Use of Anti-nectin-4 antibody-drug conjugate in treating cancer and method therefor

Abstract

The present application relates to the use of an anti-Nectin-4 antibody-drug conjugate in treating cancer and a method therefor. The method comprises administering an anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof to a subject in need thereof at a dosage of about 0.33 to about 2.0 mg / kg, with one cycle being 21 days or 28 days, and no less than two (e.g., two or three) administrations per cycle. The anti-Nectin-4 antibody-drug conjugate or the pharmaceutically acceptable salt thereof has the molecular formula of Ab-[L-CTD]m, wherein Ab represents an anti-Nectin-4 antibody or an antigen-binding fragment thereof, L represents a linker, CTD represents a drug, and m represents the average number of drug molecules conjugated to each molecule of Ab; and Ab comprises a heavy chain variable region and a light chain variable region, wherein HCDR1-3 sequentially comprise sequences set forth in SEQ ID NOs: 1-3, respectively, and LCDR1-3 sequentially comprise sequences set forth in SEQ ID NOs: 4-6, respectively.

Description

Uses and methods of anti-Nectin-4 antibody-drug conjugates in cancer treatment Technical Field

[0001] This application relates to the field of biomedicine, and specifically, to the use and methods of a drug or combination of drugs comprising an anti-Nectin-4 antibody-drug conjugate for the prevention or treatment of cancer. Background Technology

[0002] Currently, Nectin-4 (also known as "poliovirus receptor-like molecule 4 (PVRL4)") is a type I transmembrane glycoprotein with a molecular weight of approximately 66 kDa. It is a member of the Nectin family within the immunoglobulin superfamily. Its extracellular domain consists of three Ig-like domains (VCC type), and it participates in the formation and maintenance of adhesion junctions together with cadherins.

[0003] Nectin-4 is found in high concentrations in normal embryonic and fetal tissues, but its levels decline in adulthood, and its distribution in healthy tissues is limited. It is highly expressed in various tumor cells, such as colon cancer, ovarian cancer, cervical cancer, urothelial carcinoma, breast cancer, lung cancer, gastric cancer, and head and neck cancer, primarily promoting tumor cell proliferation, differentiation, migration, and invasion by activating the PI3K / Akt pathway. Therefore, targeting Nectin-4 is becoming an effective strategy for treating cancers expressing Nectin-4.

[0004] Antibody-drug conjugates (ADCs) have become a popular class of drugs for treating hematologic malignancies and solid tumors. Anti-Nectin-4 antibody-drug conjugates are composed of a monoclonal antibody targeting the specific antigen Nectin-4 and a small-molecule cytotoxic drug linked by a linker (also called a "connector"). They combine the potent killing effect of traditional small-molecule chemotherapy with the tumor-targeting properties of antibody drugs. They consist of three main parts: an antibody responsible for selectively recognizing the Nectin-4 antigen on the surface of cancer cells, a drug payload responsible for killing cancer cells, and a linker connecting the antibody and the payload.

[0005] Currently, there is still significant room for improvement in the overall survival and quality of life of patients with malignant tumors. However, the current treatment applications of anti-Nectin-4 ADC therapy are limited. Therefore, there is still considerable room for exploration in the field of malignant tumors using Nectin-4 ADCs, highlighting the urgent need for a new Nectin-4 ADC treatment method to meet the clinical treatment needs of cancer patients. Summary of the Invention

[0006] This application provides a method for preventing, alleviating, or treating tumors in a subject using an antibody-drug conjugate targeting Nectin-4, wherein the Nectin-4 antibody-drug conjugate exhibits advantages in treatment including but not limited to one or more of the following groups: the Nectin-4 antibody-drug conjugate has demonstrated good tumor prevention, alleviation, or treatment effects in clinical studies of patients with various advanced solid tumors, such as high objective response rates and disease control rates, and long progression-free survival; the Nectin-4 antibody-drug conjugate has demonstrated good therapeutic effects in patients with different Nectin-4 expression levels; the Nectin-4 antibody-drug conjugate can exert preventive and / or therapeutic effects on cancer in a synergistic manner (combination therapy).

[0007] Specifically, the antibody-drug conjugate of Nectin-4 has demonstrated high objective response rates and disease control rates, as well as long progression-free survival, for various cancers, especially advanced, recurrent, or metastatic cancers.

[0008] This application provides a method for preventing or treating cancer, the method comprising: administering to a subject in need, at a dose of about 0.33 to about 2.0 mg / kg, in cycles of 21 days or 28 days, and at least twice (e.g., twice or three times) per cycle, an anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof;

[0009] The anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt has the molecular formula Ab-[L-CTD]m, where Ab represents an anti-Nectin-4 antibody or its antigen-binding fragment, L represents a linker, CTD represents a drug, and m represents the average number of drug linkages relative to each Ab molecule.

[0010] Wherein, Ab includes a heavy chain variable region and a light chain variable region, and the heavy chain variable region includes HCDR1 shown in SEQ ID NO:1, HCDR2 shown in SEQ ID NO:2, and HCDR3 shown in SEQ ID NO:3; and the light chain variable region includes LCDR1 shown in SEQ ID NO:4, LCDR2 shown in SEQ ID NO:5, and LCDR3 shown in SEQ ID NO:6.

[0011] In some embodiments, the cancer includes tumors that highly express Nectin-4 and / or tumors that lowly express Nectin-4.

[0012] In some implementations, the cancer is described as advanced cancer, recurrent cancer, or metastatic cancer.

[0013] In some implementations, the cancer is a solid tumor or a hematologic malignancy.

[0014] In some implementations, the cancer is described as an advanced solid tumor.

[0015] In some embodiments, the cancer is selected from any of the following: urothelial carcinoma, bladder cancer, cervical cancer, esophageal cancer, breast cancer, ovarian cancer, pancreatic cancer, hepatocellular carcinoma, gastric cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, acute lymphoblastic leukemia, anaplastic large cell lymphoma, multiple myeloma, prostate cancer, non-small cell lung cancer, small cell lung cancer, malignant melanoma, squamous cell carcinoma, glioblastoma, renal cell carcinoma, gastrointestinal tumors, prostate cancer, rectal cancer, colon cancer, glioma, triple-negative breast cancer, HER-2 negative breast cancer, HR+ / HER2- breast cancer, mesothelioma, head and neck squamous cell carcinoma, malignant skin tumors, thyroid cancer, esophageal squamous cell carcinoma, endometrial cancer, fallopian tube cancer, primary peritoneal cancer, high-grade serous ovarian cancer, muscle-invasive bladder cancer, and upper urinary tract urothelial carcinoma.

[0016] In some embodiments, the cancer is selected from any of the following: urothelial carcinoma, cervical cancer, esophageal cancer, breast cancer, and triple-negative breast cancer.

[0017] In some embodiments, the subject has received chemotherapy and / or immune checkpoint inhibitor treatment.

[0018] In some implementations, the subject has received platinum-based chemotherapy.

[0019] In some embodiments, the subject has received taxane / anthracycline chemotherapy.

[0020] In some embodiments, the subject has received antibody-drug conjugate therapy loaded with a topoisomerase inhibitor.

[0021] In some embodiments, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered via intravenous infusion.

[0022] In some embodiments, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is about 0.33 to about 1.5 mg / kg.

[0023] In some embodiments, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is about 1.0 to about 1.5 mg / kg.

[0024] In some embodiments, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is about 1.25 to about 1.5 mg / kg.

[0025] In some embodiments, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is about 1.25 mg / kg, or about 1.5 mg / kg.

[0026] In some embodiments, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is about 2 mg / kg.

[0027] In some embodiments, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered at least on day 1 and day 8 of each cycle.

[0028] In some embodiments, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in 21-day cycles, and on days 1 and 8 of each cycle.

[0029] In some embodiments, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in 28-day cycles, and on days 1, 8, and 15 of each cycle.

[0030] In some embodiments, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in 28-day cycles, and on days 1 and 15 of each cycle.

[0031] In some embodiments, the cancer is breast cancer, and the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg or 1.5 mg / kg.

[0032] In some embodiments, wherein the cancer is breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg or 1.5 mg / kg, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 21-day cycle, and on day 1 and day 8 of each cycle.

[0033] In some embodiments, wherein the cancer is breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg or 1.5 mg / kg, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in 28-day cycles, and on days 1, 8 and 15 of each cycle.

[0034] In some embodiments, the cancer is breast cancer, which is advanced, recurrent, or metastatic cancer, and the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg or 1.5 mg / kg.

[0035] In some embodiments, the cancer is breast cancer, which is advanced, recurrent, or metastatic cancer, and the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg or 1.5 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in 21-day cycles, on days 1 and 8 of each cycle.

[0036] In some embodiments, the cancer is breast cancer, which is advanced, recurrent, or metastatic cancer, and the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg or 1.5 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in 28-day cycles, on days 1, 8, and 15 of each cycle.

[0037] In some embodiments, the cancer is triple-negative breast cancer, and the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg or 1.5 mg / kg.

[0038] In some embodiments, the cancer is triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg or 1.5 mg / kg, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in 21-day cycles, and on days 1 and 8 of each cycle.

[0039] In some embodiments, the cancer is triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg or 1.5 mg / kg, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in 28-day cycles, and on days 1, 8 and 15 of each cycle.

[0040] In some embodiments, the cancer is triple-negative breast cancer, the cancer is advanced cancer, recurrent or metastatic cancer, and the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg or 1.5 mg / kg.

[0041] In some embodiments, the cancer is triple-negative breast cancer, the cancer is advanced cancer, recurrent or metastatic cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg or 1.5 mg / kg, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in 21-day cycles, and on days 1 and 8 of each cycle.

[0042] In some embodiments, the cancer is triple-negative breast cancer, the cancer is advanced cancer, recurrent or metastatic cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg or 1.5 mg / kg, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in 28-day cycles, and on days 1, 8 and 15 of each cycle.

[0043] In some embodiments, the cancer is esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 21-day cycle, on day 1 and day 8 of each cycle.

[0044] In some embodiments, the cancer is esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in 28-day cycles, on days 1, 8, and 15 of each cycle.

[0045] In some embodiments, the cancer is esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.5 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 21-day cycle, on day 1 and day 8 of each cycle.

[0046] In some embodiments, the cancer is urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 21-day cycle, on day 1 and day 8 of each cycle.

[0047] In some embodiments, the cancer is urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in 28-day cycles, on days 1, 8, and 15 of each cycle.

[0048] In some embodiments, the cancer is cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 21-day cycle, on day 1 and day 8 of each cycle.

[0049] In some embodiments, the cancer is cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in 28-day cycles, on days 1, 8, and 15 of each cycle.

[0050] In some embodiments, the heavy chain variable region comprises the sequence shown in SEQ ID NO:7 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it, and the light chain variable region comprises the sequence shown in SEQ ID NO:8 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it.

[0051] In some embodiments, the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:7 or SEQ ID NO:9, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:8 or SEQ ID NO:10.

[0052] In some embodiments, the Ab comprises:

[0053] 1) The amino acid sequence of the heavy chain variable region shown in SEQ ID NO:7; and the amino acid sequence of the light chain variable region shown in SEQ ID NO:8; or,

[0054] 2) The amino acid sequence of the heavy chain variable region shown in SEQ ID NO:9; and the amino acid sequence of the light chain variable region shown in SEQ ID NO:10.

[0055] In some embodiments, the Ab is an IgG antibody.

[0056] In some embodiments, the IgG antibody is a human IgG antibody.

[0057] In some embodiments, the IgG antibody is a human IgG1 or human IgG4 antibody.

[0058] In some embodiments, the antigen-binding fragment is Fab, Fab', F(ab')2, Fv, single-chain Fv, or single-chain Fab.

[0059] In some embodiments, the CTD is a cytotoxic drug.

[0060] In some embodiments, the CTD is selected from one or more of the following: microtubule inhibitors MMAE, DM1, DM4, Tublysin, muscarinic acid, chalcogenide, eribulin and derivatives thereof; topoisomerase inhibitors SN38, eczema and derivatives thereof; DNA binders PBD, doxorubicin and derivatives thereof.

[0061] In some implementations, m is 1.0-5.0.

[0062] In some implementations, m is 3.0-4.2.

[0063] In some implementations, m is 4.0.

[0064] In some embodiments, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt has a structure as shown in formulas Ia and / or Ib:

[0065] And / or,

[0066] Wherein, Ab is any of the anti-Nectin-4 antibodies or their antigen-binding fragments described above;

[0067] Ar' is selected from any of the following: substituted or unsubstituted C6-C10 arylene and substituted or unsubstituted 5-12 heteroarylene, wherein the substitution refers to the hydrogen atom on the group being replaced by one or more substituents, wherein the substituents are selected from any of the following: halogen, haloalkyl and alkoxy.

[0068] L1 is -O(CH2CH2O)n- attached to the Ar' group, where n is selected from any integer from 1 to 24;

[0069] L2 is the enzyme digestion fragment.

[0070] In some embodiments, the halogen is F, Cl, Br, or I; the haloalkyl is a C1-C6 haloalkyl; the alkoxy is a C1-C6 alkoxy; n is any integer from 1 to 10; and / or, L2 is a polypeptide fragment consisting of 2-4 amino acids or a combination thereof with a self-releasing structural fragment.

