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

Cross-reference to Related Applications

[0001] The present application claims priority to the Chinese patent application No. 202410327589.X, filed on March 21, 2024 and entitled "USE OF ANTIBODY-DRUG CONJUGATE TARGETING NECTIN-4", the entire content of which is incorporated herein by reference in its entirety for all purposes. Technical Field

[0002] The present disclosure relates to the field of biopharmaceuticals, and in particular relates 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 manufacture of a medicament for the treatment of cancer, and a method for treating cancer using same. Background Art

[0003] Nectins are novel cell adhesion molecules (CAMs) of the immunoglobulin superfamily (Ig SF), which are involved in intercellular interactions in a Ca2+-independent manner and form intercellular adherens junctions (AJs). The Nectin protein family consists of four members: Nectin-1, Nectin-2, Nectin-3, and Nectin-4. Nectins 1-3 are widely expressed in normal human tissues. Nectins 1-2 are commonly found in immune organs (bone marrow, thymus, spleen, and lymph nodes), while Nectin-3 is mainly expressed in the testes and placenta. Nectin-4 is a type I transmembrane protein belonging to the immunoglobulin-like intercellular adhesion molecule. It participates in the formation of intercellular adherens junctions, mediates intercellular junctions, and is involved in regulating physiological processes including cell proliferation, differentiation, and migration. Unlike other members of the Nectin family, which are widely expressed in normal human tissues, Nectin-4 is highly expressed in normal embryonic and fetal tissues with minimal expression in healthy adult tissues. However, abnormally high expression of Nectin-4 can be detected in a variety of cancer samples. Nectin-4 is a type I transmembrane protein belonging to the immunoglobulin-like intercellular adhesion molecule. It mediates intercellular junctions, and is involved in regulating physiological processes including cell proliferation, differentiation, and migration and associated with the progression of various cancers. In particular, it is expressed at high levels in urothelial carcinoma, cervical cancer, breast cancer, lung cancer, and pancreatic cancer.

[0004] Based on the expression pattern and level of Nectin-4, it has become an “attractive” target for research on the treatment of various tumor diseases. To date, drug development targeting the Nectin-4 target mainly includes antibody drug conjugates (ADCs), bicycle toxin conjugates (BTCs), bicycle peptides, monoclonal antibodies, and chimeric antigen receptor T-cell immunotherapy (CAR-T).

[0005] Enfortumab vedotin (trade name: PADCEV®, abbreviated as EV, jointly developed by Astellas and Seagen) is an ADC obtained by conjugating enfortumab (a Nectin-4-targeted monoclonal antibody) with the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a cleavable dipeptide linker mc-VC-PABC. This medicament was approved by the FDA in 2019 primarily for the treatment of locally advanced or metastatic urothelial carcinoma. Notably, EV is also associated with many adverse events, including rash, peripheral neuropathy, and fatigue. EV received a Boxed Warning as it may cause serious and even fatal cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which occur primarily in the first cycle of treatment but may also occur in subsequent cycles.

[0006] Furthermore, although immune checkpoint inhibitors (CPIs) have become the standard of care for many different cancer indications in recent years, the majority of patients do not respond to CPI monotherapy. Efforts are currently underway to identify suitable drugs for use in combination to improve the clinical efficacy of CPIs. One of the relatively successful approaches recently is the clinical combination of immune CPIs and ADCs.

[0007] The U.S. Food and Drug Administration (FDA) granted accelerated approval for the combination of EV with Pembrolizumab (Keytruda®) for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are ineligible for cisplatin-based therapy. The objective response rate (ORR) was 68% (Seagen, PADCEV® Prescribing Information, 2023). However, an increased frequency of known dose-limiting toxicities was observed with the combination therapy. Among 121 participants receiving the combination therapy of EV and Keytruda®, 65% of them experienced peripheral neuropathy, and 45% experienced grade 2 peripheral neuropathy. Notably, 36% of the participants in this study experienced adverse reactions leading to EV discontinuation; and the most common adverse reaction leading to the discontinuation of EV was peripheral neuropathy (20%), indicating that the tolerability of this combination therapy remains challenging.

[0008] There is an urgent need to develop a safe and effective combination therapy for cancer treatment. Summary of the Invention

[0009] In view of the defects in the prior art, an object of the present disclosure is to provide 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 manufacture of a medicament for the treatment of cancer, and a method for treating cancer using same.

[0010] SWY2001 -Ab3-LND 1002 is a next-generation Nectin-4-targeted ADC designed to improve safety / tolerability by reducing the systemic exposure of MMAE. SWY2001-Ab3-LND1002 exhibits a reduced drug-to-antibody ratio of 2.0; the humanized antibody thereof is conjugated with a small-molecule drug via a linker by using enzyme-mediated site-directed conjugation, thereby minimizing payload release in plasma. SWY2001-Ab3-LND1002 is a novel Fc-enabled IgG1 antibody with an extended half-life, enabling once-every-three-week (Q3W) dosing in patients. These features lead to increased intratumoral delivery; following cellular uptake, the payload is released via proteolysis. Lower plasma MMAE concentrations associated with the design features of SWY2001-Ab3-LND1002 may reduce the severity and incidence of peripheral neuropathy, as well as the incidence of rash. Overall, SWY2001-Ab3-LND1002 exhibits favorable tolerability, 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 cut-off date: July 31, 2023).

[0011] Compared with patients treated with EV in combination with an anti-PD(L)-1 antibody, patients receiving the combination therapy of the antibody-drug conjugate targeting Nectin-4 of the present disclosure and the anti-PD(L)-1 antibody exhibit fewer treatment emergent adverse events and lower plasma concentrations of free MMAE, which demonstrate that the combination therapy of the antibody-drug conjugate targeting Nectin-4 of the present disclosure and the anti-PD(L)-1 antibody has improved safety.

[0012] The combined use of the antibody-drug conjugate targeting Nectin-4 of the present disclosure and the anti-PD(L)-1 antibody produces synergistic effects. Compared with patients treated with EV in combination with an anti-PD(L)-1 antibody, patients receiving the combination therapy of the antibody-drug conjugate targeting Nectin-4 of the present disclosure and the anti-PD(L)-1 antibody exhibit longer progression-free survival and longer duration of response, which demonstrate that the combination therapy of the antibody-drug conjugate targeting Nectin-4 of the present disclosure and the anti-PD(L)-1 antibody has superior therapeutic efficacy.

[0013] An object of the present disclosure is to provide 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 manufacture of a medicament for the treatment of cancer, wherein the antibody-drug conjugate targeting Nectin-4 is prepared by conjugating a drug-linker moiety represented by formula I with an antibody targeting Nectin-4 or a functional fragment thereof: Formula I.

[0014] In some embodiments, the antibody or the functional fragment thereof comprises a heavy chain and a light chain, wherein (i) the heavy chain comprises three CDR regions: a CDR1-H region, a CDR2-H region, and a CDR3-H region, wherein the CDR1-H region, CDR2-H region, and CDR3-H region have amino acid sequences as set forth in SEQ ID NOs: 1, 2 and 3, respectively; and / or (ii) the light chain comprises three CDR regions: a CDR1-L region, a CDR2-L region and a CDR3-L region, wherein the CDR1-L region, CDR2-L region and CDR3-L region have amino acid sequences as set forth in SEQ ID NOs: 4, 5 and 6, respectively.

[0015] In some embodiments, the antibody or the 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 set forth in SEQ ID NO: 7, and / or, the light chain variable region has an amino acid sequence as set forth in SEQ ID NOs: 8-10.

[0016] In some embodiments, the antibody or the functional fragment thereof comprises a heavy chain constant region and a light chain constant region, wherein the heavy chain constant region has an amino acid sequence as set forth in SEQ ID NO: 11 or SEQ ID NO: 13; and / or, the light chain constant region has an amino acid sequence as set forth in SEQ ID NO: 12.

[0017] In some embodiments, 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.

[0018] In some embodiments, the immune checkpoint inhibitor is an anti-PD-L1 antibody, and the anti-PD-L1 antibody is selected from Atezolizumab, Avelumab or Durvalumab.

[0019] In some embodiments, 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.

[0020] 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.

[0021] In some embodiments, the unit preparation of the antibody-drug conjugate targeting Nectin-4, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof comprises 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.

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

[0023] In some embodiments, the immune checkpoint inhibitor is administered at the recommended dose in the Prescribing Information (PI) or Summary of Product Characteristics (SmPC) thereof.

[0024] In some embodiments, the antibody-drug conjugate, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered prior to the immune checkpoint inhibitor in each administration cycle.

[0025] An object of the present disclosure is to provide a method for treating cancer by using 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, wherein the method comprises administering to a subject or patient a therapeutically effective amount of the antibody-drug conjugate targeting Nectin-4, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, wherein the antibody-drug conjugate targeting Nectin-4 is prepared by conjugating a drug-linker moiety represented by formula I with an antibody targeting Nectin-4 or a functional fragment thereof: Formula I.

