can be administered orally. In some embodiments. Compound (A) can be provided to a subject by the same route of administration as Compound (B) or an antibody-drug conjugate comprising Compound (B). In other embodiments, Compound (A) can be provided to a subject by a different route of administration as Compound (B) or an antibody-drug conjugate comprising Compound (B).-32-

[0091] One may also administer the compound, salt and / or composition in a local rather than systemic manner, for example, via injection or implantation of the compound directly into the affected area, often in a depot or sustained release formulation. Furthermore, one may administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the organ. For example, intranasal or pulmonary delivery to target a respiratory disease or condition may be desirable.

[0092] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions that can include a compound and / or salt described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.Uses and Methods of Treatment

[0093] As provided herein, in some embodiments, a combination of compounds that includes an effective amount of Compound (A) and an effective amount of Compound (B) or an antibody -drug conjugate comprising Compound (B) can be used to treat a cancer.

[0094] In some cases, following cancer treatment, a subject can relapse or have reoccurrence of the cancer. As used herein, the terms “relapse” and “recurrence” are used in their normal sense as understood by those skilled in the art. Thus, the cancer can be a recurrent cancer.

[0095] As used herein, a “subject” refers to an animal that is the object of treatment, observation or experiment. “Animal” includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and, in particular, humans. In some embodiments, the subject can be human. In some embodiments, the-33-subject can be a child (z.e., > 1 year and < 18 years old) and / or an infant (z.e., < 1 year old). In other embodiments, the subject can be an adult (>18 years of age).

[0096] As used herein, the terms '‘treat,” “treating,” “treatment,” “therapeutic,” and “therapy” do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of the disease or condition, to any extent can be considered treatment and / or therapy. Furthermore, treatment may include acts that may worsen the subject's overall feeling of well-being or appearance.

[0097] The term “effective amount” is used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. For example, an effective amount of compound, salt or composition can be the amount needed to prevent, alleviate or ameliorate symptoms of the disease or condition, or prolong the survival of the subject being treated. This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease or condition being treated. Determination of an effective amount is well within the capability’ of those skilled in the art, in view of the disclosure provided herein. The effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.

[0098] For example, an effective amount of a compound, or radiation, is the amount that results in: (a) the reduction, alleviation or disappearance of one or more symptoms caused by the cancer, (b) the reduction of tumor size, (c) the elimination of the tumor, and / or (d) long-term disease stabilization (growth arrest) of the tumor.

[0099] The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials, in vivo studies and in vitro studies. For example, useful dosages of Compounds (A) and Compound (B) or an antibody-drug conjugate comprising Compound (B), can be determined by comparing their in vitro activity, and in vivo activity in animal models. Such comparison can be done by comparison against an established drug, such as cisplatin and / or gemcitabine, or against monotherapy with Compound (A) or Compound (B).

[0100] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects,-34-or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vivo and / or in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, such as between 30-90% and between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration. A dosing regimen may comprise an “intermittent” dosing, during which one or more dosing parameters such as dosage amount and / or dosage interval are varied or changed. For example, an intermittent dosing phase may comprise a period of continuous administration (e.g., 6 days, 5 days, 4 days in a week) followed by a “rest” phase (e.g., 1 day, 2 days, 3 days in the same week) during which Compound (A) is not administered or is administered at a reduced dosage amount and / or less frequently. A dosing regimen may further comprise one or more repeated cycles of intermittent dosing regimens.

[0101] It should be noted that the attending physician would know how to and when to terminate, interrupt or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response was not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the disease or condition to be treated and to the route of administration. The severity of the disease or condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.

[0102] Compounds, conjugates, salts and compositions disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties, may be established by determining in vitro toxicity towards a cell line, such as a human cell line. The results of such studies are often predictive of toxicity. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, dogs or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled-35-artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and / or regime.EXAMPLES

[0103] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims. In these examples and in the accompanying figures. Compound (A) is azenosertib and is also referred to as the same.Example 1 : Azenosertib and topoisomerase I (TOPI) inhibitors exhibit synergy in vitro

[0104] HT-29 (ATCC) was cultured in McCoy's 5 A medium (ATCC) supplemented with 10% FBS (Gibco) and 1% penicillin-streptomycin (Gibco). HCC1569 was cultured in RPMI 1640 medium (ATCC modification) (Gibco) supplemented with 10% FBS (Gibco) and 1% penicillin-streptomycin (Gibco). MDA-MB-231 and MDA-MB- 468 were cultured in DMEM / F12 medium (Gibco) supplemented with 10% FBS (Gibco) and 1% penicillin-streptomycin (Gibco). Cells were maintained at 37°C in an atmosphere containing 5% CO2.

[0105] Colorectal cancer (HT-29) and breast cancer (HCC1569, MDA-MB- 231, and MDA-MB-468) cells were seeded at optimal density in 96-well plates for evaluation of combination treatments on cell viability. Treatments were performed the following day with azenosertib, irinotecan, and SN-38 as monotherapies or in a matrix combination format. Specifically, HT-29 was treated with azenosertib (0-500 nM) and irinotecan (0-10 pM); HCC1569 was treated with azenosertib (1-150 nM) and irinotecan (0-100 nM); MDA-MB-231 was treated with azenosertib (0-850 nM) and SN-38 (0-350 nM); MDA-MB-468 was treated with azenosertib (0-650 nM) and SN-38 (0-4 nM). Cell viability was then measured 3-, 4- or 6-days following treatment by CellTiter-Glo 2.0 assay. Synergies between azenosertib and Irinotecan and between azenosertib and SN-38 were then calculated using ZIP synergy score from SynergyFinder tool (http: / / www.synergyfmderplus.org / ).