[0071] In some embodiments, the haloalkyl group is a C1-C4 haloalkyl group; the alkoxy group is a C1-C4 alkoxy group; n is any integer from 3 to 5; and / or, L2 is Val-Ala, Val-Ala-PAB, Val-Cit, Val-Cit-PAB, Phe-Lys-PAB, Ala-Ala-Ala, Gly-Gly-Phe-Gly (GGFG), or MAC glucuronide phenol.

[0072] In some embodiments, the alkyl halogroup is trifluoromethyl; and / or, the alkoxy group is methoxy.

[0073] In some embodiments, the L2-CTD is VcMMAE, GGFG-Dxd, or VC-seco-DUBA.

[0074] In some embodiments, the heteroatom is N when Ar' is a substituted or unsubstituted 5-12-membered heteroaryl; or Ar' is a substituted or unsubstituted C6-membered heteroaryl or a substituted or unsubstituted 6-membered heteroaryl.

[0075] In some embodiments, the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof has the following structure:

[0076] Coupler ADC-1a:

[0077] Coupler ADC-1b:

[0078] Coupler ADC-2a:

[0079] Coupler ADC-2b:

[0080] Coupler ADC-3a:

[0081] Coupler ADC-3b:

[0082] Coupler ADC-4a:

[0083] Coupler ADC-4b:

[0084] Coupler ADC-5a:

[0085] Coupler ADC-5b:

[0086] Coupler ADC-6a:

[0087] Coupler ADC-6b:

[0088] Alternatively, the coupling ADC-7a:

[0089] Coupler ADC-7b:

[0090] In some embodiments, the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof is as follows:

[0091] And / or,

[0092] Wherein, the anti-Nectin-4 antibody is any one of the anti-Nectin-4 antibodies or its antigen-binding fragments mentioned above, and N represents the average number of drug linkages per molecule of anti-Nectin-4 antibody, which is about 1.0 to about 5.0.

[0093] In some embodiments, the method further includes the step of administering an immune checkpoint inhibitor to the subject.

[0094] In some embodiments, the immune checkpoint inhibitor is an antibody or an antigen-binding fragment thereof.

[0095] In some embodiments, the immune checkpoint inhibitor specifically binds to PD-1.

[0096] In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody or its antigen-binding fragment.

[0097] In some embodiments, the method further includes the step of administering an anti-PD-1 antibody or an antigen-binding fragment thereof to the subject.

[0098] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises:

[0099] 1) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1 shown in SEQ ID NO:11, HCDR2 shown in SEQ ID NO:12, and HCDR3 shown in SEQ ID NO:13; and the light chain variable region comprises LCDR1 shown in SEQ ID NO:14, LCDR2 shown in SEQ ID NO:15, and LCDR3 shown in SEQ ID NO:16; or,

[0100] 2) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region includes HCDR1 shown in SEQ ID NO:21, HCDR2 shown in SEQ ID NO:22, and HCDR3 shown in SEQ ID NO:23; and the light chain variable region includes LCDR1 shown in SEQ ID NO:24, LCDR2 shown in SEQ ID NO:25, and LCDR3 shown in SEQ ID NO:26.

[0101] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises:

[0102] 1) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence shown in SEQ ID NO:17 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it, and the light chain variable region comprises the sequence shown in SEQ ID NO:18 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it; or,

[0103] 2) Heavy chain variable region and light chain variable region, wherein the heavy chain variable region contains the sequence shown in SEQ ID NO:27 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with it, and the light chain variable region contains the sequence shown in SEQ ID NO:28 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with it.

[0104] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises:

[0105] 1) A heavy chain sequence of SEQ ID NO:19 or having at least 90%, 95%, 98%, or 99% identity with it, and a light chain sequence of SEQ ID NO:20 or having at least 90%, 95%, 98%, or 99% identity with it; or,

[0106] 2) SEQ ID NO:29 or a heavy chain sequence having at least 90%, 95%, 98% or 99% identity with it, and SEQ ID NO:30 or a light chain sequence having at least 90%, 95%, 98% or 99% identity with it.

[0107] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is an IgG antibody.

[0108] In some embodiments, the IgG antibody is a human IgG antibody.

[0109] In some embodiments, the IgG antibody is a human IgG1 or human IgG4 antibody.

[0110] In some embodiments, the antigen-binding fragment is Fab, Fab', F(ab')2, Fv, single-chain Fv, or single-chain Fab.

[0111] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is toripalimab or its antigen-binding fragment; or pembrolizumab or its antigen-binding fragment.

[0112] In some embodiments, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in 21-day cycles, and on days 1 and 8 of each cycle.

[0113] In some embodiments, the cancer is urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is about 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 21-day cycle, and on day 1 and day 8 of each cycle.

[0114] In some embodiments, the cancer is cervical cancer, esophageal cancer, or triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is about 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 21-day cycle, and on day 1 and day 8 of each cycle.

[0115] In some embodiments, wherein the cancer is cervical cancer, esophageal cancer, or triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is about 1.5 mg / kg, wherein the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 21-day cycle, and on day 1 and day 8 of each cycle.

[0116] In some embodiments, the cancer is cervical cancer, esophageal cancer, or triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is about 2 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in 28-day cycles, and on days 1 and 15 of each cycle.

[0117] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered via intravenous infusion.

[0118] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered in 21-day cycles, and on day 1 of each cycle.

[0119] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered in 28-day cycles, and on days 1 and 15 of each cycle.

[0120] In some embodiments, the dose of the anti-PD-1 antibody or its antigen-binding fragment is about 240 mg.

[0121] In some embodiments, the dose of the anti-PD-1 antibody or its antigen-binding fragment is about 3.0 mg / kg.

[0122] In some embodiments, the dose of the anti-PD-1 antibody or its antigen-binding fragment is about 240 mg, and the anti-PD-1 antibody or its antigen-binding fragment is administered in a 21-day cycle, and on day 1 of each cycle.

[0123] In some embodiments, the dose of the anti-PD-1 antibody or its antigen-binding fragment is about 3.0 mg / kg, and the anti-PD-1 antibody or its antigen-binding fragment is administered in a 28-day cycle, on day 1 and day 15 of each cycle.

[0124] Other aspects and advantages of this application will readily be apparent to those skilled in the art from the detailed description below. The detailed description below shows and describes only exemplary embodiments of this application. As those skilled in the art will recognize, the content of this application enables them to make modifications to the disclosed specific embodiments without departing from the spirit and scope of the invention to which this application pertains. Accordingly, the descriptions in this application are merely exemplary and not restrictive. Detailed Implementation

[0125] The following specific embodiments illustrate the implementation of the invention. Those skilled in the art can easily understand other advantages and effects of the invention from the content disclosed in this specification.

[0126] Terminology Definition

[0127] In this application, the term "antibody" generally refers to an immunoglobulin or a fragment thereof or a derivative thereof, encompassing any polypeptide including an antigen-binding site, whether produced in vitro or in vivo. This term includes, but is not limited to, polyclonal, monoclonal, single-specific, multi-specific, non-specific, humanized, single-chain, chimeric, synthetic, recombinant, hybrid, mutated, and transplanted antibodies. The antibodies described in this application encompass natural and artificial antibodies of various structures, including but not limited to complete antibodies and antigen-binding fragments of antibodies.

[0128] In this application, the terms "full-length antibody," "complete antibody," and "intact antibody" are used interchangeably to refer to a glycoprotein comprising at least two heavy chains (H) and two light chains (L) linked together by disulfide bonds. Each heavy chain consists of a heavy chain variable region (abbreviated as VH herein) and a heavy chain constant region. The heavy chain constant region consists of three domains: CH1, CH2, and CH3. Each light chain consists of a light chain variable region (abbreviated as VL herein) and a light chain constant region. The light chain constant region consists of one domain: CL. The VH and VL regions can be further subdivided into hypervariable regions (complementarity-determining regions (CDRs) interspersed with more conserved regions (framework regions (FRs)). Each VH and VL consists of three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Constant regions do not directly participate in antibody-antigen binding but exhibit various effector functions. In a given VH or VL amino acid sequence, the precise amino acid sequence boundaries of each CDR can be determined using any of a number of well-known schemes or combinations thereof, including, for example: the Chothia numbering scheme (Chothia et al., Canonical structures for the hypervariable regions of immunoglobulins, Journal of Molecular Biology, 196, 901-917 (1987)); and the Kabat numbering scheme (Kabat et al., Sequences of Proteins of Immunological Interest, 4th edition, Department of Health and Human Services, National Institutes of Health (1987)), AbM (University of Bath) and Contact (University College London); North numbering scheme (North et al., A New Clustering of Antibody CDR Loop Conformations, Journal of Molecular Biology, 406, 228-256 (2011)).

[0129] In this application, the term "bispecific antibody" refers to an antibody that can bind to two different antigens or antigenic epitopes.

[0130] In this application, the term "CDR," also known as "complementarity-determining region," typically refers to a region within the variable structural domain of an antibody whose sequence is highly variable and / or forms a structurally defining loop. Typically, antibodies comprise six CDRs: three in the VH (HCDR1, HCDR2, HCDR3) and three in the VL (LCDR1, LCDR2, LCDR3). In some embodiments, naturally occurring camel antibodies consisting only of the heavy chain can function normally and stably even in the absence of the light chain. See, for example, Hamers-Casterman et al., Nature 363:446-448 (1993); Sheriff et al., Nature Struct. Biol. 3:733-736 (1996). Antibody CDRs can be determined using various coding systems, such as CCG, Kabat, AbM, Chothia, IMGT, and a combination of Kabat / Chothia. These coding systems are known in the art, and for example, see www.bioinf.org.uk / abs / index.html#kabatnum. For example, the amino acid sequence number of the antigen-binding protein can be in accordance with the IMGT numbering scheme (IMGT, the international ImMunoGeneTics information system @imgt.cines.fr; imgt.cines.fr; Lefranc et al., 1999, Nucleic Acids Res. 27:209-212; Ruiz et al., 2000, Nucleic Acids Res. 28:219-221; Lefranc et al., 2001, Nucleic Acids Res. 29:207-209; Lefranc et al., 2003, Nucleic Acids Res. 31:307-310; Lefranc et al., 2005, DevComp Immunol 29:185-203). For example, the CDR of the antigen-binding protein can be determined according to the Kabat numbering system (see, for example, Kabat EA & Wu TT (1971) Ann NY Acad Sci 190:382-391 and Kabat EA et al., (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USD Department of Health and Human Services, NIH Publication No. 91-3242).

[0131] The CDR of anti-Nectin-4 in the anti-Nectin-4 antibody-drug conjugate of this application and the CDR of the anti-PD-1 antibody used in combination with the anti-Nectin-4 antibody-drug conjugate can be determined according to any scheme or combination thereof in the art and human evaluation. In one embodiment, the CDR of the antibody of the present invention is a CDR sequence defined according to the Kabat numbering scheme.

[0132] In this application, the term "antigen-binding fragment" refers to a portion or segment of a complete antibody with fewer amino acid residues than the complete antibody, capable of binding an antigen or competing with the complete antibody (i.e., the complete antibody from which the antigen-binding fragment originates) for antigen binding. Antigen-binding fragments can be prepared using recombinant DNA technology or by enzymatic or chemical cleavage of complete antibodies. These antigen-binding fragments include, but are not limited to, Fab, Fab', F(ab')2, Fv, single-chain Fv, diabody antibodies, and single-domain antibodies (sdAb). The Fab fragment is a monovalent fragment composed of VL, VH, CL, and CH1 domains; for example, a Fab fragment can be obtained by digesting a complete antibody with papain. Furthermore, digestion of a complete antibody with pepsin below the disulfide bonds in the hinge region produces F(ab')2, a dimer of Fab' and a divalent antibody fragment. F(ab')2 can be reduced under neutral conditions by breaking the disulfide bonds in the hinge region, thereby converting the F(ab')2 dimer into a Fab' monomer. Fab' monomers are essentially Fab fragments with hinge regions (for a more detailed description of other antibody fragments, see: Fundamental Immunology, edited by WE. Paul, Raven Press, NY (1993)). The Fv fragment consists of the VL and VH domains of the antibody single arm. Furthermore, although the two domains VL and VH of the Fv fragment are encoded by independent genes, they can be linked using recombinant methods via synthetic linker peptides that enable the two domains to be produced as a single protein chain, in which the VL and VH regions pair to form a single-stranded Fv. The antibody fragment can be obtained by chemical methods, recombinant DNA methods, or protease digestion.

[0133] In this application, the term "monoclonal antibody" generally refers to an antibody molecule preparation consisting of a single molecule. Monoclonal antibodies typically exhibit high specificity against a single antigenic site. Moreover, unlike conventional polyclonal antibody pharmaceutical compositions (which usually contain different antibodies targeting different determinants), each monoclonal antibody targets a single determinant on an antigen. In addition to their specificity, monoclonal antibodies have the advantage that they can be synthesized through hybridoma culture without contamination by other immunoglobulins. The modifier "monoclonal" indicates the characteristic of antibodies obtained from a substantially homogeneous group of antibodies and is not to be interpreted as requiring the antibody to be produced by any particular method. For example, the monoclonal antibodies used in this application can be prepared in hybridoma cells or by recombinant DNA methods.

