Use of combination of antibody-drug conjugate targeting nectin-4 and immune checkpoint inhibitor

Abstract

Provided are a product and method of a combination of an antibody-drug conjugate targeting Nectin-4 or a pharmaceutically acceptable salt, ester, solvate, tautomer, or stereoisomer thereof and an immune checkpoint inhibitor for treating cancer, and related use.

Description

Use of combination of antibody-drug conjugates targeting Nectin-4 and immune checkpoint inhibitors

[0001] Citation of relevant applications

[0002] This application claims priority to Chinese Patent Application No. 202410892343.7, filed on July 4, 2024, the entire contents of which are incorporated herein by reference and used for all purposes. Technical Field

[0003] This application relates to the field of biopharmaceuticals, and more specifically, to products, methods, and related applications of an antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer, in combination with an immune checkpoint inhibitor for the treatment of cancer. Background Technology

[0004] Nectin is a novel cell adhesion molecule belonging to the immunoglobulin superfamily, which can adhere independently of calcium. 2+ Nectin proteins participate in cell-cell interactions and form cell-cell adhesion junctions. The Nectin protein family has four members: Nectin-1, Nectin-2, Nectin-3, and Nectin-4. Nectin-1 and Nectin-3 are widely expressed in normal human tissues. Nectin-1 and Nectin-2 are commonly found in immune organs (bone marrow, thymus, spleen, and lymph nodes), while Nectin-3 is mainly expressed in the testes and placenta. Unlike other members of the Nectin family, which are widely expressed in normal human tissues, Nectin-4 is highly expressed in normal embryonic and fetal tissues, but very low in healthy adult tissues. Abnormally high expression of Nectin-4 can be detected in various cancer samples; therefore, Nectin-4 is a reliable biomarker for many cancers, especially urothelial carcinoma, cervical cancer, breast cancer, lung cancer, and pancreatic cancer.

[0005] As a member of the Nectin protein family, Nectin-4 is a type I transmembrane immunoglobulin-like cell adhesion molecule that participates in the formation of cell-cell adhesion junctions, mediates cell-cell connections, and participates in regulating physiological processes such as cell proliferation, differentiation, and migration. Although the exact molecular mechanisms in tumorigenesis and progression are not yet clear, multiple studies have shown that Nectin-4 can induce angiogenesis, promote cancer cell proliferation and migration, and induce epithelial-mesenchymal transition, and is associated with the progression of various cancers.

[0006] Based on the expression patterns and levels of Nectin-4, it has become an attractive target for research in the treatment of various cancer diseases. To date, drug development targeting Nectin-4 has primarily involved ADCs, bicyclic peptide conjugates, bicyclic peptides, monoclonal antibodies, and chimeric antigen receptor T-cell immunotherapy.

[0007] Currently, the only marketed product targeting Nectin-4 is an ADC (antibody-adjuvant drug), Enfortumab vedotin, jointly developed by Astellas and Seagen. Hereinafter referred to as "EV"), as a monotherapy, was fully approved by the FDA in 2021 for patients with locally advanced or metastatic urothelial carcinoma who are unsuitable for cisplatin-based chemotherapy and have previously received ≥1 prior therapy. It is worth noting that EV is also associated with numerous adverse events, including rash, peripheral neuropathy, and fatigue. EV can cause serious and fatal skin adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). These skin adverse reactions primarily occur in the first cycle of treatment but can also occur in subsequent cycles and are indicated by a black box warning.

[0008] PD-1 (Programmed cell death protein 1) is a cell surface receptor belonging to the immunoglobulin superfamily, expressed on T cells and pre-B cells. It plays a role in regulating the immune system's response to human cells by downregulating the immune system and promoting self-tolerance, thus preventing autoimmune diseases. PD-L1 (Programmed death ligand 1) is a ligand of PD-1. After binding to PD-1 on T cells, it inhibits T cell proliferation and activation, rendering T cells inactive. Studies have found that PD-L1 is upregulated in various tumor cells, thus promoting tumor immune escape. PD-1 monoclonal antibodies (PD-1 mAbs) can bind to PD-1 on the surface of T cells, blocking the binding of PD-1 and PD-L1, thereby upregulating T cell growth and proliferation, enhancing T cell recognition of tumor cells, activating their attack and killing functions, and achieving anti-tumor effects by mobilizing the body's own immune function.

[0009] Furthermore, although immune checkpoint inhibitors (CPIs) have become the standard treatment for many different cancer indications in recent years, the vast majority of patients do not experience remission after CPI monotherapy.

[0010] Solid tumors, especially advanced solid tumors, urgently require more effective treatments in clinical practice. Taking urothelial carcinoma as an example, after failure of first-line treatment and recurrence, the median survival time is 5-7 months, and there is currently no standard treatment in Chinese clinical practice. In current Chinese clinical practice, platinum-based chemotherapy remains the primary first-line treatment for advanced urothelial carcinoma, but a standard second-line treatment is lacking. Platinum-based treatments, especially cisplatin, are poorly tolerated, and many patients cannot undergo long-term treatment. Therefore, there is an urgent need to develop effective first- and second-line treatment regimens for advanced solid tumors, particularly urothelial carcinoma. Summary of the Invention

[0011] Firstly, the purpose of this application is to provide the use of an antibody-drug conjugate targeting Nectin-4, or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer, in combination with an immune checkpoint inhibitor in the preparation of a medicament for treating cancer, wherein the antibody-drug conjugate targeting Nectin-4 is formed by conjugating a drug-linker represented by Formula I with an antibody targeting Nectin-4 or its antigen-binding fragment:

[0012] Secondly, this application also aims to provide the use of an antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer in the preparation of a drug for the treatment of cancer in combination with an immune checkpoint inhibitor, wherein the antibody-drug conjugate targeting Nectin-4 is formed by conjugating a drug-linker represented by Formula I with an antibody targeting Nectin-4 or its antigen-binding fragment:

[0013] Thirdly, the purpose of this application is to provide a method for treating cancer by combining an antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer with an immune checkpoint inhibitor, wherein the antibody-drug conjugate targeting Nectin-4 is formed by conjugating a drug-linker represented by Formula I with an antibody targeting Nectin-4 or its antigen-binding fragment:

[0014] Fourthly, the purpose of this application is to provide a drug combination (also referred to as a "combination drug") for treating cancer, the drug combination comprising (i) an antibody-drug conjugate targeting Nectin-4 or a pharmaceutical salt, ester, solvate, tautomer or stereoisomer thereof and (ii) an immune checkpoint inhibitor, wherein the antibody-drug conjugate targeting Nectin-4 is formed by conjugating a drug-linker represented by Formula I with an antibody targeting Nectin-4 or an antigen-binding fragment thereof:

[0015] Fifthly, the purpose of this application is to provide an antibody-drug conjugate targeting Nectin-4 or a pharmaceutical salt, ester, solvate, tautomer, or stereoisomer thereof, for use in combination with an immune checkpoint inhibitor to treat cancer, wherein the antibody-drug conjugate targeting Nectin-4 is formed by conjugating a drug-linker represented by Formula I with an antibody targeting Nectin-4 or an antigen-binding fragment thereof:

[0016] Sixthly, the purpose of this application is to provide an immune checkpoint inhibitor for the treatment of cancer in combination with an antibody-drug conjugate targeting Nectin-4 or a pharmaceutical salt, ester, solvate, tautomer, or stereoisomer thereof, wherein the antibody-drug conjugate targeting Nectin-4 is formed by conjugating a drug-linker of Formula I with an antibody or antigen-binding fragment targeting Nectin-4:

[0017] Brief description of the attached figures

[0018] Figure 1 shows a schematic diagram of the antibody-drug conjugate used in the embodiments of this application, where LND1002 represents the linker + drug molecule portion, and the circled portion indicates the amide bond connection between the linker in L&D and the antibody. The Nectin-4 ADC shown in the figure is a site-specific antibody-drug conjugate. Each molecule consists of one anti-Nectin-4 monoclonal antibody coupled to an amino acid at position Q295 (EU number) of each heavy chain via a linker portion (-NH-(CH2-CH2-O)3-CH2-C(=O)-Val-Cit-pABC-). The connection between one MMAE antibody molecule and the linker portion is a stable amide bond (isopeptide bond), and the average drug-to-antibody ratio (DAR) is 2.0.

[0019] Figure 2 shows the change in tumor diameter from baseline at assessment in 39 evaluable first-line urothelial carcinoma cases. Detailed Implementation

[0020] The specific implementation schemes and embodiments listed below are for the purpose of better illustrating the content of this application, but are not intended to limit the content of this application to the specific implementation schemes and embodiments described. Any non-essential improvements and adjustments made to the implementation schemes by those skilled in the art based on the above-described invention shall still fall within the protection scope of this application.

[0021] Terminology Definition

[0022] Unless otherwise defined, all technical terms used herein have the same meaning as understood by one of ordinary skill in the art. The abbreviations for amino acid residues are the standard 3-letter and / or 1-letter codes used in the art to refer to one of the 20 commonly used L-amino acids.

[0023] Although the numerical ranges and parameter approximations shown in the broad scope of this application are intended to be as accurate as possible in the specific embodiments, any numerical value inherently contains a certain degree of error due to the standard deviation present in their respective measurements. Furthermore, all ranges disclosed herein should be understood to encompass any and all subranges contained therein. For example, the stated range “1 to 10” should be considered to include any and all subranges between the minimum value of 1 and the maximum value of 10 (inclusive); that is, all subranges beginning with a minimum value of 1 or greater, such as 1 to 6.1, and subranges ending with a maximum value of 10 or less, such as 5.5 to 10. Additionally, any references marked “incorporated herein” should be understood to be incorporated herein in their entirety.

[0024] Unless otherwise stated, as used herein, the singular forms “a,” “an,” and “the” also include the plural forms. For example, the term “a cell” includes multiple cells and mixtures thereof.

[0025] As used herein, the term "about" refers to the typical range of error for various values ​​that is readily known to those skilled in the art. The use of the term "about" in this document includes (and describes) embodiments involving that value or parameter itself.

[0026] As used herein, the terms "comprising" or "including" mean including the stated elements, integers, or steps, but do not exclude any other elements, integers, or steps. In this application, when the terms "comprising" or "including" are used, unless otherwise specified, they also cover situations consisting of the stated elements, integers, or steps. For example, when referring to an antibody variable region "comprising" a specific sequence, it is also intended to cover antibody variable regions consisting of that specific sequence.

[0027] As used herein, the term "cancer" refers to a proliferative disorder caused by or characterized by cell proliferation, in which cells have lost their susceptibility to normal growth control. The term "cancer" includes tumors and any other proliferative disorder. Cancers of the same tissue type originate in the same tissue and can be classified into different subtypes based on their biological characteristics.