[0026] In some embodiments, the antibody or the functional fragment thereof comprises a heavy chain and a light chain, wherein (i) the heavy chain comprises three CDR regions: a CDR1-H region, a CDR2-H region, and a CDR3-H region, wherein the CDR1-H region, CDR2-H region, and CDR3-H region have amino acid sequences as set forth in SEQ ID NOs: 1, 2 and 3, respectively; and / or (ii) the light chain comprises three CDR regions: a CDR1-L region, a CDR2-L region and a CDR3-L region, wherein the CDR1-L region, CDR2-L region and CDR3-L region have amino acid sequences as set forth in SEQ ID NOs: 4, 5 and 6, respectively.

[0027] In some embodiments, the antibody or the 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 set forth in SEQ ID NO: 7, and / or, the light chain variable region has an amino acid sequence as set forth in SEQ ID NOs: 8-10.

[0028] In some embodiments, the antibody or the functional fragment thereof comprises a heavy chain constant region and a light chain constant region, wherein the heavy chain constant region has an amino acid sequence as set forth in SEQ ID NO: 11 or SEQ ID NO: 13; and / or, the light chain constant region has an amino acid sequence as set forth in SEQ ID NO: 12.

[0029] In some embodiments, 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.

[0030] In some embodiments, the immune checkpoint inhibitor is an anti-PD-L1 antibody, and the anti-PD-L1 antibody is selected from Atezolizumab, Avelumab or Durvalumab.

[0031] In some embodiments, 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.

[0032] 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.

[0033] In some embodiments, the antibody-drug conjugate, or the 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; 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.

[0034] In some embodiments, the antibody-drug conjugate, or the 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 the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered for three or more administration cycles.

[0035] In some embodiments, the immune checkpoint inhibitor is administered at the recommended dose in the Prescribing Information (PI) or Summary of Product Characteristics (SmPC) thereof.

[0036] In some embodiments, the antibody-drug conjugate, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered prior to the immune checkpoint inhibitor in each administration cycle.

[0037] In some embodiments, the antibody-drug conjugate, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof and / or the immune checkpoint inhibitor are administered on day 1 of each administration cycle.

[0038] In some embodiments, the subject or patient is a subject or patient who is intolerant to Nectin-4 targeted therapy.

[0039] In some embodiments, the subject or patient is a subject or patient who has not previously received Nectin-4 targeted therapy.

[0040] In some embodiments, the subject or patient is a subject or patient who has cancer recurrence following prior Nectin-4 targeted therapy.

[0041] In some embodiments, the subject or patient is a subject or patient who has not previously received MMAE-containing drug therapy. Brief Description of the Drawings

[0042] Figure 1 shows a schematic structural diagram of the antibody-drug conjugate, in which LND1002 represents the moiety of the linker + drug molecule, and the circled part highlights the amide bond linking the linker and the antibody within the L&D moiety. The Nectin-4 targeted ADC shown in this figure is a site-specific antibody-drug conjugate. Each conjugate molecule is prepared by conjugating one molecule of MMAE derivative with one anti-Nectin-4 monoclonal antibody molecule at the amino acid position Q295 on each heavy chain via the linker (NH2-PEG3-Val-Cit). The antibody is linked to the linker via a stable amide bond (isopeptide bond), and the resultant conjugate features an average drug-to-antibody ratio (DAR) of 2.0. Detailed Description of Embodiments

[0043] The examples listed below are intended to better illustrate the content of the present disclosure, but the content of the present disclosure is not limited to the specific examples described. Non-essential improvements and adjustments made to the embodiments by those skilled in the art according to the above Summary of the Invention still fall within the scope of protection of the present disclosure. Explanation of terms:

[0044] As used herein, the singular forms “a / an”, “one” and “the” also include plural forms unless otherwise specified. For example, the term "a cell" includes multiple cells and their mixtures.

[0045] As used herein, the term "about" refers to the usual error range for the respective value readily known to those skilled in the art. The term “about” in relation to a value or parameter as used herein includes (and describes) examples directed to the value or parameter itself.

[0046] As used herein, the term "comprising" or "including" refers to the inclusion of the stated elements, integers, or steps, but not the exclusion of any other elements, integers, or steps. Unless otherwise indicated, the term “comprising” or “including” when used in the present disclosure also encompasses situations consisting of the described elements, integers or steps. For example, when referring to an antibody variable region “comprising” a particular sequence, it is intended to also encompass an antibody variable region consisting of that particular sequence.

[0047] As used herein, the term "cancer" refers to a proliferative disorder or disease caused or characterized by the proliferation of cells, which have lost susceptibility to normal growth control. The term “cancer” includes tumors and any other proliferative disorders. Cancers of the same tissue type originate in the same tissue, and may be divided into different subtypes based on their biological characteristics.

[0048] As used herein, the term "treatment" refers to clinical intervention intended to alter the natural course of the individual or cell being treated during the course of clinical pathology. Desirable effects of treatment include delaying or decreasing the rate of disease progression, ameliorating or palliating the disease state, and achieving remission or improving prognosis. For example, a patient is successfully "treated" if one or more symptoms associated with cancer are mitigated or eliminated, including but not limited to, reducing the proliferation of (or destroying) cancerous cells, decreasing symptoms resulting from the disease, increasing the quality of life of the patient suffering from the disease, reducing the dose of other medications required to treat the disease, delaying the progression of the disease, and / or prolonging survival of the patient.

[0049] As used herein, the term "antibody" includes monoclonal antibodies (including full length antibodies which have an immunoglobulin Fc region), antibodies with polyepitopic specificity, multispecific antibodies (e.g., 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.

[0050] As used herein, the term "full-length antibody" refers to an antibody in its intact or substantially intact form, as opposed to an antibody fragment. Specifically, full-length antibodies include those with heavy and light chains, including an Fc region. The constant domain may be a native-sequence constant domain (e.g., a human native-sequence constant domain) or amino acid sequence variants thereof. In certain cases, the intact antibody may have one or more effector functions.

[0051] As used herein, the terms “heavy chain constant region” or “CH” are used interchangeably in the present disclosure and comprise at least three heavy chain constant domains (CH1, CH2, and CH3). By way of example, human heavy chain constant regions include y, 5, a, e, and ^ constant regions, wherein each heavy chain constant region corresponds to an antibody isotype. For example, an antibody comprising a y constant region is an IgG antibody, an antibody comprising a 5 constant region is an IgD antibody, an antibody comprising an a constant region is an IgA antibody, an antibody comprising a ^ constant region is an IgM antibody, and an antibody comprising an e constant region is an IgE antibody. Certain isotypes can be further subdivided into subclasses. For example, IgG antibodies include, but are not limited to, IgG1 (comprising a Y1 constant region), IgG2 (comprising a Y2 constant region), IgG3 (comprising a Y3 constant region), and IgG4 (comprising a Y4 constant region) antibodies; IgA antibodies include, but are not limited to, IgA1 (comprising an a1 constant region) and IgA2 (comprising an a2 constant region) antibodies; and IgM antibodies include, but are not limited to, IgM1 and IgM2. Isotypes may also include some modified forms, wherein the modifications can alter Fc function, for example, enhancing or attenuating effector functions or increasing or decreasing the binding to Fc receptors. As described above, it will be understood by one of ordinary skill in the art that the heavy chain constant regions may be modified such that they vary in amino acid sequence from the naturally occurring immunoglobulin molecule.

[0052] As used herein, the terms “light chain constant region” or “CL” are used interchangeably in the present disclosure and comprise one light chain constant domain (CL). By way of example, light chains can be divided into two classes, X and k, according to differences in their constant regions.

[0053] As used herein, the term "heavy chain variable region (VH)" refers to an amino-terminal variable domain of an immunoglobulin heavy chain.

[0054] As used herein, the term "light chain variable region (VL)" refers to an amino-terminal variable domain of an immunoglobulin light chain.

[0055] As used herein, the term "CDR (complementarity-determining region)" refers to amino acid sequences that together define the binding affinity and specificity of the Fv region of an antibody. This is because antibody specificity lies in the structural complementarity between an antibody-binding site and an antigenic determinant. An antibody-binding site of an antibody is composed of residues primarily derived from the so-called hypervariable regions or complementarity-determining regions (CDRs). The light (L) and heavy (H) chains of an antibody each have three CDRs, designated 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, including the sets of CDRs from both the heavy chain variable region and the light chain variable region.

[0056] As used herein, the term "unit preparation" refers to the smallest subpackage of each pharmaceutical preparation comprising an appropriate amount of an active compound. For example, a unit preparation in capsules refers to one capsule, a unit preparation in tablets refers to one tablet, and a unit preparation in injections refers to one injection; this applies to other types of preparations.