[0134] In this application, the term "humanized antibody" generally refers to an antibody in which some or all of the amino acids outside the CDR region of a non-human antibody (e.g., an alpaca antibody) are replaced by corresponding amino acids derived from human immunoglobulins. Small additions, deletions, insertions, substitutions, or modifications of amino acids within the CDR region are also permissible, as long as they retain the antibody's ability to bind to a specific antigen. Humanized antibodies may optionally contain at least a portion of the constant region of human immunoglobulins. "Humanized antibodies" retain antigen specificity similar to the original antibody. The "humanized" form of a non-human (e.g., alpaca) antibody may minimally contain a chimeric antibody with a sequence derived from a non-human immunoglobulin. In some cases, CDR region residues in a human immunoglobulin (receptor antibody) may be replaced with CDR region residues from a non-human species (donor antibody) (such as an alpaca, mouse, rat, rabbit, or non-human primate) having the desired properties, affinity, and / or capabilities. In some cases, FR region residues in a human immunoglobulin may be replaced with corresponding non-human residues. Furthermore, humanized antibodies may contain amino acid modifications not found in receptor antibodies or in donor antibodies. These modifications can be made to further improve antibody performance, such as binding affinity.

[0135] In this application, the proteins, peptides, and / or amino acid sequences involved should also be understood to include at least the following range: variants or homologs that have the same or similar functions as the said protein or peptide.

[0136] In this application, the variant can be, for example, a protein or polypeptide that has undergone substitution, deletion, or addition of one or more amino acids in the amino acid sequence of the protein and / or the polypeptide (e.g., an antibody or fragment thereof capable of specifically binding to NECTIN-4). For example, the functional variant may comprise a protein or polypeptide that has undergone amino acid alterations through substitution, deletion, and / or insertion of at least one, such as 1-30, 1-20, or 1-10, or even 1, 2, 3, 4, or 5 amino acids. The functional variant may substantially retain the biological properties of the protein or polypeptide prior to the alteration (e.g., substitution, deletion, or addition). For example, the functional variant may retain at least 60%, 70%, 80%, 90%, or 100% of the biological activity (e.g., antigen-binding capacity) of the protein or polypeptide prior to the alteration. For example, the substitution may be a conserved substitution.

[0137] In this application, the homolog may be a protein or polypeptide having at least about 85% (e.g., having at least about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or higher) sequence identity with the amino acid sequence of the protein and / or the polypeptide (e.g., an antibody or fragment thereof capable of specifically binding to NECTIN-4).

[0138] In this application, the term "identity" refers to the percentage of identity between sequences. Two sequences are "identical" if they have the same amino acid or nucleotide sequence in the regions being compared. When comparing and aligning within a comparison window or specified region to seek the maximum correspondence measured using one of the following sequence comparison algorithms or by manual alignment and visual inspection, two sequences are "substantially identical" if they have a specified percentage of identity amino acid residues or nucleotides (i.e., 60% identity in the specified region or, when not specified, across the entire sequence, optionally 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identity). Sequence identity between sequences is calculated as follows.

[0139] To determine the percentage of identity between two amino acid sequences or two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., vacancies may be introduced in one or both of the first and second amino acid sequences or nucleic acid sequences for optimal alignment, or non-homologous sequences may be discarded for comparison purposes). In a preferred embodiment, for comparison purposes, the length of the reference sequence being aligned is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, and even more preferably at least 70%, 80%, 90%, 100% of the reference sequence length. The amino acid residues or nucleotides at corresponding amino acid or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide at the corresponding position in the second sequence, the molecules are identical at that position.

[0140] Mathematical algorithms can be used to compare sequences and calculate the percentage of identity between two sequences. In a preferred embodiment, the Needlema and Wunsch ((1970) J. Mol. Biol. 48: 444-453) algorithm (available at http: / / www.gcg.com) is used in the GAP program integrated into the GCG software package, employing a Blossum 62 matrix or a PAM250 matrix and vacancy weights of 16, 14, 12, 10, 8, 6, or 4, and length weights of 1, 2, 3, 4, 5, or 6, to determine the percentage of identity between two amino acid sequences. In yet another preferred embodiment, the GAP program in the GCG software package (available at http: / / www.gcg.com) is used, employing an NWSgapdna.CMP matrix and vacancy weights of 40, 50, 60, 70, or 80, and length weights of 1, 2, 3, 4, 5, or 6, to determine the percentage of identity between two nucleotide sequences. The particularly preferred set of parameters (and unless otherwise specified, a set of parameters to be used) is a Blossum 62 scoring matrix with a vacancy penalty of 12, a vacancy extension penalty of 4, and a shift vacancy penalty of 5.

[0141] Alternatively, the PAM120 weighted remainder table, gap length penalty of 12, and gap penalty of 4 can be used to determine the percentage of identity between two amino acid sequences or nucleotide sequences using the E. Meyers and W. Miller algorithm ((1989) CABIOS, 4:11-17) which has been incorporated into the ALIGN program (version 2.0).

[0142] Additionally or alternatively, the nucleic acid and protein sequences described herein may be further used as “query sequences” to perform searches against public databases, for example, to identify other family member sequences or related sequences.

[0143] In this application, the term "specific binding" and the like means the formation of a complex between an antibody and an antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, surface plasmon resonance assays, MSD assays (Estep, P. et al., High throughput solution-based measurement of antibody-antigen affinity and epitope binning, MAbs, 2013.5(2):p.270-278).

[0144] In this application, the term "antibody-drug conjugate" refers to a drug molecule comprising an antibody capable of binding to a specific target, wherein the antibody is conjugated to one or more chemical reagents. In some embodiments, the antibody-drug conjugate may be an antibody-drug conjugate targeting Nectin-4. The Nectin-4-targeting antibody-drug conjugate may be formed by linking a monoclonal antibody targeting the specific antigen Nectin-4 with a small molecule cytotoxic drug via a linker. The Nectin-4-targeting antibody-drug conjugate may comprise one or more cytotoxic drugs selected from the group consisting of: microtubule inhibitors such as MMAE, DM1, DM4, Tublysin, muscarinic acid, chalcogenide, eribulin, and derivatives thereof; topoisomerase inhibitors such as SN38, eczema, and derivatives thereof; and DNA binders such as PBD, doxorubicin, and derivatives thereof.

[0145] In this application, the term "Nectin-4" refers to a type I transmembrane glycoprotein with a molecular weight of approximately 66 kDa, belonging to the Nectin family within the immunoglobulin superfamily. The extracellular domain of Nectin-4 consists of three Ig-like domains (VCC type), which, along with cadherins, participate in the formation and maintenance of adhesion junctions. Nectin-4 is highly expressed in various tumor cells, such as colon cancer, ovarian cancer, cervical cancer, urothelial carcinoma, breast cancer, lung cancer, gastric cancer, and head and neck cancer, primarily promoting tumor cell proliferation, differentiation, migration, and invasion by activating the PI3K / Akt pathway.

[0146] In this application, the term "high Nectin-4 expression tumor" refers to a tumor with a high quantitative expression level of Nectin-4 on the surface of tumor cells. This quantitative expression level is measured by the h-score, calculated as: H-score = Σ(Pi xi), where Pi represents the proportion of positive cells with a specific staining intensity, and i represents the staining intensity, typically taking values ​​of 0, 1, 2, or 3. The h-score range is 0 to 300. The h-score range for high Nectin-4 expression tumors is typically 100-300.

[0147] In this application, the term "low-expression Nectin-4 tumor" refers to a tumor with low quantitative expression levels of Nectin-4 on the surface of tumor cells, and the h-score of the high-expression Nectin-4 tumor is typically in the range of 0-99.

[0148] In this application, the term "immune checkpoint" refers to a class of inhibitory signaling molecules present in the immune system that prevent tissue damage by regulating the persistence and intensity of immune responses in peripheral tissues and participate in maintaining tolerance to self-antigens (Pardoll DM., The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer, 2012, 12(4):252-264). Studies have found that one of the reasons why tumor cells can evade the body's immune system and proliferate uncontrollably is that they utilize the inhibitory signaling pathways of immune checkpoints, thereby inhibiting T lymphocyte activity and preventing T lymphocytes from effectively exerting their killing effect on tumors (Yao S, Zhu Y and Chen L., Advances in targeting cell surface signaling molecules for immune modulation. Nat Rev Drug Discov, 2013, 12(2):130-146). Immune checkpoint molecules include, but are not limited to, programmed death 1 (PD-1), PD-L1, PD-L2, cytotoxic T-lymphocyte antigen 4 (CTLA-4), LAG-3, TIM-3, and proteins with T cell immunoglobulin and ITIM domains (TIGIT). In this application, the term "immune checkpoint inhibitor" refers to a molecule that, holistically or partially, reduces, inhibits, interferes with, or regulates one or more checkpoint proteins. Checkpoint proteins regulate T cell activation or function. Various checkpoint proteins are known, such as CTLA-4 and its ligands CD80 and CD86; and PD-1 and its ligands PD-L1 and PD-L2 (Pardoll, Nature Reviews Cancer 12:252-264, 2012). These proteins are responsible for co-stimulatory or inhibitory interactions in T cell responses. Immune checkpoint proteins regulate and maintain self-tolerance and the duration and magnitude of physiological immune responses. Immune checkpoint inhibitors include antibodies or antibody-derived antibodies. Immune checkpoint inhibitors can be monospecific or multispecific antibodies (e.g., bispecific antibodies, such as immune checkpoint / non-immune checkpoint bispecific antibodies). For example, an immune checkpoint inhibitor can be an antibody that specifically binds to PD-1.

[0149] In this application, the term "drug combination" refers to non-fixed combination products or fixed combination products, including but not limited to cassettes and pharmaceutical compositions. The term "non-fixed combination" means that the active ingredients (e.g., (i) an anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof, and (ii) an anti-PD-1 antibody or an antigen-binding fragment thereof) are administered to a patient simultaneously, without a specific time limit, or sequentially at the same or different time intervals, in separate entities, wherein such administration to the patient provides a preventive or therapeutically effective level of the two active agents. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt used in the drug combination are administered at levels not exceeding those achieved when used alone. The term "fixed combination" means that the two active agents are administered to a patient simultaneously in the form of a single entity. Preferably, the dosage and / or time interval of the two active agents are selected so that the combined use of the portions produces an effect greater than that achieved by using either component alone in treating a disease or condition. The components may each be in separate formulations, and their formulations may be the same or different.

[0150] In this application, the terms "application" and "administration" are used interchangeably to refer to the physical introduction of the active ingredients of the pharmaceutical combination of the present invention into an individual using any of a variety of methods and delivery systems known to those skilled in the art. Routes of administration for the active ingredients of the pharmaceutical combination of the present invention include oral, intravenous (e.g., infusion (also known as drip) or injection), intramuscular, subcutaneous, intraperitoneal, spinal, local, or other parenteral administration routes. The term "parenteral administration" refers to administration methods other than gastrointestinal and local administration, typically via intravenous, and non-limitingly includes intramuscular, intra-arterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions, as well as intracorporeal electroporation. Accordingly, the active ingredients of the pharmaceutical combination of the present invention can be formulated into capsules, tablets, injections (including infusions or injection solutions), syrups, sprays, lozenges, liposomes, or suppositories, etc.

[0151] In this application, the term "dosage" refers to the amount of drug that elicits a therapeutic effect. Unless otherwise stated, dosage relates to the amount of drug in its free form. If the drug is in the form of a pharmaceutically acceptable salt, the amount of drug is increased proportionally to the amount of drug in its free form. For example, the dosage will be stated on the product packaging or product information sheet.

[0152] In this application, the term "pharmaceutical-grade" means compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0153] In this application, the term "cancer" refers to a disease characterized by the rapid and uncontrolled proliferation of abnormal cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Cancer includes, but is not limited to, solid tumors and hematologic malignancies, preferably solid tumors. Examples of various cancers include, but are not limited to, urothelial carcinoma, bladder cancer, breast cancer, ovarian cancer, pancreatic cancer, hepatocellular carcinoma, gastric cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, acute lymphoblastic leukemia, anaplastic large cell lymphoma, multiple myeloma, prostate cancer, non-small cell lung cancer, small cell lung cancer, malignant melanoma, squamous cell carcinoma, glioblastoma, renal cell carcinoma, gastrointestinal tumors, prostate cancer, rectal cancer, colon cancer, glioma, and mesothelioma. The cancer is preferably advanced cancer, recurrent and / or refractory cancer, or cancer resistant to chemotherapy, more preferably advanced solid tumors, such as (histologically or cytologically confirmed) unresectable or metastatic advanced solid tumors.

[0154] In this application, the term "inhibition" refers to a given molecule (e.g., (i) an anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt and / or (ii) an anti-PD-1 antibody or its antigen-binding fragment) causing a reduction in certain parameters (e.g., Nectin-4 activity and / or PD-1 activity). For example, the term includes inhibition of at least 5%, 10%, 20%, 30%, 40%, or more of activity. Therefore, inhibition need not be 100%.

[0155] In this application, the term "treatment" includes administering the pharmaceutical combination of the present invention to an individual in need to achieve the purpose of curing a disease or being effective in resolving or delaying the progression of a disease. When referring to a disease, the term "treatment" means alleviating the disease (i.e., slowing or stopping or reducing the development of the disease or at least one of its clinical symptoms), preventing or delaying the onset, development, or progression of the disease.

[0156] In this application, the term "prevention" includes the suppression or delay of the occurrence or frequency of a disease or condition or its symptoms, which generally refers to the administration of a drug before the onset of symptoms, particularly before the onset of symptoms in at-risk individuals.