[0028] As used herein, the term "treatment" refers to a clinical intervention aimed at altering the natural course of the disease in the individual or cells receiving the treatment during the clinicopathological process. Ideal outcomes of treatment include slowing or reducing the rate of disease progression, improving or alleviating the disease state, and mitigating or improving prognosis. For example, if one or more symptoms associated with cancer are relieved or eliminated, including but not limited to reducing the proliferation of cancer cells (or eliminating cancer cells), reducing symptoms caused by the disease, improving the patient's quality of life, reducing the dosage of other medications required to treat the disease, slowing disease progression, and / or prolonging the patient's survival, then the patient has been successfully "treated."

[0029] In this application, "Nectin-4 positive tumor" is understood in the conventional sense in the art, generally referring to tumor cells expressing Nectin-4 at least in a subset. The degree of Nectin-4 positivity in a tumor can be qualitatively, quantitatively, or semi-quantitatively analyzed using various methods in the art. One exemplary method is immunohistochemical analysis of solid tumor samples (e.g., biopsy or postoperative sections), expressed semi-quantitatively as an H-score. The H-score can be represented by a weighted sum of cell staining percentages for Nectin-4 expression in tumor cells: H-score = (3x percentage of strongly stained cells) + (2x percentage of moderately stained cells) + (1x percentage of weakly stained cells).

[0030] As used in this article, the term "neoadjuvant therapy" refers to a treatment administered to cancer patients prior to surgery or radical radiotherapy. The aim of this treatment is to reduce tumor size and stage through methods such as chemotherapy, radiotherapy, targeted therapy, or immunotherapy, thereby increasing the success rate and cure rate of surgery and improving patient prognosis.

[0031] As used in this article, the term "adjuvant therapy" refers to treatments administered to cancer patients after surgery or radical radiotherapy, with the primary aim of improving the effectiveness of the surgery or radiotherapy, reducing the risk of recurrence, or improving the patient's quality of life and prognosis.

[0032] As used in this article, the term "locally advanced" usually refers to cancer that has progressed to a relatively advanced stage in a local area, but has not yet metastasized to distant sites.

[0033] In a broad sense, "antibody" can refer to any immunoglobulin molecule capable of specifically binding to a target via at least one antigen recognition site located in the variable region of an immunoglobulin molecule. Therefore, it encompasses complete / full-length antibodies, single-chain antibodies, or any antigen-binding fragment of an antibody (also known as an "antigen-binding moiety"). When "antibody" and "antigen-binding fragment" appear in the same context, "antibody" can be understood as the complete entity relative to the "antigen-binding fragment," both corresponding to the broad concept of antibody. In this document, the term "antibody" includes monoclonal antibodies (including full-length antibodies with the Fc region of an immunoglobulin), antibodies with multi-epitope specificity, multispecific antibodies (such as bispecific antibodies), dimers and single-chain antibodies, as well as antibody fragments (including antigen-binding fragments such as Fab fragments, F(ab')2 fragments, Fab' fragments, Fv fragments, dsFv fragments, or scFv fragments).

[0034] As used herein, the term "full-length antibody" refers to a complete or substantially complete antibody, as opposed to an antibody fragment. Specifically, full-length antibodies include those containing both a heavy chain and a light chain, including an Fc region. The constant domain can be a native sequence constant domain (e.g., a human native sequence constant domain) or a variant of its amino acid sequence. In some cases, a complete antibody possesses one or more effector functions.

[0035] As used herein, the antibody-related terms “heavy chain” or “HC” are used interchangeably in this application.

[0036] As used herein, the antibody-related terms “light chain” or “LC” are used interchangeably in this application.

[0037] As used herein, the antibody-related terms “heavy chain constant region” or “CH” are used interchangeably in this application.

[0038] As used herein, the antibody-related terms “light chain constant region” or “CL” are used interchangeably in this application.

[0039] As used in this article, the antibody-related term "heavy chain variable region (VH)" refers to the amino-terminal variable region domain of the immunoglobulin heavy chain.

[0040] As used in this article, the antibody-related term "light chain variable region (VL)" refers to the amino-terminal variable region domain of the immunoglobulin light chain.

[0041] As used herein, the antibody-related term "CDR (Complementarity Determinant Region)" refers to the amino acid sequence that together defines the binding affinity and specificity of the Fv region of an antibody. This is because antibody specificity depends on the structural complementarity between the antibody binding site and the antigenic determinant. The antibody binding site is composed primarily of residues from the so-called hypervariable region or complementarity determinant (CDR). The light chain (L) and heavy chain (H) of an antibody each have three CDRs, named CDR1-L, CDR2-L, CDR3-L and CDR1-H, CDR2-H, CDR3-H, respectively. Therefore, the antigen-binding site of a conventional antibody comprises six CDRs, containing a set of CDRs from each of the variable regions of the heavy chain and the light chain.

[0042] In some instances of this application, the amino acid sequence of the CDR is as shown in the IMGT definition rules. However, it is well known to those skilled in the art that the CDR of an antibody can be defined in various ways, such as the Kabat definition rules based on sequence variability (see, Kabat et al., Protein Sequences in Immunology, 5th Edition, National Institutes of Health, Bethesda, Maryland (1991)) and the Chothia definition rules based on the location of the structural loop region (see J.Mol. Biol. 273:927-48, 1997). It will be understood by those skilled in the art that, unless otherwise specified, the terms “CDR” and “complementarity-determining region” for a given antibody or its region (e.g., a variable region) should be understood to encompass the complementarity-determining region defined as described in any of the known schemes described above.

[0043] As used herein, "solvent" refers to the physical association of the antibody-drug conjugate of this application with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. Solvent molecules in a solvate may be present in a regular and / or disordered arrangement. A solvate may contain stoichiometric or non-stoichiometric solvent molecules. "Solvent" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0044] The pharmaceutical salts of the compounds described herein are synthesized by conventional chemical methods from parent compounds containing a basic or acidic moiety. Typically, such salts are prepared, for example, by reacting the free acidic or basic form of these compounds with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture of both. Non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile are generally preferred. Examples of acid addition salts include inorganic acid addition salts such as, for example, hydrochlorides, hydrobroms, hydroiodates, sulfates, nitrates, and phosphates, and organic acid addition salts such as, for example, acetates, trifluoroacetates, maleates, fumarates, citrates, oxalates, succinates, tartrates, malates, mandelates, methanesulfonates, and p-benzenesulfonates. Examples of base addition salts include inorganic salts such as, for example, sodium salts, potassium salts, calcium salts, and ammonium salts, and organic base salts such as, for example, ethylenediamine, ethanolamine, N,N-dialkylethanolamine, triethanolamine, and basic amino acid salts.

[0045] The pharmaceutical esters used in the antibody-drug conjugates of this application are not particularly limited and can be selected by those skilled in the art. In the case of said ester, it is preferred that such esters can be cleaved by biological processes such as in vivo hydrolysis. The groups constituting said ester (groups indicated by R when its ester is represented as -COOR) can be, for example, C1-C4 alkoxy-C1-C4 alkyl groups such as methoxyethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-(isopropoxy)ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, or tert-butoxymethyl, etc.

[0046] The geometric isomers (i.e., cis and trans isomers) of the antibody-drug conjugates of this application exist as tautomers or as transisomers. Specifically, the term tautomer refers to one of two or more structural isomers of a compound that exist in equilibrium and readily transform from one isomer to another. Common tautomer pairs are amine-imine, amide-imine, ketone-enol, lactam-lactamimide, etc.

[0047] The term "stereoisomer" refers to compounds that have the same chemical structure but differ in the spatial arrangement of their atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and inhibited isomers. Any mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0048] As used herein, the term "unit dosage form" refers to the smallest unit of packaging of each pharmaceutical preparation containing an appropriate amount of the active compound. For example, a unit dosage form in capsules refers to one capsule, a unit dosage form in tablets refers to one tablet, a unit dosage form in injections refers to one vial of injection, and so on for other types of preparations.

[0049] As used in this article, the term "objective response rate (ORR)" is the proportion of patients who achieved a complete response (CR) or partial response (PR) at the optimal time point, as evaluated according to RECIST v1.1 criteria, out of the total number of evaluable cases.

[0050] As used in this article, the term “Disease Control Rate (DCR)” is the proportion of patients with a CR, PR, or stable disease (SD) at the optimal time point (i.e., CR+PR+SD) as evaluated according to RECIST v1.1 criteria, out of the total number of evaluable cases.

[0051] As used in this article, the term “progression-free survival (PFS)” is defined as the time between the start of treatment with the investigational drug and the date of first recorded PD or death, whichever comes first.

[0052] As used in this article, the term “duration of response (DOR)” is the time from the first assessment of a tumor as CR or PR to the first assessment of disease progression (PD) or death from any cause.

[0053] As used in this article, the term "overall survival (OS)" is defined as the time between the start of treatment with the investigational drug and the date of death.

[0054] In this invention, according to the Recognition of Clinical Efficacy in Solid Tumors (RECIST) v1.1, the term "Best of Response (BOR)" is defined as the best overall response across all time points. When complete response (CR) / partial response (PR) does not require confirmation: a patient who is assessed as having stable disease (SD) in the first cycle, partial response (PR) in the second cycle, and progressive disease (PD) in the last cycle has a BOR assessment of PR. When the BOR assessment is SD, it must meet the minimum time requirement specified in the protocol from baseline. If the minimum time requirement is not met, even if the BOR assessment is SD, it is not recognized, and the patient's BOR will be determined based on subsequent assessments. For example: a patient who is assessed as SD in the first cycle and PD in the second cycle, but does not meet the minimum time requirement for SD, has a BOR assessment of PD. Similarly, patients who are assessed as SD in the first cycle and then lost to follow-up will be considered unevaluable; when complete response (CR) / partial response (PR) needs to be confirmed: a complete or partial response can only be confirmed if the patient meets the criteria for partial or complete response and the efficacy is confirmed again at a subsequent time point (usually four weeks later).

[0055] As used herein, the terms “Treatment Emergent Adverse Events” or “TEAE” or “AE” mean any unfavorable, unexpected sign (including laboratory abnormalities), symptom, or illness that is related to the use of a medical or therapeutic procedure and may be temporally considered to be related to the medical or therapeutic procedure. The terms “serious adverse event” and “SAE” are used interchangeably. The terms “adverse events of special interest” and “AESI” are used interchangeably. The terms “immune-related adverse events” and “irAE” are used interchangeably. The foregoing terms are defined according to NCI CTCAE v5.0.

