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

Use 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 Antibody Drug Conjugates Targeting Nectin-4”, the entire text of which is incorporated herein by reference for all purposes. Technical Field

[0003] The present invention relates to the field of biopharmaceuticals, and more specifically, to the 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 the preparation of a drug for treating cancer, and a method for treating cancer using the conjugate. Background Art

[0004] Nectin is a new type of cell adhesion molecule (CAM) belonging to the immunoglobulin superfamily (Ig SF) that can be used to bind to cells independently of Ca 2+ It participates in cell-to-cell interactions and forms cell-to-cell adhesion junctions (AJ). The nectin protein family has four members, namely nectin-1, nectin-2, nectin-3 and nectin-4. Nectin1 to 3 are widely expressed in normal human tissues, among which nectin1 to 2 are common in immune organs (bone marrow, thymus, spleen and lymph nodes), and nectin-3 is mainly expressed in the testis and placenta. Nectin-4 is a type I transmembrane immunoglobulin-like intercellular adhesion molecule that participates in the formation of intercellular adhesion junctions, mediates intercellular connections, and participates in regulating physiological processes such as cell proliferation, differentiation, and migration. The other nectin family members are widely expressed differently in normal human tissues. Nectin-4 is expressed at higher levels in normal embryonic and fetal tissues, and at very low levels in healthy adult tissues. However, abnormally high expression of Nectin4 can be detected in a variety of cancer samples. It is a type I transmembrane immunoglobulin-like intercellular adhesion molecule that mediates intercellular connections and participates in regulating physiological processes such as cell proliferation, differentiation, and migration. It is related to the progression of various cancer diseases, especially in urothelial carcinoma, cervical cancer, breast cancer, lung cancer, and pancreatic cancer.

[0005] Considering the expression pattern and levels of nectin-4, it has become an attractive target for the treatment of various tumor diseases. To date, drug development targeting nectin-4 has primarily focused on antibody-drug conjugates (ADCs), bicyclic peptide-drug conjugates (BTCs), bicyclic peptides, monoclonal antibodies, and chimeric antigen receptor T-cell immunotherapy (CAR-T).

[0006] Enfortumab vedotin (brand name: EV, also known as enfortumab, is an ADC drug consisting of the monoclonal antibody enfortumab targeting nectin-4 and the microtubule disruptor monomethyl auristatin E (MMAE) connected by a cleavable dipeptide linker mc-VC-PABC. The drug was approved by the FDA for marketing in 2019 and is mainly used to treat locally advanced or metastatic urothelial carcinoma. It is worth noting that EV is also associated with many adverse events, including rash, peripheral neuropathy, and fatigue. EV can cause severe and fatal skin adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Such skin adverse reactions mainly occur in the first cycle of treatment, but may also occur in subsequent cycles and are subject to black box warnings.

[0007] Furthermore, although immune checkpoint inhibitors (CPIs) have become standard treatment for many different cancer indications in recent years, the vast majority of patients do not experience remission after CPI monotherapy. Efforts are underway to identify suitable combination drugs to enhance the clinical efficacy of CPIs. One of the more successful recent approaches is the clinical combination of immune CPIs with ADCs.

[0008] The U.S. Food and Drug Administration (FDA) granted accelerated approval to EV and pembrolizumab In combination with cisplatin, it is used to treat patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin treatment. The objective response rate (ORR) is 68% (Seagen Drug insert 2023). However, the frequency of known dose-limiting toxicities is increased in the combination, with EV and Of the 121 participants receiving the combination, 65% experienced peripheral neuropathy, and 45% experienced grade 2 peripheral neuropathy. Notably, in this study, 36% of participants experienced an adverse reaction leading to EV discontinuation; the most common adverse reaction leading to EV discontinuation was peripheral neuropathy (20%), indicating that tolerability of this combination remains challenging.

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

[0010] In view of the deficiencies of the prior art, the present invention aims to provide 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 for use in the preparation of a drug for treating cancer and a method for treating cancer.

[0011] SWY2001-Ab3-LND1002 is a next-generation ADC targeting Nectin-4, designed to improve safety and tolerability by reducing systemic exposure to MMAE. SWY2001-Ab3-LND1002 has a reduced drug-to-antibody ratio of 2.0 and utilizes an enzyme-mediated site-specific conjugation approach to conjugate the humanized antibody to the small molecule drug via a linker to minimize the release of the payload into plasma. SWY2001-Ab3-LND1002 is a novel Fc-enabled IgG1 antibody with an extended half-life, enabling once-three-week (Q3W) dosing for patients. These features result in enhanced intratumoral delivery, with the payload released by proteolysis after cellular uptake. Lower plasma MMAE concentrations, associated with the design features of SWY2001-Ab3-LND1002, can reduce the severity and frequency of peripheral neuropathy and the frequency of rash. Overall, SWY2001-Ab3-LND1002 was well tolerated, with most adverse events (AEs) being grade 1 or 2 in severity, e.g., anemia (45%), proteinuria (45%), hypertriglyceridemia (36%), hyponatremia (36%), and keratoconjunctivitis (36%) (data cutoff: July 31, 2023).

[0012] Patients treated with the anti-PD(L)-1 antibody combination therapy of the nectin-4 targeting antibody drug conjugate of the present invention experienced fewer treatment-related adverse events and lower plasma free MMAE compared with patients treated with the combination therapy of EV and anti-PD(L)-1 antibody, indicating that the safety of the combination therapy of the nectin-4 targeting antibody drug conjugate of the present invention and anti-PD(L)-1 antibody is improved.