[0157] In this application, the term "subject" generally refers to an animal, such as a human. For example, a subject may include "non-human animals," which may include mammals such as rats, mice, rabbits, sheep, cats, dogs, cattle, pigs, and non-human primates. In this application, the subject may include a subject in need, such as a patient with a tumor, for example, a patient with a Nectin-4 related tumor.

[0158] In this application, the term "adverse event" (AE) is any unfavorable and generally unexpected or unwanted symptom (including abnormal laboratory findings), condition, or illness associated with the use of a medical treatment. For example, an adverse event may be associated with activation of the immune system in response to treatment or expansion of immune system cells (e.g., T cells) in response to treatment. A medical treatment may have one or more associated AEs, and the AEs may have the same or different levels of severity.

[0159] In this application, the term "overall survival" or "OS" refers to the time from the first use of the study drug to death from any cause.

[0160] In this application, the term "progression-free survival" or "PFS" refers to the time from the first use of the investigational drug to the onset of disease progression or death from any cause.

[0161] Invention Details

[0162] On one hand, this application provides a method for preventing or treating cancer, the method comprising: administering to a subject in need, at a dose of about 0.33 to about 2.0 mg / kg, in cycles of 21 days or 28 days, and at least twice (e.g., twice or three times) per cycle, an anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof.

[0163] Anti-Nectin-4 antibody-drug conjugates or their pharmaceutically acceptable salts

[0164] Antibody-drug conjugates (ADCs) are a technology that utilizes the specific recognition ability of antibodies on the surface of tumor cells to precisely deliver anti-tumor drugs (such as cytotoxic agents, cell inhibitors, and small-molecule chemotherapeutic agents) to tumor target cells, causing intracellular accumulation and release, thereby precisely killing tumor cells. ADCs generally consist of three parts: an antibody or antibody-like ligand, a small-molecule drug, and a linker (connector) that conjugates the antibody or antibody-like ligand to the drug. Due to their suitable molecular weight, high stability, strong targeting, and low toxicity, ADCs are considered to be among the most promising anti-tumor drugs.

[0165] The anti-Nectin-4 antibody-drug conjugate in the drug combination of the present invention consists of three parts: an antibody that specifically binds to Nectin-4 or its antigen-binding fragment, a small molecule drug, and a linker (connector) that conjugates the antibody and the small molecule drug.

[0166] In some embodiments, the anti-Nectin-4 antibody-drug conjugate may have the molecular formula Ab-[L-CTD]m, where Ab represents an antibody against Nectin-4 or its antigen-binding fragment, L represents a linker, CTD represents a drug, and m represents the average number of drug linkages relative to each Ab molecule; wherein the Ab may comprise a heavy chain variable region and a light chain variable region, and the heavy chain variable region may comprise HCDR1 shown in SEQ ID NO:1, HCDR2 shown in SEQ ID NO:2, and HCDR3 shown in SEQ ID NO:3; and the light chain variable region may comprise LCDR1 shown in SEQ ID NO:4, LCDR2 shown in SEQ ID NO:5, and LCDR3 shown in SEQ ID NO:6.

[0167] The heavy chain variable region may contain the sequence shown in SEQ ID NO:7 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it, and the light chain variable region may contain the sequence shown in SEQ ID NO:8 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it.

[0168] The heavy chain variable region may contain the amino acid sequence shown in SEQ ID NO:7 or SEQ ID NO:9, and the light chain variable region may contain the amino acid sequence shown in SEQ ID NO:8 or SEQ ID NO:10.

[0169] The Ab may include:

[0170] 1) The amino acid sequence of the heavy chain variable region shown in SEQ ID NO:7; and the amino acid sequence of the light chain variable region shown in SEQ ID NO:8; or,

[0171] 2) The amino acid sequence of the heavy chain variable region shown in SEQ ID NO:9; and the amino acid sequence of the light chain variable region shown in SEQ ID NO:10.

[0172] The Ab may be an IgG antibody. In some embodiments, the IgG antibody may be a human IgG antibody. In some embodiments, the IgG antibody may be a human IgG1 or human IgG4 antibody.

[0173] In some embodiments, the antigen-binding fragment may be Fab, Fab', F(ab')2, Fv, single-chain Fv, or single-chain Fab.

[0174] In some embodiments, the L in the molecular formula Ab-[L-CTD]m can be any chemical part capable of covalently linking the CTD to the Ab. The crosslinking agent can be a bifunctional or multifunctional agent that can be used to link the CTD and Ab to form an antibody-drug conjugate. The antibody-drug conjugate can be prepared using a crosslinking agent that can have reactive functional groups capable of binding to both the CTD and the Ab. For example, cysteine, thiols, or amines, such as the N-terminus of an antibody, or amino acid side chains like lysine, can form bonds with the functional groups of the crosslinking agent. Alternatively, the antibody-drug conjugate can be prepared by pre-forming a drug-containing linker (i.e., a linker-drug conjugate) and reacting the drug-containing linker with an antibody. In one embodiment, L can be a cleavable linker. In another embodiment, L can be a non-cleavable linker. In some implementations, L can be an acid-instable adapter, a light-instable adapter, a peptidase-cleavable adapter, an esterase-cleavable adapter, a disulfide bond-cleavable adapter, a hydrophilic adapter, a pre-charged adapter, a glycosidase-cleavable adapter, a phosphodiesterase-cleavable adapter, a phosphatase-cleavable adapter, or a dicarboxylic acid-based adapter.

[0175] The CTD can be a cytotoxic drug.

[0176] In some embodiments, the CTD can be one or more selected from: microtubule inhibitors MMAE, DM1, DM4, Tublysin, muscarine, chalcogenide, eribulin, and derivatives of said drugs; topoisomerase inhibitors SN38, eczema, and derivatives of said drugs; DNA binders PBD, doxorubicin, and derivatives of said drugs. Wherein, m can be about 1.0 to about 5.0. In some embodiments, m can be about 3.0 to about 5.0. In some embodiments, m can be about 1.0 to about 4.2. In some embodiments, m can be about 3.0 to about 4.2. In some embodiments, m can be about 3.0 to about 4.0. In some embodiments, m can be about 4.0 to about 4.2. In some embodiments, m can be 3.0. In some embodiments, m can be 5.0. In some embodiments, m can be 4.2. In some embodiments, m can be 4.0.

[0177] In some embodiments, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may have the structure shown in formulas Ia and / or Ib:

[0178] And / or,

[0179] Wherein, Ab can be any of the anti-Nectin-4 antibodies or their antigen-binding fragments described above;

[0180] Wherein, Ar' can be any of the following: substituted or unsubstituted C6-C10 arylene and substituted or unsubstituted 5-12 heteroarylene, wherein the substitution refers to the hydrogen atom on the group being replaced by one or more substituents, wherein the substituents are selected from any of the following: halogen, haloalkyl and alkoxy; L1 can be -O(CH2CH2O)n- attached to the Ar' group, wherein n is selected from any integer from 1 to 24; L2 can be an enzyme fragment.

[0181] In some embodiments, the halogen can be F, Cl, Br, or I; the haloalkyl can be a C1-C6 haloalkyl; the alkoxy can be a C1-C6 alkoxy; n can be any integer from 1 to 10; and / or, L2 can be a polypeptide fragment consisting of 2-4 amino acids or a combination thereof with a self-releasing structural fragment.

[0182] In some embodiments, the haloalkyl group may be a C1-C4 haloalkyl group; the alkoxy group may be a C1-C4 alkoxy group; n may be any integer from 3 to 5; and / or, L2 may be Val-Ala, Val-Ala-PAB, Val-Cit, Val-Cit-PAB, Phe-Lys-PAB, Ala-Ala-Ala, Gly-Gly-Phe-Gly (GGFG), or MAC glucuronide phenol.

[0183] In some embodiments, the haloalkyl group may be trifluoromethyl; and / or, the alkoxy group may be methoxy.

[0184] In some implementations, the L2-CTD may be VcMMAE, GGFG-Dxd, or VC-seco-DUBA.

[0185] In some embodiments, the heteroatom may be N when Ar' may be a substituted or unsubstituted 5-12-membered heteroaryl group; or Ar' may be a substituted or unsubstituted C6-membered heteroaryl group or a substituted or unsubstituted 6-membered heteroaryl group.

[0186] In some embodiments, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may have the following structure:

[0187] Coupler ADC-1a:

[0188] Coupler ADC-1b:

[0189] Coupler ADC-2a:

[0190] Coupler ADC-2b:

[0191] Coupler ADC-3a:

[0192] Coupler ADC-3b:

[0193] Coupler ADC-4a:

[0194] Coupler ADC-4b:

[0195] Coupler ADC-5a:

[0196] Coupler ADC-5b:

[0197] Coupler ADC-6a:

[0198] Coupler ADC-6b:

[0199] Alternatively, the coupling ADC-7a:

[0200] Coupler ADC-7b:

[0201] In some embodiments, the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof is as follows:

[0202] And / or,

[0203] The anti-Nectin-4 antibody can be any of the anti-Nectin-4 antibodies described above or its antigen-binding fragment, where N represents the average number of drug molecules linked to each anti-Nectin-4 antibody molecule, and can be from about 1.0 to about 5.0. In some embodiments, N can be from about 3.0 to about 4.2; in some embodiments, N can be from about 3.5 to about 4.5; in some embodiments, N can be from about 3.8 to about 4.2; in some embodiments, N can be from about 3.9 to about 4.1; and in some embodiments, N can be 4.0.

[0204] Anti-PD-1 antibody or its antigen-binding fragment

[0205] The anti-PD-1 antibody or its antigen-binding fragment in the drug combination of the present invention binds to PD-1 expressed on the surface of T lymphocytes, thereby blocking the binding of PD-1 to its ligand, promoting T lymphocyte activation, proliferation and production of immune-activating cytokines such as IL-2, thereby exerting an anti-tumor effect.

[0206] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment may comprise:

[0207] 1) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region may include HCDR1 shown in SEQ ID NO:11, HCDR2 shown in SEQ ID NO:12, and HCDR3 shown in SEQ ID NO:13; and the light chain variable region may include LCDR1 shown in SEQ ID NO:14, LCDR2 shown in SEQ ID NO:15, and LCDR3 shown in SEQ ID NO:16; or,

[0208] 2) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region may include HCDR1 shown in SEQ ID NO:21, HCDR2 shown in SEQ ID NO:22, and HCDR3 shown in SEQ ID NO:23; and the light chain variable region may include LCDR1 shown in SEQ ID NO:24, LCDR2 shown in SEQ ID NO:25, and LCDR3 shown in SEQ ID NO:26.

[0209] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment may comprise:

[0210] 1) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region may contain the sequence shown in SEQ ID NO:17 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it, and the light chain variable region may contain the sequence shown in SEQ ID NO:18 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it; or,

[0211] 2) Heavy chain variable region and light chain variable region, wherein the heavy chain variable region may contain the sequence shown in SEQ ID NO:27 or a sequence that may have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with it, and the light chain variable region may contain the sequence shown in SEQ ID NO:28 or a sequence that may have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with it.

[0212] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment may comprise:

[0213] 1) A heavy chain sequence of SEQ ID NO:19 or having at least 90%, 95%, 98%, or 99% identity with it, and a light chain sequence of SEQ ID NO:20 or having at least 90%, 95%, 98%, or 99% identity with it; or,

[0214] 2) SEQ ID NO:29 or a heavy chain sequence having at least 90%, 95%, 98% or 99% identity with it, and SEQ ID NO:30 or a light chain sequence having at least 90%, 95%, 98% or 99% identity with it.

[0215] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment may be an IgG antibody.

[0216] In some embodiments, the IgG antibody may be a human IgG antibody.

[0217] In some embodiments, the IgG antibody may be a human IgG1 or human IgG4 antibody.

[0218] In some embodiments, the antigen-binding fragment may be Fab, Fab', F(ab')2, Fv, single-chain Fv, or single-chain Fab.

[0219] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment may be toripalimab or its antigen-binding fragment; or pembrolizumab or its antigen-binding fragment.

[0220] Uses and treatments

[0221] a) Monotherapy methods and uses

[0222] This invention provides a method for preventing, alleviating or treating tumors in a subject using the above-mentioned antibody-drug conjugate targeting Nectin-4 or its pharmaceutically acceptable salt.

[0223] The cancers described in this invention can include solid tumors and hematologic malignancies, wherein the cancers can include tumors that highly express Nectin-4 and / or tumors that lowly express Nectin-4.

[0224] In some implementations, the cancer is advanced cancer, recurrent cancer, or metastatic cancer.

[0225] In some implementations, the cancer is a solid tumor or a hematologic malignancy.

[0226] In some implementations, the cancer is described as an advanced solid tumor.

[0227] The cancer may be selected from any of the following: urothelial carcinoma, bladder cancer, cervical cancer, esophageal cancer, breast cancer, ovarian cancer, pancreatic cancer, hepatocellular carcinoma, gastric cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, acute lymphoblastic leukemia, anaplastic large cell lymphoma, multiple myeloma, prostate cancer, non-small cell lung cancer, small cell lung cancer, malignant melanoma, squamous cell carcinoma (e.g., esophageal squamous cell carcinoma), glioblastoma, renal cell carcinoma, gastrointestinal tumors, prostate cancer, rectal cancer, colon cancer, glioma, triple-negative breast cancer, HER-2 negative breast cancer, HR+ / HER2- breast cancer, mesothelioma, head and neck squamous cell carcinoma, malignant skin tumors, thyroid cancer, esophageal squamous cell carcinoma, endometrial cancer, fallopian tube cancer, primary peritoneal cancer, high-grade serous ovarian cancer, muscle-invasive bladder cancer, and upper urinary tract urothelial carcinoma.