[0056] As used herein, the terms “QW” indicate application once a week, “Q2W” indicate application once every two weeks, “Q3W” indicate application once every three weeks, “Q4W” indicate application once every four weeks, “Q5W” indicate application once every five weeks, and “Q6W” indicate application once every six weeks.

[0057] In this application, the term "therapeutic effective amount" or "effective amount" means an amount that has a therapeutic effect on a subject, such as: in a subject who has been given the amount, the symptoms or state of the disease are alleviated, reduced, or eliminated, or the development of the symptoms or state of the disease is delayed or suppressed compared to a subject who has not been given the amount.

[0058] As used herein, the term "pharmaceutical composition" refers to a combination of at least one drug substance and optionally a pharmaceutically acceptable carrier or excipient, brought together to achieve a particular purpose. There are no particular limitations on the type of pharmaceutically acceptable carrier; suitable buffers, stabilizers, surfactants, etc., may be added according to pharmaceutical formulation techniques in the art. The type of pharmaceutically acceptable carrier used depends particularly on whether the composition according to this application is formulated for oral, nasal, intradermal, subcutaneous, intramuscular, or intravenous administration.

[0059] In this document, when referring to a “combination” of two or more drugs, the combined product is not limited to a specific product form, as long as it conforms to the product forms permitted for combination therapy in the pharmaceutical field. For example, the two or more drugs in the combination can be formulated together, for example, in the form of a pharmaceutical composition. Furthermore, the combination can also be provided as a drug kit, wherein the two or more drugs in the combination are physically separated (e.g., in different drug delivery containers) within the drug kit. Additionally, if the instructions for use of one of the two or more drugs in the combination specify its intended use in combination with the other drugs in the combination, this is equivalent to using or recommending the combination.

[0060] In general, the purpose of this application is to provide a product, method, and related application of an antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer in combination with an immune checkpoint inhibitor for the treatment of cancer. As observed in the embodiments of this application, the combination of the two drugs has produced a synergistic effect in the treatment of various cancers.

[0061] Firstly, the purpose of this application is to provide the use of an antibody-drug conjugate targeting Nectin-4, or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer, in combination with an immune checkpoint inhibitor in the preparation of a medicament for treating cancer, wherein the antibody-drug conjugate targeting Nectin-4 is formed by conjugating a drug-linker represented by Formula I with an antibody targeting Nectin-4 or its antigen-binding fragment:

[0062] Secondly, this application also aims to provide the use of an antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer in the preparation of a drug for the treatment of cancer in combination with an immune checkpoint inhibitor, wherein the antibody-drug conjugate targeting Nectin-4 is formed by conjugating a drug-linker represented by Formula I with an antibody targeting Nectin-4 or its antigen-binding fragment:

[0063] Thirdly, the purpose of this application is to provide a method for treating cancer, the method comprising administering to an individual in need an effective amount of (i) an antibody-drug conjugate targeting Nectin-4 or a pharmaceutical salt, ester, solvate, tautomer, or stereoisomer thereof and (ii) an immune checkpoint inhibitor, wherein the antibody-drug conjugate targeting Nectin-4 is formed by conjugating a drug-linker of Formula I to an antibody targeting Nectin-4 or an antigen-binding fragment thereof:

[0064] Fourthly, the purpose of this application is to provide a pharmaceutical combination for treating cancer, the pharmaceutical combination comprising (i) an antibody-drug conjugate targeting Nectin-4 or a pharmaceutical salt, ester, solvate, tautomer, or stereoisomer thereof, and (ii) an immune checkpoint inhibitor, wherein the antibody-drug conjugate targeting Nectin-4 is formed by conjugating a drug-linker represented by Formula I with an antibody targeting Nectin-4 or an antigen-binding fragment thereof:

[0065] Fifthly, the purpose of this application is to provide an antibody-drug conjugate targeting Nectin-4 or a pharmaceutical salt, ester, solvate, tautomer, or stereoisomer thereof, for use in combination with an immune checkpoint inhibitor to treat cancer, wherein the antibody-drug conjugate targeting Nectin-4 is formed by conjugating a drug-linker represented by Formula I with an antibody targeting Nectin-4 or an antigen-binding fragment thereof:

[0066] Sixthly, the purpose of this application is to provide an immune checkpoint inhibitor for the treatment of cancer in combination with an antibody-drug conjugate targeting Nectin-4 or a pharmaceutical salt, ester, solvate, tautomer, or stereoisomer thereof, wherein the antibody-drug conjugate targeting Nectin-4 is formed by conjugating a drug-linker of Formula I with an antibody or antigen-binding fragment targeting Nectin-4:

[0067] The following details specific embodiments or technical features of the inventions described in aspects one through six above. Generally, unless there is a contradiction or conflict, the specific embodiments or technical features described below apply to the inventions described in aspects one through six above. Furthermore, those skilled in the art will understand that although specific embodiments or technical features relating to administration regimens, frequencies, dosages, etc., are more relevant to inventions concerning treatment methods, these specific embodiments or technical features should also be understood to apply to inventions concerning products or uses.

[0068] In some embodiments, the antibody targeting Nectin-4 or its antigen-binding fragment includes a heavy chain variable region VH, which comprises three CDR regions: CDR1-H, CDR2-H, and CDR3-H. The CDR1-H, CDR2-H, and CDR3-H regions have or are amino acid sequences as shown in SEQ ID NO. 1, 2, and 3, respectively, wherein the CDRs are defined according to IMGT.

[0069] In some embodiments, the antibody targeting Nectin-4 or its antigen-binding fragment comprises a light chain variable region (VL) containing three CDR regions: CDR1-L, CDR2-L, and CDR3-L. The CDR1-L, CDR2-L, and CDR3-L regions have or are amino acid sequences as shown in SEQ ID NO. 4, 5, and 6, respectively, wherein the CDRs are defined according to IMGT.

[0070] In some embodiments, the antibody targeting Nectin-4 or its antigen-binding fragment comprises a heavy chain variable region VH and a light chain variable region VL. The heavy chain variable region VH comprises three CDR regions, namely CDR1-H, CDR2-H, and CDR3-H, each having an amino acid sequence as shown in SEQ ID NO. 1, 2, and 3, or their sequences being as shown in SEQ ID NO. 1, 2, and 3, respectively. The light chain variable region VL comprises three CDR regions, namely CDR1-L, CDR2-L, and CDR3-L, each having an amino acid sequence as shown in SEQ ID NO. 4, 5, and 6, or their sequences being as shown in SEQ ID NO. 4, 5, and 6, wherein the CDRs are defined according to IMGT.

[0071] In some embodiments, the antibody targeting Nectin-4 or its antigen-binding fragment comprises a heavy chain variable region VH, the heavy chain variable region VH comprising an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 7, or the amino acid sequence of the heavy chain variable region VH is the amino acid sequence shown in SEQ ID NO. 7.

[0072] In some embodiments, the antibody targeting Nectin-4 or its antigen-binding fragment comprises a light chain variable region VL, the light chain variable region VL comprising an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in any one of SEQ ID NO. 8-10, or the amino acid sequence of the light chain variable region VL is the amino acid sequence shown in any one of SEQ ID NO. 8-10.

[0073] In some embodiments, the antibody targeting Nectin-4 or its antigen-binding fragment comprises a heavy chain variable region VH and a light chain variable region VL, wherein the heavy chain variable region VH comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 7, or the amino acid sequence of the heavy chain variable region VH is the amino acid sequence shown in SEQ ID NO. 7, and the light chain variable region VL comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in any one of SEQ ID NO. 8-10, or the amino acid sequence of the light chain variable region VL is the amino acid sequence shown in any one of SEQ ID NO. 8-10.

[0074] In some embodiments, the antibody targeting Nectin-4 or its antigen-binding fragment comprises a heavy chain constant region CH, the heavy chain constant region CH comprising an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 11 or SEQ ID NO. 13, or the amino acid sequence of the heavy chain constant region CH is the amino acid sequence shown in SEQ ID NO. 11 or SEQ ID NO. 13.

[0075] In some embodiments, the antibody targeting Nectin-4 or its antigen-binding fragment comprises a light chain constant region CL, the light chain constant region CL comprising an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 12, or the amino acid sequence of the light chain constant region CL is the amino acid sequence shown in SEQ ID NO. 12.

[0076] In some embodiments, the antibody targeting Nectin-4 or its antigen-binding fragment comprises a heavy chain constant region CH and a light chain constant region CL. The heavy chain constant region CH comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 11 or SEQ ID NO. 13, or the amino acid sequence of the heavy chain constant region CH is the amino acid sequence shown in SEQ ID NO. 11 or SEQ ID NO. 13. The light chain constant region CL comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 12, or the amino acid sequence of the light chain constant region CL is the amino acid sequence shown in SEQ ID NO. 12.

[0077] In some embodiments, the antibody targeting Nectin-4 or its antigen-binding fragment comprises a heavy chain HC, the heavy chain HC comprising an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 25, or the amino acid sequence of the heavy chain HC is the amino acid sequence shown in SEQ ID NO. 25.

[0078] In some embodiments, the antibody targeting Nectin-4 or its antigen-binding fragment comprises a light chain LC, the light chain LC comprising an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 26, or the amino acid sequence of the light chain LC is the amino acid sequence shown in SEQ ID NO. 26.

[0079] In some embodiments, the antibody targeting Nectin-4 or its antigen-binding fragment comprises a heavy chain HC and a light chain LC, wherein the heavy chain HC comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 25, or the amino acid sequence of the heavy chain HC is the amino acid sequence shown in SEQ ID NO. 25, and the light chain LC comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 26, or the amino acid sequence of the light chain LC is the amino acid sequence shown in SEQ ID NO. 26.

[0080] In some embodiments, the antibody targeting Nectin-4 or its antigen-binding fragment is selected from murine antibodies, chimeric antibodies, or humanized antibodies.

[0081] In some implementations, the antigen-binding fragment of the antibody targeting Nectin-4 is a Fab fragment, an F(ab')2 fragment, a Fab' fragment, an Fv fragment, a dsFv fragment, or a scFv fragment.

[0082] In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody or its antigen-binding fragment, or an anti-PD-L1 antibody or its antigen-binding fragment.

[0083] In some embodiments, the antigen-binding fragment of the anti-PD-1 or anti-PD-L1 antibody is a Fab fragment, an F(ab')2 fragment, a Fab' fragment, an Fv fragment, a dsFv fragment, or a scFv fragment.

[0084] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain variable region VH, the heavy chain variable region VH comprising three CDR regions, namely CDR1-H, CDR2-H and CDR3-H regions, wherein the CDR1-H region has an amino acid sequence as shown in SEQ ID NO. 15 or 27, or the amino acid sequence of the CDR1-H region is as shown in SEQ ID NO. 15 or 27, the CDR2-H region has an amino acid sequence as shown in SEQ ID NO. 16 or 28, or the amino acid sequence of the CDR2-H region is as shown in SEQ ID NO. 16 or 28, and the CDR3-H region has an amino acid sequence as shown in SEQ ID NO. 17, or the amino acid sequence of the CDR3-H region is as shown in SEQ ID NO. 17.