[0013] The combined use of the nectin-4-targeting antibody-drug conjugate of the present invention and the anti-PD(L)-1 antibody produces a synergistic effect. Patients treated with the combination of the nectin-4-targeting antibody-drug conjugate and the anti-PD(L)-1 antibody experienced longer progression-free survival and a longer duration of remission compared to patients treated with the combination of EV and the anti-PD(L)-1 antibody, demonstrating that the combined treatment of the nectin-4-targeting antibody-drug conjugate and the anti-PD(L)-1 antibody has a higher efficacy.

[0014] The present invention aims to provide a nectin-4-targeting antibody-drug conjugate or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof and an immune checkpoint inhibitor for use in the preparation of a medicament for treating cancer, wherein the nectin-4-targeting antibody-drug conjugate is conjugated with a drug-linker represented by Formula I and an antibody targeting nectin-4 or a functional fragment thereof:

[0015] In some embodiments, the antibody or functional fragment thereof comprises a heavy chain and a light chain, wherein: (i) the heavy chain comprises three CDR regions, namely, a CDR1-H region, a CDR2-H region, and a CDR3-H region, and the CDR1-H region, the CDR2-H region, and the CDR3-H region have the amino acid sequences shown in SEQ ID NOs. 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, and the CDR1-L region, CDR2-L region and CDR3-L region have the amino acid sequences shown in SEQ ID NO. 4, 5 and 6, respectively.

[0017] In some embodiments, the antibody or functional fragment thereof 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 the 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, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, the anti-PD-1 antibody is selected from Cemiplimab, Nivolumab, Pembrolizumab, Dostarlimab, Toripalimab, Tislelizumab or Retifanlimab.

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

[0021] In some embodiments, the cancer is selected from urothelial 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.

[0022] In some embodiments, 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 dosage of the antibody drug conjugate targeting nectin-4 or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof 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 a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered at a frequency of QW, Q2W, Q3W or Q4W.

[0025] In some embodiments, the immune checkpoint inhibitor is administered according to the recommended dose in its package insert (PI) or summary of medicinal product characteristics (SmPC).

[0026] In some embodiments, in each dosing cycle, the antibody drug conjugate or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered prior to the immune checkpoint inhibitor.

[0027] The present invention aims to provide a method for treating cancer by combining an antibody-drug conjugate targeting nectin-4 or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof with an immune checkpoint inhibitor, comprising administering a therapeutically effective amount of the antibody-drug conjugate targeting nectin-4 or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof to a subject or patient, wherein the antibody-drug conjugate targeting nectin-4 is conjugated to a drug-linker represented by Formula I and an antibody targeting nectin-4 or a functional fragment thereof:

[0028] In some embodiments, the antibody or functional fragment thereof comprises a heavy chain and a light chain, wherein: (i) the heavy chain comprises three CDR regions, namely, a CDR1-H region, a CDR2-H region, and a CDR3-H region, and the CDR1-H region, the CDR2-H region, and the CDR3-H region have the amino acid sequences shown in SEQ ID NOs. 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, and the CDR1-L region, CDR2-L region and CDR3-L region have the amino acid sequences shown in SEQ ID NO. 4, 5 and 6, respectively.

[0030] In some embodiments, the antibody or functional fragment thereof 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 the 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, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, the anti-PD-1 antibody is selected from Cemiplimab, Nivolumab, Pembrolizumab, Dostarlimab, Toripalimab, Tislelizumab or Retifanlimab.

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

[0034] In some embodiments, the cancer is selected from urothelial 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.

[0035] In some embodiments, 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 pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered at a dose range of 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; further 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, wherein the antibody drug conjugate or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered at a frequency of QW, Q2W, Q3W or Q4W; the antibody drug conjugate or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered for three or more dosing cycles.

[0038] In some embodiments, the immune checkpoint inhibitor is administered according to the recommended dose in its package insert (PI) or summary of medicinal product characteristics (SmPC).

[0039] In some embodiments, the antibody drug conjugate or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered prior to the immune checkpoint inhibitor in each dosing cycle.

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

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

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

[0043] In some embodiments, the subject or patient is a subject or patient whose cancer has relapsed after prior nectin-4 targeted therapy.

[0044] In some embodiments, the subject or patient is a subject or patient who has not previously received treatment with an MMAE-containing drug. Description of the drawings:

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

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

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

[0048] Explanation of terms:

[0049] Unless otherwise indicated, as used herein, the singular forms "a", "an" and "the" include the plural forms as well. For example, the term "a cell" includes a plurality of cells and mixtures thereof.

[0050] As used herein, the term "about" refers to the usual error range of each value that is readily known to those skilled in the art. The use of "about" values ​​or parameters herein includes (and describes) embodiments involving the value or parameter itself.

[0051] As used herein, the terms "comprising" or "including" are intended to include the stated elements, integers, or steps, but do not exclude any other elements, integers, or steps. In the present invention, when the terms "comprising" or "including" are used, unless otherwise indicated, the context of consisting of the stated elements, integers, or steps is also encompassed. For example, when referring to an antibody variable region "comprising" a specific sequence, it is also intended to encompass an antibody variable region consisting of the specific sequence.