[0228] In some embodiments, the cancer may be selected from any of the following: urothelial carcinoma, cervical cancer, esophageal cancer, breast cancer, and triple-negative breast cancer.

[0229] In some embodiments, the cancer may be advanced cancer, recurrent or metastatic cancer (e.g., recurrent or metastatic cervical cancer), refractory cancer, and / or cancer resistant to chemotherapy, more preferably advanced solid tumors, (histologically or cytologically confirmed) unresectable or metastatic advanced solid tumors. In some embodiments, the cancer is preferably advanced recurrent or metastatic cancer (advanced malignancy, e.g., advanced, recurrent, or metastatic esophageal squamous cell carcinoma). In some embodiments, the cancer may be locally advanced or metastatic cancer (e.g., locally advanced or metastatic urothelial carcinoma, locally advanced or metastatic triple-negative breast cancer).

[0230] In some embodiments, the subject has received chemotherapy and / or immune checkpoint inhibitor therapy. In some embodiments, the subject has received platinum-based chemotherapy. In some embodiments, the subject has received taxane / anthracycline chemotherapy. In some embodiments, the subject has received antibody-drug conjugate therapy with a topoisomerase inhibitor as a payload. In some embodiments, the subject has not previously received systemic therapy for advanced tumors (e.g., recurrent, locally advanced and incurable, or metastatic). In some embodiments, the subject's disease has progressed after standard treatment.

[0231] In some embodiments, the Nectin-4-targeting antibody-drug conjugate or its pharmaceutically acceptable salt described in this invention is used for perioperative cancer treatment. In some embodiments, the Nectin-4-targeting antibody-drug conjugate or its pharmaceutically acceptable salt described in this invention is used to treat perioperative urothelial carcinoma.

[0232] The Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt described in this invention can be administered via various routes, including oral, intravenous (e.g., infusion (also known as drip) or injection), intramuscular, subcutaneous, intraperitoneal, spinal, local, or other parenteral routes. In some embodiments, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered via intravenous infusion.

[0233] The Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt described in this invention can be administered to individuals in need at one or more doses. For example, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt can be about 0.33 to about 1.5 mg / kg.

[0234] In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be about 0.33 to about 1.0 mg / kg. In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be about 0.33 to about 1.25 mg / kg. In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be about 0.33 to about 1.5 mg / kg. In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be about 0.33 to about 1.75 mg / kg. In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be about 0.33 to about 2.0 mg / kg. In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be about 0.33 to about 2.25 mg / kg.

[0235] In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be about 1.0 to about 1.25 mg / kg. In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be about 1.0 to about 1.5 mg / kg. In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be about 1.0 to about 1.75 mg / kg. In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be about 1.0 to about 2.0 mg / kg. In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be about 1.0 to about 2.25 mg / kg.

[0236] In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be about 1.25 to about 1.5 mg / kg. In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be about 1.25 to about 1.75 mg / kg. In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be about 1.25 to about 2.0 mg / kg. In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be about 1.25 to about 2.25 mg / kg.

[0237] In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be about 1.5 to about 1.75 mg / kg. In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be about 1.5 to about 2.0 mg / kg. In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be about 1.5 to about 2.25 mg / kg.

[0238] In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be about 1.75 to about 2.0 mg / kg. In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be about 1.75 to about 2.25 mg / kg.

[0239] In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be about 2.0 to about 2.25 mg / kg.

[0240] In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be about 0.33 mg / kg, about 1.0 mg / kg, about 1.25 mg / kg, about 1.5 mg / kg, about 1.75 mg / kg, about 2.0 mg / kg, or about 2.25 mg / kg.

[0241] In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be about 1.25 mg / kg, or about 1.5 mg / kg.

[0242] In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be about 2 mg / kg.

[0243] Specifically, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered at least on day 1 and day 8 of each cycle.

[0244] In some embodiments, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be used as a cycle every 21 days, and is administered on day 1 and day 8 of each cycle.

[0245] In some embodiments, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle, at a dose of about 0.33 to about 1.5 mg / kg.

[0246] In some embodiments, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a 28-day cycle, and on days 1, 8, and 15 of each cycle.

[0247] In some embodiments, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in cycles of 28 days, and on days 1, 8 and 15 of each cycle, at a dose of about 0.33 to about 1.5 mg / kg.

[0248] In some embodiments, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a 28-day cycle, and on days 1 and 15 of each cycle.

[0249] In some embodiments, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle, at a dose of about 0.33 to about 2 mg / kg.

[0250] In some embodiments, the cancer may be triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 0.33 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0251] In some embodiments, the cancer may be triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0252] In some embodiments, the cancer may be triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0253] In some embodiments, the cancer may be triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.5 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0254] In some embodiments, the cancer may be triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.75 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0255] In some embodiments, the cancer may be triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 2.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0256] In some embodiments, the cancer may be triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 2.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0257] In some embodiments, the cancer may be triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 0.33 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0258] In some embodiments, the cancer may be triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0259] In some embodiments, the cancer may be triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0260] In some embodiments, the cancer may be triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.5 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0261] In some embodiments, the cancer may be triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.75 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0262] In some embodiments, the cancer may be triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 2.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0263] In some embodiments, the cancer may be triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 2.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0264] In some embodiments, the cancer may be triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 0.33 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0265] In some embodiments, the cancer may be triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0266] In some embodiments, the cancer may be triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0267] In some embodiments, the cancer may be triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.5 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0268] In some embodiments, the cancer may be triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.75 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0269] In some embodiments, the cancer may be triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 2.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0270] In some embodiments, the cancer may be triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 2.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0271] In some embodiments, the cancer may be esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 0.33 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0272] In some embodiments, the cancer may be esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0273] In some embodiments, the cancer may be esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0274] In some embodiments, the cancer may be esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.5 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0275] In some embodiments, the cancer may be esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.75 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0276] In some embodiments, the cancer may be esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 2.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0277] In some embodiments, the cancer may be esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 2.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0278] In some embodiments, the cancer may be esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 0.33 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0279] In some embodiments, the cancer may be esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0280] In some embodiments, the cancer may be esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0281] In some embodiments, the cancer may be esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.5 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0282] In some embodiments, the cancer may be esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.75 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0283] In some embodiments, the cancer may be esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 2.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0284] In some embodiments, the cancer may be esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 2.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0285] In some embodiments, the cancer may be esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 0.33 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0286] In some embodiments, the cancer may be esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0287] In some embodiments, the cancer may be esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0288] In some embodiments, the cancer may be esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.5 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0289] In some embodiments, the cancer may be esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.75 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0290] In some embodiments, the cancer may be esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 2.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0291] In some embodiments, the cancer may be esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 2.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0292] In some embodiments, the cancer may be urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 0.33 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0293] In some embodiments, the cancer may be urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0294] In some embodiments, the cancer may be urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0295] In some embodiments, the cancer may be urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.5 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0296] In some embodiments, the cancer may be urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.75 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0297] In some embodiments, the cancer may be urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 2.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0298] In some embodiments, the cancer may be urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 2.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0299] In some embodiments, the cancer may be urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 0.33 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0300] In some embodiments, the cancer may be urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0301] In some embodiments, the cancer may be urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0302] In some embodiments, the cancer may be urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.5 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0303] In some embodiments, the cancer may be urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.75 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0304] In some embodiments, the cancer may be urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 2.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0305] In some embodiments, the cancer may be urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 2.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0306] In some embodiments, the cancer may be urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 0.33 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0307] In some embodiments, the cancer may be urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0308] In some embodiments, the cancer may be urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0309] In some embodiments, the cancer may be urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.5 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0310] In some embodiments, the cancer may be urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.75 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0311] In some embodiments, the cancer may be urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 2.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0312] In some embodiments, the cancer may be urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 2.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0313] In some embodiments, the cancer may be cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 0.33 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0314] In some embodiments, the cancer may be cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0315] In some embodiments, the cancer may be cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0316] In some embodiments, the cancer may be cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.5 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0317] In some embodiments, the cancer may be cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.75 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0318] In some embodiments, the cancer may be cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 2.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0319] In some embodiments, the cancer may be cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 2.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0320] In some embodiments, the cancer may be cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 0.33 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0321] In some embodiments, the cancer may be cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0322] In some embodiments, the cancer may be cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0323] In some embodiments, the cancer may be cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.5 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0324] In some embodiments, the cancer may be cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.75 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0325] In some embodiments, the cancer may be cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 2.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0326] In some embodiments, the cancer may be cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 2.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0327] In some embodiments, the cancer may be cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 0.33 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0328] In some embodiments, the cancer may be cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0329] In some embodiments, the cancer may be cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0330] In some embodiments, the cancer may be cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.5 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0331] In some embodiments, the cancer may be cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 1.75 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0332] In some embodiments, the cancer may be cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 2.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0333] In some embodiments, the cancer may be cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be 2.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0334] b) Use of combination therapy

[0335] This invention provides a method for preventing, alleviating or treating tumors in a subject using the above-mentioned antibody-drug conjugate targeting Nectin-4 or its pharmaceutically acceptable salt and anti-PD-1 antibody or its antigen-binding fragment.

[0336] The anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt and the anti-PD-1 antibody or its antigen-binding fragment described in this invention can be administered separately, simultaneously, or sequentially.

[0337] The cancers described in this invention can include solid tumors and hematologic malignancies, wherein the cancers can include tumors that highly express Nectin-4 and / or tumors that lowly express Nectin-4.

[0338] The cancer can be selected from any of the following: urothelial carcinoma, bladder cancer, cervical cancer, esophageal cancer, breast cancer, ovarian cancer, pancreatic cancer, hepatocellular carcinoma, gastric cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, acute lymphoblastic leukemia, anaplastic large cell lymphoma, multiple myeloma, prostate cancer, non-small cell lung cancer, small cell lung cancer, malignant melanoma, squamous cell carcinoma, glioblastoma, renal cell carcinoma, gastrointestinal tumors, prostate cancer, rectal cancer, colon cancer, glioma, triple-negative breast cancer, HER-2 negative breast cancer, HR+ / HER2- breast cancer, mesothelioma, head and neck squamous cell carcinoma, malignant skin tumors, thyroid cancer, esophageal squamous cell carcinoma, endometrial cancer, fallopian tube cancer, primary peritoneal cancer, high-grade serous ovarian cancer, muscle-invasive bladder cancer, and upper urinary tract urothelial carcinoma.

[0339] In some embodiments, the cancer may be selected from any of the following: urothelial carcinoma, cervical cancer, esophageal cancer, breast cancer, and triple-negative breast cancer.

[0340] In some embodiments, the cancer may be advanced cancer, refractory cancer, and / or cancer resistant to chemotherapy, more preferably advanced solid tumors, (histologically or cytologically confirmed) unresectable or metastatic advanced solid tumors. In some embodiments, the cancer is preferably advanced recurrent or metastatic cancer (advanced malignancy).

[0341] In some embodiments, the subject has received chemotherapy and / or immune checkpoint inhibitor treatment. In some embodiments, the subject has received platinum-based chemotherapy. In some embodiments, the subject has received taxane / anthracycline chemotherapy. In some embodiments, the subject has received antibody-drug conjugate therapy with a topoisomerase inhibitor as a payload.

[0342] The Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt described in this invention can be administered via various routes, including oral, intravenous (e.g., infusion (also known as drip) or injection), intramuscular, subcutaneous, intraperitoneal, spinal, local, or other parenteral routes. In some embodiments, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered via intravenous infusion.

[0343] In some embodiments, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be used as a cycle every 21 days, and is administered on day 1 and day 8 of each cycle.

[0344] In some embodiments, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a 28-day cycle, and on days 1, 8, and 15 of each cycle.

[0345] In some embodiments, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a 28-day cycle, and on days 1 and 15 of each cycle.

[0346] In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be about 1.0 to about 2.0 mg / kg. In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be about 1.0 mg / kg, about 1.25 mg / kg, about 1.5 mg / kg, or about 2.0 mg / kg.

[0347] In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be about 1.25 to about 2.0 mg / kg.

[0348] In some embodiments, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle, at a dose of 1.25 to about 2.0 mg / kg.

[0349] In some embodiments, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle, at a dose of 1.25 to about 2.0 mg / kg.

[0350] In some embodiments, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a 28-day cycle, and on days 1, 8 and 15 of each cycle, at a dose of 1.25 to about 2.0 mg / kg.

[0351] In some embodiments, the cancer may be urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be about 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0352] In some embodiments, the cancer may be urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be about 1.5 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0353] In some embodiments, the cancer may be urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be about 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0354] In some embodiments, the cancer may be urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be about 2.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0355] In some embodiments, the cancer may be cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be about 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0356] In some embodiments, the cancer may be cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be about 1.5 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0357] In some embodiments, the cancer may be cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be about 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0358] In some embodiments, the cancer may be cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be about 2.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on day 1 and day 15 of each cycle.