[0057] As used herein, the term "therapeutically effective amount" refers to an amount that produces a therapeutic effect on a subject. For example, in a subject to which the amount is administered, the symptoms or states of a disease are mitigated, palliated, or eliminated, or the progression of the symptoms or states of a disease is delayed or inhibited, compared to a subject to which the amount is not administered.

[0058] As used herein, the following terms are determined by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. As used herein, the terms “complete response” or “CR” refer to the disappearance of all target lesions and non-target lesions, and no new lesions. As used herein, the terms “partial response” or “PR” refer to at least 30% reduction in the sum of the longest diameters (SLD) of target lesions relative to baseline (lasting longer than four weeks), with no progression of non-target lesions and no new lesions. As used herein, the terms “progressive disease” or “PD” refer to an increase of > 20% in the SLD of target lesions relative to the nadir value, an absolute increase of > 5 mm in the sum of diameters (SoD), unequivocal progression of non-target lesions, or the appearance of new unequivocal metastatic lesions. As used herein, the terms “stable disease” or “SD” refer to target lesion measurements that do not meet the criteria for either PD or PR relative to the nadir value, with one or more non-target lesions present and / or tumor marker levels remaining above normal values, and no new lesions.

[0059] As used herein, the following terms are determined by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Disease control rate (DCR) is defined as the percentage of participants who achieve responses (PR+CR) and stable disease lasting for four months following treatment, wherein DCR=CR+PR+SD. Objective response rate (ORR) is defined as the percentage of participants who achieve complete response (CR) or partial response (PR) during the study period. Clinical benefit rate (CBR) is defined as the percentage of participants who achieve CR, PR or SD. Progression-free survival (PFS) is defined as the time from the initiation of study treatment to the first documentation of disease progression or death from any cause during the study period, whichever comes first. Time to progress (TTP) is defined as the time from the initiation of study treatment to the first documentation of disease progression. Overall survival (OS) is defined as the time from the initiation of study treatment to death from any cause. Duration of response (DoR) is 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 period, whichever comes first. Time to response (TTR) is defined as the time from the initiation of study treatment to the first documented CR or PR.

[0060] As used herein, the terms "treatment emergent adverse events" or "TEAE" or "AE" refer to any unfavorable and unintended sign (including abnormal laboratory findings), symptom, or disease associated with the use of a medical or therapeutic procedure, or considered temporally related thereto. 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 terms described above are determined according to NCI CTCAE v5.0.

[0061] As used herein, the term “intolerance” refers to the circumstance in which a subject has received prior anticancer therapy and develops adverse-event-related symptoms (e.g., peripheral neuropathy, skin toxicity, hyperglycemia, or gastrointestinal symptoms) during the first two cycles; such symptoms are not alleviated despite adherence to dose-adjustment guidelines, resulting in treatment discontinuation, with no evidence of disease progression.

[0062] As used herein, the term “recurrence” refers to the circumstance in which the cancer once responded to an anticancer therapy, but no longer achieves responses to such therapy or achieves a response that is no longer adequate.

[0063] As used herein, the term “MMAE” refers to monomethyl auristatin E, a tubulin inhibitor.

[0064] Herein, the immune checkpoint inhibitor may be commercially available or may be prepared by methods known to those skilled in the art.

[0065] In a first aspect, an object of the present disclosure is to provide 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 manufacture of a medicament for the treatment of cancer, wherein the antibody-drug conjugate targeting Nectin-4 is prepared by conjugating a drug-linker moiety represented by formula I with an antibody targeting Nectin-4 or a functional fragment thereof: Formula I. In some embodiments, the antibody or the functional fragment thereof comprises a heavy chain, wherein the heavy chain comprises three CDR regions: a CDR1-H region, a CDR2-H region, and a CDR3-H region, wherein the CDR1-H region, CDR2-H region, and CDR3-H region have amino acid sequences as set forth in SEQ ID NOs: 1, 2 and 3, respectively.

[0066] In some embodiments, the antibody or the functional fragment thereof comprises a light chain, wherein the light chain comprises three CDR regions: a CDR1-L region, a CDR2-L region and a CDR3-L region, wherein the CDR1-L region, CDR2-L region and CDR3-L region have amino acid sequences as set forth in SEQ ID NOs: 4, 5 and 6, respectively.

[0067] In some embodiments, the antibody or the functional fragment thereof comprises a heavy chain and a light chain, wherein the heavy chain comprises three CDR regions: a CDR1-H region, a CDR2-H region, and a CDR3-H region, wherein the CDR1-H region, CDR2-H region, and CDR3-H region have amino acid sequences as set forth in SEQ ID NOs: 1, 2 and 3, respectively; and the light chain comprises three CDR regions: a CDR1-L region, a CDR2-L region and a CDR3-L region, wherein the CDR1-L region, CDR2-L region and CDR3-L region have amino acid sequences as set forth in SEQ ID NOs: 4, 5 and 6, respectively.

[0068] In some embodiments, the antibody or the functional fragment thereof comprises a heavy chain variable region, wherein the heavy chain variable region has an amino acid sequence as set forth in SEQ ID NO: 7.

[0069] In some embodiments, the antibody or the functional fragment thereof comprises a light chain variable region, wherein the light chain variable region has an amino acid sequence as set forth in SEQ ID NOs: 8-10.

[0070] In some embodiments, the antibody or the 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 set forth in SEQ ID NO: 7, and the light chain variable region has an amino acid sequence as set forth in SEQ ID NOs: 8-10.

[0071] In some embodiments, the antibody or the functional fragment thereof comprises a heavy chain constant region, wherein the heavy chain constant region has an amino acid sequence as set forth in SEQ ID NO: 11 or SEQ ID NO: 13.

[0072] In some embodiments, the antibody or the functional fragment thereof comprises a light chain constant region, wherein the light chain constant region has an amino acid sequence as set forth in SEQ ID NO: 12.

[0073] In some embodiments, the antibody or the functional fragment thereof comprises a heavy chain constant region and a light chain constant region, wherein the heavy chain constant region has an amino acid sequence as set forth in SEQ ID NO: 11 or SEQ ID NO: 13, and the light chain constant region has an amino acid sequence as set forth in SEQ ID NO: 12.

[0074] In some embodiments, 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.

[0075] In some embodiments, the immune checkpoint inhibitor is an anti-PD-L1 antibody, and the anti-PD-L1 antibody is selected from Atezolizumab, Avelumab or Durvalumab.

[0076] 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.

[0077] 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.

[0078] In some embodiments, the unit preparation of the antibody-drug conjugate targeting Nectin-4, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof comprises 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; such as, 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 of the above 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 of the above values.

[0079] In some embodiments, the antibody-drug conjugate, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered at a frequency of QW (once weekly), Q2W (once every two weeks), Q3W (once every three weeks), or Q4W (once every four weeks).

[0080] In some embodiments, the immune checkpoint inhibitor is administered at the recommended dose in the Prescribing Information (PI) or Summary of Product Characteristics (SmPC) thereof.

[0081] In some embodiments, the antibody-drug conjugate, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered prior to the immune checkpoint inhibitor in each administration cycle.

[0082] In a second aspect, an object of the present disclosure is to provide a method for treating cancer by using 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, wherein the method comprises administering to a subject or patient a therapeutically effective amount of the antibody-drug conjugate targeting Nectin-4, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, wherein the antibody-drug conjugate targeting Nectin-4 is prepared by conjugating a drug-linker moiety represented by formula I with an antibody targeting Nectin-4 or a functional fragment thereof: Formula I.

[0083] In some embodiments, the antibody or the functional fragment thereof comprises a heavy chain, wherein the heavy chain comprises three CDR regions: a CDR1-H region, a CDR2-H region, and a CDR3-H region, wherein the CDR1-H region, CDR2-H region, and CDR3-H region have amino acid sequences as set forth in SEQ ID NOs: 1, 2 and 3, respectively.

[0084] In some embodiments, the antibody or the functional fragment thereof comprises a light chain, wherein the light chain comprises three CDR regions: a CDR1-L region, a CDR2-L region and a CDR3-L region, wherein the CDR1-L region, CDR2-L region and CDR3-L region have amino acid sequences as set forth in SEQ ID NOs: 4, 5 and 6, respectively.

[0085] In some embodiments, the antibody or the functional fragment thereof comprises a heavy chain and a light chain, wherein the heavy chain comprises three CDR regions: a CDR1-H region, a CDR2-H region, and a CDR3-H region, wherein the CDR1-H region, CDR2-H region, and CDR3-H region have amino acid sequences as set forth in SEQ ID NOs: 1, 2 and 3, respectively; and the light chain comprises three CDR regions: a CDR1-L region, a CDR2-L region and a CDR3-L region, wherein the CDR1-L region, CDR2-L region and CDR3-L region have amino acid sequences as set forth in SEQ ID NOs: 4, 5 and 6, respectively.