[0052] As used herein, the term "cancer" refers to a proliferative disorder caused by or characterized by the proliferation of cells that 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 from the same tissue and can be divided into different subtypes based on their biological characteristics.

[0053] As used herein, the term "treatment" refers to a clinical intervention intended to change the natural course of the individual or cell being treated during the clinical pathological process. The desired effects of treatment include delaying or reducing the rate of disease progression, improving or alleviating the disease state, and alleviating or improving prognosis. For example, if one or more symptoms associated with cancer are alleviated or eliminated, including but not limited to reducing the proliferation of cancer cells (or eliminating cancer cells), reducing the symptoms caused by the disease, improving the quality of life of patients with the disease, reducing the dosage of other drugs required to treat the disease, delaying the progression of the disease 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 having an immunoglobulin Fc region), antibodies with multiple epitope specificities, 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)" is used interchangeably with "antibody" herein.

[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 with heavy and light chains that include an Fc region. The constant domains can be native sequence constant domains (e.g., human native sequence constant domains) or amino acid sequence variants thereof. In some cases, the complete antibody has one or more effector functions.

[0056] As used herein, the term "heavy chain constant region" or "CH" is used interchangeably in the present invention and comprises at least three heavy chain constant domains (CH1, CH2, and CH3). Exemplary, human heavy chain constant regions include γ, δ, α, ε, and μ, each heavy chain constant region corresponding to an antibody isotype. For example, an antibody comprising a γ constant region is an IgG antibody, an antibody comprising a δ constant region is an IgD antibody, an antibody comprising an α constant region is an IgA antibody, an antibody comprising a μ constant region is an IgM antibody, and an antibody comprising an ε constant region is an IgE antibody. Certain isotypes can be further divided into subclasses, for example, IgG antibodies include but are not limited to IgG1 (comprising a γ1 constant region), IgG2 (comprising a γ2 constant region), IgG3 (comprising a γ3 constant region), and IgG4 (comprising a γ4 constant region); IgA antibodies include but are not limited to IgA1 (comprising an α1 constant region) and IgA2 (comprising an α2 constant region); IgM antibodies include but are not limited to IgM1 and IgM2. Isotypes may also include modifications that alter Fc function, such as enhancing or diminishing effector function or enhancing or diminishing binding to Fc receptors. As described above, one of ordinary skill in the art will appreciate that the heavy chain constant regions may be modified such that they differ in amino acid sequence from naturally occurring immunoglobulin molecules.

[0057] As used herein, the term "light chain constant region" or "CL" is used interchangeably in the present invention and comprises one light chain constant domain CL. Exemplarily, light chains can be divided into two categories, λ and κ, based on the difference in the light chain constant region.

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

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

[0060] As used herein, the term "CDR (complementarity determining region)" refers to an amino acid sequence that together defines the binding affinity and specificity of the Fv region of an antibody. Because the specificity of an antibody lies in the structural complementarity between the antibody binding site and the antigenic determinant. The antibody binding site is composed mainly of residues from the so-called hypervariable region or complementary determining region (CDR). The light chain (L) and heavy chain (H) of an antibody each have three CDRs, namely CDR1-L, CDR2-L, CDR3-L and CDR1-H, CDR2-H, CDR3-H. Therefore, the antigen binding site of a conventional antibody includes six CDRs, which include a CDR group from each of the heavy chain variable region and the light chain variable region.

[0061] As used herein, the term "unit preparation" refers to the smallest sub-package of each pharmaceutical preparation containing an appropriate amount of active compound, such as a unit preparation in a capsule refers to a capsule, a unit preparation in a tablet refers to a tablet, a unit preparation in an injection refers to an injection, and so on for other types of preparations.

[0062] As used herein, the term "therapeutically effective amount" refers to an amount that brings a therapeutic effect to a subject, for example, in a subject to which the amount is administered, 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 inhibited, compared to a subject not administered the amount.

[0063] As used herein, the following terms are determined by the investigator according to RECIST v1.1, the solid tumor efficacy evaluation criteria. As used herein, the term "complete response" or "CR" refers to the disappearance of all target lesions and non-target lesions, with no new lesions. As used herein, the term "partial response" or "PR" refers to a decrease of at least 30% (longer than four weeks) in the sum of the longest diameters (SLD) of target lesions compared to baseline, no progression of non-target lesions, and no new lesions. As used herein, the term "progressive disease" or "PD" refers to an increase of greater than or equal to 20% in the SLD of target lesions compared to the minimum Nadir, and an increase of greater than or equal to 5 mm in the absolute value of the sum of diameters (SoD), or a clear progression of non-target lesions, or the appearance of new, clear metastatic lesions. As used herein, the term "stable disease" or "SD" means that the target lesion does not reach PD or PR compared with the minimum Nadir value, one or more non-target lesions and / or tumor markers are greater than normal values, and no new lesions are generated.

[0064] As used herein, the following terms were determined by the investigator according to RECIST v1.1. Disease control rate (DCR): defined as the percentage of participants who achieved a response (PR+CR) and stable disease lasting 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. Clinical benefit rate (CBR): defined as the percentage of participants who achieved a CR, PR, or SD. Progression-free survival (PFS): defined as the time from the first dose of study treatment to the first occurrence of disease progression or death from any cause during the study, whichever occurs first. Time to progression (TTP): defined as the time from the first dose of study treatment to the first occurrence of disease progression. Overall survival (OS): defined as the time from the first dose of study treatment to death from any cause. Duration of Response (DoR): defined as the time from the date of initial CR or PR to the date of PD or death from any cause during the study, whichever occurs first. Time to response (TTR): defined as the time from the first dose of study treatment to the first documented CR or PR.