[0106] As shown in FIGS. 1A-1B, azenosertib demonstrates synergy in combination with irinotecan or SN-38 in vitro. All tested cell lines demonstrated clear synergy' (ZIP synergy' score > 10) at depicted dose ranges. Overall, the results showed that azenosertib and topoisomerase I (TOPI) inhibitors exhibited synergy in vitro.Example 2: Azenosertib in combination with topoisomerase I (TOPI) inhibitors increases DNA damage and apoptosis in vitro

[0107] Colorectal cancer (HT-29) and breast cancer (HCC1569, and MDA- MB-468) cells were seeded at optimal density in 6-well plates for the evaluation of combination treatments on biomarker changes. Treatment doses were determined from combination CellTiter-Glo assays and treatments were performed the following day with azenosertib, irinotecan, and SN-38 as monotherapies or as combination therapies. Specifically, HT-29 was treated with azenosertib (350 nM) and / or irinotecan (5 pM); HCC1569 was treated with azenosertib (150 nM) and / or irinotecan (30 nM); MDA-MB- 468 was treated with azenosertib (650 nM) and / or SN-38 (2 nM). After indicated time of drug exposure, cells were harvested, rinsed with PBS, lysed in cold RIP A buffer (Sigma) containing protease and phosphatase inhibitors for 15 minutes, and centrifuged at 4°C, 15,000 rpm for 15 minutes. Protein concentrations were measured using the Pierce BCA Protein Assay kit (Thermo Fisher). JESS plates were loaded and run according to the manufacturer’s instructions. Primary antibodies anti-Cyclin El was purchased from Abeam, anti-GAPDH was purchased from Invitrogen, anti-yH2AX, anti-phospho-CDKl, anti-phsopho-Chkl, anti-cleaved caspase 3, anti-Weel, and anti-CDKl were purchased from Cell Signaling Technology.

[0108] As shown in FIGS. 2A-2B, azenosertib in combination with irinotecan or SN-38 increases DNA damage and apoptosis in vitro. Colorectal (HT-29) and breast (HCC1569 and MDA-MB-468) cell lines were treated with monotherapies or combination therapies for indicated time points. DNA damage and apoptosis levels were increased as indicated by yH2AX and cleaved caspase 3 respectively, when cells were treated with combination doses compared to monotherapies. The results showed that azenosertib in combination with topoisomerase I (TOPI) inhibitors increased DNA damage and apoptosis in vitro.Example 3: Azenosertib in combination with topoisomerase I (TOPI) inhibitors improves efficacy in ovarian cancer model in vivo

[0109] The anti-tumor activity of azenosertib, irinotecan, and topotecan hydrochloride, as monotherapy or as combination therapies, was evaluated in an ovarian cancer model OV90. Table 1 summarizes the groups and treatments. Tumor measurements and animal body weights were monitored twice weekly throughout the study. As shown in FIGS. 3A-3B, the combinations of azenosertib / irinotecan or azenosertib / topotecan both-37-resulted in greater tumor growth inhibition (z'.e., 89% TGI for azenosertib / irinotecan combination. 72% TGI for azenosertib / topotecan combination) than their respective monotherapies (i.e., 53% TGI for azenosertib monotherapy, 60% TGI for irinotecan monotherapy, 9.5% TGI for topotecan monotherapy) on Day 25 of treatment. In FIGS. 3A- 3B, the top lines are Vehicle, the middle lines are monotherapies and the bottom lines are combination therapies. Azenosertib in combination with irinotecan or topotecan led to significant tumor growth inhibition of 89% and 72%. respectively. Treatment with single agents azenosertib, irinotecan or topotecan resulted in tumor growth inhibition of 53%, 60% and 9.5%, respectively. The results showed that combination therapy resulted in greater tumor growth inhibition than monotherapy in an ovarian cancer model in vivo. Furthermore, the body weight changes shown in FIG. 3C indicated that the combination therapies were well-tolerated by the mice.Table 1. OV90-xenografted mice treatment groups and dosing regimensExample 4: Azenosertib in combination with irinotecan improves efficacy in breast cancer model in vivo

[0110] The anti -tumor activity of azenosertib and irinotecan, as monotherapy or as combination therapies, was evaluated in a breast cancer model HCC1569. Table 2 summarizes the groups and treatments. Tumor measurements and animal body weights were monitored twice weekly throughout the study. As shown in FIG. 4A, the combination of azenosertib / irinotecan resulted in greater tumor grow th inhibition than their respective monotherapies on Day 25 of treatment. In FIG. 4A, the top line is Vehicle, the middle lines are monotherapies and the bottom line is combination therapy. Azenosertib in combination-38-with irinotecan led to significant tumor growth inhibitions of 99% (azenosertib 60 mg / kg QD 5:2) and 100% (azenosertib 80 mg / kg QD 5:2). Treatment with single agents azenosertib or irinotecan resulted in tumor growth inhibitions of 42% (azenosertib 60 mg / kg QD 5:2), 69% (azenosertib 80 mg / kg QD 5:2), and 80% (irinotecan 30 mg / kg QW), respectively. As shown in FIG. 4B, the combination treatments of azenosertib and irinotecan were well-tolerated. The results showed that azenosertib in combination with irinotecan led to increased tumor growth inhibition and showed improved efficacy in a breast cancer model in vivo.Table 2. HCC1569-xenografted mice treatment groups and dosing regimensExample 5: Azenosertib and sacituzumab govitecan exhibit synergy in vitro

[0111] Culturing of cancer cells, maintenance of cell cultures, setting up of in vitro monotherapy and combination treatment of MDA-MB-468 and MDA-MB-431 breast cancer cells, in vitro synergy studies, and immunoblotting are as described in Examples 1 and 2, with azenosertib and the TROP2-directed antibody-drug conjugate sacituzumab govitecan as the therapeutic agents. Compared to MDA-MB-468, MDA-MB-231 breast cancer cells have a TROP2-low (TROP2low) status and are less sensitive to sacituzumab govitecan.