[0085] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a light chain variable region VL, the light chain variable region VL comprising three CDR regions, namely CDR1-L, CDR2-L and CDR3-L regions, wherein the CDR1-L, CDR2-L and CDR3-L regions have amino acid sequences as shown in SEQ ID NO. 18, 19 and 20, or their amino acid sequences are as shown in SEQ ID NO. 18, 19 and 20, respectively.

[0086] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain variable region VH and a light chain variable region VL. The heavy chain variable region VH comprises three CDR regions: CDR1-H, CDR2-H, and CDR3-H. The CDR1-H region has the amino acid sequence shown in SEQ ID NO. 15 or 27, or the amino acid sequence of the CDR1-H region is as shown in SEQ ID NO. 15 or 27. The CDR2-H region has the amino acid sequence shown in SEQ ID NO. 16 or 28, or the amino acid sequence of the CDR2-H region is as shown in SEQ ID NO. 16 or 28. The CDR3-H region has the amino acid sequence shown in SEQ ID NO. 17, or the amino acid sequence of the CDR3-H region is as shown in SEQ ID NO. 18. The amino acid sequence shown in NO.17, wherein the light chain variable region VL comprises three CDR regions, namely CDR1-L region, CDR2-L region and CDR3-L region, wherein the CDR1-L region, CDR2-L region and CDR3-L region have amino acid sequences as shown in SEQ ID NO.18, 19 and 20, or their amino acid sequences are as shown in SEQ ID NO.18, 19 and 20, respectively.

[0087] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain variable region VH, the heavy chain variable region VH comprising an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 21, or the amino acid sequence of the heavy chain variable region VH is the amino acid sequence shown in SEQ ID NO. 21.

[0088] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a light chain variable region VL, the light chain variable region VL comprising an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 22, or the amino acid sequence of the light chain variable region VL is the amino acid sequence shown in SEQ ID NO. 22.

[0089] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain variable region VH and a light chain variable region VL, wherein the heavy chain variable region VH comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 21, or the amino acid sequence of the heavy chain variable region VH is the amino acid sequence shown in SEQ ID NO. 21, and the light chain variable region VL comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 22, or the amino acid sequence of the light chain variable region VL is the amino acid sequence shown in SEQ ID NO. 22.

[0090] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain HC, the heavy chain HC comprising an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 23, or the amino acid sequence of the heavy chain HC is the amino acid sequence shown in SEQ ID NO. 23.

[0091] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a light chain LC, the light chain LC comprising an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 24, or the amino acid sequence of the light chain LC is the amino acid sequence shown in SEQ ID NO. 24.

[0092] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain HC and a light chain LC, wherein the heavy chain HC comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 23, or the amino acid sequence of the heavy chain HC is the amino acid sequence shown in SEQ ID NO. 23, and the light chain LC comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 24, or the amino acid sequence of the light chain LC is the amino acid sequence shown in SEQ ID NO. 24.

[0093] In some embodiments, the antibody-drug conjugate targeting Nectin-4 is formed by conjugating a drug-linker of Formula I with an antibody targeting Nectin-4: Formula I, wherein the antibody targeting Nectin-4 comprises a heavy chain HC and a light chain LC, wherein the amino acid sequence of the heavy chain HC is as shown in SEQ ID NO.25, and the amino acid sequence of the light chain LC is as shown in SEQ ID NO.26; and wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, wherein the anti-PD-1 antibody comprises a heavy chain HC and a light chain LC, wherein the amino acid sequence of the heavy chain HC is as shown in SEQ ID NO.23, and the amino acid sequence of the light chain LC is as shown in SEQ ID NO.24.

[0094] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is an advanced solid tumor.

[0095] In some implementations, the cancer is selected from urothelial carcinoma, cervical cancer, esophageal cancer, head and neck cancer, breast cancer, and lung cancer.

[0096] In some embodiments, the cancer is urothelial carcinoma. In some embodiments, the urothelial carcinoma is renal pelvis cancer, ureteral cancer, bladder cancer, or urethral cancer.

[0097] In some embodiments, Nectin-4 expression is positive or negative in the tumor tissue of the cancer. In some embodiments, Nectin-4 expression is positive in the tumor tissue of the cancer. In some embodiments, Nectin-4 is not expressed, moderately expressed, highly expressed, or overexpressed in the tumor tissue of the cancer.

[0098] In some embodiments, the individual suffering from the cancer is a mammal. In some embodiments, the individual suffering from the cancer is a human patient.

[0099] In some embodiments, the cancer is a cancer that has not received systemic antitumor therapy. In some embodiments, the cancer is urothelial carcinoma, and the cancer is urothelial carcinoma that has not received systemic antitumor therapy.

[0100] In some embodiments, the cancer is cancer in which the time interval between the end of previous neoadjuvant or adjuvant therapy and disease progression exceeds 12 months. In some embodiments, the cancer is urothelial carcinoma, and the cancer is urothelial carcinoma in which the time interval between the end of previous neoadjuvant or adjuvant therapy and disease progression exceeds 12 months. In some embodiments, the cancer is urothelial carcinoma, and the neoadjuvant / adjuvant therapy is PD-1 or PD-L1 inhibitor therapy. In some embodiments, the cancer is urothelial carcinoma, the neoadjuvant / adjuvant therapy is PD-1 or PD-L1 inhibitor therapy, and the cancer is urothelial carcinoma in which the time interval between the end of previous neoadjuvant or adjuvant therapy and disease progression exceeds 12 months.

[0101] In some embodiments, the cancer is cancer in which the time interval between the end of prior neoadjuvant or adjuvant therapy and disease progression exceeds 6 months. In some embodiments, the cancer is urothelial carcinoma, and the cancer is urothelial carcinoma in which the time interval between the end of prior neoadjuvant or adjuvant therapy and disease progression exceeds 6 months. In some embodiments, the cancer is locally advanced cancer. In some embodiments, the cancer is locally advanced urothelial carcinoma. In some embodiments, the cancer is locally advanced urothelial carcinoma, and the cancer is locally advanced urothelial carcinoma that has not received systemic antitumor therapy.

[0102] In some embodiments, the cancer is metastatic cancer. In some embodiments, the cancer is metastatic urothelial carcinoma. In some embodiments, the cancer is metastatic urothelial carcinoma, and the cancer is metastatic urothelial carcinoma that has not received systemic antitumor therapy.

[0103] In some embodiments, the cancer is a cancer that has not previously been treated with a Nectin-4 antibody-drug conjugate containing MMAE toxin. In some embodiments, the cancer is urothelial carcinoma, and the cancer is urothelial carcinoma that has not previously been treated with a Nectin-4 antibody-drug conjugate containing MMAE toxin.

[0104] In some embodiments, the cancer is cancer that has not previously received PD-1 or PD-L1 inhibitor treatment. In some embodiments, the cancer is urothelial carcinoma, and the cancer is urothelial carcinoma that has not previously received PD-1 or PD-L1 inhibitor treatment.

[0105] In some embodiments, the cancer is cancer that has not previously received treatment with a Nectin-4 antibody conjugate containing MMAE toxin and has not received treatment with PD-1 or PD-L1 inhibitors. In some embodiments, the cancer is urothelial carcinoma, and the cancer is urothelial carcinoma that has not previously received treatment with a Nectin-4 antibody conjugate containing MMAE toxin and has not received treatment with PD-1 or PD-L1 inhibitors.

[0106] In some embodiments, the patient with the cancer has not received systemic antitumor therapy. In some embodiments, the cancer is urothelial carcinoma, and the patient with the cancer has not received systemic antitumor therapy.

[0107] In some embodiments, the time interval between the completion of neoadjuvant or adjuvant therapy and disease progression in the patient with the cancer is more than 12 months. In some embodiments, the cancer is urothelial carcinoma, and the time interval between the completion of neoadjuvant or adjuvant therapy and disease progression in the patient with the cancer is more than 12 months. In some embodiments, the neoadjuvant or adjuvant therapy is PD-1 or PD-L1 inhibitor therapy.

[0108] In some embodiments, the time interval between the completion of neoadjuvant or adjuvant therapy and disease progression in the patient with the cancer exceeds 6 months. In some embodiments, the cancer is urothelial carcinoma, and the time interval between the completion of neoadjuvant or adjuvant therapy and disease progression in the patient with the cancer exceeds 6 months.

[0109] In some embodiments, the cancer is locally advanced cancer. In some embodiments, the cancer is locally advanced urothelial carcinoma. In some embodiments, the cancer is locally advanced urothelial carcinoma, and the patient with the cancer has not received systemic antitumor therapy.

[0110] In some embodiments, the cancer is metastatic cancer. In some embodiments, the cancer is metastatic urothelial carcinoma. In some embodiments, the cancer is metastatic urothelial carcinoma, and the patient with the cancer has not received systemic antitumor therapy.

[0111] In some embodiments, the patient with the cancer has not previously received treatment with a Nectin-4 antibody-drug conjugate containing MMAE toxin. In some embodiments, the cancer is urothelial carcinoma, and the patient with the cancer has not previously received treatment with a Nectin-4 antibody-drug conjugate containing MMAE toxin.

[0112] In some embodiments, the patient with the cancer has not previously received PD-1 or PD-L1 inhibitor treatment. In some embodiments, the cancer is urothelial carcinoma, and the patient with the cancer has not previously received PD-1 or PD-L1 inhibitor treatment.

[0113] In some embodiments, the cancer is a patient who has not previously received treatment with a Nectin-4 antibody conjugate containing MMAE toxin and has not received treatment with PD-1 or PD-L1 inhibitors. In some embodiments, the cancer is urothelial carcinoma, and the patient has not previously received treatment with a Nectin-4 antibody conjugate containing MMAE toxin and has not received treatment with PD-1 or PD-L1 inhibitors.

[0114] In some embodiments, the antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer is administered at a dose range of about 0.03 mg / kg to about 20.0 mg / kg per administration. In some embodiments, the dose range is about 1.0 mg / kg to about 10.0 mg / kg per administration, preferably about 2.0 mg / kg to about 8.0 mg / kg per administration. In some embodiments, the dose range is about 1.8 mg / kg to about 4.5 mg / kg per administration, or about 2.5 mg / kg to about 3.0 mg / kg, or about 3.0 mg / kg to about 3.5 mg / kg, or about 3.5 mg / kg to about 4.0 mg / kg, or about 4.0 mg / kg to about 4.5 mg / kg per administration. In some implementations, the dosage per administration is approximately 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2.0 mg / kg, 2.1 mg / kg, 2.2 mg / kg, 2.3 mg / kg, 2.4 mg / kg, 2.5 mg / kg, 2.6 mg / kg, 2.7 mg / kg, 2.8 mg / kg, 2.9 mg / kg, etc. mg / kg, 3.0 mg / kg, 3.1 mg / kg, 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 5.0 mg / kg, 5.5 mg / kg, or 6.0 mg / kg, or a range of values ​​selected from any two points.

