Use of antibody-drug conjugate targeting nectin-4

Abstract

The present application provides a use of an antibody-drug conjugate targeting Nectin-4, or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, in combination with an immune checkpoint inhibitor in preparation of a drug for treating cancer, and a method for treating cancer using same.

Description

Uses of antibody-drug conjugates targeting Nectin-4

[0001] Related applications

[0002] This application claims priority to Chinese Patent Application No. 202410327589.X, filed on March 21, 2024, entitled “Use of an antibody-drug conjugate targeting Nectin-4”, the entire contents of which are incorporated herein by reference for all purposes. Technical Field

[0003] This invention relates to the field of biopharmaceuticals, and more specifically, to 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, and a method thereof for treating cancer. Background Technology

[0004] Nectin is a novel cell adhesion molecule (CAM) belonging to the immunoglobulin superfamily (IgSF), which can be independent of Ca2+. 2+ Involved in intercellular interactions, Nectin forms adherens junctions (AJs). The Nectin protein family comprises four members: Nectin-1, Nectin-2, Nectin-3, and Nectin-4. Nectin 1–3 are widely expressed in normal human tissues, with Nectin 1–2 commonly found in immune organs (bone marrow, thymus, spleen, and lymph nodes), and Nectin-3 primarily expressed in the testes and placenta. Nectin-4 is a type I transmembrane immunoglobulin-like cell adhesion molecule that participates in the formation of adherens junctions, mediates cell-cell connections, and participates in regulating physiological processes such as cell proliferation, differentiation, and migration. Unlike other members of the Nectin family, which are widely expressed in normal human tissues, Nectin-4 is expressed at higher levels in normal embryonic and fetal tissues, but at very low levels in healthy adult tissues. However, abnormally high expression of Nectin4 can be detected in various cancer samples. Nectin4 is a type I transmembrane immunoglobulin-like cell adhesion molecule that mediates cell-cell connections and participates in regulating physiological processes such as cell proliferation, differentiation, and migration. It is associated with the progression of various cancers, especially in urothelial carcinoma, cervical cancer, breast cancer, lung cancer, and pancreatic cancer.

[0005] 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 antibody-drug conjugates (ADCs), bicycle toxin conjugates (BTCs), bicyclic peptides, monoclonal antibodies, and chimeric antigen receptor T-cell immunotherapy (CAR-T).

[0006] Enfortumab vedotin (product name: Astellas and Seagen jointly developed) EV (explained as EV) is an adjuvant drug (ADC) composed of the Nectin-4-targeting monoclonal antibody enfortumab and the microtubule disruptor methylaurestatin E (MMAE) linked by a cleavable dipeptide linker mc-VC-PABC. This drug was approved by the FDA in 2019, primarily for the treatment of locally advanced or metastatic urothelial carcinoma. Notably, 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.

[0007] 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. Efforts are currently underway to find suitable combination therapies to improve the clinical efficacy of CPIs. One of the more recent successful approaches is the clinical combination of immune CPIs with anti-inflammatory drug receptor agonists (ADCs).

[0008] The U.S. Food and Drug Administration (FDA) granted accelerated approval to EV and pembrolizumab. It is used in combination with cisplatin to treat patients with locally advanced or metastatic urothelial carcinoma (mUC) who are ineligible for cisplatin therapy. The objective response rate (ORR) was 68% (Seagen). (Drug package insert 2023). However, the frequency of known dose-limiting toxicities in combination therapy has increased, particularly in EVs and Of the 121 participants receiving the combination therapy, 65% developed peripheral neuropathy, and 45% developed grade 2 peripheral neuropathy. Notably, 36% of participants experienced adverse events leading to EV discontinuation in this study; and the most common adverse event leading to EV discontinuation was peripheral neuropathy (20%), indicating that tolerability of this combination therapy remains challenging.

[0009] There is an urgent need to develop a safe and effective combination therapy for cancer. Summary of the Invention

[0010] To address the shortcomings of existing technologies, the present invention aims 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 drug for treating cancer, and a method thereof for treating cancer.

[0011] SWY2001-Ab3-LND1002 is a next-generation Nectin-4-targeting ADC designed to improve safety and tolerability by reducing systemic exposure to MMAEs. SWY2001-Ab3-LND1002 features a reduced drug-to-antibody ratio of 2.0 and employs an enzyme-mediated site-directed conjugation method to link the humanized antibody to the small molecule drug via a linker, minimizing payload release in plasma. SWY2001-Ab3-LND1002 is a novel Fc-enabled IgG1 antibody with an extended half-life, supporting three-week (Q3W) dosing. These characteristics result in increased intratumoral delivery, with the payload released via proteolysis after cellular uptake. The lower plasma MMAE concentrations, associated with the design features of SWY2001-Ab3-LND1002, may reduce the severity and frequency of peripheral neuropathy and the frequency of rashes. Overall, SWY2001-Ab3-LND1002 was well tolerated, with most adverse events (AEs) being grade 1 or 2 in severity, such as anemia (45%), proteinuria (45%), hypertriglyceridemia (36%), hyponatremia (36%), and keratoconjunctivitis (36%) (data cutoff date: July 31, 2023).

[0012] Patients treated with the anti-PD(L)-1 antibody in combination with the Nectin-4-targeting antibody conjugate of this invention experienced fewer treatment-related adverse events and lower plasma free MMAEs compared to patients treated with EV in combination with the anti-PD(L)-1 antibody, indicating that the combination therapy of the Nectin-4-targeting antibody conjugate and the anti-PD(L)-1 antibody of this invention has improved safety.

[0013] The combination of the Nectin-4-targeting antibody-drug conjugate and the anti-PD(L)-1 antibody of this invention produces a synergistic effect. Patients treated with this combination of the Nectin-4-targeting antibody-drug conjugate and the anti-PD(L)-1 antibody had longer progression-free survival and longer duration of remission compared to patients treated with EV and the anti-PD(L)-1 antibody alone, indicating that the combination therapy of the Nectin-4-targeting antibody-drug conjugate and the anti-PD(L)-1 antibody of this invention has higher efficacy.

[0014] The present invention aims 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 functional fragment:

[0015] In some embodiments, the antibody or its functional fragment comprises a heavy chain and a light chain, wherein (i) the heavy chain comprises three CDR regions, namely CDR1-H, CDR2-H and CDR3-H regions, 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

[0016] (ii) The light chain 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.

[0017] In some embodiments, the antibody or its functional fragment comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence as shown in SEQ ID NO. 7; and / or, the light chain variable region is selected from amino acid sequences as shown in SEQ ID NO. 8-10.

[0018] In some embodiments, the antibody or its functional fragment comprises a heavy chain constant region and a light chain constant region, wherein the heavy chain constant region has an amino acid sequence as shown in SEQ ID NO. 11 or SEQ ID NO. 13; and / or, the light chain constant region has an amino acid sequence as shown in SEQ ID NO. 12.

[0019] In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody selected from cimiplimab, nivolumab, pembrolizumab, dostarlimab, toripalimab, tislelizumab, or retifanlimab.

[0020] In some embodiments, the immune checkpoint inhibitor is an anti-PD-L1 antibody selected from atezolizumab, avelumab, or durvalumab.

[0021] In some implementations, the cancer is selected from urothelial carcinoma, breast cancer, head and neck cancer, colorectal cancer, pancreatic cancer, penile cancer, skin cancer, cervical cancer, endometrial cancer, ovarian cancer, prostate cancer, or lung cancer.

[0022] In some implementations, the cancer is selected from locally advanced or metastatic urothelial carcinoma (mUC), bladder cancer, triple-negative breast cancer (TNBC), head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), or cutaneous adnexal carcinoma.

[0023] 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; preferably 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.