[0359] In some embodiments, the cancer may be esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be about 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0360] In some embodiments, the cancer may be esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be about 1.5 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0361] In some embodiments, the cancer may be esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be about 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0362] In some embodiments, the cancer may be esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be about 2.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0363] In some embodiments, the cancer may be triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be about 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0364] In some embodiments, the cancer may be triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be about 1.5 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 21 days, and on days 1 and 8 of each cycle.

[0365] In some embodiments, the cancer may be triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be about 1.25 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1, 8 and 15 of each cycle.

[0366] In some embodiments, the cancer may be triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be about 2.0 mg / kg, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0367] The anti-PD-1 antibody or its antigen-binding fragment is administered via intravenous infusion.

[0368] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment can be administered in 21-day cycles, and on day 1 of each cycle. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment can be administered in 28-day cycles, and on days 1 and 15 of each cycle.

[0369] In some embodiments, the dose of the anti-PD-1 antibody or its antigen-binding fragment may be about 240 mg. In some embodiments, the dose of the anti-PD-1 antibody or its antigen-binding fragment may be about 3.0 mg / kg.

[0370] In some embodiments, the dose of the anti-PD-1 antibody or its antigen-binding fragment may be about 240 mg, and the anti-PD-1 antibody or its antigen-binding fragment may be administered in a cycle of 21 days, and on day 1 of each cycle. In some embodiments, the dose of the anti-PD-1 antibody or its antigen-binding fragment may be about 240 mg, and the anti-PD-1 antibody or its antigen-binding fragment may be administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

[0371] In some embodiments, the dose of the anti-PD-1 antibody or its antigen-binding fragment may be about 3.0 mg / kg, and the anti-PD-1 antibody or its antigen-binding fragment may be administered in a 21-day cycle, with administration on day 1 of each cycle. In some embodiments, the dose of the anti-PD-1 antibody or its antigen-binding fragment may be about 3.0 mg / kg, and the anti-PD-1 antibody or its antigen-binding fragment may be administered in a 28-day cycle, with administration on day 1 and day 15 of each cycle.

[0372] In some embodiments, the dosage combination provided by the present invention may be: anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt, 1.25 mg / kg, every 21 days can be one treatment cycle, intravenously infused on day 1 and day 8 of each cycle; toripalimab, 240 mg, every 21 days can be one treatment cycle, intravenously infused on day 1 of each cycle.

[0373] In some embodiments, the dosage combination provided by the present invention may be: anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt, 1.5 mg / kg, every 21 days can be one treatment cycle, intravenously infused on day 1 and day 8 of each cycle; toripalimab, 240 mg, every 21 days can be one treatment cycle, intravenously infused on day 1 of each cycle.

[0374] In some embodiments, the dosage combination provided by the present invention may be: anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt, 2 mg / kg, every 21 days can be one treatment cycle, intravenously infused on day 1 and day 8 of each cycle; toripalimab, 240 mg, every 21 days can be one treatment cycle, intravenously infused on day 1 of each cycle.

[0375] In some embodiments, the dosage combination provided by the present invention may be: anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt, 1.25 mg / kg, every 28 days can be one treatment cycle, intravenously infused on day 1 and day 15 of each cycle; toripalimab, 240 mg, every 21 days can be one treatment cycle, intravenously infused on day 1 of each cycle.

[0376] In some embodiments, the dosage combination provided by the present invention may be: anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt, 1.5 mg / kg, every 28 days can be one treatment cycle, intravenously infused on day 1 and day 15 of each cycle; toripalimab, 240 mg, every 21 days can be one treatment cycle, intravenously infused on day 1 of each cycle.

[0377] In some embodiments, the dosage combination provided by the present invention may be: anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt, 2 mg / kg, every 28 days can be one treatment cycle, intravenously infused on day 1 and day 15 of each cycle; toripalimab, 240 mg, every 21 days can be one treatment cycle, intravenously infused on day 1 of each cycle.

[0378] In some embodiments, the dosage combination provided by the present invention may be: anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt, 1.25 mg / kg, every 21 days can be one treatment cycle, intravenously infused on day 1 and day 8 of each cycle; toripalimab, 3 mg / kg, every 21 days can be one treatment cycle, intravenously infused on day 1 of each cycle.

[0379] In some embodiments, the dosage combination provided by the present invention may be: anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt, 1.5 mg / kg, every 21 days can be one treatment cycle, intravenously infused on day 1 and day 8 of each cycle; toripalimab, 3 mg / kg, every 21 days can be one treatment cycle, intravenously infused on day 1 of each cycle.

[0380] In some embodiments, the dosage combination provided by the present invention may be: anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt, 2 mg / kg, every 21 days can be one treatment cycle, intravenously infused on day 1 and day 8 of each cycle; toripalimab, 3 mg / kg, every 21 days can be one treatment cycle, intravenously infused on day 1 of each cycle.

[0381] In some embodiments, the dosage combination provided by the present invention may be: anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt, 1.25 mg / kg, every 28 days can be one treatment cycle, intravenously infused on day 1 and day 15 of each cycle; toripalimab, 3 mg / kg, every 21 days can be one treatment cycle, intravenously infused on day 1 of each cycle.

[0382] In some embodiments, the dosage combination provided by the present invention may be: anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt, 1.5 mg / kg, every 28 days can be one treatment cycle, intravenously infused on day 1 and day 15 of each cycle; toripalimab, 3 mg / kg, every 21 days can be one treatment cycle, intravenously infused on day 1 of each cycle.

[0383] In some embodiments, the dosage combination provided by the present invention may be: anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt, 2 mg / kg, every 28 days can be one treatment cycle, intravenously infused on day 1 and day 15 of each cycle; toripalimab, 3 mg / kg, every 21 days can be one treatment cycle, intravenously infused on day 1 of each cycle.

[0384] In some embodiments, the dosage combination provided by the present invention may be: anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt, 1.25 mg / kg, every 21 days can be one treatment cycle, intravenously infused on day 1 and day 8 of each cycle; toripalimab, 240 mg, every 28 days can be one treatment cycle, intravenously infused on day 1 and day 15 of each cycle.

[0385] In some embodiments, the dosage combination provided by the present invention may be: anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt, 1.5 mg / kg, every 21 days can be one treatment cycle, intravenously infused on day 1 and day 8 of each cycle; toripalimab, 240 mg, every 28 days can be one treatment cycle, intravenously infused on day 1 and day 15 of each cycle.

[0386] In some embodiments, the dosage combination provided by the present invention may be: anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt, 2 mg / kg, every 21 days can be one treatment cycle, intravenously infused on day 1 and day 8 of each cycle; toripalimab, 240 mg, every 28 days can be one treatment cycle, intravenously infused on day 1 and day 15 of each cycle.

[0387] In some embodiments, the dosage combination provided by the present invention may be: anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt, 1.25 mg / kg, every 28 days can be one treatment cycle, intravenously infused on day 1 and day 15 of each cycle; toripalimab, 240 mg, every 28 days can be one treatment cycle, intravenously infused on day 1 and day 15 of each cycle.

[0388] In some embodiments, the dosage combination provided by the present invention may be: anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt, 1.5 mg / kg, every 28 days can be one treatment cycle, intravenously infused on day 1 and day 15 of each cycle; toripalimab, 240 mg, every 28 days can be one treatment cycle, intravenously infused on day 1 and day 15 of each cycle.

[0389] In some embodiments, the dosage combination provided by the present invention may be: anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt, 2 mg / kg, every 28 days can be one treatment cycle, intravenously infused on day 1 and day 15 of each cycle; toripalimab, 240 mg, every 28 days can be one treatment cycle, intravenously infused on day 1 and day 15 of each cycle.

[0390] In some embodiments, the dosage combination provided by the present invention may be: anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt, 1.25 mg / kg, every 21 days can be one treatment cycle, intravenously infused on day 1 and day 8 of each cycle; toripalimab, 3 mg / kg, every 28 days can be one treatment cycle, intravenously infused on day 1 and day 15 of each cycle.

[0391] In some embodiments, the dosage combination provided by the present invention may be: anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt, 1.5 mg / kg, every 21 days can be one treatment cycle, intravenously infused on day 1 and day 8 of each cycle; toripalimab, 3 mg / kg, every 28 days can be one treatment cycle, intravenously infused on day 1 and day 15 of each cycle.

[0392] In some embodiments, the dosage combination provided by the present invention may be: anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt, 2 mg / kg, every 21 days can be one treatment cycle, intravenously infused on day 1 and day 8 of each cycle; toripalimab, 3 mg / kg, every 28 days can be one treatment cycle, intravenously infused on day 1 and day 15 of each cycle.

[0393] In some embodiments, the dosage combination provided by the present invention may be: anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt, 1.25 mg / kg, every 28 days can be one treatment cycle, intravenously infused on day 1 and day 15 of each cycle; toripalimab, 3 mg / kg, every 28 days can be one treatment cycle, intravenously infused on day 1 and day 15 of each cycle.

[0394] In some embodiments, the dosage combination provided by the present invention may be: anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt, 1.5 mg / kg, every 28 days can be one treatment cycle, intravenously infused on day 1 and day 15 of each cycle; toripalimab, 3 mg / kg, every 28 days can be one treatment cycle, intravenously infused on day 1 and day 15 of each cycle.

[0395] In some embodiments, the dosage combination provided by the present invention may be: anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt, 2 mg / kg, every 28 days can be one treatment cycle, intravenously infused on day 1 and day 15 of each cycle; toripalimab, 3 mg / kg, every 28 days can be one treatment cycle, intravenously infused on day 1 and day 15 of each cycle.

[0396] In some embodiments, the Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt described in this invention, as well as the anti-PD-1 antibody or its antigen-binding fragment described in this invention, can be used for perioperative cancer treatment, for example, for the treatment of perioperative urothelial carcinoma.

[0397] In some embodiments, the dosage combination provided by the present invention can be used for perioperative cancer treatment, for example, for the treatment of perioperative urothelial carcinoma. For example, the dosage combination provided by the present invention may be: anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt, 1.25 mg / kg, administered intravenously on days 1 and 8 of each 21-day treatment cycle; and toripalimab, 240 mg, administered intravenously on day 1 of each 21-day treatment cycle.

[0398] In some implementations, four cycles of the following combination of doses may be administered prior to radical surgery and regional lymph node dissection: anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt, 1.25 mg / kg, administered intravenously on days 1 and 8 of each cycle, for every 21 days as one treatment cycle; and toripalimab, 240 mg, administered intravenously on day 1 of each cycle, for every 21 days as one treatment cycle (neoadjuvant therapy).

[0399] In some implementations, following radical surgery and regional lymph node dissection, the following combination of doses can be administered for six cycles: anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt, 1.25 mg / kg, administered intravenously on days 1 and 8 of each cycle, every 21 days; toripalimab, 240 mg, administered intravenously on day 1 of each cycle, every 21 days; then toripalimab can be continued for seven cycles at the following dose: toripalimab, 240 mg, administered intravenously on day 1 of each cycle, every 21 days (adjuvant therapy).

[0400] Table 1 Examples of sequences used in this application

[0401] The embodiments described below are not intended to be limited by any theory, but are merely for illustrating the fusion protein, preparation method and use of this application, and are not intended to limit the scope of the invention.

[0402] Example

[0403] Example 1: Preparation of anti-Nectin-4 antibody-drug conjugate

[0404] According to the method described in Chinese patent application CN202210475286.3, an anti-Nectin-4 antibody-drug conjugate (also referred to as "anti-Nectin-4-ADC") was prepared using hH2L1 (an anti-Nectin-4 antibody) and a drug-containing linker (i.e., a linker-drug conjugate) as shown below. The DAR was calculated by hydrophobic interaction chromatography (HIC): N = 4.0.

[0405] and / or

[0406] Example 2: Preclinical pharmacodynamics and toxicology studies of anti-Nectin-4-ADC

[0407] 2.1 Preclinical pharmacodynamic studies of anti-Nectin-4-ADC

[0408] 1) Study on the efficacy of anti-Nectin-4-ADC against subcutaneous xenografts of human non-small cell lung cancer NCI-H322 in nude mice

[0409] Human non-small cell lung cancer (NSCLC) NCI-H322 cells were subcutaneously inoculated into BALB / cA nude mice to establish a human NSCLC NCI-H322 xenograft model. The experiment was divided into a negative control group (saline), groups treated with anti-Nectin-4-ADC at doses of 1, 3, and 10 mg / kg, and a positive control group. The 3 and 10 mg / kg groups, the negative control group (n=12), and the remaining groups (n=8 per group) were administered the drug intravenously in a single dose.

[0410] Results at the end of the trial (day 26 post-administration) showed that tumor volume was significantly reduced in all treatment groups compared to the negative control group (P < 0.001). The tumor volume TGI (1 - (tumor weight in treatment group / tumor weight in control group) * 100%) corresponding to anti-Nectin-4-ADC doses of 1, 3, and 10 mg / kg were 63%, 83%, and 134%, respectively. The TGI values ​​for the 3 mg / kg and 10 mg / kg groups were 64% and 123%, respectively. At the same dose, anti-Nectin-4-ADC showed significantly stronger inhibitory effects on tumor growth than... (P < 0.05). Tumor-bearing mice were resistant to Nectin-4-ADC and Both are well tolerated.