[0112] As shown in FIG. 5A, azenosertib and sacituzumab govitecan exhibit synergy' in vitro. Azenosertib in combination with sacituzumab govitecan showed significant synergy' in TROP2-high (TROP2hlgh) MDA-MB-468 tiple negative breast cancer cell line with increased DNA damage and apoptosis as indicated by phospho-Chkl / yH2AX and cleaved caspase 3, respectively (see FIG. 5B). The results showed that azenosertib and sacituzumab govitecan exhibited synergy in vitro.Example 6: Azenosertib in combination with TROP2-directed antibody-drug conjugates improves efficacy in breast cancer model in vivo

[0113] The anti-tumor activity of azenosertib and a TROP2-directed antibodydrug conjugate (i.e., either sacituzumab govitecan or datopotamab deruxtecan or Dato- DXd), as monotherapy or as combination therapies, was evaluated in the triple negative breast cancer model MDA-MB-231 that expresses low levels of TROP2 and is also known to be less sensitive to TROP2-directed antibody -drug conjugates. Table 3 summarizes the groups and treatments. Tumor measurements and animal body weights were monitored twice weekly throughout the study. As shown in FIGS. 6A-6B, the combinations of azenosertib / sacituzumab govitecan or azenosertib / datopotamab deruxtecan both resulted in greater tumor growth inhibition than their respective monotherapies on Day 46 of treatment. In FIGS. 6A-6B. the top lines are vehicle, the middle lines are monotherapies and the bottom lines are combination therapies. Azenosertib in combination with sacituzumab govitecan led to significant tumor growth inhibition of 91%, whereas treatment with single agent azenosertib or single agent sacituzumab govitecan resulted in tumor growth inhibitions of 28% and 71%. respectively. Although treatment with single agent datopotamab deruxtecan already resulted in 98% tumor growth inhibition, its combination with azenosertib led to 103% tumor growth inhibition. The results showed that azenosertib in combination with TROP2-directed antibody-drug conjugates improved efficacy in a breast cancer model in vivo. Furthermore, the body weight changes shown in FIG. 6C indicated that the combination therapies were well-tolerated by the mice.Table 3. MDA-MB-231 -xenografted mice treatment groups and dosing regimens

[0114] Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather to also cover all modification and alternatives coming with the true scope and spirit of the present disclosure.SEQUENCE LISTINGSSEQ ID NO:1 - Sacituzumab CDRH1GYFMNSEQ ID N0:2 - Sacituzumab CDRH2RIHPYDGDTFYNQKFQGSEQ ID N0:3 - Sacituzumab CDRH3YDGSRAMDYSEQ ID N0:4 - Sacituzumab CDRL1KASQSVSFAGTSLMHSEQ ID N0:5 - Sacituzumab CDRL2RASNLEASEQ ID N0:6 - Sacituzumab CDRL3QQSREYPYTSEQ ID N0:7 - Sacituzumab heavy chainQVQLQQSGSELKKPGASVKVSCKASGYTFTNYGMNWVKQAPGQGLKWMGWINTYTGEPTYTDDFKGRFAFSLDTSVSTAYLQISSLKADDTAVYFCARGGFGSSYWYFDVWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSEQ ID NO: 8 - Sacituzumab light chainDIQLTQSPSSLSASVGDRVSITCKASQDVSIAVAWYQQKPGKAPKLLIYSASYRYTGVPDRFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYITPLTFGAGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 9 - Datopotamab CDRH1TAGMQSEQ ID NO: 10 - Datopotamab CDRH2WINTHSGVPKYAEDFKGSEQ ID NO: 11 Datopotamab CDRH3SGFGSSYWYFDVSEQ ID NO: 12 - Datopotamab CDRL1 KASQDVSTAVASEQ ID NO: 13 - Datopotamab CDRL2 SASYRYTSEQ ID NO: 14 - Datopotamab CDRL3QQHYITPLTSEQ ID NO: 15 - Datopotamab heavy chainQVQLVQSGAEVKKPGASVKVSCKASGYTFTTAGMQWVRQAPGQGLEWMGWINTHSGVPKYAEDFKGRVTISADTSTSTAYLQLSSLKSEDTAVYYCARSGFGSSYWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSEQ ID NO: 16 - Datopotamab light chainDIQMTQSPSSLSASVGDRVTITCKASQDVSTAVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYITPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 17 - Patritumab CDRH1GGSFSGYYWSSEQ ID NO: 18 - Patritumab CDRH2EINHSGSTNYNPSLKSSEQ ID NO: 19 - Patritumab CDRH3DKWTWYFDLSEQ ID NO:20 - Patritumab CDRL1RSSQSVLYSSSNRNYLSEQ ID NO:21 - Patritumab CDRL2WASTRESSEQ ID NO:22 - Patritumab CDRL3QQYYSTPRTSEQ ID NO:23 - Patritumab heavy chainQVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVETSKNQFSLKLSSVTAADTAVYYCARDKWTWYFDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPGKSEQ ID NO:24 - Patritumab light chainDIEMTQSPDSLAVSLGERATINCRSSQSVLYSSSNRNYLAWYQQNPGQPPKLLIY WASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPRTFGQGTKV EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO:25 - Ifinatamab CDRH1NYVMHSEQ ID NO:26 - Ifinatamab CDRH2YINPYNDDVKYNEKFKGSEQ ID NO: 27 - Ifinatamab CDRH3WGYYGSPLYYFDYSEQ ID NO:28 - Ifinatamab CDRL1RASSRLIYMHSEQ ID NO: 29 - Ifinatamab CDRL2ATSNLASSEQ ID NO:30 - Ifinatamab CDRL3QQWNSNPPTSEQ ID NO:31 - Ifinatamab heavy chainQVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYVMHWVRQAPGQGLEWMGYIN PYNDDVKYNEKFKGRVTITADESTSTAYMELSSLRSEDTAVYYCARWGYYGSPL YYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV DKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGKSEQ ID NO:32 - Ifinatamab light chainEIVLTQSPATLSLSPGERATLSCRASSRLIYMHWYQQKPGQAPRPLIYATSNLASG IPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQWNSNPPTFGQGTKVEIKRTVAAP SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO 33 - Raludotatug CDRH1GYTFTRNFMHSEQ ID NO: 34 - Raludotatug CDRH2WIYPGDGETESEQ ID NO:35 - Raludotatug CDRH3 GVYGGFAGGYFDFSEQ ID NO:36 - Raludotatug CDRL1KASQNIYKNLASEQ ID NO:37 - Raludotatug CDRL2DANTLQTSEQ ID NO: 38 - Raludotatug CDRL3QQYYSGWASEQ ID NO:39 - Raludotatug heavy chainEVQLVQSGAEVKKPGASVKVSCKASGYTFTRNFMHWVRQAPGQGLEWMGWIYPGDGETEYAQKFQGRVTITADTSTSTAYMELSSLRSEDTAVYYCARGVYGGFAGGYFDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSEQ ID NO:40 - Raludotatug light chainDIQMTQSPSSLSASVGDRVTITCKASQNIYKNLAWYQQKPGKAPKLLIYDANTLQTGVPSRFSGSGSGSDFTLTISSLQPEDFATYFCQQYYSGWAFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Claims