[0024] In some embodiments, the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer is administered at a frequency of QW, Q2W, Q3W or Q4W.

[0025] In some implementations, the immune checkpoint inhibitor is administered at the recommended dose in its product information label (PI) or pharmaceutical product characteristics summary (SmPC).

[0026] In some implementations, the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer is administered prior to the immune checkpoint inhibitor during each treatment cycle.

[0027] The present invention aims 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, comprising administering to a subject or patient a therapeutically effective amount of the antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer, 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 functional fragment:

[0028] In some embodiments, the antibody or its functional fragment comprises a heavy chain and a light chain, wherein (i) the heavy chain comprises three CDR regions, namely CDR1-H, CDR2-H and CDR3-H regions, 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

[0029] (ii) The light chain 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.

[0030] In some embodiments, the antibody or its functional fragment comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence as shown in SEQ ID NO. 7; and / or, the light chain variable region is selected from amino acid sequences as shown in SEQ ID NO. 8-10.

[0031] In some embodiments, the antibody or its functional fragment comprises a heavy chain constant region and a light chain constant region, wherein the heavy chain constant region has an amino acid sequence as shown in SEQ ID NO. 11 or SEQ ID NO. 13; and / or, the light chain constant region has an amino acid sequence as shown in SEQ ID NO. 12.

[0032] In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody selected from cimiplimab, nivolumab, pembrolizumab, dostarlimab, toripalimab, tislelizumab, or retifanlimab.

[0033] In some embodiments, the immune checkpoint inhibitor is an anti-PD-L1 antibody selected from atezolizumab, avelumab, or durvalumab.

[0034] In some implementations, the cancer is selected from urothelial carcinoma, breast cancer, head and neck cancer, colorectal cancer, pancreatic cancer, penile cancer, skin cancer, cervical cancer, endometrial cancer, ovarian cancer, prostate cancer, or lung cancer.

[0035] In some implementations, the cancer is selected from locally advanced or metastatic urothelial carcinoma (mUC), bladder cancer, triple-negative breast cancer (TNBC), head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), or cutaneous adnexal carcinoma.

[0036] In some embodiments, the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer is administered at a dose range from about 0.03 mg / kg to about 20.0 mg / kg per administration; preferably, from about 1.0 mg / kg to about 10.0 mg / kg; more preferably, from about 2.0 mg / kg to about 8.0 mg / kg; even more preferably, from about 1.8 mg / kg to about 2.5 mg / kg, or from about 2.5 mg / kg to about 3.0 mg / kg, or from about 3.0 mg / kg to about 3.5 mg / kg, or from about 3.5 mg / kg to about 4.0 mg / kg, or from about 4.0 mg / kg to about 4.5 mg / kg.

[0037] In some embodiments, the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer is administered at a frequency of QW, Q2W, Q3W or Q4W; the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer is administered over three or more dosing cycles.

[0038] In some implementations, the immune checkpoint inhibitor is administered at the recommended dose in its product information label (PI) or pharmaceutical product characteristics summary (SmPC).

[0039] In some implementations, the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer is administered prior to the immune checkpoint inhibitor in each treatment cycle.

[0040] In some embodiments, the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer and / or immune checkpoint inhibitor is administered on day 1 of each dosing cycle.

[0041] In some implementations, the subject or patient is a subject or patient who is intolerant to Nectin-4 targeted therapy.

[0042] In some implementations, the subject or patient is a subject or patient who has not previously received Nectin-4 targeted therapy.

[0043] In some implementations, the subject or patient is a subject or patient whose cancer has recurred after previous Nectin-4 targeted therapy.

[0044] In some implementations, the subject or patient is a subject or patient who has not previously received drug treatment containing MMAE. Attached image description:

[0045] Figure 1: Schematic diagram of the structure of antibody drug conjugate.

[0046] In this diagram, LND1002 represents the linker + drug molecule portion, and the circled area indicates the amide bond connection between the linker and the antibody in the L&D. The Nectin-4 ADC shown in this figure is a site-specific antibody-drug conjugate. Each molecule consists of one anti-Nectin-4 monoclonal antibody coupled to one MMAE derivative molecule at the Q295 amino acid position of each heavy chain via a linker (NH2-PEG3-Val-Cit). The antibody and linker are linked by a stable amide bond (isopeptide bond), and the average drug molecule to antibody ratio (DAR) is 2.0. Detailed implementation method:

[0047] The following examples are provided to better illustrate the content of the present invention, but are not intended to limit the scope of the invention to the illustrated examples. Non-essential improvements and adjustments made to the implementation schemes by those skilled in the art based on the above description are still within the protection scope of the present invention.

[0048] Terminology Explanation:

[0049] 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.

[0050] 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.

[0051] 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 invention, 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.

[0052] 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.

[0053] 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."

[0054] As used herein, the term “antibody” includes monoclonal antibodies (including full-length antibodies containing the Fc region of immunoglobulins), 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, F(ab')2, and Fv). The term “immunoglobulin (Ig)” may be used interchangeably with “antibody” in this document.

[0055] 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.

[0056] As used herein, the terms "heavy chain constant region" or "CH" are used interchangeably in this invention and refer to a heavy chain constant region comprising at least three heavy chain constant domains (CH1, CH2, and CH3). Exemplarily, human heavy chain constant regions include γ, δ, α, ε, and μ, each corresponding to an antibody isotype. For example, antibodies containing a γ constant region are IgG antibodies, antibodies containing a δ constant region are IgD antibodies, antibodies containing an α constant region are IgA antibodies, antibodies containing a μ constant region are IgM antibodies, and antibodies containing an ε constant region are IgE antibodies. Certain isotypes can be further subdivided into subclasses; for example, IgG antibodies include, but are not limited to, IgG1 (containing a γ1 constant region), IgG2 (containing a γ2 constant region), IgG3 (containing a γ3 constant region), and IgG4 (containing a γ4 constant region); IgA antibodies include, but are not limited to, IgA1 (containing an α1 constant region) and IgA2 (containing an α2 constant region); and IgM antibodies include, but are not limited to, IgM1 and IgM2. The isotype may also include modifications that alter Fc function, such as enhancing or weakening effector function or enhancing or weakening its binding to the Fc receptor. As described above, those skilled in the art will understand that the heavy chain constant regions may be modified so that they differ in amino acid sequence from naturally occurring immunoglobulin molecules.

[0057] As used herein, the terms "light chain constant region" or "CL" are used interchangeably in this invention, referring to a light chain constant structural domain CL. For example, light chains can be classified into two categories, λ and κ, depending on the type of light chain constant region.

[0058] As used in this article, the term "heavy chain variable region (VH)" refers to the amino-terminal variable region domain of the immunoglobulin heavy chain.

[0059] As used in this article, the term "light chain variable region (VL)" refers to the amino-terminal variable region domain of the immunoglobulin light chain.

[0060] As used herein, the term "CDR (Complementarity Determinant Region)" refers to the amino acid sequence that 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.

[0061] 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.

[0062] As used herein, the term “therapeutic effective dose” refers to a dose that has a therapeutic effect on a subject, such as: in subjects who have been given the dose, 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 subjects who have not been given the dose.

[0063] As used in this article, the following terms were determined by the investigators according to RECIST v1.1 criteria for evaluating the efficacy of treatment in solid tumors. As used in this article, the term "Complete response" or "CR" means the disappearance of all target and non-target lesions, with no new lesions appearing. As used in this article, the term "Partial response" or "PR" means that, compared to baseline, the sum of the longest diameters (SLD) of target lesions decreased by at least 30% (more than four weeks), with no progression of non-target lesions and no new lesions appearing. As used in this article, the term "Progressive disease" or "PD" means that, compared to the minimum Nadir, the SLD of target lesions increased by ≥20%, and the absolute value of the sum of diameters (SoD) increased by ≥5 mm, or there was clear progression of non-target lesions, or the appearance of new, clearly defined metastatic lesions. As used in this article, the term "Stable Disease" or "SD" means that the target lesion has not reached PD or PR compared with the minimum Nadir value, one or more non-target lesions and / or tumor markers are greater than normal, and no new lesions are generated.