[0115] In some embodiments, the antibody-drug conjugate targeting Nectin-4, or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer, is administered at a frequency of QW, Q2W, Q3W, Q4W, Q5W, or Q6W. In some embodiments, the antibody-drug conjugate targeting Nectin-4, or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer, is administered at a frequency of Q2W or Q3W.

[0116] In some embodiments, the antibody-drug conjugate targeting Nectin-4, or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer, is administered at a dose of 0.2-4.5 mg / kg every two weeks. In some embodiments, the antibody-drug conjugate targeting Nectin-4, or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer, is administered at doses of 0.2 mg / kg, 0.6 mg / kg, 1.2 mg / kg, 1.8 mg / kg, 2.4 mg / kg, 2.7 mg / kg, 3.6 mg / kg, 4.0 mg / kg, 4.2 mg / kg, or 4.5 mg / kg every two weeks.

[0117] In some embodiments, the antibody-drug conjugate targeting Nectin-4, or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer, is administered at a dose of 0.2-4.5 mg / kg every 3 weeks. In some embodiments, the antibody-drug conjugate targeting Nectin-4, or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer, is administered at a dose of 0.2-4.5 mg / kg every 3 weeks for a 21-day cycle. In some embodiments, the antibody-drug conjugate targeting Nectin-4, or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer, is administered at doses of 0.2 mg / kg, 0.6 mg / kg, 1.2 mg / kg, 1.8 mg / kg, 2.7 mg / kg, 3.6 mg / kg, 4.0 mg / kg, 4.2 mg / kg, or 4.5 mg / kg every 3 weeks.

[0118] In some embodiments, the antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer may be administered for one or more dosing cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more dosing cycles). In some embodiments, the antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer may be administered for three or more dosing cycles. In some embodiments, the administration cycle of the antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer continues until the clinical benefit is lost (e.g., confirmed as disease progression, drug resistance, death or unacceptable toxicity).

[0119] In some embodiments, the length of each of the one or more dosing cycles is 14 days. In some embodiments, the length of each of the one or more dosing cycles is 21 days. In some embodiments, the length of each of the one or more dosing cycles is 28 days. In some embodiments, the length of each of the one or more dosing cycles is 21 days.

[0120] In some embodiments, the antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer and / or immune checkpoint inhibitor is administered once every 3 weeks (Q3W), with 21 days as one treatment cycle.

[0121] In some implementations, the antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer and / or immune checkpoint inhibitor is administered once every 4 weeks (Q4W), with 28 days constituting one treatment cycle.

[0122] In some embodiments, the antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer and / or immune checkpoint inhibitor is administered once every 2 weeks (Q2W), with a treatment cycle of 14 or 28 days.

[0123] In some implementations, the antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer and / or immune checkpoint inhibitor is administered once weekly (QW) for 3 weeks, followed by a 1-week break, with 28 days constituting one treatment cycle.

[0124] In some implementations, the antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer and / or immune checkpoint inhibitor is administered once weekly (QW) for two weeks, followed by a one-week break, with a treatment cycle of 21 days.

[0125] In some embodiments, the antibody-drug conjugate targeting Nectin-4 or a pharmaceutically acceptable salt thereof is administered at a Q2W frequency, and the antibody-drug conjugate targeting Nectin-4 or a pharmaceutically acceptable salt thereof (by weight of the antibody-drug conjugate) is administered at a dose range of about 2.0 mg / kg to about 3.0 mg / kg per dose, preferably about 2.4 mg / kg or about 2.7 mg / kg.

[0126] In some embodiments, the antibody-drug conjugate targeting Nectin-4 or a pharmaceutically acceptable salt thereof is administered at a frequency of Q3W, and the antibody-drug conjugate targeting Nectin-4 or a pharmaceutically acceptable salt thereof (by weight of the antibody-drug conjugate) is administered at a dose range of about 2.0 mg / kg to about 4.0 mg / kg per dose, preferably about 1.8 mg / kg, about 2.4 mg / kg, about 2.7 mg / kg, about 3.6 mg / kg, about 4.0 mg / kg, about 4.2 mg / kg or about 4.5 mg / kg.

[0127] In some embodiments, the antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer is administered approximately on day 1 of each dosing cycle.

[0128] In some embodiments, the antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer is administered intravenously. In some embodiments, the antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer is administered via intravenous infusion for more than 30 ± 5 minutes to 60 ± 5 minutes (e.g., about 45 minutes, about 50 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, or about 65 minutes).

[0129] In some embodiments, the immune checkpoint inhibitor is administered in a dose range of about 100 mg to 720 mg per dose. In some embodiments, the dose range is about 240 mg to 480 mg per dose, for example, about 240 mg, 360 mg, or 480 mg.

[0130] In some embodiments, the immune checkpoint inhibitor is administered at a frequency of QW, Q2W, Q3W, Q4W, Q5W, or Q6W. In some embodiments, the immune checkpoint inhibitor is administered at a frequency of Q2W or Q3W.

[0131] In some embodiments, the immune checkpoint inhibitor is administered at a dose range of about 100 mg to 720 mg per dose, on a Q3-week cycle, for 21 days. In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody (e.g., the PD-1-001 antibody in the embodiments of this application). The anti-PD-1 antibody (e.g., the PD-1-001 antibody in the embodiments of this application) is administered at a dose range of about 100 mg to 720 mg per dose, on a Q3-week cycle, for 21 days. In some embodiments, the anti-PD-1 antibody (e.g., the PD-1-001 antibody in the embodiments of this application) is administered at a dose range of about 360 mg per dose, on a Q3-week cycle, for 21 days.

[0132] In some embodiments, the immune checkpoint inhibitor (e.g., an anti-PD-1 antibody, such as the PD-1-001 antibody in the embodiments of this application) may be administered for one or more dosing cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more dosing cycles). In some embodiments, the immune checkpoint inhibitor (e.g., an anti-PD-1 antibody, such as the PD-1-001 antibody in the embodiments of this application) may be administered for three or more dosing cycles. In some implementations, the dosing cycle of the immune checkpoint inhibitor (e.g., an anti-PD-1 antibody, such as the PD-1-001 antibody in the embodiments of this application) continues until the clinical benefit is lost (e.g., confirmed as disease progression, drug resistance, death, or unacceptable toxicity).

[0133] In some embodiments, the length of each of the one or more dosing cycles is 14 days. In some embodiments, the length of each of the one or more dosing cycles is 21 days. In some embodiments, the length of each of the one or more dosing cycles is 28 days. In some embodiments, the length of each of the one or more dosing cycles is 21 days.

[0134] In some embodiments, the immune checkpoint inhibitor (e.g., an anti-PD-1 antibody, such as the PD-1-001 antibody in the embodiments of this application) is administered on approximately day 1 of each dosing cycle (e.g., day 1, 2, 3, or 4).

[0135] In some embodiments, the immune checkpoint inhibitor (e.g., an anti-PD-1 antibody, such as the PD-1-001 antibody in the embodiments of this application) is administered by intravenous injection. In some embodiments, the immune checkpoint inhibitor (e.g., an anti-PD-1 antibody, such as the PD-1-001 antibody in the embodiments of this application) is administered by intravenous infusion over 60-90 minutes (e.g., about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, 85 minutes, about 90 minutes). In some embodiments, the antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer is administered before the immune checkpoint inhibitor in each dosing cycle. In some embodiments, the immune checkpoint inhibitor is administered at least 30 minutes after the completion of administration of the antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer in each dosing cycle. In some implementations, the antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer and immune checkpoint inhibitor are administered on the same day for each treatment cycle.

[0136] In some embodiments, the antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer and / or immune checkpoint inhibitor is administered on day 1 of each dosing cycle.

[0137] For the drug combination described in this application (also referred to as "combination drug"), the antibody-drug conjugate targeting Nectin-4 (e.g., SWY2001-Ab3-LND1002 in the embodiments of this application) or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer, and an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody, such as the PD-1-001 antibody in the embodiments of this application) can be contained in the same formulation unit to form a combination product, or they can be separately formulated into clinically acceptable formulations and then combined and packaged to obtain the drug combination. Whether it is a combination product or a separate formulation, the formulation can be an injectable dosage form, such as a liquid injection, an injectable powder, or an injectable tablet.

[0138] In some embodiments, the pharmaceutical combination described herein includes components that are separated in time and / or space, which work together to achieve the purpose of this application. For example, the components contained in the pharmaceutical combination may be administered to a patient or subject as a whole or individually. When the components contained in the pharmaceutical combination are administered to a subject separately, these components may be administered to the patient or subject simultaneously or sequentially.

[0139] In some embodiments, the unit formulation of the antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer contains about 1 mg to about 500 mg of the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer. In some embodiments, the unit formulation contains about 5 mg to about 400 mg, or about 10 mg to about 300 mg, or about 10 mg to about 250 mg, or about 10 mg to about 200 mg, or about 20 mg to about 200 mg; more preferably, about 10 mg to about 160 mg, or about 20 mg to about 160 mg, or about 80 mg to about 160 mg; or about 120 mg to about 240 mg; or about 160 mg to about 220 mg; for example, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, or a range of values ​​selected between any two points, the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer. In some embodiments, the unit formulation contains about 10 mg, 30 mg, about 50 mg, about 80 mg, about 120 mg, about 160 mg, or about 240 mg, or a range of values ​​selected from any two points, the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer.

[0140] In some embodiments, antibody-drug conjugates targeting Nectin-4, or pharmaceutical salts, esters, solvates, tautomers, or stereoisomers thereof, and combination pharmaceutical products with immune checkpoint inhibitors, or their individual formulations, may contain pharmaceutically acceptable carriers or excipients. In some embodiments, the type of pharmaceutically acceptable carrier depends primarily on the administration method of the drug or drug combination formulated according to this application. In some embodiments, the drug or drug combination formulated according to this application may contain wetting agents, emulsifiers, or buffering substances as additives.