WHAT IS CLAIMED IS:

1. Use of a combination of Compound (A) and:(i) Compound (B); or(ii) an antibody-drug conjugate comprising Compound (B) for treating a cancer in a subject, wherein:derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing; and the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target selected from the extracellular domain of human receptor tyrosine kinase-like orphan receptor 1 (R0R1), human epidermal growth factor receptor 3 (HER3), folate receptor alpha (FRa), cadherin 6 (CDH6), sodium-dependent phosphate transporter NaPi2b, tissue factor (TF or also known as platelet tissue factor, coagulation factor III (F3)) and CD142), mesothelin (MSLN), mucin 16 (MUC16 or also known as ovarian cancer-related tumor marker CAI 25), protein tyrosine kinase 7 (PTK7), receptor tyrosine kinase AXL (AXL), antigen CD166 (CD166), ectonucleotide pyrophosphatase / phosphodiesterase family member 3 (ENPP3), T-cell immunoglobulin and mucin domain 1 (TIM-1), cluster of differentiation 70 (CD70, also known as CD27L), B7 homolog 3 (B7-H3, also known as CD276), B7 homolog 4 (B7-H4), trophoblast cell surface antigen 2 (TROP2), Nectin-4, CD22, CD30, CD79b, CD 19, B-cell maturation antigen (BCMA), mucin short variant SI (MUC1), Claudin 18.2 (CLDN 18.2),-47-carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), c-Met tyrosine kinase (c-Met). interleukin-3 receptor (CD 123). epidermal growth factor receptor (EFGR) and a combination thereof.

2. Use of a combination of Compound (A) and an antibody-drug conjugate comprising Compound (B) for treating a cancer in a subject, wherein:derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing; and the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target selected from the extracellular domain of human receptor tyrosine kinase-like orphan receptor 1 (R0R1), human epidermal growth factor receptor 3 (HER3), folate receptor alpha (FRa), cadherin 6 (CDH6), sodium-dependent phosphate transporter NaPi2b, tissue factor (TF or also known as platelet tissue factor, coagulation factor III (F3)) and CD142), mesothelin (MSLN), mucin 16 (MUC16 or also known as ovarian cancer-related tumor marker CAI 25), protein tyrosine kinase 7 (PTK7), receptor tyrosine kinase AXL (AXL), antigen CD166 (CD166), ectonucleotide pyrophosphatase / phosphodiesterase family member 3 (ENPP3), T-cell immunoglobulin and mucin domain 1 (TIM-1), cluster of differentiation 70 (CD70, also known as CD27L), B7 homolog 3 (B7-H3, also known as CD276), B7 homolog 4 (B7-H4), trophoblast cell surface antigen 2 (TROP2), Nectin-4, CD22, CD30, CD79b, CD 19, B-cell maturation antigen (BCMA), mucin short variant SI (MUC1), Claudin 18.2 (CLDN 18.2),carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), c-Met tyrosine kinase (c-Met). interleukin-3 receptor (CD123), epidermal growth factor receptor (EFGR) and a combination thereof.

3. The use of claim 1 or 2, wherein the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target selected from human epidermal growth factor receptor 3 (HER3), cadherin 6 (CDH6), trophoblast cell surface antigen 2 (TR0P2), B7 homolog 3 (B7-H3, also known as CD276) and a combination thereof.

4. Use of a combination of Compound (A) and an antibody-drug conjugate comprising Compound (B) for treating a cancer in a subject, wherein:derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing; and the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target selected from human epidermal grow th factor receptor 3 (HER3), cadherin 6 (CDH6), trophoblast cell surface antigen 2 (TR0P2), B7 homolog 3 (B7-H3, also known as CD276) and a combination thereof.

5. The use of any one of claims 1 to 4, wherein Compound (B) is topotecan or a derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing.

6. The use of any one of claims 1 to 4, wherein Compound (B) is irinotecan or a derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing.

7. The use of any one of claims 1 to 4, wherein Compound (B) is SN-38 or a derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing.

8. The use of any one of claims 1 to 4. wherein Compound (B) is govitecan, or a pharmaceutically acceptable salt thereof.

9. The use of any one of claims 1 to 4, wherein Compound (B) is exatecan or a derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing.