[0065] As used herein, the term "Treatment Emergent Adverse Events" or "TEAE" or "AE" refers to any unfavorable, unexpected sign (including abnormal laboratory findings), symptom, or disease associated with the use of a medical treatment or therapeutic procedure that may be considered to be related to the medical treatment or therapeutic procedure in time. 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 determined according to NCI CTCAE v5.0.

[0066] As used herein, the term "intolerant" refers to a subject who has previously received anticancer therapy but developed symptoms of an adverse event (e.g., peripheral neuropathy, skin toxicity, hyperglycemia, gastrointestinal symptoms) during the first two cycles, which did not improve despite following dose adjustment guidelines, leading to treatment discontinuation, without evidence of disease progression.

[0067] As used herein, the term "relapse" refers to a cancer that was once responsive to an anticancer treatment but has become no longer responsive to that treatment or has no longer responded adequately to that treatment.

[0068] As used herein, the term "MMAE" refers to the tubulin inhibitor monomethyl aurisin E.

[0069] Herein, the immune checkpoint inhibitors can be obtained from commercial sources or can be prepared by methods known to those skilled in the art.

[0070] In a first aspect, the present invention aims to provide a nectin-4-targeting antibody-drug conjugate or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof and an immune checkpoint inhibitor for use in the preparation of a medicament for treating cancer. The nectin-4-targeting antibody-drug conjugate is formed by conjugating a drug-linker represented by Formula I to an antibody targeting nectin-4 or a functional fragment thereof:

[0071] Formula I. In some embodiments, the antibody or functional fragment thereof comprises a heavy chain, wherein the heavy chain comprises three CDR regions, namely, CDR1-H region, CDR2-H region and CDR3-H region, wherein the CDR1-H region, CDR2-H region and CDR3-H region have the amino acid sequences shown in SEQ ID NOs. 1, 2 and 3, respectively.

[0072] In some embodiments, the antibody or its functional fragment comprises a light chain, which comprises three CDR regions, namely CDR1-L region, CDR2-L region and CDR3-L region, and the CDR1-L region, CDR2-L region and CDR3-L region have the amino acid sequences 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 comprises three CDR regions, namely, CDR1-H region, CDR2-H region and CDR3-H region, and the CDR1-H region, CDR2-H region and CDR3-H region have the amino acid sequences shown in SEQ ID NO.1, 2 and 3, respectively; and the light chain comprises three CDR regions, namely, CDR1-L region, CDR2-L region and CDR3-L region, and the CDR1-L region, CDR2-L region and CDR3-L region have the amino acid sequences shown in SEQ ID NO.4, 5 and 6, respectively.

[0074] In some embodiments, the antibody or 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 functional fragment thereof comprises a light chain variable region, and the light chain variable region is selected from the group consisting of the amino acid sequences shown in SEQ ID NOs. 8-10.

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

[0077] In some embodiments, the antibody or 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 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 functional fragment thereof comprises a heavy chain constant region and a light chain constant region, wherein the heavy chain constant region has the amino acid sequence shown in SEQ ID NO.11 or SEQ ID NO.13, and the light chain constant region has the amino acid sequence shown in SEQ ID NO.12.

[0080] In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody selected from Cemiplimab, 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 embodiments, 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 embodiments, 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 dosage of the antibody drug conjugate targeting nectin-4 or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof 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 a range between any two values; further more preferably, about 10 mg, 30 mg, about 50 mg, about 80 mg, about 120 mg, about 160 mg or about 240 mg, or a range between any two values.

[0085] In some embodiments, the antibody drug conjugate, or a pharmaceutically acceptable salt, ester, solvate, tautomer, or stereoisomer thereof, 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 embodiments, the immune checkpoint inhibitor is administered according to the recommended dose in its package insert (PI) or Summary of Medicinal Product Characteristics (SmPC).

[0087] In some embodiments, the antibody drug conjugate or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered prior to the immune checkpoint inhibitor in each dosing cycle.

[0088] In a second aspect, the present invention aims to provide a method for treating cancer by combining an antibody-drug conjugate targeting nectin-4 or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof with an immune checkpoint inhibitor, comprising administering a therapeutically effective amount of the antibody-drug conjugate targeting nectin-4 or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof to a subject or patient, wherein the antibody-drug conjugate targeting nectin-4 is conjugated to a drug-linker represented by Formula I and an antibody targeting nectin-4 or a functional fragment thereof:

[0089] In some embodiments, the antibody or its functional fragment comprises a heavy chain, which comprises three CDR regions, namely CDR1-H region, CDR2-H region and CDR3-H region, and the CDR1-H region, CDR2-H region and CDR3-H region have the amino acid sequences shown in SEQ ID NO.1, 2 and 3, respectively.