[0411] 2) Efficacy study of anti-Nectin-4-ADC on subcutaneous xenografts of human breast cancer MDA-MB-468 in nude mice

[0412] Human breast cancer MDA-MB-468 cells were subcutaneously inoculated into BALB / c Nude mice to establish a human breast cancer MDA-MB-468 xenograft model. The experiment was divided into a negative control group (saline), groups treated with anti-Nectin-4-ADC at doses of 1, 3, and 10 mg / kg, and a positive control group. The 3 and 10 mg / kg groups, the negative control group (n=10), and the remaining groups (n=8) were administered the drug intravenously in a single dose.

[0413] Results at the end of the trial (day 21 post-drug administration) showed that, except for the 1 mg / kg anti-Nectin-4-ADC dose group, tumor volume was significantly different from the negative control group (P < 0.001). The tumor volume TGI corresponding to the 1, 3, and 10 mg / kg anti-Nectin-4-ADC dose groups were 18%, 64%, and 111%, respectively. The TGI values ​​for the 3 mg / kg and 10 mg / kg groups were 37% and 72%, respectively. At the same dose, anti-Nectin-4-ADC showed significantly stronger tumor growth inhibition than [other treatments]. (P < 0.05 and P < 0.01). Tumor-bearing mice against Nectin-4-ADC and Both are well tolerated.

[0414] 3) Study on the efficacy of anti-Nectin-4-ADC against subcutaneous xenografts of human bladder cancer HT1376 in nude mice

[0415] Human bladder cancer HT1376 cells were subcutaneously inoculated into BALB / c nude mice to establish a human bladder cancer HT1376 xenograft model. The experiment was divided into a negative control group (saline), anti-Nectin-4-ADC groups (1, 3, and 10 mg / kg), and a positive control group. The 3 and 10 mg / kg groups, the negative control group (n=10), and the remaining groups (n=8) were administered the drug intravenously in a single dose.

[0416] Results at the end of the trial (day 21 after administration) showed that, except for the group receiving 1 mg / kg of anti-Nectin-4-ADC, tumor volume was significantly different from the negative control group (P < 0.001). The tumor volume TGI corresponding to the anti-Nectin-4-ADC doses of 1, 3, and 10 mg / kg were 22%, 77%, and 95%, respectively. The TGI values ​​for the 3 mg / kg and 10 mg / kg groups were 70% and 93%, respectively. At the same dose, anti-Nectin-4-ADC showed similar inhibitory effects on tumor growth compared to... Comparable (P>0.05). Tumor-bearing mice against Nectin-4-ADC and Both can be tolerated quite well.

[0417] 2.2 Repeated-dose toxicity study of anti-Nectin-4-ADC in cynomolgus monkeys

[0418] Fifty cynomolgus macaques were randomly divided into five groups: a solvent control group (physiological saline), low-, medium-, and high-dose anti-Nectin-4-ADC groups (corresponding to anti-Nectin-4-ADC doses of 1, 3, and 6 mg / kg), and a naked anti-Nectin-4-ADC group (6 mg / kg), with 10 macaques in each group, half male and half female. The macaques in each group received the drug intravenously once a week for five consecutive weeks. Three male and two female macaques from each group were dissected at the end of the drug administration period (day 31) and at the end of the recovery period (day 58), respectively.

[0419] During the experiment, no animals died in any group. Compared with the solvent control group and / or before administration, no significant effects on the cardiovascular system were observed in cynomolgus monkeys intravenously infused with 1, 3, and 6 mg / kg of anti-Nectin-4-ADC or in the naked anti-Nectin-4-ADC group at 6 mg / kg. No drug-related changes were observed in the weight, food consumption, ophthalmology, lymphocyte immunophenotype, and urine of the cynomolgus monkeys. No drug-related irritation was observed at the administration sites in any group of animals.

[0420] The results of this embodiment show that all cynomolgus monkeys tolerated repeated intravenous infusions of 6 mg / kg of naked anti-Nectin-4-ADC or 1, 3, and 6 mg / kg of anti-Nectin-4-ADC (administered once weekly for a total of 5 times) for 4 weeks. No test-drug-related irritation was observed at the administration sites in either the naked anti-Nectin-4-ADC group or the naked anti-Nectin-4-ADC group; no significant abnormalities were observed in the cardiovascular system either. The no-observed adverse reaction dose (NOAEL) for naked anti-Nectin-4-ADC was 6 mg / kg. The highest non-serious toxicity dose (HNSTD) for anti-Nectin-4-ADC was 6 mg / kg. Recovery was observed 4 weeks after drug withdrawal, and no delayed toxicity was observed.

[0421] Example 3: Clinical study of anti-Nectin-4-ADC in patients with solid tumors 1

[0422] 3.1 Clinical study design

[0423] This example is an open-label, multicenter phase I and IIa clinical study evaluating the safety, tolerability, pharmacokinetic characteristics, and preliminary efficacy of anti-Nectin-4-ADC in patients with advanced solid tumors.

[0424] This implementation plan comprises two phases: Phase I dose escalation, dose expansion, and dose exploration, and Phase IIa cohort expansion. Phase I dose escalation and dose expansion will enroll patients with advanced solid tumors who have progressed after standard therapy, cannot tolerate standard therapy, or refuse or have no standard therapy. The Phase I dose exploration study will enroll patients with triple-negative breast cancer, esophageal cancer, and other solid tumors (including ovarian cancer, head and neck squamous cell carcinoma, etc.) whose tumor tissue is positive for Nectin-4 as determined by immunohistochemistry. Phase IIa dose expansion includes seven cohorts, including patients with urothelial carcinoma, cervical cancer, HER-2 negative breast cancer, esophageal cancer, and non-small cell lung cancer, prostate cancer, and other solid tumors (including ovarian cancer, gastric cancer, colorectal cancer, head and neck squamous cell carcinoma, skin malignancies, thyroid cancer, etc.) whose tumor tissue is positive for Nectin-4 as determined by immunohistochemistry. Safety and efficacy will be monitored in all subjects throughout the study (according to RECIST 1.1), and pharmacokinetic and immunogenicity-related blood and tumor tissue samples will be collected.

[0425] 3.2 Subject Selection

[0426] Subjects must meet all of the following inclusion criteria to be included in this implementation example: age 18-80 years, gender not limited; patients with histopathologically confirmed advanced solid tumors who have failed or are intolerant of standard treatment, have no standard treatment or refuse standard treatment; and have at least one measurable lesion during the screening period according to RECIST 1.1 criteria.

[0427] 3.3 Research Intervention

[0428] test drug

[0429] Appearance: White or slightly yellow loose material.

[0430] Dosage form: Injection (lyophilized powder for injection).

[0431] Specification: 20mg / bottle.

[0432] Validity period: tentatively 24 months.

[0433] Storage conditions: Store at 2-8℃, away from light.

[0434] Implementation of research intervention

[0435] Phase I dose escalation: Accelerated titration and a "3+3+3" design were used to escalate the dose in seven groups: 0.33 mg / kg, 1.0 mg / kg, 1.25 mg / kg, 1.5 mg / kg, 1.75 mg / kg, 2.0 mg / kg, and 2.25 mg / kg. Patients in the 0.33–1.5 mg / kg dose group received intravenous infusion of anti-Nectin-4-ADC, administered once on days 1, 8, and 15, with each treatment cycle lasting 28 days. Patients in the 1.75–2.25 mg / kg dose group received intravenous infusion of anti-Nectin-4-ADC, administered once on days 1 and 15, with each treatment cycle lasting 28 days.

[0436] Phase I dose expansion phase: Patients will be enrolled at a dose expansion rate of 1.25 mg / kg and will receive intravenous infusion of anti-Nectin-4-ADC once on days 1, 8 and 15, with each treatment cycle lasting 28 days.

[0437] Phase I dose exploration: Select 2-3 dose groups for dose exploration.

[0438] Phase IIa cohort expansion: Based on previous data, the 1.25 mg / kg dose group was selected. Patients received intravenous infusion of anti-Nectin-4-ADC on days 1, 8, and 15, with each treatment cycle lasting 28 days. All enrolled patients received anti-Nectin-4-ADC treatment according to the prescribed dosing regimen until disease progression, intolerable toxicity, death, withdrawal of consent, or fulfillment of withdrawal criteria, or 12 cycles of anti-Nectin-4-ADC treatment for Phase I subjects, or 24 cycles of anti-Nectin-4-ADC treatment for Phase II cohort expansion subjects (whichever occurs earliest).

[0439] 3.4 Evaluation Indicators

[0440] Safety assessment

[0441] Safety evaluation includes adverse events, ECOG performance score, laboratory tests, vital signs, physical examination, 12-lead electrocardiogram, ophthalmological examination, etc.

[0442] In this embodiment, adverse events are recorded from the date the subject signs the informed consent form until a 28-day follow-up period after the subject finishes medication. If the subject has received other treatment within 28 days after finishing medication, the adverse event collection period ends before receiving other treatment. After the follow-up period, only spontaneous reports are collected.

[0443] Validity evaluation

[0444] Patients with solid tumors enrolled in this study will undergo efficacy evaluation according to RECIST 1.1. Tumor imaging assessments will be performed every 8 weeks until week 48. Thereafter, efficacy evaluations will be performed every 12 weeks until disease progression, death, withdrawal of consent, or fulfillment of withdrawal criteria (whichever occurs earliest). The efficacy evaluation indicators are as follows:

[0445] 1) Objective response rate (ORR): The proportion of subjects who achieved complete remission (CR) or partial remission (PR) during the study period, according to RECIST 1.1 criteria.

[0446] 2) Progression-free survival (PFS): defined as the time between the date of first administration of the investigational drug and disease progression or death (whichever comes first).

[0447] 3) Disease control rate (DCR): According to RECIST 1.1 criteria, the proportion of subjects who achieved complete remission (CR), partial remission (PR), or stable disease (SD) during the study period.

[0448] 4) Duration of Remission (DOR): Defined as the time from the first observation of PR (partial remission) or above to the first occurrence of disease progression (PD) or death from any cause.

[0449] 5) Time to response (TTR): defined as the time between the first administration of the study drug and the first confirmed complete response (CR) or partial response (PR).

[0450] 6) Overall survival (OS): The time from the start of anti-Nectin-4-ADC treatment to death (from any cause).

[0451] Pharmacokinetic evaluation

[0452] In this embodiment, venous blood was collected at each predetermined time point for drug concentration detection, including: total antibody concentration, ADC concentration, and free microtubule-associated inhibitor (Monomethyl auristatin E, MMAE) concentration. For the dose escalation and dose expansion phases, pharmacokinetic parameters for different dose groups were calculated using a non-compartmental model (Winnonlin 8.0 and above). The main pharmacokinetic parameters are:

[0453] C1W1D1: Area under the plasma concentration-time curve (AUC) 0-t AUC 0-inf and AUC 0-7d ), time to reach maximum blood drug concentration (T) max ), maximum blood concentration (C max ), half-life (t)1 / 2 Mean Time of Stay (MRT) inf Apparent volume of distribution (V) ss ), clearance rate (CL), etc.

[0454] C1W3D15 (or C2W5D1): Area under the plasma concentration-time curve (AUC) 0-t AUC 0-inf and AUC 0-tau ), lowest concentration (C min ), peak concentration (C) max ), mean steady-state plasma concentration (Cav), time to reach maximum plasma concentration (T) max,ss ), half-life (t) 1 / 2,ss Mean Time of Stay (MRT) inf Apparent volume of distribution (V) ss ), clearance rate (CL) ss ), accumulation ratio (Rac), trough concentration (C) trough ), the concentration immediately after administration (CEOI), etc.

[0455] Immunogenicity evaluation

[0456] At each predetermined time point, venous blood was collected for the detection of anti-drug antibodies (ADA), and the ADA positivity rate, antibody titer, and time of antibody appearance at each visit were statistically analyzed. If necessary, neutralizing antibodies (NAb) were further detected.

[0457] Biomarker evaluation

[0458] Tumor tissue samples were collected during the screening period to detect the expression level of Nectin-4 in the tumor tissue.

[0459] 3.5 Research Results

[0460] A total of 254 subjects were enrolled under a treatment regimen of 1.25 mg / kg, administered every 28 days, with doses given on days 1, 8, and 15 of each cycle. These included 37 patients with urothelial carcinoma, 53 with cervical cancer, 43 with esophageal cancer, and 20 with triple-negative breast cancer. Among the 37 patients with urothelial carcinoma, all had previously received platinum-based chemotherapy and immune checkpoint inhibitor therapy. The confirmed objective response rate (ORR) was 54.05% (95% CI 36.92–70.51), the disease control rate (DCR) was 89.19% (95% CI 74.58–96–97), the median progression-free survival (PFS) was 7.4 months (95% CI 3.8–9.4), and the median overall survival (OS) was 14.6 months (95% CI 12.3–18.5). In a study of 53 patients with cervical cancer, all of whom had previously received platinum-based doublet chemotherapy, the confirmed objective response rate (ORR) was 32.08% (95% CI 19.92–46.32), the disease control rate (DCR) was 81.13% (95% CI 68.03–90.56), the median progression-free survival (PFS) was 3.9 months (95% CI 3.7–5.7), and the median overall survival (OS) was 16.0 months (95% CI 14–NA). In a study of 43 patients with esophageal cancer, all of whom had received platinum-based chemotherapy and 95% had received immune checkpoint inhibitor therapy, the confirmed objective response rate (ORR) was 13.95% (95% CI 5.3–27.93), the disease control rate (DCR) was 67.44% (95% CI 51.46–80.92), the median progression-free survival (PFS) was 3.7 months (95% CI 1.9–4.8), and the median overall survival (OS) was 8.2 months (95% CI 5.7–NA). In a study of 20 patients with triple-negative breast cancer, all patients had received at least one first-line chemotherapy, and had previously received taxane or anthracycline chemotherapy. The confirmed objective response rate (ORR) was 50% (95% CI 27.2–72.8), the disease control rate (DCR) was 80% (95% CI 56.34–94.27), the median progression-free survival (PFS) was 5.8 months (95% CI 2.7–7.4), and the median overall survival (OS) was 12.2 months (95% CI 8.2–NA). 10% of the patients had previously received taxane chemotherapy and antibody-drug conjugates loaded with topoisomerase inhibitors, and their efficacy assessment was progression-free survival (PD).