10. The use of any one of claims 1 to 4, wherein Compound (B) deruxtecan, or a pharmaceutically acceptable salt thereof.

11. The use of any one of claims 1 to 4, 7 or 8, wherein the antibody-drug conjugate is represented by the following structural formula:or a pharmaceutically acceptable salt thereof, wherein:Ab is the antibody or an antigen-binding fragment thereof; and n represents an average number of govitecan compounds conjugated to a single Ab and is in a range of about 1 to about 10.

12. The use of any one of claims 1 to 4, 9 or 10, wherein the antibody-drug conjugate is represented by the following structural formula:or a pharmaceutically acceptable salt thereof, wherein:-52-Ab is an antibody or an antigen-binding fragment thereof; and n represents an average number of deruxtecan compounds conjugated to a single Ab and is in a range of about 1 to about 10.

13. The use of any one of claims 1 to 12, wherein the antibody or an antigenbinding fragment thereof comprises:(a) a heavy chain CDRH1 comprising SEQ ID NOT; a heavy chain CDRH2 comprising SEQ ID NO:2; and a heavy chain CDRH3 comprising SEQ ID NO:3; and(b) a light chain CDRL1 comprising SEQ ID NO:4; a light chain CDRL2 comprising SEQ ID NO:5; and a light chain CDRL3 comprising SEQ ID NO:6.

14. The use of any one of claims 1 to 13, wherein the antibody or an antigenbinding fragment thereof comprises a heavy chain comprising SEQ ID NO:7 and a light chain comprising SEQ ID NO: 8.

15. The use of any one of claims 1 to 12, wherein the antibody or an antigenbinding fragment thereof comprises:(a) a heavy chain CDRH1 comprising SEQ ID NO:9; a heavy chain CDRH2 comprising SEQ ID NOTO; and a heavy chain CDRH3 comprising SEQ ID NO: 11; and(b) a light chain CDRL1 comprising SEQ ID NO: 12; a light chain CDRL2 comprising SEQ ID NO: 13; and a light chain CDRL3 comprising SEQ ID NO: 14.

16. The use of any one of claims 1 to 12 or 15, wherein the antibody or an antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO: 15 and a light chain comprising SEQ ID NO: 1 .

17. The use of any one of claims 1 to 12, wherein the antibody or an antigenbinding fragment thereof comprises:(a) a heavy chain CDRH1 comprising SEQ ID NO: 17; a heavy chain CDRH2 comprising SEQ ID NO: 18; and a heavy chain CDRH3 comprising SEQ ID NO: 19; and(b) a light chain CDRL1 comprising SEQ ID NO:20; a light chain CDRL2 comprising SEQ ID NO:21; and a light chain CDRL3 comprising SEQ ID NO:22.

18. The use of any one of claims 1 to 12 or 17, wherein the antibody or an antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO:23 and a light chain comprising SEQ ID NO:24.

19. The use of any one of claims 1 to 12, wherein the antibody or an antigenbinding fragment thereof comprises:(a) a heavy chain CDRH1 comprising SEQ ID NO:25; a heavy chain CDRH2 comprising SEQ ID NO:26; and a heavy chain CDRH3 comprising SEQ ID NO:27; and-53-(b) a light chain CDRL1 comprising SEQ ID NO:28; a light chain CDRL2 comprising SEQ ID NO:29; and a light chain CDRL3 comprising SEQ ID NO:30.

20. The use of any one of claims 1 to 12 or 19, wherein the antibody or an antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO: 31 and a light chain comprising SEQ ID NO:32.

21. The use of any one of claims 1 to 12, wherein the antibody or an antigenbinding fragment thereof comprises:(a) a heavy chain CDRH1 comprising SEQ ID NO:33; a heavy chain CDRH2 comprising SEQ ID NO:34; and a heavy chain CDRH3 comprising SEQ ID NO:35; and(b) a light chain CDRL1 comprising SEQ ID NO:36; a light chain CDRL2 comprising SEQ ID NO:37; and a light chain CDRL3 comprising SEQ ID NO:38.

22. The use of any one of claims 1 to 12 or 21, wherein the antibody or an antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO:39 and a light chain comprising SEQ ID NO:40.

23. Use of a combination of Compound (A) and an antibody-drug conj ugate for treating a cancer in a subject, wherein:Compound (pharmaceutically acceptable salt thereof; and the antibody-drug conjugate is represented by the following structural formula:-54-or a pharmaceutically acceptable salt thereof, wherein:Ab is an antibody or an antigen-binding fragment thereof that comprises:(a) a heavy chain CDRH1 comprising SEQ ID NO: 1; a heavy chain CDRH2 comprising SEQ ID NO:2; and a heavy chain CDRH3 comprising SEQ ID NO:3; and(b) a light chain CDRL1 comprising SEQ ID NO:4; a light chain CDRL2 comprising SEQ ID NO:5; and a light chain CDRL3 comprising SEQ ID NO:6; and n is in a range of about 1 to about 10.

24. Use of a combination of Compound (A) and an antibody-drug conjugate for treating a cancer in a subject, wherein:acceptable salt thereof; and the antibody-drug conjugate is represented by the following structural formula:or a pharmaceutically acceptable salt thereof, wherein:Ab is an antibody or an antigen-binding fragment thereof that comprises:(a) a heavy chain CDRH1 comprising SEQ ID NO:9; a heavy chain CDRH2 comprising SEQ ID NOTO; and a heavy chain CDRH3 comprising SEQ ID NO: 11; and(b) a light chain CDRL1 comprising SEQ ID NO: 12; a light chain CDRL2 comprising SEQ ID NO:13; and a light chain CDRL3 comprising SEQ ID NO:14; and n is in a range of about 1 to about 10.