[0086] In some embodiments, the antibody or the functional fragment thereof comprises a heavy chain variable region, wherein the heavy chain variable region has an amino acid sequence as set forth in SEQ ID NO: 7.

[0087] In some embodiments, the antibody or the functional fragment thereof comprises a light chain variable region, wherein the light chain variable region has an amino acid sequence as set forth in SEQ ID NOs: 8-10.

[0088] In some embodiments, the antibody or the 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 set forth in SEQ ID NO: 7; and the light chain variable region has an amino acid sequence as set forth in SEQ ID NOs: 8-10.

[0089] In some embodiments, the antibody or the functional fragment thereof comprises a heavy chain constant region, wherein the heavy chain constant region has an amino acid sequence as set forth in SEQ ID NO: 11 or SEQ ID NO: 13.

[0090] In some embodiments, the antibody or the functional fragment thereof comprises a light chain constant region, wherein the light chain constant region has an amino acid sequence as set forth in SEQ ID NO: 12.

[0091] In some embodiments, the antibody or the functional fragment thereof comprises a heavy chain constant region and a light chain constant region, wherein the heavy chain constant region has an amino acid sequence as set forth in SEQ ID NO: 11 or SEQ ID NO: 13; and the light chain constant region has an amino acid sequence as set forth in SEQ ID NO: 12.

[0092] In some embodiments, 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.

[0093] In some embodiments, the immune checkpoint inhibitor is an anti-PD-L1 antibody, and the anti-PD-L1 antibody is selected from Atezolizumab, Avelumab or Durvalumab.

[0094] 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.

[0095] 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.

[0096] In some embodiments, the antibody-drug conjugate, or the 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, such as, 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, 2.8 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 a range between any two of the above values. In some embodiments, the dose per administration preferably ranges 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.

[0097] In some embodiments, the antibody-drug conjugate, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered at a low dose. The low dose is a dose ranging from about 0.1 mg / kg to about 2.0 mg / kg per administration, such as 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, 2.0mg / kg, or a range between any two of the above values.

[0098] In some embodiments, the antibody-drug conjugate, or the 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, such as 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, 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 of the above values.

[0099] In some embodiments, the antibody-drug conjugate, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered at a frequency of QW, Q2W, Q3W, or Q4W.

[0100] In some embodiments, the immune checkpoint inhibitor (such as an anti-PD-L1 antibody or an anti-PD-1 antibody) is administered at the recommended dose in the Prescribing Information (PI) or Summary of Product Characteristics (SmPC) thereof.

[0101] In some embodiments, the antibody-drug conjugate, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered prior to the immune checkpoint inhibitor in each administration cycle.

[0102] In a third aspect, an object of the present disclosure is to provide a pharmaceutical composition comprising the antibody-drug conjugate targeting Nectin-4, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof as described above and the immune checkpoint inhibitor as described above.

[0103] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

[0104] In some embodiments, the pharmaceutical composition comprises temporally and / or spatially separated ingredients that act together to achieve the object of the present disclosure. For example, the ingredients contained in the pharmaceutical composition can be administered to a patient or subject as a whole or individually. When the ingredients contained in the pharmaceutical composition are administered separately to a subject, these ingredients may be administered to the patient or subject simultaneously or sequentially.

[0105] In some embodiments, the pharmaceutically acceptable carrier is selected from water, buffered aqueous solutions, isotonic saline solutions (e.g., phosphate buffered saline (PBS)), glucose, mannitol, lactose, starch, magnesium stearate, cellulose, magnesium carbonate, 0.3% glycerol, hyaluronic acid, ethanol, polyalkylene glycols (e.g., polypropylene glycol), triglycerides, etc.

[0106] In some embodiments, the type of pharmaceutically acceptable carrier depends primarily on whether the composition formulated according to the present disclosure is for oral, nasal, intradermal, or subcutaneous administration, intramuscular injection, or intravenous injection. The composition formulated according to the present disclosure may contain wetting agents, emulsifiers, or buffering substances as additives.

[0107] In the present disclosure, the amino acid sequences of the CDRs described above are shown according to the rules of the IMGT definition (the sequences in the claims of the present disclosure are also shown according to the rules of the IMGT definition). However, it is well known to those skilled in the art that the CDRs of an antibody can be defined in the art by a variety of methods, such as the rules of Kabat definition based on sequence variability (see, Kabat et al., Sequences of Proteins of Immunological Interest, fifth edition, National Institutes of Health, Bethesda, Maryland (1991)), and the rules of Chothia definition based on the location of a structural loop region (see JMol 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 a region thereof (such as a variable region) should be understood to encompass complementarity-determining regions as defined by any of the above known solutions described by the present disclosure. Although the scope of protection as claimed in the claims of the present disclosure is based on the sequences shown according to the rules of the IMGT definition, corresponding amino acid sequences according to the rules of other CDR definitions shall also fall within the scope of protection of the present disclosure.

[0108] In the first aspect to the third aspect:

[0109] In some embodiments, the antibody-drug conjugate targeting Nectin-4 has a structure shown in formula I: Formula I wherein A is any one of the antibodies targeting Nectin-4 or the functional fragments thereof described above; d is an integer or decimal from 1 to 12; preferably, d is 2.

[0110] In some embodiments, the antibody targeting Nectin-4 or the functional fragment thereof comprises Q295 (according to EU numbering) in the constant region of the heavy chain thereof, and the linker moiety is linked to the side chain of the Q295 via an amide bond.

[0111] In some embodiments, the method achieves complete response or partial response.

[0112] In some embodiments, the method results in lower levels of free MMAE in plasma compared with EV treatment.

[0113] In some embodiments, the method results in fewer treatment emergent adverse events compared with EV treatment.

[0114] In some embodiments of the present disclosure, the antibody targeting Nectin-4 or the functional fragment thereof is selected from a murine antibody, a chimeric antibody, a humanized antibody, or a fully human antibody.

[0115] In some embodiments of the present disclosure, the functional fragment is selected from Fab fragments, F(ab')2 fragments, Fab' fragments, Fv fragments, dsFv fragments, or scFv fragments.

[0116] In some embodiments of the present disclosure, the immune checkpoint inhibitor may be commercially available or prepared in-house.

[0117] In some embodiments of the present disclosure, the heavy chain of Pembrolizumab has the following sequence: QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNG GTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQG TTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEF LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPRE EQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVD KSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 21); the light chain of Pembrolizumab has the following sequence: EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESG VPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKRTVAAPSVFIFP PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 22).

[0118] In some embodiments of the present disclosure, the heavy chain of Cemiplimab has the following sequence: EVQLLESGGVLVQPGGSLRLSCAASGFTFSNFGMTWVRQAPGKGLEWVSGISGGGRDT YFADSVKGRFTISRDNSKNTLYLQMNSLKGEDTAVYYCVKWGNIYFDYWGQGTLVTVS SASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST YRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRW QEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 15); the light chain of Cemiplimab has the following sequence: DIQMTQSPSSLSASVGDSITITCRASLSINTFLNWYQQKPGKAPNLLIYAASSLHGGVPSRF SGSGSGTDFTLTIRTLQPEDFATYYCQQSSNTPFTFGPGTVVDFRRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 16).

[0119] In some embodiments of the present disclosure, the heavy chain of Atezolizumab has the following sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGST YYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELL GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 17); the light chain of Atezolizumab has the following sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 18).

[0120] In some embodiments of the present disclosure, the heavy chain of Avelumab has the following sequence: EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPSGGITFY ADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTLVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 19); the light chain of Avelumab has the following sequence: QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGV SNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRVFGTGTKVTVLGQPKANPTVT LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAAS SYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 20).

[0121] In some embodiments of the present disclosure, the immune checkpoint inhibitor (such as an anti-PD-L1 antibody or an anti-PD-1 antibody) is administered at a dose of about 200 mg to about 2000 mg (such as about 200 mg to about 300 mg, such as about 300 mg to about 400mg, such as about 400 mg to about 500 mg, such as about 500 mg to about 600 mg, such as about 600 mg to about 700 mg, such as about 700 mg to about 800 mg, such as about 800 mg to about 900 mg, such as about 900 mg to about 1000 mg, such as about 1000 mg to about 1100 mg, such as about 1100 mg to about 1200 mg, such as about 1200 mg to about 1300 mg, such as about 1300 mg to about 1400 mg, such as about 1400 mg to about 1500 mg, such as about 1500 mg to about 1600 mg, such as about 1600 mg to about 1700 mg, such as about 1700 mg to about 1800 mg, such as about 1800 mg to about 1900 mg, such as about 1900 mg to about 2000 mg).