[0090] In some embodiments, the antibody or its functional fragment comprises a light chain, which comprises three CDR regions, namely CDR1-L region, CDR2-L region and CDR3-L region, and the CDR1-L region, CDR2-L region and CDR3-L region have the amino acid sequences 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 comprises three CDR regions, namely, CDR1-H region, CDR2-H region and CDR3-H region, and the CDR1-H region, CDR2-H region and CDR3-H region have the amino acid sequences shown in SEQ ID NO.1, 2 and 3, respectively; and the light chain comprises three CDR regions, namely, CDR1-L region, CDR2-L region and CDR3-L region, and the CDR1-L region, CDR2-L region and CDR3-L region have the amino acid sequences shown in SEQ ID NO.4, 5 and 6, respectively.

[0092] In some embodiments, the antibody or 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 functional fragment thereof comprises a light chain variable region, and the light chain variable region is selected from the group consisting of the amino acid sequences shown in SEQ ID NOs. 8-10.

[0094] 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 the amino acid sequence shown in SEQ ID NO.7; and the light chain variable region is selected from the amino acid sequences shown in SEQ ID NO.8-10.

[0095] In some embodiments, the antibody or 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 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 functional fragment thereof comprises a heavy chain constant region and a light chain constant region, the heavy chain constant region having the amino acid sequence shown in SEQ ID NO.11 or SEQ ID NO.13; and the light chain constant region having the amino acid sequence shown in SEQ ID NO.12.

[0098] In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody selected from Cemiplimab, 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 embodiments, 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 embodiments, 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 a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered at a dose ranging 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 , 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, 4.5mg / kg, 5.0mg / kg, 5.5mg / kg, 6.0mg / kg, or a range between any two values. In some embodiments, preferably, the dosage range for each administration is from about 1.8mg / kg to about 4.5mg / kg, or from about 2.5mg / kg to about 3.0mg / kg, or from about 3.0mg / kg to about 3.5mg / kg, or from about 3.5mg / kg to about 4.0mg / kg, or from about 4.0mg / kg to about 4.5mg / kg.

[0103] In some embodiments, the antibody drug conjugate or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered in a low dose. The low dose is a dose ranging 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 a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered at a high dose. The high dose is a dose ranging 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, g / kg, 4.0mg / kg, 4.1mg / kg, 4.2mg / kg, 4.3mg / kg, 4.4mg / kg, 4.5mg / kg, 4.6mg / kg, 4.7mg / kg, 4.8mg / kg, 4.9mg / kg, 5.0mg / kg, 5.1mg / kg, 5.2mg / kg, 5.3mg / kg, 5.4mg / kg, 5.5mg / kg, 5.6mg / kg, 5.7mg / kg, 5.8mg / kg, 5.9mg / kg, 6.0mg / kg, or a range value between any two points.

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

[0106] In some embodiments, the immune checkpoint inhibitor (e.g., anti-PD-L1 antibody or anti-PD-1 antibody) is administered according to the recommended dose in its package insert (PI) or Summary of Medicinal Product Characteristics (SmPC).

[0107] In some embodiments, the antibody drug conjugate or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered prior to the immune checkpoint inhibitor in each dosing cycle.

[0108] In a third aspect, the present invention aims to provide a pharmaceutical composition comprising the aforementioned antibody-drug conjugate targeting nectin-4 or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof and the aforementioned immune checkpoint inhibitor.

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

[0110] In some embodiments, the pharmaceutical composition includes temporally and / or spatially separated components that work together to achieve the objectives of the present invention. For example, the components of the pharmaceutical composition can be administered to a patient or subject as a whole or individually. When the components of the pharmaceutical composition are administered to a subject separately, the components can be administered to the patient or subject simultaneously or sequentially.

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

[0112] In some embodiments, the type of pharmaceutically acceptable carrier depends mainly on whether the composition formulated in the present invention is for oral, nasal, intradermal, subcutaneous, intramuscular or intravenous injection. The composition formulated in accordance with the present invention may contain a wetting agent, an emulsifier or a buffer substance as an additive.

[0113] In the present invention, the amino acid sequences of the aforementioned CDRs are all shown in accordance with the IMGT definition rules (the sequences shown in the claims of the present invention are also defined in accordance with the IMGT rules). However, it is well known in the art that the CDRs of antibodies can be defined in the art by various methods, for example, the Kabat definition rules based on sequence variability (see, Kabat et al., Protein Sequences in Immunology, 5th ed., National Institutes of Health, Bethesda, MD (1991)) and the Chothia definition rules based on the position of structural loop regions (see J Mol Biol 273:927-48, 1997). It should be understood by those skilled in the art that, unless otherwise specified, the terms "CDR" and "complementarity determining region" of a given antibody or region thereof (e.g., variable region) should be understood to encompass the complementary determining regions defined by any of the above-mentioned known schemes described in the present invention. Although the scope of protection claimed in the claims of the present invention is based on the sequences shown in the IMGT definition rules, amino acid sequences corresponding to other CDR definition rules should also fall within the scope of protection of the present 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 a functional fragment thereof;

[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 comprises Q295 (EU numbering) in the constant region of its heavy chain, and the linker moiety is linked to the side chain of Q295 via an amide bond.

[0120] In some embodiments, the method results in a complete remission or a partial remission.

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

[0122] In some embodiments, 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 a functional fragment thereof is selected from a murine antibody, a chimeric antibody, a humanized antibody or a fully human antibody.