[0141] In some embodiments, in the standalone formulation of the antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer, or in combination with an immune checkpoint inhibitor, the antibody-drug conjugate targeting Nectin-4 (e.g., SWY2001-Ab3-LND1002 in the embodiments of this application) or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer comprises: histidine-histidine hydrochloride: 5-30 mM, polysorbate 20 or polysorbate 80: 0.02 wt%-0.08 wt%, trehalose: 4 wt%-8 wt%, and the aforementioned antibody-drug conjugate targeting Nectin-4 (e.g., SWY2001-Ab3-LND1002) or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer: 5-50 mg / ml, pH 5.0-6.5.

[0142] In some embodiments, the formulation of the Nectin-4-targeting antibody-drug conjugate (e.g., SWY2001-Ab3-LND1002) or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer in the drug or drug combination described in this application comprises: histidine-histidine hydrochloride: 10-30 mM, polysorbate 20 or polysorbate 80: 0.02 wt%-0.04 wt%, trehalose: 5 wt%-7 wt%, and the aforementioned Nectin-4-targeting antibody-drug conjugate (e.g., SWY2001-Ab3-LND1002) or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer: 10-20 mg / ml, pH 5.0-6.0.

[0143] In some embodiments, in a standalone formulation of an immune checkpoint inhibitor or a combination product of an antibody drug conjugate targeting Nectin-4 or a pharmaceutical salt, ester, solvate, tautomer, or stereoisomer thereof, the formulation of the immune checkpoint inhibitor comprises: an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody, such as the PD-1-001 antibody in the embodiments of this application): 5 mg / ml-20 mg / ml, histidine 2 mg / ml-4 mg / ml, methionine 1 mg / ml-3 mg / ml, sodium chloride 2 mg / ml-4 mg / ml, mannitol 20 mg / ml-40 mg / ml, polysorbate 80 0.1 mg / ml-0.4 mg / ml, 10% dilute hydrochloric acid as needed, pH 5.0-6.0.

[0144] Example

[0145] Preparation Example

[0146] In this document, SWY2001-Ab3-LND1002, as a representative drug conjugate of this application, refers to a drug conjugate formed by conjugating the drug-linker represented by Formula I with an antibody targeting Nectin-4, wherein the antibody is the humanized antibody SWY2001-Ab3, the heavy chain variable region is SWY2001-Ab3-VH (SEQ ID NO. 7), the light chain variable region is SWY2001-Ab3-VL (SEQ ID NO. 10), the heavy chain constant region is HC (SEQ ID NO. 11), and the light chain constant region is LC (SEQ ID NO. 12). The preparation method of the antibody in SWY2001-Ab3-LND1002 and the antibody-drug conjugate is as described in WO2023025243A1, which uses the mTgase (sequence shown in SEQ ID NO. 14 in Table 3) enzymatic conjugation method. The entire contents of this patent application are incorporated herein by reference. The specific preparation method of the pharmaceutical formulation of SWY2001-Ab3-LND1002 is based on PCT application PCT / CN2024 / 078768, the full text of which is incorporated herein by reference.

[0147] In this document, the PD-1-001 antibody, as a representative immune checkpoint inhibitor of this application, has a heavy chain with the amino acid sequence shown in SEQ ID NO.23 and a light chain with the amino acid sequence shown in SEQ ID NO.24. The specific preparation method is described in Chinese patent application CN108473580A. The formulation of the PD-1-001 antibody comprises: PD-1-001 antibody: 5 mg / ml-20 mg / ml, histidine 2 mg / ml-4 mg / ml, methionine 1 mg / ml-3 mg / ml, sodium chloride 2 mg / ml-4 mg / ml, mannitol 20 mg / ml-40 mg / ml, polysorbate 80 0.1 mg / ml-0.4 mg / ml, and an appropriate amount of 10% dilute hydrochloric acid, pH 5.0-6.0, and can be prepared using conventional techniques in the art.

[0148] Example of a trial: An open-label, multicenter clinical trial evaluating the safety, tolerability, pharmacokinetic characteristics, and preliminary efficacy of SWY2001-Ab3-LND1002 in combination with PD-1-001 antibody in patients with advanced urothelial carcinoma and other advanced solid tumors.

[0149] 1. Drug Information

[0150] SWY2001-Ab3-LND1002 (recombinant humanized anti-human Nectin-4 monoclonal antibody-MMAE conjugate for injection), provided by CSPC Jushi Biopharmaceutical Co., Ltd.

[0151] Specification: 30mg / bottle

[0152] Dosage form: Lyophilized powder for injection

[0153] Storage conditions: Store at 2-8℃, away from light.

[0154] PD-1-001 antibody (recombinant anti-PD-1 fully human monoclonal antibody injection), provided by CSPC Jushi Biopharmaceutical Co., Ltd.

[0155] Specification: 10ml:100mg

[0156] Dosage form: Injection

[0157] Storage conditions: Store at 2-8℃, away from light, and avoid freezing.

[0158] 2. Dosage and administration method

[0159] In this study, SWY2001-Ab3-LND1002 was administered at doses of 2.7 mg / kg, Q3W, 3.6 mg / kg, Q3W, 2.4 mg / kg, Q2W, or 4.5 mg / kg, Q3W, all via intravenous infusion.

[0160] In this study, the PD-1-001 antibody was administered at a dose of 360 mg every 3 weeks or 240 mg every 2 weeks, both via intravenous infusion.

[0161] 3. Study population

[0162] Advanced urothelial carcinoma and other advanced solid tumors.

[0163] 4. Inclusion criteria

[0164] Participants must meet all of the following inclusion criteria to be eligible for this study:

[0165] 1) Patients with pathologically confirmed advanced solid tumors; among them, patients with urothelial carcinoma are required to be as follows: locally advanced or metastatic urothelial carcinoma that has not received systemic anti-tumor therapy. If they have previously received neoadjuvant or adjuvant therapy, the time interval between the end of neoadjuvant or adjuvant therapy and disease progression is more than 6 months, and they can be enrolled.

[0166] 2) Able to provide well-preserved or fresh tumor tissue, and the tumor tissue is positive for Nectin-4 expression [based on immunohistochemical (IHC) detection in the central laboratory]. For patients with urothelial carcinoma, the Nectin-4 expression status is not limited, but tumor tissue must be provided.

[0167] 3) According to the Evaluation Criteria for Treatment of Solid Tumors (RECIST) v1.1, there is at least one measurable lesion confirmed by CT or MRI;

[0168] 4) Eastern Cooperative Oncology Group (ECOG) Performance Status Scale score of 0-1;

[0169] 5) Expected survival ≥ 3 months;

[0170] 5. Exclusion criteria: Participants meeting any of the following criteria will not be eligible for this study:

[0171] 1. Previous treatment:

[0172] a. Previous treatment with drugs targeting Nectin-4;

[0173] b. Patients who have previously received ADC or drug therapy containing MMAE / toxin, and whose time from the end of adjuvant / neoadjuvant ADC drug therapy containing MMAE / toxin to disease progression exceeds 12 months, are eligible for enrollment (only applicable to the dose expansion phase Part 1).

[0174] 2. Known allergy to any component of the SWY2001-Ab3-LND1002 and / or PD-1-001 antibody products, or allergy to humanized monoclonal antibody products;

[0175] 6. Effectiveness Assessment

[0176] In this study, efficacy assessments were conducted every 6 weeks during the screening period and the 24-week study period using imaging techniques (including CT and MRI) according to RECIST v1.1 criteria. After 24 weeks, efficacy assessments were conducted every 9 weeks. Participants who received a CR or PR on their first assessment needed to confirm their CR status 4 weeks later (or at the next efficacy assessment specified in the protocol). For participants who received a SD on their first assessment, the time interval between the first imaging examination and the first dose of medication must be at least 42 days. Investigators may add examination sites and unplanned examinations as appropriate based on the participants' actual situation.

[0177] Validity endpoints include:

[0178] Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS).

[0179] 7. Security Assessment

[0180] Safety assessment includes adverse events, vital signs, physical examination, 12-lead electrocardiogram, laboratory tests, and ophthalmological examination.

[0181] 8. Test Results

[0182] Treatment efficacy data:

[0183] As of June 13, 2025, this study included 114 participants, including 96 cases of urothelial carcinoma (including cases of renal pelvis cancer, ureteral cancer, bladder cancer, and urethral cancer), 2 cases of breast cancer, 1 case of lung cancer, 1 case of cervical cancer, 1 case of esophageal cancer, and 1 case of head and neck cancer. Among all participants, 82 had at least one efficacy assessment result, with an overall ORR of 51.2% (42 / 82) and a DCR of 86.6% (71 / 82).

[0184] This combination regimen demonstrated clear efficacy in first-line urothelial carcinoma. In two potentially effective dose groups—SWY2001-AB3-LND1002 2.4 mg / kg combined with PD-1-001 240 mg Q2W and SWY2001-AB3-LND1002 3.6 mg / kg combined with PD-1-001 360 mg Q3W—the objective response rate (ORR) for first-line urothelial carcinoma was 73.7% and 70%, respectively, and the disease control rate (DCR) was 84.2% and 100%, respectively. Specific efficacy results are shown in Table 1 and Figure 2. In addition to urothelial carcinoma, one case of cervical cancer achieved a complete remission (CR), one case of head and neck cancer achieved a partial remission (PR), one case of lung cancer showed a reduction in stable disease (SD), and one case of breast cancer showed a reduction in SD, as shown in Table 2.

[0185] Table 1

[0186] Table 2

[0187] Safety data: As of June 13, 2025, 113 patients had used the investigational drug at least once. AEs associated with the investigational drug, with an incidence rate ≥20%, included corneal disease (57.5%), rash (36.3%), dry eye (31%), pruritus (26.6%), proteinuria (26.6%), anemia (22.1%), elevated aspartate aminotransferase (22.1%), and anemia (21.2%), most of which were grade 1-2. The incidence of grade ≥3 investigational drug-related AEs was only 17.7%, of which corneal disease (4.42%), rash (2.65%), and blurred vision (2.65%) occurred in ≥2% of cases. No grade 4-5 investigational drug-related AEs occurred. The safety characteristics of combination therapy and monotherapy were basically similar, and no new safety signals were found.

[0188] The results showed that the combination of SWY2001-Ab3-LND1002 and PD-1-001 antibody was effective in patients with advanced urothelial carcinoma and various other advanced solid tumors, with good clinical safety. Furthermore, based on the efficacy of SWY2001-Ab3-LND1002 and PD-1-001 antibody as monotherapy in previous studies (data not listed), it is preliminarily judged that the combination of the two drugs produces a synergistic effect.

[0189] Table 3. Sequence information of the antibodies and their components involved in this application.