[0064] As used herein, the following terms were determined by the investigators according to RECIST v1.1 criteria for evaluating treatment efficacy in solid tumors. Disease control rate (DCR): Defined as the percentage of participants who achieved a response (PR+CR) or stable disease for four months after treatment; DCR = CR+PR+SD. Objective response rate (ORR): Defined as the percentage of participants who achieved a complete response (CR) or partial response (PR) during the study period. Clinical benefit rate (CBR): Defined as the percentage of participants who achieved CR, PR, or SD. Progression-free survival (PFS): Defined as the time from first treatment to first disease progression or death from any cause during the study period, whichever comes first. Time to progress (TTP): Defined as the time from first treatment to first disease progression. Overall survival (OS): Defined as the time from first treatment to death from any cause. Duration of Response (DoR): Defined as the time from the initial CR or PR date to the PD date or death from any cause during the study, whichever occurs first. Time to Response (TTR): Defined as the time from the first treatment received in the study to the first documented CR or PR.

[0065] 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.

[0066] As used in this article, the term "intolerance" refers to a subject who has previously received anticancer treatment but experienced adverse events (such as peripheral neuropathy, skin toxicity, hyperglycemia, gastrointestinal symptoms) in the first two cycles, and whose symptoms did not improve despite following dose adjustment guidelines, leading to treatment discontinuation, without evidence of disease progression.

[0067] As used in this article, the term "relapse" refers to a cancer that was once effective against a certain anticancer treatment but has become less effective or less effective against that treatment.

[0068] As used in this article, the term "MMAE" refers to the microtubule inhibitor monomethylorestine E.

[0069] In this article, the immune checkpoint inhibitors may be commercially available or prepared by methods known to those skilled in the art.

[0070] In a first aspect, the present invention aims 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 functional fragment:

[0071] Formula I. In some embodiments, the antibody or its functional fragment comprises a heavy chain containing three CDR regions, namely CDR1-H, CDR2-H and CDR3-H regions, 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.

[0072] In some embodiments, the antibody or its functional fragment comprises a light chain containing three CDR regions, namely CDR1-L, CDR2-L and CDR3-L, wherein the CDR1-L, CDR2-L and CDR3-L regions have amino acid sequences as shown in SEQ ID NO.4, 5 and 6, respectively.

[0073] In some embodiments, the antibody or its functional fragment comprises a heavy chain and a light chain, the heavy chain comprising 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 the light chain comprises three CDR regions, namely CDR1-L, CDR2-L and CDR3-L, wherein the CDR1-L, CDR2-L and CDR3-L regions have amino acid sequences as shown in SEQ ID NO. 4, 5 and 6, respectively.

[0074] In some embodiments, the antibody or a functional fragment thereof comprises a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO.7.

[0075] In some embodiments, the antibody or a functional fragment thereof comprises a light chain variable region selected from amino acid sequences as shown in SEQ ID NO. 8-10.

[0076] In some embodiments, the antibody or its functional fragment comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region having an amino acid sequence as shown in SEQ ID NO. 7, and the light chain variable region being selected from amino acid sequences as shown in SEQ ID NO. 8-10.

[0077] In some embodiments, the antibody or a functional fragment thereof comprises a heavy chain constant region having an amino acid sequence as shown in SEQ ID NO. 11 or SEQ ID NO. 13.

[0078] In some embodiments, the antibody or a functional fragment thereof comprises a light chain constant region having an amino acid sequence as shown in SEQ ID NO.12.

[0079] In some embodiments, the antibody or its functional fragment comprises a heavy chain constant region and a light chain constant region, the heavy chain constant region having an amino acid sequence as shown in SEQ ID NO.11 or SEQ ID NO.13, and the light chain constant region having an amino acid sequence as shown in SEQ ID NO.12.

[0080] In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody selected from cimiplimab, nivolumab, pembrolizumab, dostarlimab, toripalimab, tislelizumab, or retifanlimab.

[0081] In some embodiments, the immune checkpoint inhibitor is an anti-PD-L1 antibody selected from atezolizumab, avelumab, or durvalumab.

[0082] In some implementations, the cancer is selected from bladder cancer, breast cancer, head and neck cancer, colorectal cancer, pancreatic cancer, penile cancer, skin cancer, cervical cancer, endometrial cancer, ovarian cancer, prostate cancer, or lung cancer.

[0083] In some implementations, the cancer is selected from locally advanced or metastatic urothelial carcinoma (mUC), triple-negative breast cancer (TNBC), head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), or cutaneous adnexal carcinoma.

[0084] 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; preferably, 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 any range between two points; more preferably, about 10 mg, 30 mg, about 50 mg, about 80 mg, about 120 mg, about 160 mg, or about 240 mg, or any range between two points.

[0085] In some embodiments, the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer is administered at a frequency of QW (once a week), Q2W (once every two weeks), Q3W (once every three weeks) or Q4W (once every four weeks).

[0086] In some implementations, the immune checkpoint inhibitor is administered at the recommended dose in its product information label (PI) or pharmaceutical product characteristics summary (SmPC).

[0087] In some implementations, during each treatment cycle, the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer is administered prior to the immune checkpoint inhibitor.

[0088] Secondly, the present invention aims to provide a method for treating cancer in combination with an antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer, and an immune checkpoint inhibitor, comprising administering to a subject or patient a therapeutically effective amount of the antibody-drug conjugate targeting Nectin-4 or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer, 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 functional fragment:

[0089] In some embodiments, the antibody or its functional fragment comprises a heavy chain containing three CDR regions, namely CDR1-H, CDR2-H and CDR3-H regions, 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.

[0090] In some embodiments, the antibody or its functional fragment comprises a light chain containing three CDR regions, namely CDR1-L, CDR2-L and CDR3-L, wherein the CDR1-L, CDR2-L and CDR3-L regions have amino acid sequences as shown in SEQ ID NO.4, 5 and 6, respectively.

[0091] In some embodiments, the antibody or its functional fragment comprises a heavy chain and a light chain, the heavy chain comprising 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 the light chain comprises three CDR regions, namely CDR1-L, CDR2-L and CDR3-L, wherein the CDR1-L, CDR2-L and CDR3-L regions have amino acid sequences as shown in SEQ ID NO. 4, 5 and 6, respectively.

[0092] In some embodiments, the antibody or a functional fragment thereof comprises a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO.7.

[0093] In some embodiments, the antibody or a functional fragment thereof comprises a light chain variable region selected from amino acid sequences as shown in SEQ ID NO. 8-10.

[0094] In some embodiments, the antibody or its functional fragment comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region having an amino acid sequence as shown in SEQ ID NO. 7; and the light chain variable region being selected from amino acid sequences as shown in SEQ ID NO. 8-10.

[0095] In some embodiments, the antibody or a functional fragment thereof comprises a heavy chain constant region having an amino acid sequence as shown in SEQ ID NO. 11 or SEQ ID NO. 13.

[0096] In some embodiments, the antibody or a functional fragment thereof comprises a light chain constant region having an amino acid sequence as shown in SEQ ID NO.12.

[0097] In some embodiments, the antibody or its functional fragment comprises a heavy chain constant region and a light chain constant region, the heavy chain constant region having an amino acid sequence as shown in SEQ ID NO. 11 or SEQ ID NO. 13; and the light chain constant region having an amino acid sequence as shown in SEQ ID NO. 12.