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

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

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

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

[0128] In some embodiments of the present invention, the heavy chain of cemiplizumab 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 invention, the heavy chain of atezolizumab has the following sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK VDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO.17); the light chain of atezolizumab has the following sequence:

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

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

[0133] In some embodiments of the present invention, the immune checkpoint inhibitor (e.g., anti-PD-L1 antibody or anti-PD-1 antibody) is administered at a dose of about 200 mg to about 2000 mg (e.g., between about 200 mg to about 300 mg, for example, between about 300 mg to about 400 mg, for example, between about 400 mg to about 500 mg, for example, between about 500 mg to about 600 mg, for example, between about 600 mg to about 700 mg, for example, between about 700 mg to about 800 mg, for example, between about 800 mg to about 900 mg, for example, between about 900 mg to 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 dosage 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 dosage 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 dosage 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 dosage 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 dosage 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 by intravenous infusion once every two weeks, 1200 mg by intravenous infusion once every three weeks, or 1680 mg by intravenous infusion once every four weeks.

[0136] In some embodiments of the present invention, the dosage of cemiplimab is 350 mg administered by intravenous infusion once every three weeks.

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

[0138] In some embodiments of the present invention, the antibody drug conjugate targeting nectin-4 or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof can be administered in 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 a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered in three or more dosing cycles. In some embodiments of the present invention, the administration cycle of the antibody drug conjugate targeting nectin-4 or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof 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., anti-PD-L1 antibody or anti-PD-1 antibody) can be administered in 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., anti-PD-L1 antibody or anti-PD-1 antibody) is administered in three or more dosing cycles. In some embodiments of the present invention, the administration 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 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 pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer and / or immune checkpoint inhibitor is administered once every 3 weeks (Q3W), with 21 days as a treatment cycle.

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

[0143] In some embodiments of the present invention, the antibody drug conjugate or its pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer and / or immune checkpoint inhibitor is administered once every 2 weeks (Q2W), with a treatment cycle of 14 days or 28 days.

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

[0145] In some embodiments of the present invention, the antibody drug conjugate or its pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer and / or immune checkpoint inhibitor is administered once a week (QW) for 2 consecutive weeks, followed by a one-week rest, with 21 days as a treatment cycle.

[0146] In some embodiments of the present 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 (based on the 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 present 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 (based on the 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 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 invention, the antibody drug conjugate, or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, is administered on about day 1 of each dosing cycle.

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

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

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

[0154] In some embodiments of the present invention, the cancer is a cancer that expresses, overexpresses 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 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 relapsed 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 invention, the subject or patient is one who has failed standard therapy or has failed a previous therapy.

[0162] In some embodiments of the present invention, the antibody drug conjugate or its pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer is administered by intravenous injection. In some embodiments, the antibody drug conjugate or its pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer is administered by 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 present invention, the immune checkpoint inhibitor (e.g., anti-PD-L1 antibody or anti-PD-1 antibody) is administered by intravenous injection. In some embodiments of the present invention, the immune checkpoint inhibitor (e.g., anti-PD-L1 antibody or anti-PD-1 antibody) is administered by 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., anti-PD-L1 antibody or anti-PD-1 antibody) is administered by 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] Herein, SWY2001-Ab3-LND1002 refers to a drug conjugate formed by coupling a drug-linker represented by Formula I of the present invention to an antibody targeting nectin-4. The antibody is the humanized antibody SWY2001-Ab3, with a heavy chain variable region of SWY2001-Ab3-VH (SEQ ID NO. 7), a light chain variable region of SWY2001-Ab3-VL (SEQ ID NO. 10), a heavy chain constant region of HCl (SEQ ID NO. 11), and a light chain constant region of LC (SEQ ID NO. 12). The antibody and antibody-drug conjugate in SWY2001-Ab3-LND1002 are prepared using the enzymatic conjugation method using mTgase (sequence shown in SEQ ID NO. 14 in Table 3) as described in WO2023025243A1, which is incorporated herein by reference in its entirety.

[0165] DETAILED DESCRIPTION

[0166] Example 1: 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] To determine the recommended Phase II dose (RP2D) of SWY2001-Ab3-LND1002 in combination with approved or standardized dose regimens of anti-PD(L)-1 therapies.

[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 PK. The combination therapy was evaluated in two patient populations: mUC (naive to nectin-4 targeted therapy) and / or cervical cancer (naive to MMAE-containing therapy).

[0169] 1. Drug information and experimental plan

[0170] 1.1 Drug Information

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

[0172] Specification: 30mg / bottle.

[0173] Dosage form: powder injection.

[0174] Storage conditions: Store at 2-8°C in the dark. Avoid light and shaking before use.

[0175] Trial drug 2: pembrolizumab.

[0176] 1.2 Experimental objectives and corresponding endpoints

[0177] Table 1 Objectives and corresponding endpoints

[0178] 1.3 Study Design

[0179] This is an open-label, Phase I / II clinical trial designed to evaluate the safety, PK, and efficacy of SWY2001-Ab3-LND1002 combined 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] The sponsor may, at its sole discretion, decide to add more participants, suspend or discontinue enrollment, or terminate the study based on adverse safety data, the rate of participant accrual, or other reasonable reasons. This protocol may be amended to include additional cohorts exploring SWY2001-Ab3-LND1002 in different regimens, combinations, or tumor types.