Claims

1. Use of an antibody-drug conjugate targeting Nectin-4 or a pharmaceutical salt, ester, solvate, tautomer, or stereoisomer thereof, in combination with an immune checkpoint inhibitor in the preparation of a medicament for treating cancer, wherein the antibody-drug conjugate targeting Nectin-4 is formed by conjugating a drug-linker of Formula I with an antibody targeting Nectin-4 or an antigen-binding fragment thereof (e.g., Fab fragment, F(ab')2 fragment, Fab' fragment, Fv fragment, dsFv fragment, or scFv fragment):

2. Use of an antibody-drug conjugate targeting Nectin-4 or a pharmaceutical salt, ester, solvate, tautomer, or stereoisomer thereof in the preparation of a medicament for the treatment of cancer in combination with an immune checkpoint inhibitor, wherein the antibody-drug conjugate targeting Nectin-4 is formed by conjugating a drug-linker of Formula I with an antibody targeting Nectin-4 or an antigen-binding fragment thereof (e.g., Fab fragment, F(ab')2 fragment, Fab' fragment, Fv fragment, dsFv fragment, or scFv fragment):

3. The use according to claim 1 or 2, wherein the antibody targeting Nectin-4 or its antigen-binding fragment comprises a heavy chain variable region VH and a light chain variable region VL, wherein, (i) The heavy chain variable region VH comprises three CDR regions, namely CDR1-H, CDR2-H, and CDR3-H, wherein the CDR1-H, CDR2-H, and CDR3-H regions have amino acid sequences as shown in SEQ ID NO. 1, 2, and 3, respectively, and / or (ii) The light chain variable region VL comprises three CDR regions, namely CDR1-L region, CDR2-L region and CDR3-L region, wherein the CDR1-L region, CDR2-L region and CDR3-L region have amino acid sequences as shown in SEQ ID NO.4, 5 and 6, respectively; The CDR mentioned above is defined according to IMGT.

4. The use according to any one of claims 1-3, wherein the antibody targeting Nectin-4 or its antigen-binding fragment comprises a heavy chain variable region VH and a light chain variable region VL, wherein, The heavy chain variable region VH comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 7; and / or, the light chain variable region VL comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in any one of SEQ ID NO. 8-10.

5. The use according to any one of claims 1-4, wherein the antibody targeting Nectin-4 or its antigen-binding fragment comprises a heavy chain constant region CH and a light chain constant region CL, wherein, The heavy chain constant region CH contains an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 11 or SEQ ID NO. 13; and / or, the light chain constant region CL contains an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO.

12.

6. The use according to any one of claims 1-5, wherein the antibody targeting Nectin-4 or its antigen-binding fragment comprises a heavy chain HC and a light chain LC, wherein, The heavy chain HC comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 25; and / or, the light chain LC comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO.

26.

7. The use according to any one of claims 1-6, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., Fab fragment, F(ab')2 fragment, Fab' fragment, Fv fragment, dsFv fragment or scFv fragment), or an anti-PD-L1 antibody or an antigen-binding fragment thereof (e.g., Fab fragment, F(ab')2 fragment, Fab' fragment, Fv fragment, dsFv fragment or scFv fragment).

8. The use according to claim 7, wherein the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain variable region VH and a light chain variable region VL, wherein, (i) The heavy chain variable region VH comprises three CDR regions, namely CDR1-H, CDR2-H, and CDR3-H, wherein the CDR1-H region has the amino acid sequence shown in SEQ ID NO. 15 or 27, the CDR2-H region has the amino acid sequence shown in SEQ ID NO. 16 or 28, and the CDR3-H region has the amino acid sequence shown in SEQ ID NO. 17; and / or (ii) The light chain variable region VL comprises three CDR regions, namely CDR1-L region, CDR2-L region and CDR3-L region, wherein the CDR1-L region, CDR2-L region and CDR3-L region have amino acid sequences as shown in SEQ ID NO.18, 19 and 20, respectively.

9. The use according to claim 7 or 8, wherein the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain variable region VH and a light chain variable region VL, wherein, The heavy chain variable region VH comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 21; and / or, the light chain variable region VL comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO.

22.

10. The use according to any one of claims 7-9, wherein the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain HC and a light chain LC, wherein, The heavy chain HC comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 23; and / or, the light chain LC comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO.

24.

11. The use according to any one of claims 1-10, wherein the cancer is selected from advanced solid tumors; preferably, the cancer is selected from urothelial carcinoma, cervical cancer, esophageal cancer, head and neck cancer, breast cancer, and lung cancer; more preferably, the cancer is urothelial carcinoma.

12. The use according to claim 11, wherein the urothelial carcinoma is renal pelvis carcinoma, ureteral carcinoma, bladder carcinoma or urethral carcinoma.

13. The use according to any one of claims 1-12, wherein the tumor tissue of the cancer is positive or negative for Nectin-4 expression, preferably positive.

14. The use according to any one of claims 1-13, wherein the tumor tissue of the cancer does not express, moderately expresses, highly expresses, or overexpresses Nectin-4.

15. The use according to any one of claims 1-14, wherein the cancer is a cancer that has not received systemic antitumor therapy.

16. The use according to any one of claims 1-14, wherein the cancer is a cancer in which the time interval between the end of previous neoadjuvant or adjuvant therapy and disease progression exceeds 6 months or 12 months.

17. The use according to any one of claims 1-16, wherein the cancer is a locally advanced cancer.

18. The use according to any one of claims 1-16, wherein the cancer is a metastatic cancer.

19. The use according to any one of claims 1-18, wherein the cancer is a cancer that has not previously been treated with a Nectin-4 antibody-drug conjugate containing MMAE toxin.

20. The use according to any one of claims 1-19, wherein the cancer is a cancer that has not previously been treated with PD-1 or PD-L1 inhibitor drugs.

21. A method of treating cancer, the method comprising administering to an individual in need an effective amount of (i) an antibody-drug conjugate targeting Nectin-4 or a pharmaceutical salt, ester, solvate, tautomer, or stereoisomer thereof, and (ii) an immune checkpoint inhibitor, wherein the antibody-drug conjugate targeting Nectin-4 is composed of a drug-linker represented by Formula I conjugated to an antibody targeting Nectin-4 or an antigen-binding fragment thereof (e.g., a Fab fragment, an F(ab')2 fragment, a Fab' fragment, an Fv fragment, a dsFv fragment, or a scFv fragment):

22. The method of claim 21, wherein the antibody targeting Nectin-4 or its antigen-binding fragment comprises a heavy chain variable region VH and a light chain variable region VL, wherein, (i) The heavy chain variable region VH comprises three CDR regions, namely CDR1-H, CDR2-H, and CDR3-H, wherein the CDR1-H, CDR2-H, and CDR3-H regions have amino acid sequences as shown in SEQ ID NO. 1, 2, and 3, respectively, and / or (ii) The light chain variable region VL comprises three CDR regions, namely CDR1-L region, CDR2-L region and CDR3-L region, wherein the CDR1-L region, CDR2-L region and CDR3-L region have amino acid sequences as shown in SEQ ID NO.4, 5 and 6, respectively; The CDR mentioned above is defined according to IMGT.

23. The method according to any one of claims 21-22, wherein the antibody targeting Nectin-4 or its antigen-binding fragment comprises a heavy chain variable region VH and a light chain variable region VL, wherein, The heavy chain variable region VH comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 7; and / or, the light chain variable region VL comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in any one of SEQ ID NO. 8-10.

24. The method according to any one of claims 21-23, wherein the antibody targeting Nectin-4 or its antigen-binding fragment comprises a heavy chain constant region CH and a light chain constant region CL, wherein, The heavy chain constant region CH contains an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 11 or SEQ ID NO. 13; and / or, the light chain constant region CL contains an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO.

12.

25. The method according to any one of claims 21-24, wherein the antibody targeting Nectin-4 or its antigen-binding fragment comprises a heavy chain HC and a light chain LC, wherein, The heavy chain HC comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 25; and / or, the light chain LC comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO.

26.

26. The method according to any one of claims 21-25, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., Fab fragment, F(ab')2 fragment, Fab' fragment, Fv fragment, dsFv fragment or scFv fragment), or an anti-PD-L1 antibody or an antigen-binding fragment thereof (e.g., Fab fragment, F(ab')2 fragment, Fab' fragment, Fv fragment, dsFv fragment or scFv fragment).

27. The method of claim 26, wherein the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain variable region VH and a light chain variable region VL, wherein, (i) The heavy chain variable region VH comprises three CDR regions, namely CDR1-H, CDR2-H, and CDR3-H, wherein the CDR1-H region has the amino acid sequence shown in SEQ ID NO. 15 or 27, the CDR2-H region has the amino acid sequence shown in SEQ ID NO. 16 or 28, and the CDR3-H region has the amino acid sequence shown in SEQ ID NO. 17; and / or (ii) The light chain variable region VL comprises three CDR regions, namely CDR1-L region, CDR2-L region and CDR3-L region, wherein the CDR1-L region, CDR2-L region and CDR3-L region have amino acid sequences as shown in SEQ ID NO.18, 19 and 20, respectively.

28. The method according to claim 26 or 27, wherein the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain variable region VH and a light chain variable region VL, wherein, The heavy chain variable region VH comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 21; and / or, the light chain variable region VL comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO.

22.

29. The method according to any one of claims 26-28, wherein the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain HC and a light chain LC, wherein, The heavy chain HC comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 23; and / or, the light chain LC comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO.

24.

30. The method according to any one of claims 21-29, wherein the cancer is selected from advanced solid tumors; preferably, the cancer is selected from urothelial carcinoma, cervical cancer, esophageal cancer, head and neck cancer, breast cancer, and lung cancer; more preferably, the cancer is urothelial carcinoma.

31. The method of claim 30, wherein the urothelial carcinoma is renal pelvis carcinoma, ureteral carcinoma, bladder carcinoma, or urethral carcinoma.

32. The method according to any one of claims 21-31, wherein the tumor tissue of the cancer is positive or negative for Nectin-4 expression, preferably positive.

33. The method according to any one of claims 21-31, wherein the tumor tissue of the cancer does not express, moderately expresses, highly expresses, or overexpresses Nectin-4.

34. The method according to any one of claims 21-33, wherein the patient with the cancer has not received systemic antitumor therapy.

35. The method according to any one of claims 21-33, wherein the time interval between the completion of neoadjuvant or adjuvant therapy and disease progression in the patient with said cancer is more than 6 months or 12 months.

36. The method according to any one of claims 21-35, wherein the cancer is locally advanced cancer.

37. The method according to any one of claims 21-35, wherein the cancer is a metastatic cancer.

38. The method according to any one of claims 21-37, wherein the patient with said cancer has not previously received treatment with a Nectin-4 antibody-drug conjugate containing MMAE toxin.

39. The method according to any one of claims 21-38, wherein the patient with said cancer has not previously received PD-1 or PD-L1 inhibitor treatment.