[0122] In some embodiments of the present disclosure, the immune checkpoint inhibitor (such as an anti-PD-L1 antibody or an anti-PD-1 antibody) is administered at a dose of 350 mg. In some embodiments of the present disclosure, the immune checkpoint inhibitor (such as an anti-PD-L1 antibody or an anti-PD-1 antibody) is administered at a dose of 800 mg. In some embodiments of the present disclosure, the immune checkpoint inhibitor (such as an anti-PD-L1 antibody or an anti-PD-1 antibody) is administered at a dose of 850 mg. In some embodiments of the present disclosure, the immune checkpoint inhibitor (such as an anti-PD-L1 antibody or an anti-PD-1 antibody) is administered at a dose of 1200 mg. In some embodiments of the present disclosure, the immune checkpoint inhibitor (such as an anti-PD-L1 antibody or an anti-PD-1 antibody) is administered at a dose of 1680 mg.

[0123] In some embodiments of the present disclosure, the administration dose of Atezolizumab is an intravenous infusion of 850 mg once every two weeks, 1200 mg once every three weeks, or 1680 mg once every four weeks.

[0124] In some embodiments of the present disclosure, the administration dose of Cemiplimab is an intravenous infusion of 350 mg once every three weeks.

[0125] In some embodiments of the present disclosure, the administration dose of Avelumab is an intravenous infusion of 800 mg once every two weeks.

[0126] In some embodiments of the present disclosure, the antibody-drug conjugate targeting Nectin-4, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof can be administered for one or more administration cycles (such as, 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 administration cycles). In some embodiments of the present disclosure, the antibody-drug conjugate targeting Nectin-4, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered for three or more administration cycles. In some embodiments of the present disclosure, the antibody-drug conjugate targeting Nectin-4, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered for an administration cycle that continues until loss of clinical benefits (e.g., confirmed disease progression, drug resistance, death, or unacceptable toxicity).

[0127] In some embodiments of the present disclosure, the immune checkpoint inhibitor (such as an anti-PD-L1 antibody or an anti-PD-1 antibody) can be administered for one or more administration cycles (such as, 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 administration cycles). In some embodiments of the present disclosure, the immune checkpoint inhibitor (such as an anti-PD-L1 antibody or an anti-PD-1 antibody) is administered for three or more administration cycles. In some embodiments of the present disclosure, the immune checkpoint inhibitor (such as an anti-PD-L1 antibody or an anti-PD-1 antibody) is administered for an administration cycle that continues until loss of clinical benefits (e.g., confirmed disease progression, drug resistance, death, or unacceptable toxicity).

[0128] In some embodiments of the present disclosure, each of the one or more administration cycles has a duration of 14 days. In some embodiments of the present disclosure, each of the one or more administration cycles has a duration of 21 days. In some embodiments of the present disclosure, each of the one or more administration cycles has a duration of 28 days. Preferably, each of the one or more administration cycles has a duration of 21 days.

[0129] In some embodiments of the present disclosure, the antibody-drug conjugate, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof and / or the immune checkpoint inhibitor are administered on a dosing regimen of once every three weeks (Q3W), with a treatment cycle of 21 days.

[0130] In some embodiments of the present disclosure, the antibody-drug conjugate, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof and / or the immune checkpoint inhibitor are administered on a dosing regimen of once every four weeks (Q4W), with a treatment cycle of 28 days.

[0131] In some embodiments of the present disclosure, the antibody-drug conjugate, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof and / or the immune checkpoint inhibitor are administered on a dosing regimen of once every two weeks (Q2W), with a treatment cycle of 14 or 28 days.

[0132] In some embodiments of the present disclosure, the antibody-drug conjugate, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof and / or the immune checkpoint inhibitor are administered on a dosing regimen of once weekly (QW) for three consecutive weeks, followed by a one-week break, with a treatment cycle of 28 days.

[0133] In some embodiments of the present disclosure, the antibody-drug conjugate, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof and / or the immune checkpoint inhibitor are administered on a dosing regimen of once weekly (QW) for two consecutive weeks, followed by a one-week break, with a treatment cycle of 21 days.

[0134] In some embodiments of the present disclosure, preferably, the antibody-drug conjugate or the pharmaceutically acceptable salt thereof is administered at a frequency of Q2W, and the antibody-drug conjugate or the pharmaceutically acceptable salt thereof is administered (based on the weight of the antibody-drug conjugate) at a dose ranging from 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.

[0135] In some embodiments of the present disclosure, preferably, the antibody-drug conjugate or the pharmaceutically acceptable salt thereof is administered at a frequency of Q3W, and the antibody-drug conjugate or the pharmaceutically acceptable salt thereof is administered (based on the weight of the antibody-drug conjugate) at a dose ranging 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.

[0136] In some embodiments of the present disclosure, the antibody-drug conjugate, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered on about day 1 of each administration cycle.

[0137] In some embodiments of the present disclosure, the antibody-drug conjugate, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered at 2.7 mg / kg at a frequency of Q3W.

[0138] In some embodiments of the present disclosure, the antibody-drug conjugate, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered at a dose of 3.6 mg / kg per administration and at a frequency of Q3W.

[0139] In some embodiments of the present disclosure, the immune checkpoint inhibitor is Pembrolizumab.

[0140] In some embodiments of the present disclosure, the Pembrolizumab is administered at a dose of 200 mg per administration and at a frequency of Q3W.

[0141] In some embodiments of the present disclosure, the immune checkpoint inhibitor (such as an anti-PD-L1 antibody or an anti-PD-1 antibody) is administered on about day 1 (such as day 1, 2, 3, or 4) of each administration cycle.

[0142] In some embodiments of the present disclosure, the cancer is a cancer that expresses, highly expresses, or over-expresses Nectin-4.

[0143] In some embodiments of the present disclosure, the cancer is preferably a solid tumor.

[0144] In some embodiments of the present disclosure, the subject or patient is a subject or patient who has not previously received Nectin-4 targeted therapy.

[0145] In some embodiments of the present disclosure, the subject or patient is a subject or patient who has not previously received EV treatment.

[0146] In some embodiments of the present disclosure, the subject or patient is a subject or patient who is intolerant to Nectin-4 targeted therapy.

[0147] In some embodiments of the present disclosure, the subject or patient is a subject or patient who has cancer recurrence following prior Nectin-4 targeted therapy.

[0148] In some embodiments of the present disclosure, the subject or patient is a subject or patient who has not previously received MMAE-containing drug therapy.

[0149] In some embodiments of the present disclosure, the subject or patient is a subject or patient that has failed standard of care or prior treatment.

[0150] In some embodiments of the present disclosure, the antibody-drug conjugate, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered via intravenous injection. In some embodiments, the antibody-drug conjugate, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered via intravenous infusion for over 60 ± 5 minutes (such as 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).

[0151] In some embodiments of the present disclosure, the immune checkpoint inhibitor (such as an anti-PD-L1 antibody or an anti-PD-1 antibody) is administered via intravenous injection. In some embodiments of the present disclosure, the immune checkpoint inhibitor (such as an anti-PD-L1 antibody or an anti-PD-1 antibody) is administered via intravenous infusion for over 30 ± 5 minutes (such as 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 certain cases, the immune checkpoint inhibitor (such as an anti-PD-L1 antibody or an anti-PD-1 antibody) is administered via intravenous infusion for over 60 ± 5 minutes (such as 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).

[0152] Herein, SWY2001-Ab3-LND1002 refers to the drug conjugate prepared by conjugating the drug-linker moiety represented by formula I of the present disclosure with an antibody targeting Nectin-4, wherein the antibody refers to the humanized antibody SWY2001-Ab3, which has 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 HC1 (SEQ ID NO: 11), and a light chain constant region of LC (SEQ ID NO: 12). The antibody in SWY2001-Ab3-LND1002 and the antibody-drug conjugate itself are prepared using the enzymatic conjugation method involving mTgase (with the sequence as shown in SEQ ID NO. 14 in Table 3) as described in WO 2023025243 A1, which is incorporated herein by reference in its entirety. Examples Example 1: Phase I / H clinical trial to evaluate safety, pharmacokinetic characteristics and efficacy of SWY2001-Ab3-LND1002 in combination with anti-PD(L)-1 therapy in patients with advanced solid tumors

[0153] The recommended phase II dose (RP2D) of SWY2001-Ab3-LND1002 in combination with an approved or standard-of-care dosage regimen of an anti-PD(L)-1 therapy was determined.

[0154] SWY2001-Ab3-LND1002 was assessed for the efficacy (measured by DCR), safety, tolerability, and PK at two dose levels by using a TOP (time-to-event Bayesian optimal phase II) study design (Zhou et al., 2017; Lin et al., 2020). The combination therapy was assessed in two patient populations, namely mUC (naive to Nectin-4 targeted therapy) and / or cervical cancer (naive to treatment with MMAE-containing drug therapy). 1.     Drug information and experimental protocol 1.1 Drug information

[0155] Trial drug 1: SWY2001-Ab3-LND1002 (recombinant humanized anti-human Nectin-4 monoclonal antibody-MMAE conjugate for injection).