[0181] For all enrolled participants, study treatment will continue until unacceptable toxicity, death, withdrawal of consent, or investigator-confirmed progressive disease (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Confirmed progressive disease requires a new imaging assessment ≥ 4 weeks after the first radiographic progression. If PD is confirmed on a repeat scan according to RECIST v1.1, the PD date will be the date of the first tumor assessment showing progression.

[0182] All study participants will undergo standard (clinical and laboratory) evaluations as outlined in the active schedule, as well as assessments for 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 Terminology Criteria for Adverse Events (NCI-CTCAE) (v5.0). Guidelines for dose interruptions (e.g., due to toxicity) will be included in the protocol.

[0183] Table 2 Patient population and number

[0184] 1.4 Dosage

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

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

[0187] The dose of anti-PD(L)-1 therapy will be administered according to the recommended dose in the package insert (PI) or Summary of Medicinal Product Characteristics (SmPC).

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

[0189] SWY2001-Ab3-LND1002 and anti-PD(L)-1 will be administered intravenously (IV) over 30 minutes on Day 1 of each 21-day cycle. SWY2001-Ab3-LND1002 will be administered 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 do not meet any exclusion criteria will be included in the study. The Sponsor will not acknowledge waivers of the eligibility criteria.

[0193] 1. Sign the informed consent form (ICF).

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

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

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

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

[0198] ii. Patients with cervical cancer who have not received treatment with MMAE-containing drugs

[0199] 4. At least one target lesion measurable by imaging (computed tomography [CT] or magnetic resonance imaging [MRI]) as assessed by RECIST v1.1.

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

[0201] 6. Expected survival period ≥12 weeks.

[0202] 7. Normal hematological and internal organ function, based on the following laboratory results obtained within 14 days prior to Cycle 1 Day 1 (C1D1):

[0203] Blood function:

[0204] a. Within 2 weeks before C1D1, no blood component transfusion or human granulocyte colony-stimulating factor

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

[0206] (EPO).

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

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

[0209] d. Hemoglobin ≥90 g / L (9 g / dL) or ≥5.6 mmol / L. Patients may receive blood transfusion or erythropoiesis-stimulating therapy within 14 days before 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 have their doses stabilized. For patients receiving other oral anticoagulants, aPTT / PTT must be within the intended therapeutic range for 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 syndrome).

[0214] Kidney function:

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

[0216] 8. Females: Postmenopausal women may be able to comply with the contraceptive requirements of the plan.

[0217] Men: Agree to the contraceptive requirements of the plan. Partners: Postmenopausal (women) or able to comply with the contraceptive requirements of the plan (male or female).

[0218] Exclusion criteria

[0219] Patients were excluded from the study if they met any of the following criteria:

[0220] Medical conditions

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

[0222] 2. History of malignant tumors other than the disease in this study diagnosed within three years prior to enrollment in this study, excluding adequately treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer, in situ breast cancer, or in situ prostate cancer (patients must have no evidence of active disease within 2 years prior to enrollment).

[0223] 3. Have a history of ascites or pleural effusion, unless successfully treated, asymptomatic, and not requiring treatment more than 4 months before the first dose of this study.

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

[0225] a. 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 in New York Heart Association (NYHA) class II-IV congestive heart failure;

[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, the presence or history of clinically significant (investigator's opinion) electrocardiogram (ECG) abnormalities; QT interval corrected by Fridericia method (QTcF) > 480ms during the screening period.

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

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

[0231] i. Note: Assessment of LVEF by echocardiography (ECHO) or multi-detector acquisition (MUGA) scan as part of the patient's routine care within 4 weeks prior to the Screening Visit may be used to confirm eligibility for Screening.

[0232] 5. Previous history of neuropathy ≥ grade 2.

[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 within the first four weeks of C1D1, including but not limited to:

[0235] a. Bacteremia and severe pneumonia requiring hospitalization

[0236] b. Active infection requiring systemic antibiotic, antiviral, or antifungal treatment according to the Common Terminology Assessment Criteria for Adverse Events (CTCAE v 5) ≥ 2 within the first two weeks of C1D1.

[0237] 8. Tested positive for any of the following during the screening period:

[0238] a. Human immunodeficiency virus (HIV). Patients who have received established antiretroviral therapy (ART) for at least 4 weeks, have a viral load less than 400 copies / mL, and have CD 4+ HIV patients with T cell counts ≥350 μL were eligible for enrollment.

[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 have started anti-HBV treatment at least 14 days before C1D1, and are willing to continue anti-HBV treatment during the study period

[0243] (According to institutional standards of care.) Patients whose infection has been controlled should have their HBV DNA monitored regularly as directed by their treating physician.

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

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

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

[0247] 9. Active thrombophlebitis, thromboembolism, rapid coagulation or uncontrolled bleeding.

[0248] 10. Active ocular surface disease at baseline (based on ophthalmological examination during 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 well controlled by thyroid replacement hormone, eczema, psoriasis, or chronic simple lichen planus that does not exceed 10% of the body surface area during the screening period.

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

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

[0253] 15. Any mental illness or other condition that would limit compliance with the study requirements.

[0254] 16. Any other significant complication, disease, metabolic dysfunction, physical examination, or clinical laboratory finding that prohibits the administration of study drug, or may result in an unacceptable risk of treatment complications, or may affect compliance with study procedures or the interpretation of results.