[0098] In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody selected from cimiplimab, nivolumab, pembrolizumab, dostarlimab, toripalimab, tislelizumab, or retifanlimab.

[0099] In some embodiments, the immune checkpoint inhibitor is an anti-PD-L1 antibody selected from atezolizumab, avelumab, or durvalumab.

[0100] In some implementations, the cancer is selected from bladder cancer, breast cancer, head and neck cancer, colorectal cancer, pancreatic cancer, penile cancer, skin cancer, cervical cancer, endometrial cancer, ovarian cancer, prostate cancer, or lung cancer.

[0101] In some implementations, the cancer is selected from locally advanced or metastatic urothelial carcinoma (mUC), triple-negative breast cancer (TNBC), head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), or cutaneous adnexal carcinoma.

[0102] In some embodiments, the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer is administered at a dose range from about 0.03 mg / kg to about 20.0 mg / kg per administration; preferably, from about 1.0 mg / kg to about 10.0 mg / kg, more preferably, from 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, 2.0 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. The dosage ranges are 2.8 mg / kg, 2.9 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, 4.5 mg / kg, 5.0 mg / kg, 5.5 mg / kg, 6.0 mg / kg, or any range between two points. In some embodiments, preferably, the dosage range for each administration is from about 1.8 mg / kg to about 4.5 mg / kg, or from about 2.5 mg / kg to about 3.0 mg / kg, or from about 3.0 mg / kg to about 3.5 mg / kg, or from about 3.5 mg / kg to about 4.0 mg / kg, or from about 4.0 mg / kg to about 4.5 mg / kg.

[0103] In some embodiments, the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer is administered in low doses. The low dose is a range of doses from about 0.1 mg / kg to about 2.0 mg / kg per administration; for example, about 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 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, or a range between any two values.

[0104] In some embodiments, the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer is administered in high doses. These high doses range from about 2.1 mg / kg to about 6.0 mg / kg per administration; for example, about 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, 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, etc. g / 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, 4.6 mg / kg, 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5.0 mg / kg, 5.1 mg / kg, 5.2 mg / kg, 5.3 mg / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7 mg / kg, 5.8 mg / kg, 5.9 mg / kg, 6.0 mg / kg, or a range between any two values.

[0105] In some embodiments, the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer is administered at a frequency of QW, Q2W, Q3W or Q4W.

[0106] In some implementations, the immune checkpoint inhibitor (e.g., anti-PD-L1 antibody or anti-PD-1 antibody) is administered at the recommended dose in its product information label (PI) or pharmaceutical product characteristics summary (SmPC).

[0107] In some implementations, the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer is administered prior to the immune checkpoint inhibitor in each treatment cycle.

[0108] Thirdly, the object of the present invention is to provide a pharmaceutical composition comprising an antibody-drug conjugate targeting Nectin-4 as described above, or a pharmaceutical salt, ester, solvate, tautomer or stereoisomer thereof, and an immune checkpoint inhibitor as described above.

[0109] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

[0110] In some embodiments, the pharmaceutical composition includes components that are separated in time and / or space, which work together to achieve the objectives of the invention. For example, the components contained in the pharmaceutical composition may be administered to a patient or subject as a whole or individually. When the components contained in the pharmaceutical composition are administered to a subject separately, these components may be administered to the patient or subject simultaneously or sequentially.

[0111] In some implementations, the pharmaceutically acceptable carrier is selected from water, buffered aqueous solutions, isotonic salt solutions (e.g., phosphate-buffered saline solution PBS), glucose, mannitol, lactose, starch, magnesium stearate, cellulose, magnesium carbonate, 0.3% glycerol, hyaluronic acid, ethanol, polyolefin alcohols (e.g., polypropylene glycol), and triglycerides.

[0112] In some embodiments, the type of pharmaceutically acceptable carrier depends primarily on whether the composition formulated according to the present invention is intended for oral, nasal, intradermal, subcutaneous, intramuscular, or intravenous administration. The compositions formulated according to the present invention may contain wetting agents, emulsifiers, or buffering substances as additives.

[0113] In this invention, the amino acid sequences of the aforementioned CDRs are all as shown in the IMGT definition rules (the sequences in the claims of this invention are also defined according to the IMGT rules). However, it is well known to those skilled in the art that antibody CDRs can be defined in various ways, such as the Kabat definition rules based on sequence variability (see, Kabat et al., Immunological Protein Sequences, 5th Edition, National Institutes of Health, Bethesda, Maryland (1991)) and the Chothia definition rules based on the location of structural loop regions (see J.Mol. Biol 273:927-48, 1997). Those skilled in the art should understand 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 complementarity-determining regions defined by any of the known schemes described above. Although the scope of protection claimed in the claims of this invention is based on the sequences shown in the IMGT definition rules, the amino acid sequences corresponding to other CDR definition rules should also fall within the scope of protection of this invention.

[0114] In the first to third aspects:

[0115] In some embodiments, the antibody-drug conjugate targeting Nectin-4 has a structure represented by Formula I:

[0116] in,

[0117] A is any of the aforementioned antibodies targeting Nectin-4 or its functional fragments;

[0118] d is an integer or decimal from 1 to 12; preferably, d is 2.

[0119] In some embodiments, the antibody targeting Nectin-4 or a functional fragment thereof contains Q295 (EU number) in the constant region of its heavy chain, and the linker portion is linked to the side chain of the Q295 via an amide bond.

[0120] In some implementations, the method results in complete or partial relief.

[0121] In some implementations, the method results in lower plasma free MMAE levels compared to EV treatment.

[0122] In some implementations, the method results in fewer treatment-related adverse events compared to EV treatment.

[0123] In some embodiments of the present invention, the antibody targeting Nectin-4 or its functional fragment is selected from murine antibodies, chimeric antibodies, humanized antibodies or fully human antibodies.

[0124] In some embodiments of the present invention, the functional fragment is selected from the Fab fragment, F(ab')2 fragment, Fab' fragment, Fv fragment, dsFv fragment, or scFv fragment.

[0125] In some embodiments of the present invention, the immune checkpoint inhibitor may be commercially available or homemade.

[0126] In some embodiments of the present invention, the heavy chain of the pembrolizumab has the following sequence:

[0127] QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQ GTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP CPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO. 21); The light chain of the pembrolizumab has the following sequence:

[0128] In some embodiments of the present invention, the heavy chain of the cimipril imab has the following sequence:

[0129] EVQLLESGGVLVQPGGSLRLSCAASGFTFSNFGMTWVRQAPGKGLEWVSGISGGGRDTYFADSVKGRFTISRDNSKNTLYLQMNSLKGEDTAVYYCVKWGNIYFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO.15); The light chain of the cemiplimab has the following sequence:

[0130] In some embodiments of the present invention, the heavy chain of the atezolizumab has the following sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK VDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO.17); The light chain of the atezolizumab has the following sequence:

[0131] In some embodiments of the present invention, the heavy chain of the avelumab has the following sequence:

[0132] EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPSGGITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQG TLVTVSSASTKGPSVFPLAPSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO.19); The light chain of the avirumab has the following sequence:

[0133] In some embodiments of the present invention, the dosage of the immune checkpoint inhibitor (e.g., anti-PD-L1 antibody or anti-PD-1 antibody) is from about 200 mg to about 2000 mg (e.g., between about 200 mg and about 300 mg, for example, between about 300 mg and about 400 mg, for example, between about 400 mg and about 500 mg, for example, between about 500 mg and about 600 mg, for example, between about 600 mg and about 700 mg, for example, between about 700 mg and about 800 mg, for example, between about 800 mg and about 900 mg, for example, between about 900 mg and about 1000 mg). For example, between about 1000 mg and about 1100 mg, for example, between about 1100 mg and about 1200 mg, for example, between about 1200 mg and about 1300 mg, for example, between about 1300 mg and about 1400 mg, for example, between about 1400 mg and about 1500 mg, for example, between about 1500 mg and about 1600 mg, for example, between about 1600 mg and about 1700 mg, for example, between about 1700 mg and about 1800 mg, for example, between about 1800 mg and about 1900 mg, for example, between about 1900 mg and about 2000 mg).