[0156] Specification: 30 mg / vial.

[0157] Dosage form: powder for injection.

[0158] Storage conditions: store at 2°C-8°C, protected from light; keep away from light prior to use and avoid shaking.

[0159] Trial drug 2: Pembrolizumab. 1.2 Experimental objectives and corresponding endpoints Table 1 Objectives and corresponding endpoints Objectives Corresponding endpoint Primary objectives To assess the efficacy (in terms of DCR) within a pharmacologically active dose range (PADR) following administration to participants with Nectin-4-positive mUC and / or cervical cancer who have progressed after at least first-line therapy, and for whom no other standard of care that has proven clinical benefits or is recommended based on the investigator’s individual risk-benefit assessment for the participant is currently available. DCR (CR + PR + SD for at least 4 months). At each tumor assessment time point, objective responses were determined by the investigator per RECIST v1.1. Secondary objectives To evaluate the safety of SWY2001-Ab3-LND1002. Incidence of TEAEs (severity determined using NCI CTCAE v5.0), grade > 3 TEAEs, SAEs, and AESIs (including irAEs). Clinically significant abnormalities / changes in electrocardiogram, vital signs, and physical examination relative to baseline. Clinically significant laboratory abnormalities / changes, as assessed per NCI CTCAE v5.0, with safety laboratory detection results serving as baseline. To evaluate the efficacy of SWY2001-Ab3-LND1002 via PFS, TTP, OS, CBR, ORR, DoR and TTR. PFS, TTP, OS, CBR, ORR, DoR and TTR (per RECIST v1.1). To assess the immunogenicity of SWY2001-Ab3-LND1002 based on the ADA emerging following exposure to SWY2001-Ab3-LND1002. Assessment of circulating anti-SWY2001-Ab3-LND1002 antibodies over time. Assessment of the correlation over time between anti-SWY2001-Ab3-LND1002 antibodies and the PK parameters of Tab and ADC. Assessment of key AE categories (e.g., irAEs, SAEs, grade > 3 TEAEs, infusion-related AEs) based on ADA status. To evaluate the PK properties of SWY2001- Ab3-LND1002 Standard serum PK parameters for ADC, Tab, and free payload MMAE, including but not limited to AUCo-t, AUCo-^, Cmax, Tmax, t1 / 2, CL, Vss, MRT and Rac at selected time points. Exploratory objectives: To assess biomarkers predictive of response to SWY2001-Ab3-LND1002 (i.e., Nectin-4 levels) in baseline tumor tissue and blood, as well as their correlation with response to SWY2001 -Ab3-LND 1002. Relationships between baseline tumor surface biomarkers (Nectin-4 expression), blood biomarkers, and response to SWY2001-Ab3-LND1002 treatment. Other candidate biomarkers with potential significance for predicting outcomes or treatment responses may also be assessed. To explore the relationships between (i) PK and safety, if data permit, and / or (ii) PK and PmD markers, and (iii) PK and tumor responses. Relationships between the PK parameters of SWY2001-Ab3-LND1002 (ADC, Tab, MMAE) and safety endpoints. Relationships between the PK parameters of SWY2001-Ab3-LND1002 (ADC, Tab, MMAE) and PmD endpoints. Relationships between the PK parameters of SWY2001-Ab3-LND1002 (ADC, Tab, MMAE) and tumor responses. 1.3 Study design

[0160] This is an open-label, phase I / II clinical trial designed to assess the safety, PK, and efficacy of SWY2001-Ab3-LND1002 in combination with an anti-PD(L)-1 antibody in patients with advanced solid tumors expressing Nectin-4. Table 2 summarizes the study population and the treatments they receive.

[0161] Based on adverse safety data, the rate of participant accrual, or other reasonable causes, the sponsor may, at its discretion, decide to enroll additional participants, suspend or halt enrollment, or terminate the study. Cohorts exploring SWY2001-Ab3-LND1002 in different regimens, different combinations, or different tumor types may be added via amendments to this protocol.

[0162] For all enrolled participants, the study treatment would continue until the occurrence of intolerable toxicity, death, withdrawal of consent, or investigator-confirmed progressive disease (PD) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Confirmed progressive disease required a new imaging assessment to be performed > 4 weeks after initial radiologic progression. Per RECIST v1.1, upon confirmation of PD by repeat scanning, the date of PD was defined as the date of the first tumor assessment showing progression.

[0163] All study participants underwent standard (clinical and laboratory) assessments outlined in the activity schedule, as well as assessments for PK and immunogenicity (anti-drug antibodies [ADA]). Clinical and laboratory AEs were reported and graded per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (v5.0). Guidelines for dose interruptions (e.g., for toxicity) were included in the protocol. Table 2 Patient population and number Cohorts Patient population Treatment Approximate number of patients (N) Optimized cohort 1 mUC patients who have not received Nectin-4 targeted therapy High and low doses of SWY2001-Ab3-LND1002 + standard dose of anti-PD(L)-1 antibody drug 40 Optimized cohort 2 Cervical cancer patients who have not received MMAE-containing drug therapy High and low doses of SWY2001-Ab3-LND1002 + standard dose of anti-PD(L)-1 antibody drug 40 Optimized cohort 3 Patients with locally advanced or metastatic head and neck squamous cell carcinoma (HNSCC) who have not received Nectin-4 targeted therapy or MMAE-containing drug therapy High and low doses of SWY2001-Ab3-LND1002 + standard dose of anti-PD(L)-1 antibody drug 20 Optimized cohort 4 Patients with urothelial carcinoma recurring following prior Nectin-4 targeted therapy High and low doses of SWY2001-Ab3-LND1002 + standard dose of anti-PD(L)-1 antibody drug 20 1.4 Administration dose

[0164] The dose of SWY2001 -Ab3-LND 1002 in combination with an anti-PD(L)-1 antibody was determined based on the safety, PK, PmD and preliminary efficacy data from the results of SWY2001-Ab3-LND1002 monotherapy clinical trial. The high dose did not exceed the maximum tolerated dose (MTD) defined in the monotherapy clinical trial results; however, the dose of SWY2001-Ab3-LND1002 differed from the monotherapy dose depending on the selected anti-PD(L)-1 antibody therapy.

[0165] The anti-PD(L)-1 antibody therapy was administered at the recommended dose in the Prescribing Information (PI) or Summary of Product Characteristics (SmPC).

[0166] Subjects received each intravenous infusion of SWY2001-Ab3-LND1002 at 2.7 mg / kg or 3.6 mg / kg, together with Pembrolizumab at a dose of 200 mg.

[0167] SWY2001-Ab3-LND1002 and the anti-PD(L)-1 antibody were injected intravenously (IV) for 30 minutes or more on day 1 of each 21-day cycle. SWY2001-Ab3-LND1002 was administered first, followed by the anti-PD(L)-1 antibody drug. 2.1 Study population 2.1.1 Inclusion criteria

[0168] Only patients who met all inclusion criteria and none of the exclusion criteria were eligible for study enrollment. The sponsor did not grant waivers to eligibility criteria.

[0169] 1.      Sign the informed consent form (ICF).

[0170] 2.      Male or female patients aged > 18 years at the time of signing the informed consent form.

[0171] 3.      Histologically and / or cytologically confirmed advanced or metastatic solid tumor (relapsed / refractory disease) with disease progression following at least first-line therapy, or with no other currently available standard of care that has proven clinical benefits or is recommended based on the investigator’s individual risk-benefit assessment for the participant. d: patients with Nectin-4-positive tumors were divided into groups: i. mUC patients who have not received Nectin-4 targeted therapy ii. cervical cancer patients who have not received MMAE-containing drug therapy

[0172] 4.     At least one radiologically measurable target lesion (computed tomography [CT] or magnetic resonance imaging [MRI]) as assessed per RECIST v1.1.

[0173] 5.     Eastern Cooperative Oncology Group (ECOG) performance status scores < 2.

[0174] 6.     Life expectancy > 12 weeks.