[0255] Previous / concomitant treatment

[0256] 17. Have you ever received anti-cancer treatment within the following timeframe:

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

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

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

[0260] 18. Anyone who has received an organ transplant (including allogeneic bone marrow transplant).

[0261] 19. Receiving systemic corticosteroids for any indication, including replacement therapy for adrenal insufficiency within 7 days prior to the first dose of the drug.

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

[0263] b. Patients who have been on a stable daily oral prednisolone dose ≤ 10 mg (or equivalent) for at least 7 days before the first dose can participate in the study.

[0264] 20. Those who have received a live attenuated vaccine within 28 days before the first dose of the drug, or are expected to receive such a vaccine during the first dose of the drug. Coronavirus disease 2019 (COVID-19) vaccine is acceptable.

[0265] 21. Any other treatment prohibited during the study.

[0266] Other exclusion criteria

[0267] 22. Hypersensitivity to study drug or any component of study drug.

[0268] 23. Have a history of drug-induced allergic reactions or other severe hypersensitivity reactions.

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

[0270] 25. Pregnancy and breastfeeding.

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

[0272] According to the methods disclosed herein, a physician can treat a subject (e.g., a human patient) 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 a subject, the physician administers SWY2001-Ab3-LND1002 in combination with pembrolizumab.

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

[0274] In certain embodiments, the subject's cancer relapsed after treatment with a drug targeting nectin-4 (e.g., PADCEV). For example, some subjects have mUC and have relapsed after treatment with PADCEV.

[0275] SWY2001-Ab3-LND1002 can be administered intravenously at a dose of about 2.7 mg / kg or about 3.6 mg / kg, and pembrolizumab can be administered intravenously at a dose of about 200 mg. The two drugs can be combined on day 1 of each 21-day dosing cycle (Q3W), and SWY2001-Ab3-LND1002 should be administered before pembrolizumab.

[0276] After initiating combination therapy, physicians can monitor patient response to treatment using a variety of methods. For example, they can assess the objective response rate (ORR), which is the proportion of patients achieving a complete response (CR) or partial response (PR) according to RECIST v1.1 criteria. Subsequent dose adjustments can be made 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 pharmaceutically acceptable 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 conjugated with a drug-linker represented by Formula I and 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 region, CDR2-H region and CDR3-H region, wherein the CDR1-H region, CDR2-H region and CDR3-H region have the amino acid sequences shown in SEQ ID NOs. 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, and the CDR1-L region, CDR2-L region and CDR3-L region have the amino acid sequences shown in SEQ ID NO. 4, 5 and 6, respectively.

3. The use according to claim 1 or 2, 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 the amino acid sequence shown in SEQ ID NO.7; and / or, the light chain variable region is selected from the amino acid sequences shown in SEQ ID NO.8-10.

4. The use according to any one of claims 1 to 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 the amino acid sequence shown in SEQ ID NO.11 or SEQ ID NO.13; and / or the light chain constant region has the amino acid sequence shown in SEQ ID NO.

12.

5. The use according to any one of claims 1 to 4, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, and the anti-PD-1 antibody is selected from Cemiplimab, Nivolumab, Pembrolizumab, Dostarlimab, Toripalimab, Tislelizumab or Retifanlimab.

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

7. The method of claim 1 , 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 method according to any one of claims 1 to 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 to 8, wherein a unit dosage of the antibody drug conjugate targeting nectin-4 or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof 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 to 9, wherein the antibody drug conjugate or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered at a frequency of QW, Q2W, Q3W or Q4W.

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

12. The use according to any one of claims 1 to 11, wherein in each medication cycle, the antibody drug conjugate or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered prior to the immune checkpoint inhibitor.

13. A method for treating cancer using 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, comprising administering to a subject or patient a therapeutically effective amount of the antibody-drug conjugate targeting nectin-4, or a pharmaceutically acceptable salt, ester, solvate, tautomer, or stereoisomer thereof, wherein the antibody-drug conjugate targeting nectin-4 is conjugated to an antibody targeting nectin-4, or a functional fragment thereof, represented by Formula I:

14. The method according to claim 13, 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 region, CDR2-H region and CDR3-H region, wherein the CDR1-H region, CDR2-H region and CDR3-H region have the amino acid sequences shown in SEQ ID NOs. 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, and the CDR1-L region, CDR2-L region and CDR3-L region have the amino acid sequences shown in SEQ ID NO. 4, 5 and 6, respectively.

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

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

12.

17. The method according to any one of claims 13 to 16, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody selected from Cemiplimab, Nivolumab, Pembrolizumab, Dostarlimab, Toripalimab, Tislelizumab or Retifanlimab.

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

19. The method of any one of claims 13-18, wherein the cancer is selected from urothelial 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.

20. The method of 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 of any one of claims 13-20, wherein the antibody drug conjugate, or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, is administered at a dose range of 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; further 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 to 21, wherein the antibody drug conjugate or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered at a frequency of QW, Q2W, Q3W or Q4W; and the antibody drug conjugate or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered in three or more dosing cycles.

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

24. The method according to any one of claims 13 to 23, wherein the antibody drug conjugate or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered prior to the immune checkpoint inhibitor in each dosing cycle.

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

26. The method according to any one of claims 13 to 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 to 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 relapsed 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 treatment with a drug 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 a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof 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 a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof 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 of claim 32, wherein the pembrolizumab is administered at a dose of 200 mg per administration, at a frequency of Q3W.

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