[0134] In some embodiments of the present invention, the dose of the immune checkpoint inhibitor (e.g., anti-PD-L1 antibody or anti-PD-1 antibody) is 350 mg. In some embodiments of the present invention, the dose of the immune checkpoint inhibitor (e.g., anti-PD-L1 antibody or anti-PD-1 antibody) is 800 mg. In some embodiments of the present invention, the dose of the immune checkpoint inhibitor (e.g., anti-PD-L1 antibody or anti-PD-1 antibody) is 850 mg. In some embodiments of the present invention, the dose of the immune checkpoint inhibitor (e.g., anti-PD-L1 antibody or anti-PD-1 antibody) is 1200 mg. In some embodiments of the present invention, the dose of the immune checkpoint inhibitor (e.g., anti-PD-L1 antibody or anti-PD-1 antibody) is 1680 mg.

[0135] In some embodiments of the present invention, the dosage of atezolizumab is 850 mg intravenously every two weeks, 1200 mg intravenously every three weeks, or 1680 mg intravenously every four weeks.

[0136] In some embodiments of the present invention, the dosage of the cimiprimab is 350 mg administered intravenously every three weeks.

[0137] In some embodiments of the present invention, the dosage of the avelumab is 800 mg administered intravenously every two weeks.

[0138] In some embodiments of the present invention, 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 of the present invention, 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 of the present invention, 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).

[0139] In some embodiments of the present invention, the immune checkpoint inhibitor (e.g., an anti-PD-L1 antibody or an anti-PD-1 antibody) 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 of the present invention, the immune checkpoint inhibitor (e.g., an anti-PD-L1 antibody or an anti-PD-1 antibody) may be administered for three or more dosing cycles. In some embodiments of the present invention, the dosing cycle of the immune checkpoint inhibitor (e.g., anti-PD-L1 antibody or anti-PD-1 antibody) continues until the clinical benefit is lost (e.g., confirmed as disease progression, drug resistance, death, or unacceptable toxicity).

[0140] In some embodiments of the invention, the length of each of the one or more dosing cycles is 14 days. In some embodiments of the invention, the length of each of the one or more dosing cycles is 21 days. In some embodiments of the invention, the length of each of the one or more dosing cycles is 28 days. Preferably, the length of each of the one or more dosing cycles is 21 days.

[0141] In some embodiments of the present invention, the antibody-drug conjugate 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.

[0142] In some embodiments of the present invention, the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer and / or immune checkpoint inhibitor is administered once every 4 weeks (Q4W), with 28 days as one treatment cycle.

[0143] In some embodiments of the present invention, the antibody-drug conjugate 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.

[0144] In some embodiments of the present invention, the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer and / or immune checkpoint inhibitor is administered once weekly (QW) for 3 consecutive weeks, followed by a 1-week break, with 28 days constituting one treatment cycle.

[0145] In some embodiments of the present invention, the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer and / or immune checkpoint inhibitor is administered once weekly (QW) for two consecutive weeks, followed by a one-week break, with 21 days constituting one treatment cycle.

[0146] In some embodiments of the invention, preferably, the antibody drug conjugate or a pharmaceutically acceptable salt thereof is administered at a frequency of Q2W, and the antibody drug conjugate 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 administration, more preferably about 2.4 mg / kg or about 2.7 mg / kg.

[0147] In some embodiments of the invention, preferably, the antibody drug conjugate or a pharmaceutically acceptable salt thereof is administered at a frequency of Q3W, and the antibody drug conjugate or a pharmaceutically acceptable salt thereof (by weight of the antibody drug conjugate) is administered at a dose range from about 2.0 mg / kg to about 4.0 mg / kg per administration, more preferably, about 1.8 mg / kg, about 2.4 mg / kg, about 2.7 mg / kg, about 3.6 mg / kg or about 4.5 mg / kg.

[0148] In some embodiments of the present invention, the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer is administered approximately on day 1 of each dosing cycle.

[0149] In some embodiments of the present invention, the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer is administered at a frequency of 2.7 mg / kg, Q3W.

[0150] In some embodiments of the present invention, the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer is administered at a dose of 3.6 mg / kg per administration at a frequency of Q3W.

[0151] In some embodiments of the present invention, the immune checkpoint inhibitor is pembrolizumab.

[0152] In some embodiments of the present invention, the pembrolizumab is administered at a dose of 200 mg every 3 weeks.

[0153] In some embodiments of the invention, the immune checkpoint inhibitor (e.g., an anti-PD-L1 antibody or an anti-PD-1 antibody) is administered approximately on day 1 of each dosing cycle (e.g., day 1, 2, 3, or 4).

[0154] In some embodiments of the present invention, the cancer is a cancer that expresses, highly expresses, or overexpresses Nectin-4.

[0155] In some embodiments of the present invention, the cancer is preferably a solid tumor.

[0156] In some embodiments of the present invention, the subject or patient is a subject or patient who has not previously received Nectin-4 targeted therapy.

[0157] In some embodiments of the present invention, the subject or patient is a subject or patient who has not previously received EV treatment.

[0158] In some embodiments of the present invention, the subject or patient is a subject or patient who is intolerant to Nectin-4 targeted therapy.

[0159] In some embodiments of the present invention, the subject or patient is a subject or patient whose cancer has recurred after previous Nectin-4 targeted therapy.

[0160] In some embodiments of the present invention, the subject or patient is a subject or patient who has not previously received treatment with a drug containing MMAE.

[0161] In some embodiments of the present invention, the subject or patient is a subject or patient who has failed standard treatment or has previously failed treatment.

[0162] In some embodiments of the present invention, the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer is administered intravenously. In some embodiments, the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer, or stereoisomer is administered via intravenous infusion for more than 60 ± 5 minutes (e.g., 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).

[0163] In some embodiments of the invention, the immune checkpoint inhibitor (e.g., an anti-PD-L1 antibody or an anti-PD-1 antibody) is administered via intravenous injection. In some embodiments of the invention, the immune checkpoint inhibitor (e.g., an anti-PD-L1 antibody or an anti-PD-1 antibody) is administered via intravenous infusion for more than 30 ± 5 minutes (e.g., about 25 minutes, about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, about 30 minutes, about 31 minutes, about 32 minutes, about 33 minutes, about 34 minutes, or about 35 minutes). In some cases, the immune checkpoint inhibitor (e.g., an anti-PD-L1 antibody or an anti-PD-1 antibody) is administered via intravenous infusion for more than 60 ± 5 minutes (e.g., 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).

[0164] In this document, SWY2001-Ab3-LND1002 refers to the drug-linker represented by Formula I of this invention, conjugated 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 HC1 (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 enzymatic conjugation method (sequence shown in SEQ ID NO. 14 in Table 3). This patent is incorporated herein by reference in its entirety.

[0165] Detailed Implementation

[0166] Example 1: A Phase I / II clinical trial evaluating the safety, pharmacokinetic characteristics, and efficacy of SWY2001-Ab3-LND1002 combined with anti-PD(L)-1 therapy in patients with advanced solid tumors.

[0167] Determine the Phase II recommended dose (RP2D) for the combination of SWY2001-Ab3-LND1002 with an approved or standardized dose regimen of anti-PD(L)-1 therapy.