[0175] 7.     Normal hematologic and visceral organ function based on the following laboratory results obtained within 14 days prior to Cycle 1, Day 1 (C1D1): Hematological function: a. No transfusion of blood components, or administration of human granulocyte colonystimulating factor (GCSF), thrombopoietin (TPO), interleukin-11, or erythropoietin (EPO) within 2 weeks prior to C1D1. b. Absolute neutrophil count (ANC) > 1.0 x 109 / L (1500 / ^L) without G-CSF support. Acceptable use of G-CSF more than 14 days prior to C1D1. c. Platelet count > 100*109 / L (100,000 / ^L) without transfusion. d. Hemoglobin > 90 g / L (9 g / dL) or > 5.6 mmol / L. Acceptable blood transfusion or erythropoiesis-stimulating therapy in patients more than 14 days prior to C1D1. e. For patients not receiving therapeutic anticoagulants: international normalized ratio (INR) and (activated) partial thromboplastin time (aPTT or PTT) < 1.5xupper limit of normal (ULN). For patients receiving therapeutic anticoagulants, the anticoagulant dose should be stable. For patients receiving other oral anticoagulant therapies, the aPTT / PTT must remain within the expected therapeutic ranges for the anticoagulants and should be monitored per local standards. Liver function: f. Aspartate transferase (AST) and alanine amino-transferase (ALT) < 3XULN (< 5XULN for patients with liver metastases). g. Total bilirubin < 1.5XULN (< 3XULN for Gilbert syndrome patients). Renal function: h. Creatinine clearance (CrCl) > 30 mL / min, calculated using the institution’s standard method (e.g., Cockcroft-Gault equation).

[0176] 8.     Female patients: post-menopausal or capable of complying with contraceptive requirements specified in the protocol.

[0177] Male patients: agree to comply with contraceptive requirements specified in the protocol. Partners: post-menopausal (female partners) or capable of complying with contraceptive requirements specified in the protocol (male or female partners). Exclusion criteria

[0178] Patients meeting any of the following criteria were excluded from the study. Medical conditions

[0179] 1.      Active and uncontrolled central nervous system (CNS) metastases. Patients with central nervous system (CNS) metastatic tumors may be eligible provided that they have received standard of care, are asymptomatic, are on a stable dose of systemic steroids (i.e., < 10 mg / day prednisone or equivalent) and anticonvulsants, and have no evidence of disease progression for at least 4 weeks prior to the initiation of study treatment.

[0180] 2.      History of a malignancy diagnosed within three years prior to study enrollment, other than the disease under investigation, except for adequately treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix, breast or prostate (patient must have no evidence of active disease within 2 years prior to enrollment).

[0181] 3.      History of ascites or pleural effusion, except for those successfully treated, asymptomatic, and requiring no treatment for more than 4 months prior to the first dose in the study.

[0182] 4.      History and / or current evidence of cardiovascular events or conditions within 6 months prior to C1D1: a. History of myocardial infarction, unstable or severe angina pectoris, or arterial thromboembolic events (e.g., cerebrovascular attack (CVA) or transient ischemic attack (TIA)); b. Current New York Heart Association (NYHA) Class II-IV congestive heart failure; c. Left ventricular ejection fraction (LVEF) of less than 50%; d. Severe PR-related cardiac conduction abnormalities, such as ventricular arrhythmia, ventricular arrhythmia requiring clinical intervention, and third-degree atrioventricular block; unstable arrhythmia, or clinically significant (as judged by the investigator) electrocardiogram (ECG) abnormalities or history thereof; Fridericia-corrected QT interval (QTcF) > 480 ms at screening. e. Uncontrolled hypertension defined as systolic blood pressure (SBP) > 150 mmHg and / or diastolic blood pressure (DBP) > 100 mmHg despite optimal antihypertensive therapy. i. Note: Assessment of LVEF by echocardiography (ECHO) or multigated acquisition (MUGA) scan performed as part of routine patient care within 4 weeks prior to the screening visit was used to confirm screening eligibility.

[0183] 5.      Preexisting neuropathy of grade > 2.

[0184] 6.     Glycated hemoglobin A1C (HbA1C) > 8%, uncontrolled diabetes mellitus, or known diabetic neuropathy. Definition of uncontrolled diabetes mellitus: HbA1C > 8% or HbA1C > 7% accompanied by diabetes-related symptoms (polydipsia or polyuria).

[0185] 7.      Severe infection occurring within four weeks prior to C1D1, including but not limited to: a. Bacteremia and severe pneumonia requiring hospitalization b. Active infection of grade > 2 per the Common Terminology Criteria for Adverse Events (CTCAE v 5), requiring systemic antibiotic, antiviral or antifungal therapy within two weeks prior to C1D1.

[0186] 8.      Positive results for any of the following tests at screening: a. Human immunodeficiency virus (HIV). HIV-positive patients who received established antiretroviral therapy (ART) for at least 4 weeks, with a viral load of less than 400 copies / mL and CD4+T cell count > 350 pL, may be enrolled. b. Hepatitis B surface antigen (HBsAg) c. Hepatitis B core antibody (HBcAb) i. Patients with positive HBcAb results but negative hepatitis B virus (HBV) deoxyribonucleic acid (DNA) detection results at screening may be enrolled. ii. Patients with positive HBV DNA results (load < 500 IU / L) at screening who initiated anti-HBV therapy at least 14 days prior to C1D1 and agreed to continue the anti-HBV therapy during the study (per institutional standard of care). For patients with controlled infection, periodic monitoring of HBV DNA as directed by the treating physician was required. d. Hepatitis C virus (HCV) antibody test i. Patients with positive HCV antibody test results but negative HCV ribonucleic acid (RNA) test results at screening may be enrolled. ii. Patients with positive hepatitis C virus antibody results (HCV Ab+) who underwent PCR either spontaneously or as a response to a prior course of anti-HCV therapy.

[0187] 9.      Active thrombophlebitis, thromboembolism, hypercoagulability, or uncontrolled bleeding.

[0188] 10.    Active ocular surface disease at baseline (based on ophthalmological examination at screening).

[0189] 11.     Severe chronic liver disease or cirrhosis.

[0190] 12.     Patients with systemic autoimmune diseases (e.g., systemic lupus erythematosus [SLE], active rheumatoid arthritis, and inflammatory bowel disease [ulcerative colitis, Crohn’s disease, etc.]), except for patients with autoimmune-mediated hypothyroidism well-controlled with thyroid replacement hormone, or patients with eczema, psoriasis, or lichen simplex chronicus (involving no more than 10% of body surface area at screening).

[0191] 13. Patients with interstitial lung disease (e.g., idiopathic pulmonary fibrosis) or pneumonia, except for patients with radiation pneumonia (pulmonary fibrosis) within the radiation field that occurred more than 6 months prior to C1D1.

[0192] 14. Any active or symptomatic persistent (bacterial, viral, or fungal) infection requiring systemic therapy within 14 days prior to the initiation of study treatment. Routine antimicrobial prophylaxis is permitted.

[0193] 15.    Any mental disease or any other situation limiting compliance with the requirements of the study.

[0194] 16.    Any other significant comorbidities, diseases, metabolic disorders, physical examination findings, or clinical laboratory findings, precluding administration of the study drug, posing a risk of unacceptable treatment-related complications, or interfering with adherence to study procedures or interpretation of results. Prior / concomitant treatment

[0195] 17. Received anticancer therapy within the following time frame: a. Use of cytotoxic chemotherapy, mAbs, and / or small-molecule tyrosine kinase inhibitors within 14 days prior to C1D1; b. Use of nitrosourea or mitomycin-C within 42 days prior to C1D1; c. Received any investigational cancer therapy within 28 days prior to C1D1 or within 5 half-lives of the treatment drug (whichever is shorter).

[0196] 18.     Received organ transplantation (including allogeneic bone marrow transplant).

[0197] 19.     Systemic corticosteroid therapy for any indication, including replacement therapy for adrenal insufficiency received within 7 days prior to the first dose. a. Patients receiving inhaled or topical corticosteroids or local steroid injections are eligible for the study. b. Patients on a stable daily oral prednisolone dose of < 10 mg (or equivalent dose) for at least 7 days prior to the first dose are eligible for the study.

[0198] 20. Vaccinated with live-attenuated vaccines within 28 days prior to the first dose, or expected to require such vaccination during the period of the first dose. Coronavirus disease 2019 (COVID-19) vaccination is acceptable.

[0199] 21. Any other therapies prohibited during the study. Additional exclusion criteria

[0200] 22.

[0201] 23.

[0202] 24. Hypersensitivity to the study drug or any ingredient in the study drug. History of drug-induced allergy or other severe hypersensitivity reactions. History of any of the following: drug-induced severe cutaneous adverse reactions (SCARs; 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.

[0203] 25. Pregnancy and lactation. Example 2: Treatment of HNSCC, mUC, or cervical cancer with SWY2001-Ab3-LND1002 in combination with Pembrolizumab

[0204] In accordance with the methods disclosed herein, physicians can treat subjects (e.g., human patients) suffering from locally advanced or metastatic head and neck squamous cell carcinoma (HNSCC), locally advanced or metastatic urothelial carcinoma (mUC), or cervical cancer. SWY2001-Ab3-LND1002 was administered in combination with Pembrolizumab to treat such subjects.

[0205] In some embodiments, the subjects did not receive prior therapeutic agents targeting Nectin-4. In some embodiments, the subjects did not receive prior MMAE (monomethyl auristatin E)-containing therapeutic agents. For example, in some embodiments, the subjects had HNSCC and did not receive Nectin-4 targeted drug therapy or MMAE-containing drug therapy. In other embodiments, the subjects had cervical cancer and did not receive Nectin-4 targeted drug therapy or MMAE-containing drug therapy.