25. The use of any one of claims 1 to 24, wherein the cancer is selected from a brain cancer, a cervicocerebral cancer, an esophageal cancer, a thyroid cancer, a small cell cancer, a non-small cell cancer, a breast cancer, a lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), a stomach cancer, a urothelial cancer, a gallbladder / bile duct cancer, a kidney cancer (e.g. , renal cell carcinoma), a liver cancer, a pancreatic cancer, a colon cancer, a rectal cancer, a colorectal cancer, an ovarian cancer (e.g., epithelial ovarian cancer), a fallopian tube cancer, a primary peritoneal cancer, an uterine cancer, a choriocarcinoma, an uterus body cancer, an uterocervical cancer, a renal pelvis / ureter cancer, a bladder cancer, a prostate cancer, a penis cancer, a testicular cancer, a fetal cancer, Wilms' cancer, a skin cancer, malignant melanoma, a neuroblastoma, an osteosarcoma, an Ewing's tumor, a soft part sarcoma, an acute leukemia, a chronic lymphatic leukemia, a chronic myelocytic leukemia, polycythemia vera, a malignant lymphoma, multiple myeloma, a Hodgkin's lymphoma and a non-Hodgkin’s lymphoma.

26. The use of any one of claims 1 to 25. wherein the cancer is a breast cancer.

27. The use of claim 25 or 26, wherein the breast cancer has a hormone receptor (HR)-positive (HR+) status.

28. The use of claim 25 or 26, wherein the breast cancer has a hormone receptor (HR)-low (HRlow) status.

29. The use of claim 25 or 26, wherein the breast cancer has a hormone receptor (HR)-positive (HR+) status.

30. The use of any one of claims 25 to 29, wherein the breast cancer has a HER2 -negative (HER-) status.

31. The use of any one of claims 25 to 29, wherein the breast cancer has a HER2 -positive (HER+) status.

32. The use of any one of claims 25 to 30, wherein the breast cancer is triple negative breast cancer (TNBC).

33. The use of any one of claims 25 to 32, wherein the breast cancer has a TROP2-low (TROP2low) status.

34. The use of any one of claims 25 to 32, wherein the breast cancer has a TROP2-high (TROP2hl"h) status.

35. The use of any one of claims 1 to 25, wherein the cancer is a urothelial cancer.

36. The use of any one of claims 1 to 25, wherein the cancer is a non-small cell lung cancer (NSCLC).

37. The use of any one of claims 1 to 25, wherein the cancer is a neuroblastoma.

38. The use of any one of claims 1 to 25, wherein the cancer is a colorectal cancer (CRC).

39. The use of any one of claims 1 to 25, wherein the cancer is a renal cell carcinoma.

40. The use of any one of claims 1 to 25, wherein the cancer is an ovarian cancer.

41. The use of claim 40, wherein the ovarian cancer is high-grade serous ovarian carcinoma (HGSOC).

42. The use of claim 40 or 41, wherein the ovarian cancer has a Cyclin Ellowstatus.

43. The use of any one of claims 1 to 42, wherein the cancer has one or more mutations in a gene selected from TP 53, PIK3CA, BRAF, BRCA1, BRCA2, PTEN, KRAS and RBI.

44. The use of any one of claims 1 to 43, wherein the subject has received at least one prior systemic treatment regimens (e. , one to three prior systemic treatment regimens).-57-45. The use of claim 44, wherein the at least one prior systemic treatment regimen comprises immunotherapy, platinum-based chemotherapy or a combination thereof.

46. The use of any one of claims 1 to 45, wherein Compound (A) is provided on an intermittent dosing schedule.

47. The use of claim 46, wherein the intermittent dosing schedule comprises 5 days on, 2 days off in one or more dosing weeks.-58-WHAT IS CLAIMED IS:

1. Use of a combination of Compound (A) and:(i) Compound (B); or(ii) an antibody-drug conjugate comprising Compound (B) for treating a cancer in a subject, wherein:derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing; and the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target selected from the extracellular domain of human receptor tyrosine kinase-like orphan receptor 1 (R0R1), human epidermal growth factor receptor 3 (HER3), folate receptor alpha (FRa), cadherin 6 (CDH6), sodium-dependent phosphate transporter NaPi2b, tissue factor (TF or also known as platelet tissue factor, coagulation factor III (F3)) and CD142), mesothelin (MSLN), mucin 16 (MUC16 or also known as ovarian cancer-related tumor marker CAI 25), protein tyrosine kinase 7 (PTK7), receptor tyrosine kinase AXL (AXL), antigen CD166 (CD166), ectonucleotide pyrophosphatase / phosphodiesterase family member 3 (ENPP3), T-cell immunoglobulin and mucin domain 1 (TIM-1), cluster of differentiation 70 (CD70, also known as CD27L), B7 homolog 3 (B7-H3, also known as CD276), B7 homolog 4 (B7-H4), trophoblast cell surface antigen 2 (TROP2), Nectin-4, CD22, CD30, CD79b, CD 19, B-cell maturation antigen (BCMA), mucin short variant SI (MUC1), Claudin 18.2 (CLDN 18.2),-47-carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), c-Met tyrosine kinase (c-Met). interleukin-3 receptor (CD 123). epidermal growth factor receptor (EFGR) and a combination thereof.