[0168] Using a TOP (time-to-event Bayesian optimal phase II) study design (Zhou et al., 2017; Lin et al., 2020), two dose levels of SWY2001-Ab3-LND1002 were evaluated in terms of efficacy (measured by DCR), safety, tolerability, and pharmacokinetics. This combination therapy was evaluated in two patient populations: mUC (nearly Nectin-4 targeted therapy) and / or cervical cancer (nearly MMAE-containing drugs).

[0169] 1. Drug Information and Experimental Protocol

[0170] 1.1 Drug Information

[0171] Test drug 1: SWY2001-Ab3-LND1002 (recombinant humanized anti-human Nectin-4 monoclonal antibody-MMAE conjugate for injection).

[0172] Specification: 30mg / bottle.

[0173] Dosage form: Powder for injection.

[0174] Storage conditions: Store at 2-8℃, away from light. Avoid light and shaking before use.

[0175] Investigational drug 2: Pembrolizumab.

[0176] 1.2 Experimental Objectives and Endpoints

[0177] Table 1 Objectives and corresponding endpoints

[0178] 1.3 Research Design

[0179] This is an open-label, phase I / II clinical trial designed to evaluate the safety, pharmacokinetic (PK) profile, and efficacy of SWY2001-Ab3-LND1002 in combination with a PD(L)-1 antibody in patients with advanced solid tumors expressing Nectin-4. Table 2 summarizes the study population and the treatments they will receive.

[0180] Sponsors may, at their discretion, add more participants, suspend or terminate enrollment, or decide to terminate the program, based on adverse safety data, the rate of participant accumulation, or other reasonable reasons. This protocol may be revised to expand the cohort exploring SWY2001-Ab3-LND1002 in different regimens, combinations, or tumor types.

[0181] For all enrolled participants, study treatment will continue until intolerable toxicity, death, withdrawal of consent, or confirmed disease progression (PD) by the investigator according to the Remedial Evaluation Criteria for Solid Tumors (RECIST) v1.1. Confirmed disease progression requires a new imaging evaluation ≥4 weeks after the initial radiographic progression. According to RECIST v1.1, if a repeat scan confirms PD, the PD date should be the date the initial tumor assessment showed progression.

[0182] All study participants will undergo standard (clinical and laboratory) assessments as per the activity schedule, as well as assessments for pharmacokinetic (PK) and immunogenicity (anti-drug antibodies [ADA]). Clinical and laboratory adverse events (AEs) will be reported and graded according to the National Cancer Institute Common Adverse Event Terminology Assessment (NCI-CTCAE) (v5.0). Guidelines for dose interruptions (such as toxicity) will be included in the protocol.

[0183] Table 2 Patient Population and Number

[0184] 1.4 Dosage

[0185] The dosage of SWY2001-Ab3-LND1002 in combination with anti-PD(L)-1 is based on

[0186] Safety, pharmacokinetic (PK), prognostic dose (PmD), and preliminary efficacy data from the SWY2001-Ab3-LND1002 monotherapy clinical trial were established. The high dose will not exceed the maximum tolerated dose (MTD) defined in the monotherapy clinical trial results, but the dose of SWY2001-Ab3-LND1002 may differ from the monotherapy dose depending on the selected anti-PD(L)-1 therapy.

[0187] The dosage of anti-PD(L)-1 therapy will be administered according to the recommended dosage in the drug information sheet (PI) or pharmaceutical product characteristics summary (SmPC).

[0188] Subjects received an intravenous infusion of SWY2001-Ab3-LND1002 at a dose of 2.7 mg / kg or 3.6 mg / kg, and pembrolizumab at a dose of 200 mg per infusion.

[0189] SWY2001-Ab3-LND1002 and anti-PD(L)-1 will be administered intravenously (IV) over 30 minutes on day 1 of every 21-day cycle. SWY2001-Ab3-LND1002 will be given first, followed by the anti-PD(L)-1 drug.

[0190] 2.1 Study population

[0191] 2.1.1 Inclusion criteria

[0192] Only patients who meet all inclusion criteria and not any exclusion criteria will be included in the study. Sponsors will not recognize waivers of eligibility criteria.

[0193] 1. Sign the Informed Consent Form (ICF).

[0194] 2. Male or female patients aged ≥18 years when signing the informed consent form.

[0195] 3. Histologically and / or cytologically confirmed advanced or metastatic solid tumors (relapsed / refractory disease), with disease progression after at least one first-line treatment, or no other currently available standard therapy that has demonstrated clinical benefit or is recommended based on the investigator's personal risk-benefit assessment of the participant.

[0196] d: Grouping patients with Nectin-4 positive tumors:

[0197] i. mUC patients who have not received Nectin-4 targeted therapy

[0198] ii. Cervical cancer patients who have not received drug therapy containing MMAE

[0199] 4. Assess at least one radiographically measurable target lesion according to RECIST v1.1.

[0200] 5. Eastern Cooperative Oncology Group (ECOG) performance status score ≤2.

[0201] 6. Expected survival ≥ 12 weeks.

[0202] 7. Hematological and visceral organ function are normal, based on the following laboratory results obtained within 14 days prior to day 1 of the first cycle (C1D1):

[0203] Blood function:

[0204] a. No component blood transfusions or human granulocyte colony-stimulating factor were received within 2 weeks prior to C1D1.

[0205] (GCSF), thrombopoietin (TPO), interleukin-11, or erythropoietin

[0206] (EPO).

[0207] b. Absolute neutrophil count (ANC) ≥ 1.0 x 10⁻⁶ 9 / L (1500 / μL), without G-CSF support. G-CSF can be used up to 14 days prior to C1D1.

[0208] c. Platelet count ≥100×109 / L (100,000 / μL), no blood transfusion required.

[0209] d. Hemoglobin ≥90g / L (9g / dL) or ≥5.6mmol / L. Patients may receive blood transfusions or erythropoiesis-stimulating therapy up to 14 days prior to C1D1.

[0210] e. For patients not receiving therapeutic anticoagulants: International Normalized Ratio (INR) and (activated partial thromboplastin time) (aPTT or PTT) ≤ 1.5 × Upper Limit of Normal (ULN). Patients receiving therapeutic anticoagulants should maintain a stable dose. For patients receiving other oral anticoagulant therapy, aPTT / PTT must be within the expected therapeutic range of the anticoagulant and should be monitored according to local standards.

[0211] Liver function:

[0212] f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3×ULN (≤5×ULN for patients with liver metastases).

[0213] g. Total bilirubin ≤1.5×ULN (≤3×ULN for patients with Gilbert's syndrome).

[0214] Kidney function:

[0215] h. Creatinine clearance (CrCl) ≥ 30 mL / min, calculated using the institution’s standard methods (e.g., the Cockcroft-Gault equation).

[0216] 8. Women: Postmenopausal women may be able to adhere to the contraceptive requirements of the plan.

[0217] Male: Agrees to the contraceptive requirements in the plan. Partner: Postmenopausal (female) or able to adhere to the contraceptive requirements in the plan (male or female).

[0218] Exclusion criteria

[0219] Patients will be excluded from the study if they meet any of the following criteria.

[0220] Medical condition

[0221] 1. Active and uncontrolled central nervous system (CNS) metastases. Patients with CNS metastases are eligible if they have received standard treatment, are asymptomatic, are on a stable dose of systemic steroids (i.e., ≤10 mg / day of prednisone or equivalent) and anticonvulsants, and have shown no signs of disease progression for at least 4 weeks prior to receiving the first treatment in this study.