40. The use or method according to any one of claims 1-39, wherein the antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer is administered at a dose range of about 0.03 mg / kg to about 20.0 mg / kg per administration; preferably, the dose range is about 1.0 mg / kg to about 10.0 mg / kg, more preferably about 2.0 mg / kg to about 8.0 mg / kg, for example: about 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2. 0mg / kg, 2.1mg / kg, 2.2mg / kg, 2.3mg / kg, 2.4mg / kg, 2.5mg / kg, 2.6mg / kg, 2.7mg / kg, 2.8mg / kg, 2.9mg / kg, 3.0mg / kg, 3.1mg / kg, 3.2mg / kg, 3.3mg / kg, 3.4mg / kg, 3.5mg / kg, 3.6mg / kg, 3.7mg / kg, 3.8mg / kg, 3.9mg / kg, 4.0mg / kg, 4.1mg / kg, 4.2mg / kg, 4.3mg / kg, 4.4mg / kg, 4.5mg / kg, 5.0mg / kg, 5.5mg / kg or 6.0mg / kg.

41. The use or method according to any one of claims 1-40, wherein the antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer is administered at a frequency of QW, Q2W, Q3W, Q4W, Q5W or Q6W; preferably, administered at a frequency of Q2W or Q3W.

42. The use or method according to any one of claims 1-41, wherein the immune checkpoint inhibitor is administered in a dose range of about 100 mg to 720 mg per administration; preferably, the dose range is about 240 mg to 480 mg per administration, for example, about 240 mg, 360 mg or 480 mg.

43. The use or method according to any one of claims 1-42, wherein the immune checkpoint inhibitor is administered at a frequency of QW, Q2W, Q3W, Q4W, Q5W or Q6W; preferably, at a frequency of Q2W or Q3W.

44. A pharmaceutical combination for treating cancer, the pharmaceutical combination comprising (i) an antibody-drug conjugate targeting Nectin-4 or a pharmaceutical salt, ester, solvate, tautomer, or stereoisomer thereof, and (ii) an immune checkpoint inhibitor, wherein the antibody-drug conjugate targeting Nectin-4 is formed by conjugating a drug-linker of Formula I to an antibody targeting Nectin-4 or an antigen-binding fragment thereof (e.g., Fab fragment, F(ab')2 fragment, Fab' fragment, Fv fragment, dsFv fragment, or scFv fragment):

45. The drug combination of claim 44, wherein the antibody targeting Nectin-4 or its antigen-binding fragment comprises a heavy chain variable region VH and a light chain variable region VL, wherein, (i) The heavy chain variable region VH comprises three CDR regions, namely CDR1-H, CDR2-H, and CDR3-H, wherein the CDR1-H, CDR2-H, and CDR3-H regions have amino acid sequences as shown in SEQ ID NO. 1, 2, and 3, respectively, and / or (ii) The light chain variable region VL comprises three CDR regions, namely CDR1-L region, CDR2-L region and CDR3-L region, wherein the CDR1-L region, CDR2-L region and CDR3-L region have amino acid sequences as shown in SEQ ID NO.4, 5 and 6, respectively; The CDR mentioned above is defined according to IMGT.

46. ​​The drug combination according to any one of claims 44-45, wherein the antibody targeting Nectin-4 or its antigen-binding fragment comprises a heavy chain variable region VH and a light chain variable region VL, wherein, The heavy chain variable region VH comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 7; and / or, the light chain variable region VL comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in any one of SEQ ID NO. 8-10.

47. The drug combination according to any one of claims 44-46, wherein the antibody targeting Nectin-4 or its antigen-binding fragment comprises a heavy chain constant region CH and a light chain constant region CL, wherein, The heavy chain constant region CH contains an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 11 or SEQ ID NO. 13; and / or, the light chain constant region CL contains an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO.

12.

48. The pharmaceutical combination according to any one of claims 44-47, wherein the antibody targeting Nectin-4 or its antigen-binding fragment comprises a heavy chain HC and a light chain LC, wherein, The heavy chain HC comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 25; and / or, the light chain LC comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO.

26.

49. The pharmaceutical combination according to any one of claims 44-48, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., Fab fragment, F(ab')2 fragment, Fab' fragment, Fv fragment, dsFv fragment, or scFv fragment), or an anti-PD-L1 antibody or an antigen-binding fragment thereof (e.g., Fab fragment, F(ab')2 fragment, Fab' fragment, Fv fragment, dsFv fragment, or scFv fragment).

50. The pharmaceutical combination of claim 49, wherein the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain variable region VH and a light chain variable region VL, wherein, (i) The heavy chain variable region VH comprises three CDR regions, namely CDR1-H, CDR2-H, and CDR3-H, wherein the CDR1-H region has the amino acid sequence shown in SEQ ID NO. 15 or 27, the CDR2-H region has the amino acid sequence shown in SEQ ID NO. 16 or 28, and the CDR3-H region has the amino acid sequence shown in SEQ ID NO. 17; and / or (ii) The light chain variable region VL comprises three CDR regions, namely CDR1-L region, CDR2-L region and CDR3-L region, wherein the CDR1-L region, CDR2-L region and CDR3-L region have amino acid sequences as shown in SEQ ID NO.18, 19 and 20, respectively.

51. The pharmaceutical combination according to claim 49 or 50, wherein the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain variable region VH and a light chain variable region VL, wherein, The heavy chain variable region VH comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 21; and / or, the light chain variable region VL comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO.

22.

52. The pharmaceutical combination according to any one of claims 49-51, wherein the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain HC and a light chain LC, wherein, The heavy chain HC comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 23; and / or, the light chain LC comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO.

24.

53. The pharmaceutical combination according to any one of claims 44-52, wherein the cancer is selected from advanced solid tumors; preferably, the cancer is selected from urothelial carcinoma, cervical cancer, esophageal cancer, head and neck cancer, breast cancer, and lung cancer; more preferably, the cancer is urothelial carcinoma.

54. The pharmaceutical combination according to claim 53, wherein the urothelial carcinoma is renal pelvis carcinoma, ureteral carcinoma, bladder carcinoma, or urethral carcinoma.

55. The drug combination according to any one of claims 44-54, wherein the tumor tissue of the cancer is positive or negative for Nectin-4 expression, preferably positive.

56. The drug combination according to any one of claims 44-54, wherein Nectin-4 is not expressed, moderately expressed, highly expressed, or overexpressed in the tumor tissue of said cancer.

57. The pharmaceutical combination according to any one of claims 44-56, wherein the patient with said cancer has not received systemic antitumor therapy.

58. The drug combination according to any one of claims 44-56, wherein the time interval between the completion of neoadjuvant or adjuvant therapy and disease progression in the patient with said cancer is more than 6 months or 12 months.

59. The pharmaceutical combination according to any one of claims 44-58, wherein the cancer is locally advanced cancer.

60. The pharmaceutical combination according to any one of claims 44-58, wherein the cancer is a metastatic cancer.

61. The pharmaceutical combination according to any one of claims 44-60, wherein the patient with said cancer has not previously received treatment with a Nectin-4 antibody-drug conjugate containing MMAE toxin.

62. The drug combination according to any one of claims 44-61, wherein the patient with said cancer has not previously received PD-1 or PD-L1 inhibitor treatment.

63. The pharmaceutical combination according to any one of claims 44-62, wherein the antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer is administered at a dose range of about 0.03 mg / kg to about 20.0 mg / kg per administration; preferably, the dose range is about 1.0 mg / kg to about 10.0 mg / kg, more preferably about 2.0 mg / kg to about 8.0 mg / kg, for example: about 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2. 0mg / kg, 2.1mg / kg, 2.2mg / kg, 2.3mg / kg, 2.4mg / kg, 2.5mg / kg, 2.6mg / kg, 2.7mg / kg, 2.8mg / kg, 2.9mg / kg, 3.0mg / kg, 3.1mg / kg, 3.2mg / kg, 3.3mg / kg, 3.4mg / kg, 3.5mg / kg, 3.6mg / kg, 3.7mg / kg, 3.8mg / kg, 3.9mg / kg, 4.0mg / kg, 4.1mg / kg, 4.2mg / kg, 4.3mg / kg, 4.4mg / kg, 4.5mg / kg, 5.0mg / kg, 5.5mg / kg or 6.0mg / kg.

64. The pharmaceutical combination according to any one of claims 44-63, wherein the antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer is administered at a frequency of QW, Q2W, Q3W, Q4W, Q5W or Q6W; preferably, administered at a frequency of Q2W or Q3W.

65. The pharmaceutical combination according to any one of claims 44-64, wherein the immune checkpoint inhibitor is administered in a dose range of about 100 mg to 720 mg per administration; preferably, the dose range is about 240 mg to 480 mg per administration, for example: about 240 mg, 360 mg or 480 mg.

66. The pharmaceutical combination according to any one of claims 44-65, wherein the immune checkpoint inhibitor is administered at a frequency of QW, Q2W, Q3W, Q4W, Q5W or Q6W; preferably, at a frequency of Q2W or Q3W.

67. The pharmaceutical combination according to any one of claims 44-66, wherein the (i) antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer and (ii) immune checkpoint inhibitor are contained in the same formulation unit to form a compound product.

68. The pharmaceutical combination according to any one of claims 44-66, wherein the (i) antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer and the (ii) immune checkpoint inhibitor are each independently formulated into clinically acceptable formulations, and then combined and packaged to obtain the pharmaceutical combination.

69. The pharmaceutical combination according to any one of claims 67-68, wherein the formulation is an injectable dosage form, such as a liquid injection, an injectable powder, or an injectable tablet.

70. An antibody-drug conjugate targeting Nectin-4 or a pharmaceutical salt, ester, solvate, tautomer, or stereoisomer thereof, for use in combination with an immune checkpoint inhibitor for the treatment of cancer, wherein the antibody-drug conjugate targeting Nectin-4 is composed of a drug-linker represented by Formula I conjugated to an antibody targeting Nectin-4 or an antigen-binding fragment thereof (e.g., Fab fragment, F(ab')2 fragment, Fab' fragment, Fv fragment, dsFv fragment, or scFv fragment):

71. An immune checkpoint inhibitor, used in combination with an antibody-drug conjugate targeting Nectin-4 or a pharmaceutical salt, ester, solvate, tautomer, or stereoisomer thereof for the treatment of cancer, wherein the antibody-drug conjugate targeting Nectin-4 is composed of a drug-linker represented by Formula I conjugated to an antibody targeting Nectin-4 or an antigen-binding fragment thereof (e.g., Fab fragment, F(ab')2 fragment, Fab' fragment, Fv fragment, dsFv fragment, or scFv fragment):

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