2. Use of a combination of Compound (A) and an antibody-drug conjugate comprising Compound (B) for treating a cancer in a subject, wherein:derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing; and the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target selected from the extracellular domain of human receptor tyrosine kinase-like orphan receptor 1 (R0R1), human epidermal growth factor receptor 3 (HER3), folate receptor alpha (FRa), cadherin 6 (CDH6), sodium-dependent phosphate transporter NaPi2b, tissue factor (TF or also known as platelet tissue factor, coagulation factor III (F3)) and CD142), mesothelin (MSLN), mucin 16 (MUC16 or also known as ovarian cancer-related tumor marker CAI 25), protein tyrosine kinase 7 (PTK7), receptor tyrosine kinase AXL (AXL), antigen CD166 (CD166), ectonucleotide pyrophosphatase / phosphodiesterase family member 3 (ENPP3), T-cell immunoglobulin and mucin domain 1 (TIM-1), cluster of differentiation 70 (CD70, also known as CD27L), B7 homolog 3 (B7-H3, also known as CD276), B7 homolog 4 (B7-H4), trophoblast cell surface antigen 2 (TROP2), Nectin-4, CD22, CD30, CD79b, CD 19, B-cell maturation antigen (BCMA), mucin short variant SI (MUC1), Claudin 18.2 (CLDN 18.2),-49-carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), c-Met tyrosine kinase (c-Met). interleukin-3 receptor (CD123), epidermal growth factor receptor (EFGR) and a combination thereof.

3. The use of claim 1 or 2, wherein the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target selected from human epidermal growth factor receptor 3 (HER3), cadherin 6 (CDH6), trophoblast cell surface antigen 2 (TR0P2), B7 homolog 3 (B7-H3, also known as CD276) and a combination thereof.

4. Use of a combination of Compound (A) and an antibody-drug conjugate comprising Compound (B) for treating a cancer in a subject, wherein:derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing; and the antibody-drug conjugate comprises an antibody or an antigen-binding fragment thereof that specifically binds to a target selected from human epidermal grow th factor receptor 3 (HER3), cadherin 6 (CDH6), trophoblast cell surface antigen 2 (TR0P2), B7 homolog 3 (B7-H3, also known as CD276) and a combination thereof.

5. The use of any one of claims 1 to 4, wherein Compound (B) is topotecan or a derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing.

6. The use of any one of claims 1 to 4, wherein Compound (B) is irinotecan or a derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing.

7. The use of any one of claims 1 to 4, wherein Compound (B) is SN-38 or a derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing.

8. The use of any one of claims 1 to 4. wherein Compound (B) is govitecan, or a pharmaceutically acceptable salt thereof.

9. The use of any one of claims 1 to 4, wherein Compound (B) is exatecan or a derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing.

10. The use of any one of claims 1 to 4, wherein Compound (B) deruxtecan, or a pharmaceutically acceptable salt thereof.

11. The use of any one of claims 1 to 4, 7 or 8, wherein the antibody-drug conjugate is represented by the following structural formula:or a pharmaceutically acceptable salt thereof, wherein:Ab is the antibody or an antigen-binding fragment thereof; and n represents an average number of govitecan compounds conjugated to a single Ab and is in a range of about 1 to about 10.

12. The use of any one of claims 1 to 4, 9 or 10, wherein the antibody-drug conjugate is represented by the following structural formula:or a pharmaceutically acceptable salt thereof, wherein:-52-Ab is an antibody or an antigen-binding fragment thereof; and n represents an average number of deruxtecan compounds conjugated to a single Ab and is in a range of about 1 to about 10.

13. The use of any one of claims 1 to 12, wherein the antibody or an antigenbinding fragment thereof comprises:(a) a heavy chain CDRH1 comprising SEQ ID NOT; a heavy chain CDRH2 comprising SEQ ID NO:2; and a heavy chain CDRH3 comprising SEQ ID NO:3; and(b) a light chain CDRL1 comprising SEQ ID NO:4; a light chain CDRL2 comprising SEQ ID NO:5; and a light chain CDRL3 comprising SEQ ID NO:6.

14. The use of any one of claims 1 to 13, wherein the antibody or an antigenbinding fragment thereof comprises a heavy chain comprising SEQ ID NO:7 and a light chain comprising SEQ ID NO: 8.

15. The use of any one of claims 1 to 12, wherein the antibody or an antigenbinding fragment thereof comprises:(a) a heavy chain CDRH1 comprising SEQ ID NO:9; a heavy chain CDRH2 comprising SEQ ID NOTO; and a heavy chain CDRH3 comprising SEQ ID NO: 11; and(b) a light chain CDRL1 comprising SEQ ID NO: 12; a light chain CDRL2 comprising SEQ ID NO: 13; and a light chain CDRL3 comprising SEQ ID NO: 14.

16. The use of any one of claims 1 to 12 or 15, wherein the antibody or an antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO: 15 and a light chain comprising SEQ ID NO: 1 .

17. The use of any one of claims 1 to 12, wherein the antibody or an antigenbinding fragment thereof comprises:(a) a heavy chain CDRH1 comprising SEQ ID NO: 17; a heavy chain CDRH2 comprising SEQ ID NO: 18; and a heavy chain CDRH3 comprising SEQ ID NO: 19; and(b) a light chain CDRL1 comprising SEQ ID NO:20; a light chain CDRL2 comprising SEQ ID NO:21; and a light chain CDRL3 comprising SEQ ID NO:22.

18. The use of any one of claims 1 to 12 or 17, wherein the antibody or an antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO:23 and a light chain comprising SEQ ID NO:24.

19. The use of any one of claims 1 to 12, wherein the antibody or an antigenbinding fragment thereof comprises:(a) a heavy chain CDRH1 comprising SEQ ID NO:25; a heavy chain CDRH2 comprising SEQ ID NO:26; and a heavy chain CDRH3 comprising SEQ ID NO:27; and-53-(b) a light chain CDRL1 comprising SEQ ID NO:28; a light chain CDRL2 comprising SEQ ID NO:29; and a light chain CDRL3 comprising SEQ ID NO:30.

20. The use of any one of claims 1 to 12 or 19, wherein the antibody or an antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO: 31 and a light chain comprising SEQ ID NO:32.