[0222] 2. Except for the diseases studied, a history of malignant tumors diagnosed within three years prior to enrollment in this study, excluding fully treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or cervical cancer in situ, breast cancer in situ, or prostate cancer in situ (patients must have no evidence of active disease within 2 years prior to enrollment).

[0223] 3. A history of ascites or pleural effusion, asymptomatic unless successfully treated, and not requiring treatment for more than 4 months prior to the first dose in this study.

[0224] 4. A history of cardiovascular events or conditions within the 6 months prior to receiving C1D1 and / or a current history of cardiovascular events or conditions:

[0225] a. History of myocardial infarction, unstable or severe angina, or arterial thrombotic events (such as cerebrovascular attack (CVA) or transient ischemic attack (TIA));

[0226] b. Currently classified as congestive heart failure by the New York Heart Association (NYHA) in class II-IV;

[0227] c. Left ventricular ejection fraction (LVEF) less than 50%;

[0228] d. Severe PR conduction abnormalities, such as ventricular arrhythmias and ventricular arrhythmias requiring clinical intervention and third-degree atrioventricular block; unstable arrhythmias, presence or clinically significant (investigator's opinion) ECG abnormalities or history; QT interval (QTcF) > 480 ms corrected using the Fridericia method during the screening period.

[0229] e. Uncontrolled hypertension, i.e., systolic blood pressure (SBP) > 150 mmHg after optimal antihypertensive treatment.

[0230] mmHg and / or diastolic (DBP) >100 mmHg.

[0231] i. Note: Within 4 weeks prior to the screening visit, as part of routine patient care, LVEF can be assessed by echocardiography (ECHO) or multi-probe acquisition (MUGA) scans to confirm eligibility for screening.

[0232] 5. History of grade ≥2 neuropathy.

[0233] 6. Glycated hemoglobin A1C (HbA1C) ≥ 8%, uncontrolled diabetes or known diabetic neuropathy. Uncontrolled diabetes is defined as HbA1C > 8% or HbA1C > 7% accompanied by diabetes-related symptoms (polydipsia or polyuria).

[0234] 7. Severe infection occurring within the four weeks prior to C1D1, including but not limited to:

[0235] a. Bacteremia and severe pneumonia requiring hospitalization

[0236] b. Active infection requiring systemic antibiotic, antiviral and antifungal treatment within two weeks prior to C1D1 with a common adverse reaction terminology rating (CTCAE v 5) ≥2.

[0237] 8. A positive result for any of the following tests during the screening period:

[0238] a. Human Immunodeficiency Virus (HIV). Patients must have received established antiretroviral therapy (ART) for at least 4 weeks, have a viral load of less than 400 copies / mL, and have CD4+. 4+ HIV patients with a T-cell count ≥350 μL are eligible to enroll.

[0239] b. Hepatitis B surface antigen (HBsAg)

[0240] c. Hepatitis B core antibody (HBcAb)

[0241] i. Patients who test positive for HBcAb but negative for hepatitis B virus (HBV) deoxyribonucleic acid (DNA) during the screening period can be enrolled.

[0242] ii. Patients with HBV DNA positive <500 IU / L during the screening period, who started anti-HBV therapy at least 14 days before C1D1, and who are willing to continue anti-HBV therapy during the study period.

[0243] (According to institutional care standards). Patients whose infection has been controlled must have their HBV DNA monitored regularly as required by their attending physician.

[0244] d. Hepatitis C virus (HCV) antibody test

[0245] i. Patients who test positive for HCV antibodies but negative for HCV ribonucleic acid (RNA) during the screening period can be enrolled.

[0246] ii. Patients who test positive for hepatitis C virus antibodies (HCV Ab+) by PCR spontaneously or as a response to a previous course of anti-HCV treatment.

[0247] 9. Active thrombophlebitis, thromboembolism, rapid clotting, or uncontrollable bleeding.

[0248] 10. Active ocular surface disease at baseline (based on ophthalmological examination at the screening period).

[0249] 11. Chronic severe liver disease or cirrhosis.

[0250] 12. Systemic autoimmune diseases (e.g., systemic lupus erythematosus [SLE], active rheumatoid arthritis, inflammatory bowel disease [ulcerative colitis, Crohn's disease, etc.]), except for patients with autoimmune-mediated hypothyroidism with well-controlled thyroid replacement hormone, eczema, psoriasis, or chronic simple lichen simplex covering no more than 10% of the body surface area at the screening period.

[0251] 13. Patients with interstitial lung disease (such as idiopathic pulmonary fibrosis) or pneumonia, except those who had radiation-induced pneumonia (pulmonary fibrosis) in the radiation field more than 6 months prior to C1D1.

[0252] 14. Any active or symptomatic persistent infection (bacterial, viral, or fungal) requiring systemic treatment within 14 days prior to the first treatment received in the study. Routine antibiotic prophylaxis is permitted.

[0253] 15. Any mental illness or other condition that would restrict compliance with research requirements.

[0254] 16. Any other significant complications, illnesses, metabolic disorders, physical examinations, or clinical laboratory findings that would preclude the administration of the study drug, or risks that could lead to unacceptable treatment complications, or could affect compliance with study procedures or the interpretation of results.

[0255] Previous / Concomitant Treatment

[0256] 17. Received anti-cancer treatment within the following timeframes:

[0257] a. Use of cytotoxic chemotherapy, mAb and / or small molecule tyrosine kinase inhibitors within 14 days prior to C1D1;

[0258] b. Use of nitrosourea or mitomycin-C within 42 days prior to C1D1;

[0259] c. Receive any investigational cancer treatment within 28 days or 5 half-lives of C1D1 (whichever is shorter).

[0260] 18. Has received an organ transplant (including an allogeneic bone marrow transplant).

[0261] 19. Systemic corticosteroid therapy for any indication, including replacement therapy for adrenal insufficiency within 7 days prior to the first dose.

[0262] a. Patients receiving inhaled or topical corticosteroid treatment or topical steroid injections may participate in the study.

[0263] b. Patients who have a stable daily oral prednisolone dose of ≤10 mg (or equivalent) for at least 7 days prior to their first dose are eligible to participate in the study.

[0264] 20. Received a live attenuated vaccine within 28 days prior to the first dose, or is expected to receive such a vaccine during the first dose. Coronavirus Disease 2019 (COVID-19) vaccines are acceptable.

[0265] 21. Any other therapies that are prohibited during the study period.

[0266] Other exclusion criteria

[0267] 22. Allergic to the investigational drug or any component of the investigational drug.

[0268] 23. History of drug-induced allergies or other severe hypersensitivity reactions.

[0269] 24. History of any of the following: severe adverse skin reaction to a drug (SCAR; including but not limited to Stevens-Johnson syndrome / toxic epidermal necrolysis SJS / TEN], or a drug reaction with eosinophilia and systemic symptoms [DRESS]), or an immune-mediated dose-limiting reaction.

[0270] 25. Pregnancy and lactation.

[0271] Example 2: Treatment of HNSCC, mUC or cervical cancer with SWY2001-Ab3-LND1002 in combination with pembrolizumab

[0272] Using the methods disclosed herein, physicians can treat subjects (e.g., human patients) with locally advanced or metastatic head and neck squamous cell carcinoma (HNSCC), locally advanced or metastatic urothelial carcinoma (mUC), or cervical cancer. To treat such subjects, physicians administer SWY2001-Ab3-LND1002 in combination with pembrolizumab.

[0273] In some implementations, the subject has not previously received treatment targeting nectin-4. In some implementations, the subject has not previously received treatment containing a MMAE (monomethylolpropionate E). For example, in some implementations, the subject has HNSCC and has not received treatment targeting nectin-4 or a MMAE-containing drug. In other implementations, the subject has cervical cancer and has not received treatment targeting nectin-4 or a MMAE-containing drug.