[0206] In certain embodiments, the subjects had cancer recurrence following treatment with a Nectin-4 targeted drug (e.g., PADCEV). For example, some subjects had mUC and experienced recurrence following PADCEV treatment.

[0207] SWY2001-Ab3-LND1002 was administered via intravenous injection at a dose of about 2.7 mg / kg or about 3.6 mg / kg, and Pembrolizumab was administered via intravenous injection at a dose of about 200 mg. The two drugs were administered in combination on day 1 of each 21-day administration cycle (Q3W), with SWY2001-Ab3-LND1002 administered prior to Pembrolizumab.

[0208] Following the administration of the combination therapy, physicians can monitor the patients' responses to treatment using various methods. For example, the objective response rate (ORR), i.e., the proportion of patients achieving complete response (CR) or partial response (PR) per RECIST v1.1 criteria, can be assessed. The subsequent doses can be adjusted and administered as needed. Table 3 Sequence information involved in the present application Antibody Sequence information Antibody CDR Heavy chain CDR1-H: GYTFTSYY       SEQ ID NO.1 CDR2-H: IYPGNVNT       SEQ ID NO.2 CDR3-H: ARGIYYFDY      SEQ ID NO.3 Light chain CDR1-L: QSVNND        SEQ ID NO.4 CDR2-L: YAS             SEQ ID NO.5 CDR3-L: HQDYSSPFT     SEQ ID NO.6 Humanized antibody 1 SWY2001-Ab1 SWY2001-Ab1-VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIHWVRQAPGQRLEW MGWIYPGNVNTKYNENFRDRVTITRDTSASTAYMELSSLRSEDTAVYY CARGIYYFDYWGQGTLVTVSS SEQ ID NO.7 SWY2001-Ab1-VL IIQMTQSPKFLSASVGDRVTITCKASQSVNNDVAWYQQKPGQSPKLLIY YASNRDTGVPDRFSGSGSGTDFTLTISSLQPEDFATYFCHQDYSSPFTFG GGTKVEIK SEQ ID NO.8 Humanized antibody 2 SWY2001-Ab2 SWY2001-Ab2-VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIHWVRQAPGQRLEW MGWIYPGNVNTKYNENFRDRVTITRDTSASTAYMELSSLRSEDTAVYY CARGIYYFDYWGQGTLVTVSS SEQ ID NO.7 SWY2001-Ab2-VL AIQMTQSPSSLSASVGDRVTITCKASQSVNNDVAWYQQKPGKAPKLLI YYASNRDTGVPSRFSGSGSGTDFTLTISSLQAEDLAVYFCHQDYSSPFT FGGGTKVEIK SEQ ID NO.9 Humanized antibody 3 SWY2001-Ab3 SWY2001-Ab3-VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIHWVRQAPGQRLEW MGWIYPGNVNTKYNENFRDRVTITRDTSASTAYMELSSLRSEDTAVYY CARGIYYFDYWGQGTLVTVSS SEQ ID NO.7 SWY2001-Ab3-VL AIQMTQSPSSLSASVGDRVTITCKASQSVNNDVAWYQQKPGKAPKLLI YYASNRDTGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCHQDYSSPFTF GGGTKVEIK SEQ ID NO.10 Constant region HC1 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRV EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO.11) LC RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSS PVTKSFNRGEC (SEQ ID NO.12) HC2 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKV EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO.13) Transglutaminase DSDERVTPPAEPLDRMPDPYRPSYGRAETIVNNYIRKWQQVYSHRDGR KQQMTEEQREWLSYGCVGVTWVNSGQYPTNRLAFAFFDEDKYKNEL KNGRPRSGETRAEFEGRVAKDSFDEAKGFQRARDVASVMNKALENAH DEGAYLDNLKKELANGNDALRNEDARSPFYSALRNTPSFKDRNGGNH DPSKMKAVIYSKHFWSGQDRSGSSDKRKYGDPEAFRPDRGTGLVDMS RDRNIPRSPTSPGESFVNFDYGWFGAQTEADADKTVWTHGNHYHAPN GSLGAMHVYESKFRNWSDGYSDFDRGAYVVTFVPKSWNTAPDKVTQ GWP (SEQ ID NO.14)

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 manufacture of a medicament for the treatment of cancer, wherein the antibodydrug conjugate targeting Nectin-4 is prepared by conjugating a drug-linker moiety represented by formula I with an antibody targeting Nectin-4 or a functional fragment thereof:Formula I.

2. The use according to claim 1, wherein the antibody or the functional fragment thereof comprises a heavy chain and a light chain, wherein (i) the heavy chain comprises three CDR regions which are a CDR1-H region, a CDR2-H region, and a CDR3-H region, wherein the CDR1-H region, CDR2-H region, and CDR3-H region have the amino acid sequences as set forth in SEQ ID NOs: 1, 2 and 3, respectively; and / or(ii) the light chain comprises three CDR regions which are a CDR1-L region, a CDR2-L region and a CDR3-L region, wherein the CDR1-L region, CDR2-L region and CDR3-L region have the amino acid sequences as set forth in SEQ ID NOs: 4, 5 and 6, respectively.

3. The use according to claim 1 or 2, wherein the antibody or the 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 as set forth in SEQ ID NO: 7, and / or, the light chain variable region has the amino acid sequence as set forth in SEQ ID NOs: 8-10.

4. The use according to any one of claims 1-3, wherein the antibody or the 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 as set forth in SEQ ID NO: 11 or SEQ ID NO: 13; and / or, the light chain constant region has the amino acid sequence as set forth 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, and the anti-PD-1 antibody is selected from the group consisting of Cemiplimab, Nivolumab, Pembrolizumab, Dostarlimab, Toripalimab, Tislelizumab, and Retifanlimab.

6. The use according to any one of claims 1-4, wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody, and the anti-PD-L1 antibody is selected from the group consisting of Atezolizumab, Avelumab and Durvalumab.

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

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

9. The use according to any one of claims 1-8, wherein a unit preparation of the antibody-drug conjugate targeting Nectin-4, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof comprises 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 the 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 1-10, wherein the immune checkpoint inhibitor is administered at a recommended dose in the Prescribing Information (PI) or Summary of Product Characteristics (SmPC) of the immune checkpoint inhibitor.

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

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

14. The method according to claim 13, wherein the antibody or the functional fragment thereof comprises a heavy chain and a light chain, wherein (i) the heavy chain comprises three CDR regions which are a CDR1-H region, a CDR2-H region, and a CDR3-H region, wherein the CDR1-H region, CDR2-H region, and CDR3-H region have the amino acid sequences as set forth in SEQ ID NOs: 1, 2 and 3, respectively; and / or(ii) the light chain comprises three CDR regions which are a CDR1-L region, a CDR2-L region and a CDR3-L region, wherein the CDR1-L region, CDR2-L region and CDR3-L region have the amino acid sequences as set forth in SEQ ID NOs: 4, 5 and 6, respectively.

15. The method according to claim 13 or 14, wherein the antibody or the 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 as set forth in SEQ ID NO: 7, and / or, the light chain variable region has the amino acid sequence as set forth in SEQ ID NOs: 8-10.

16. The method according to any one of claims 13-15, wherein the antibody or the 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 as set forth in SEQ ID NO: 11 or SEQ ID NO: 13; and / or, the light chain constant region has the amino acid sequence as set forth 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, and the anti-PD-1 antibody is selected from the group consisting of Cemiplimab, Nivolumab, Pembrolizumab, Dostarlimab, Toripalimab, Tislelizumab, and Retifanlimab.

18. The method according to any one of claims 13-17, wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody, and the anti-PD-L1 antibody is selected from the group consisting of Atezolizumab, Avelumab and Durvalumab.

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

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

21. The method according to any one of claims 13-20, wherein the antibody-drug conjugate, or the 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; 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 13-21, wherein the antibody-drug conjugate, or the 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 the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered for three or more administration cycles.

23. The method according to any one of claims 13-22, wherein the immune checkpoint inhibitor is administered at a recommended dose in the Prescribing Information (PI) or Summary of Product Characteristics (SmPC) of the immune checkpoint inhibitor.

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

25. The method according to any one of claims 13-24, wherein the antibody-drug conjugate, or the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof and / or the immune checkpoint inhibitor are administered on day 1 of each administration 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 a 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 a 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 who has recurrent cancer after a 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 an MMAE-containing drug therapy.

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 the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered at 2.7 mg / kg and at a frequency of 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 the pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is administered at a dose of 3.6 mg / kg per administration and at a frequency of Q3W.

32. The use according to any one of claims 1-5 and 7-12, the method according to any one of claims 13-17 and 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 and at a frequency of Q3W.

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