21. The use of any one of claims 1 to 12, wherein the antibody or an antigenbinding fragment thereof comprises:(a) a heavy chain CDRH1 comprising SEQ ID NO:33; a heavy chain CDRH2 comprising SEQ ID NO:34; and a heavy chain CDRH3 comprising SEQ ID NO:35; and(b) a light chain CDRL1 comprising SEQ ID NO:36; a light chain CDRL2 comprising SEQ ID NO:37; and a light chain CDRL3 comprising SEQ ID NO:38.

22. The use of any one of claims 1 to 12 or 21, wherein the antibody or an antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO:39 and a light chain comprising SEQ ID NO:40.

23. Use of a combination of Compound (A) and an antibody-drug conj ugate for treating a cancer in a subject, wherein:Compound (pharmaceutically acceptable salt thereof; and the antibody-drug conjugate is represented by the following structural formula:-54-or a pharmaceutically acceptable salt thereof, wherein:Ab is an antibody or an antigen-binding fragment thereof that comprises:(a) a heavy chain CDRH1 comprising SEQ ID NO: 1; a heavy chain CDRH2 comprising SEQ ID NO:2; and a heavy chain CDRH3 comprising SEQ ID NO:3; and(b) a light chain CDRL1 comprising SEQ ID NO:4; a light chain CDRL2 comprising SEQ ID NO:5; and a light chain CDRL3 comprising SEQ ID NO:6; and n is in a range of about 1 to about 10.

24. Use of a combination of Compound (A) and an antibody-drug conjugate for treating a cancer in a subject, wherein:acceptable salt thereof; and the antibody-drug conjugate is represented by the following structural formula:or a pharmaceutically acceptable salt thereof, wherein:Ab is an antibody or an antigen-binding fragment thereof that comprises:(a) a heavy chain CDRH1 comprising SEQ ID NO:9; a heavy chain CDRH2 comprising SEQ ID NOTO; and a heavy chain CDRH3 comprising SEQ ID NO: 11; and(b) a light chain CDRL1 comprising SEQ ID NO: 12; a light chain CDRL2 comprising SEQ ID NO:13; and a light chain CDRL3 comprising SEQ ID NO:14; and n is in a range of about 1 to about 10.

25. The use of any one of claims 1 to 24, wherein the cancer is selected from a brain cancer, a cervicocerebral cancer, an esophageal cancer, a thyroid cancer, a small cell cancer, a non-small cell cancer, a breast cancer, a lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), a stomach cancer, a urothelial cancer, a gallbladder / bile duct cancer, a kidney cancer (e.g. , renal cell carcinoma), a liver cancer, a pancreatic cancer, a colon cancer, a rectal cancer, a colorectal cancer, an ovarian cancer (e.g., epithelial ovarian cancer), a fallopian tube cancer, a primary peritoneal cancer, an uterine cancer, a choriocarcinoma, an uterus body cancer, an uterocervical cancer, a renal pelvis / ureter cancer, a bladder cancer, a prostate cancer, a penis cancer, a testicular cancer, a fetal cancer, Wilms' cancer, a skin cancer, malignant melanoma, a neuroblastoma, an osteosarcoma, an Ewing's tumor, a soft part sarcoma, an acute leukemia, a chronic lymphatic leukemia, a chronic myelocytic leukemia, polycythemia vera, a malignant lymphoma, multiple myeloma, a Hodgkin's lymphoma and a non-Hodgkin’s lymphoma.

26. The use of any one of claims 1 to 25. wherein the cancer is a breast cancer.

27. The use of claim 25 or 26, wherein the breast cancer has a hormone receptor (HR)-positive (HR+) status.

28. The use of claim 25 or 26, wherein the breast cancer has a hormone receptor (HR)-low (HRlow) status.

29. The use of claim 25 or 26, wherein the breast cancer has a hormone receptor (HR)-positive (HR+) status.

30. The use of any one of claims 25 to 29, wherein the breast cancer has a HER2 -negative (HER-) status.

31. The use of any one of claims 25 to 29, wherein the breast cancer has a HER2 -positive (HER+) status.

32. The use of any one of claims 25 to 30, wherein the breast cancer is triple negative breast cancer (TNBC).

33. The use of any one of claims 25 to 32, wherein the breast cancer has a TROP2-low (TROP2low) status.

34. The use of any one of claims 25 to 32, wherein the breast cancer has a TROP2-high (TROP2hl"h) status.

35. The use of any one of claims 1 to 25, wherein the cancer is a urothelial cancer.

36. The use of any one of claims 1 to 25, wherein the cancer is a non-small cell lung cancer (NSCLC).

37. The use of any one of claims 1 to 25, wherein the cancer is a neuroblastoma.

38. The use of any one of claims 1 to 25, wherein the cancer is a colorectal cancer (CRC).

39. The use of any one of claims 1 to 25, wherein the cancer is a renal cell carcinoma.

40. The use of any one of claims 1 to 25, wherein the cancer is an ovarian cancer.

41. The use of claim 40, wherein the ovarian cancer is high-grade serous ovarian carcinoma (HGSOC).

42. The use of claim 40 or 41, wherein the ovarian cancer has a Cyclin Ellowstatus.

43. The use of any one of claims 1 to 42, wherein the cancer has one or more mutations in a gene selected from TP 53, PIK3CA, BRAF, BRCA1, BRCA2, PTEN, KRAS and RBI.

44. The use of any one of claims 1 to 43, wherein the subject has received at least one prior systemic treatment regimens (e. , one to three prior systemic treatment regimens).-57-45. The use of claim 44, wherein the at least one prior systemic treatment regimen comprises immunotherapy, platinum-based chemotherapy or a combination thereof.

46. The use of any one of claims 1 to 45, wherein Compound (A) is provided on an intermittent dosing schedule.

47. The use of claim 46, wherein the intermittent dosing schedule comprises 5 days on, 2 days off in one or more dosing weeks.-58-

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