[0274] In some implementations, the subject's cancer recurred after treatment with a Nectin-4 targeted drug (such as PADCEV). For example, some subjects had mUC and recurred after receiving PADCEV treatment.

[0275] SWY2001-Ab3-LND1002 can be administered intravenously at a dose of approximately 2.7 mg / kg or approximately 3.6 mg / kg, while pembrolizumab can be administered intravenously at a dose of approximately 200 mg. Both drugs can be used in combination on day 1 of each 21-day dosing cycle (Q3W), and SWY2001-Ab3-LND1002 should be administered before pembrolizumab.

[0276] After administering combination therapy, physicians can monitor patient response to treatment using various methods. For example, the objective response rate (ORR) can be assessed, which is the proportion of patients achieving complete remission (CR) or partial remission (PR) according to RECIST v1.1 criteria. Subsequent doses can be adjusted and administered as needed.

[0277] Table 3 Sequence information 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 a functional fragment thereof:

2. The use according to claim 1, wherein the antibody or its functional fragment comprises a heavy chain and a light chain, wherein, (i) The heavy chain 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 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.

3. In the use according to claim 1 or 2, the antibody or its functional fragment comprises a heavy chain variable region and a light chain variable region, wherein, The heavy chain variable region has an amino acid sequence as shown in SEQ ID NO. 7; and / or, the light chain variable region is selected from amino acid sequences as shown in SEQ ID NO. 8-10.

4. The use according to any one of claims 1-3, wherein the antibody or its functional fragment comprises a heavy chain constant region and a light chain constant region, wherein, The heavy chain constant region has an amino acid sequence as shown in SEQ ID NO. 11 or SEQ ID NO. 13; and / or, the light chain constant region has an amino acid sequence as shown in SEQ ID NO.

12.

5. The use according to any one of claims 1-4, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, wherein the anti-PD-1 antibody is selected from cimiplimab, nivolumab, pembrolizumab, dostarlimab, toripalimab, tislelizumab, or retifanlimab.

6. The use according to any one of claims 1-4, wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody is selected from atezolizumab, avelumab, or durvalumab.

7. The use according to any one of claims 1-6, wherein the cancer is selected from urothelial carcinoma, breast cancer, head and neck cancer, colorectal cancer, pancreatic cancer, penile cancer, skin cancer, cervical cancer, endometrial cancer, ovarian cancer, prostate cancer, or lung cancer.

8. The use according to any one of claims 1-7, wherein the cancer is selected from locally advanced or metastatic urothelial carcinoma (mUC), bladder cancer, triple-negative breast cancer (TNBC), head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), or cutaneous adnexal carcinoma.

9. The use according to any one of claims 1-8, wherein 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; preferably 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.

10. The use according to any one of claims 1-9, wherein the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer is administered at a frequency of QW, Q2W, Q3W or Q4W.

11. The use according to any one of claims 1-10, wherein the immune checkpoint inhibitor is administered at the recommended dose in its product information label (PI) or pharmaceutical product characteristics summary (SmPC).

12. The use according to any one of claims 1-11, wherein in each treatment cycle, the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer is administered prior to the immune checkpoint inhibitor.

13. A method for treating cancer using an antibody-drug conjugate targeting Nectin-4 or a pharmaceutical salt, ester, solvate, tautomer, or stereoisomer thereof in combination with an immune checkpoint inhibitor, comprising administering to a subject or patient a therapeutically effective amount of the 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 targeting Nectin-4 or a functional fragment thereof:

14. The method of claim 13, wherein the antibody or a functional fragment thereof comprises a heavy chain and a light chain, wherein, (i) The heavy chain 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 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.

15. The method according to claim 13 or 14, wherein the antibody or its functional fragment comprises a heavy chain variable region and a light chain variable region, wherein, The heavy chain variable region has an amino acid sequence as shown in SEQ ID NO. 7; and / or, the light chain variable region is selected from amino acid sequences as shown in SEQ ID NO. 8-10.

16. The method according to any one of claims 13-15, wherein the antibody or its functional fragment comprises a heavy chain constant region and a light chain constant region, wherein, The heavy chain constant region has an amino acid sequence as shown in SEQ ID NO. 11 or SEQ ID NO. 13; and / or, the light chain constant region has an amino acid sequence as shown in SEQ ID NO.

12.

17. The method according to any one of claims 13-16, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, said anti-PD-1 antibody being selected from cimiplimab, nivolumab, pembrolizumab, dostarlimab, toripalimab, tislelizumab, or retifanlimab.

18. The method according to any one of claims 13-17, wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody selected from atezolizumab, avelumab, or durvalumab.

19. The method according to any one of claims 13-18, wherein the cancer is selected from urothelial carcinoma, breast cancer, head and neck cancer, colorectal cancer, pancreatic cancer, penile cancer, skin cancer, cervical cancer, endometrial cancer, ovarian cancer, prostate cancer, or lung cancer.

20. The method according to any one of claims 13-19, wherein the cancer is selected from locally advanced or metastatic urothelial carcinoma (mUC), bladder cancer, triple-negative breast cancer (TNBC), head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), or cutaneous adnexal carcinoma.

21. The method according to any one of claims 13-20, wherein the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer is administered at a dose range from about 0.03 mg / kg to about 20.0 mg / kg per administration; preferably, from about 1.0 mg / kg to about 10.0 mg / kg; more preferably, from about 2.0 mg / kg to about 8.0 mg / kg; even more preferably, from about 1.8 mg / kg to about 2.5 mg / kg, or from about 2.5 mg / kg to about 3.0 mg / kg, or from about 3.0 mg / kg to about 3.5 mg / kg, or from about 3.5 mg / kg to about 4.0 mg / kg, or from about 4.0 mg / kg to about 4.5 mg / kg.

22. The method according to any one of claims 13-21, wherein the antibody drug conjugate or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer is administered at a frequency of QW, Q2W, Q3W or Q4W; and the antibody drug conjugate or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer is administered over three or more dosing cycles.

23. The method according to any one of claims 13-22, wherein the immune checkpoint inhibitor is administered at the recommended dose in its product information label (PI) or pharmaceutical product characteristics summary (SmPC).

24. The method according to any one of claims 13-23, wherein the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer is administered prior to the immune checkpoint inhibitor in each treatment cycle.

25. The method according to any one of claims 13-24, wherein the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer and / or immune checkpoint inhibitor is administered on day 1 of each dosing cycle.

26. The method according to any one of claims 13-25, wherein the subject or patient is a subject or patient who is intolerant to Nectin-4 targeted therapy.

27. The method according to any one of claims 13-25, wherein the subject or patient is a subject or patient who has not previously received Nectin-4 targeted therapy.

28. The method according to any one of claims 13-25, wherein the subject or patient is a subject or patient whose cancer has recurred after previous Nectin-4 targeted therapy.

29. The method according to any one of claims 13-28, wherein the subject or patient is a subject or patient who has not previously received drug treatment containing MMAE.

30. The use according to any one of claims 1-12 or the method according to any one of claims 13-29, wherein the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer is administered at a frequency of 2.7 mg / kg, Q3W.

31. The use according to any one of claims 1-12 or the method according to any one of claims 13-29, wherein the antibody-drug conjugate or its pharmaceutical salt, ester, solvate, tautomer or stereoisomer is administered at a dose of 3.6 mg / kg per administration at a frequency of Q3W.

32. The use according to any one of claims 1-5, 7-12, the method according to any one of claims 13-17, 19-29, or the use or method according to any one of claims 30-31, wherein the immune checkpoint inhibitor is pembrolizumab.

33. The use or method according to claim 32, wherein the pembrolizumab is administered at a dose of 200 mg per administration, at a frequency of 3 weeks.

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