[0461] Meanwhile, the expression of Nectin-4 in tumor tissue was detected in the study, and the specific results are as follows:

[0462] Table 2. Results of studies on anti-Nectin-4-ADC in the treatment of patients with advanced solid tumors.

[0463] The study found that, at different expression levels, there were no significant differences in the efficacy (ORR and PFS) of anti-Nectin-4-ADC in treating patients with advanced solid tumors, and the overall results were similar. In patients with urothelial carcinoma, patients with lower Nectin-4 expression had even better ORR and PFS than those with higher Nectin-4 expression (ORR 59.1% vs 50%; PFS 9.1 months vs 6.7 months). In patients with triple-negative breast cancer, patients with lower Nectin-4 expression had better ORR (ORR 66.7% vs 47.1%).

[0464] The above results indicate that anti-Nectin-4-ADC can also show good therapeutic effects in patients with advanced solid tumors who have relatively low Nectin-4 expression levels.

[0465] In terms of safety, the treatment of solid tumors with anti-Nectin-4-ADC is safe and manageable. Common adverse events are easily resolved with symptomatic treatment, and there are few cases of discontinuation of the drug due to adverse events.

[0466] Example 4: Clinical study of anti-Nectin-4-ADC in patients with solid tumors 2

[0467] 4.1 Clinical study design

[0468] This example is an open-label, multicenter phase I and IIa clinical study evaluating the safety, tolerability, pharmacokinetic characteristics, and preliminary efficacy of anti-Nectin-4-ADC in patients with advanced solid tumors.

[0469] This study comprises two phases: Phase I dose escalation, dose expansion, and dose exploration, and Phase IIa cohort expansion. Phase I dose escalation and dose expansion will enroll patients with advanced solid tumors who have progressed after standard therapy, cannot tolerate standard therapy, or refuse or do not have standard therapy. Safety and efficacy will be monitored throughout the study (according to RECIST 1.1), and pharmacokinetic and immunogenic blood samples and tumor tissue samples will be collected.

[0470] 4.2 Subject Selection

[0471] Subjects must meet all of the following inclusion criteria to be included in this implementation example: age 18-80 years, gender not limited; patients with histopathologically confirmed advanced solid tumors who have failed or are intolerant of standard treatment, have no standard treatment or refuse standard treatment; and have at least one measurable lesion during the screening period according to RECIST 1.1 criteria.

[0472] 4.3 Research Intervention

[0473] test drug

[0474] Appearance: White or slightly yellow loose material.

[0475] Dosage form: Injection (lyophilized powder for injection).

[0476] Specification: 20mg / bottle.

[0477] Validity period: tentatively 24 months.

[0478] Storage conditions: Store at 2-8℃, away from light.

[0479] Implementation of research intervention

[0480] Accelerated titration and a "3+3+3" design were used to escalate the dose in seven groups: 0.33 mg / kg, 1.0 mg / kg, 1.25 mg / kg, 1.5 mg / kg, 1.75 mg / kg, 2.0 mg / kg, and 2.25 mg / kg. Patients in the 1.75–2.25 mg / kg dose groups received intravenous infusion of anti-Nectin-4-ADC twice daily on days 1 and 15, with each treatment cycle lasting 28 days. Two to three dose groups were selected for further dose exploration.

[0481] 4.4 Evaluation Indicators

[0482] Safety assessment

[0483] Safety evaluation includes adverse events, ECOG performance score, laboratory tests, vital signs, physical examination, 12-lead electrocardiogram, ophthalmological examination, etc.

[0484] In this embodiment, adverse events are recorded from the date the subject signs the informed consent form until a 28-day follow-up period after the subject finishes medication. If the subject has received other treatment within 28 days after finishing medication, the adverse event collection period ends before receiving other treatment. After the follow-up period, only spontaneous reports are collected.

[0485] Validity evaluation

[0486] Patients with solid tumors enrolled in this study will undergo efficacy evaluation according to RECIST 1.1. Tumor imaging assessments will be performed every 8 weeks until week 48. Thereafter, efficacy assessments will be performed every 12 weeks until disease progression, death, withdrawal of consent, or fulfillment of withdrawal criteria (whichever occurs earliest).

[0487] 4.5 Research Results

[0488] The treatment regimen was administered at 2.0 mg / kg, with each 28-day cycle consisting of two doses on days 1 and 15 of each cycle. A total of 7 subjects were enrolled: 1 with ovarian cancer and 6 with breast cancer (4 with triple-negative breast cancer and 2 with HR+ / HER2- breast cancer). Safety data were obtained for all subjects. Six subjects completed at least one efficacy assessment: 1 was assessed as PR, 2 as SD, and 3 as PD. Among the 4 patients with triple-negative breast cancer, all had received at least one first-line chemotherapy, including prior taxane or anthracycline chemotherapy; 1 was assessed as PR, 1 as SD, 1 as PD, and 1 withdrew early without tumor evaluation. Among the 4 patients with triple-negative breast cancer, 2 had previously received taxane chemotherapy and ADC therapy with a topoisomerase inhibitor loading; 1 was assessed as PD, and 1 withdrew early without tumor evaluation.

[0489] In terms of safety, the anti-Nectin-4-ADC treatment for solid tumors is safe and manageable. Common adverse events are easily resolved with symptomatic treatment, and there have been no cases of discontinuation of the drug due to adverse events.

[0490] Example 5: Clinical study of anti-Nectin-4-ADC in triple-negative breast cancer patients 1

[0491] 5.1 Research Design

[0492] This example is an open-label, multicenter phase II clinical trial designed to evaluate the efficacy and safety of anti-Nectin-4-ADC in patients with locally advanced or metastatic triple-negative breast cancer.

[0493] The study included patients with locally advanced or metastatic triple-negative breast cancer who had previously received taxane / anthracycline chemotherapy and antibody-drug conjugates loaded with topoisomerase inhibitors, and who received anti-Nectin-4-ADC therapy.

[0494] The study was divided into a screening period, a treatment period, and a follow-up period. Participants in the screening period were evaluated within 28 days prior to their first dose to determine eligibility for the study. Eligible participants entered the treatment period and received anti-Nectin-4-ADC therapy.

[0495] 5.2 Subject Selection

[0496] To be eligible for this study, participants must meet all of the following inclusion criteria: age 18–75 years, regardless of sex; histopathologically confirmed locally advanced or metastatic triple-negative breast cancer; at least one measurable extracranial lesion during the screening period according to RECIST 1.1 criteria; and prior treatment with taxane / anthracycline drugs and antibody-drug conjugates loaded with topoisomerase inhibitors.

[0497] 5.3 Research Intervention

[0498] test drug

[0499] Appearance: White or slightly yellow loose material.

[0500] Dosage form: Injection (lyophilized powder for injection).

[0501] Specification: 20mg / bottle.

[0502] Validity period: tentatively 24 months.

[0503] Storage conditions: Store at 2-8℃, away from light.

[0504] Dosing regimen

[0505] Anti-Nectin-4-ADC, 1.25 mg / kg, every 21 days is one treatment cycle, intravenous infusion on days 1 and 8 of each cycle.

[0506] Subjects received anti-Nectin-4-ADC treatment until disease progression, intolerable toxicity, death, withdrawal of informed consent, loss to follow-up, or completion of 2 years of treatment, whichever occurred first.

[0507] 5.4 Evaluation Indicators

[0508] Validity evaluation

[0509] All subjects underwent tumor assessment every 6 weeks (or every 12 weeks after 48 weeks from the first dose), and efficacy was assessed according to RECIST v1.1. The efficacy indicators are as follows:

[0510] 1) Objective response rate (ORR): The proportion of subjects who achieved a complete response (CR) or partial response (PR) during the study period, according to RECIST v1.1 criteria.

[0511] 2) Duration of response (DOR): The time from the first observed objective response (CR or PR) to disease progression (PD) or death from any cause (whichever comes first).

[0512] 3) Time to Remission (TTR): The time between the date of first administration of the study drug and the first observed objective response.

[0513] 4) Disease control rate (DCR): The proportion of subjects who achieved the best overall response of complete remission (CR), partial remission (PR), or stable disease (SD) during the study period, according to RECIST 1.1 criteria.

[0514] 5) Progression-free survival (PFS): The time from the date of first administration of the study drug to disease progression or death from any cause (whichever comes first).

[0515] 6) Overall survival (OS): The time from the date of first administration of the study drug to death from any cause.

[0516] Safety assessment

[0517] All subjects underwent safety checks before each dose during the treatment period. Adverse events (AEs) and serious adverse events (SAEs) occurring throughout the study were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Indicators included vital signs, physical examination, ECOG performance status, 12-lead electrocardiogram, ophthalmological examination, clinical laboratory test results, AEs, and SAEs.

[0518] Pharmacokinetic evaluation

[0519] At each predetermined time point, venous blood samples were collected for drug concentration assays, including: TAb (only applicable to subjects with intensive PK sampling), ADC concentration, and free MMAE concentration. Pharmacokinetic characteristics: PK parameters include, but are not limited to, peak concentration (C). max Peak time (T) max ), area under the plasma concentration-time curve (AUC), elimination half-life (t) 1 / 2 Clearance rate (CL), volume of distribution (V), etc. (applicable to subjects in intensive PK sampling); distribution of drug concentration in the blood of subjects (applicable to all subjects).

[0520] Immunogenicity evaluation

[0521] At each predetermined time point, venous blood was collected for ADA testing. If ADA was positive, neutralizing antibody testing was performed as appropriate. The positivity rate and titer of anti-drug antibody (ADA) in subjects receiving anti-Nectin-4-ADC treatment were assessed, as well as the occurrence of neutralizing antibody (NAb).

[0522] Biomarker evaluation

[0523] Tumor tissue samples were collected during the screening period to explore the relationship between the expression level of the biomarker Nectin-4 in tumor tissue and the therapeutic effect.

[0524] 5.5 Research Results

[0525] In a treatment regimen of 1.25 mg / kg, administered once every 21 days on days 1 and 8 of each cycle, patients had previously received taxane-based chemotherapy and antibody-drug conjugates loaded with topoisomerase inhibitors. As of January 2025, in the 1.25 mg / kg dose group, 16 subjects completed at least one efficacy assessment, with an ORR of 50.0% and a DCR of 87.5%, demonstrating excellent treatment efficacy.

[0526] In terms of safety, the anti-Nectin-4-ADC treatment for triple-negative breast cancer is safe and manageable. Common adverse events are easily resolved with symptomatic treatment, and there have been no cases of discontinuation of the drug due to adverse events.

[0527] Example 6: Clinical study of anti-Nectin-4-ADC in triple-negative breast cancer patients 2

[0528] 6.1 Research Design

[0529] This example is an open-label, multicenter phase Ib clinical trial designed to evaluate the efficacy and safety of anti-Nectin-4-ADC in patients with metastatic triple-negative breast cancer.

[0530] The study included patients with metastatic triple-negative breast cancer who had previously received taxane-based chemotherapy and antibody-drug conjugates loaded with topoisomerase inhibitors, and who received anti-Nectin-4-ADC therapy.

[0531] The study was divided into a screening period, a treatment period, and a follow-up period. Participants in the screening period were evaluated within 28 days prior to their first dose to determine eligibility for the study. Eligible participants entered the treatment period and received anti-Nectin-4-ADC therapy.

[0532] 6.2 Subject Selection

[0533] To be eligible for this study, participants must meet all of the following inclusion criteria: age ≥18 years, regardless of sex; histopathologically confirmed metastatic triple-negative breast cancer; at least one measurable lesion during the screening period according to RECIST 1.1 criteria; and prior treatment with taxane-based chemotherapy and antibody-drug conjugates loaded with topoisomerase inhibitors.

[0534] 6.3 Research Intervention

[0535] test drug

[0536] Appearance: White or slightly yellow loose material.

[0537] Dosage form: Injection (lyophilized powder for injection).

[0538] Specification: 20mg / bottle.

[0539] Validity period: tentatively 24 months.

[0540] Storage conditions: Store at 2-8℃, away from light.

[0541] Dosing regimen

[0542] Anti-Nectin-4-ADC, 1.5 mg / kg, every 21 days is one treatment cycle, intravenous infusion on days 1 and 8 of each cycle.

[0543] Subjects received anti-Nectin-4-ADC treatment until disease progression, intolerable toxicity, or other criteria for discontinuation of treatment, whichever occurred first.

[0544] 6.4 Evaluation Indicators

[0545] Validity evaluation

[0546] All subjects underwent tumor assessment every 6 weeks (or every 12 weeks after 48 weeks from the first dose), and efficacy was assessed according to RECIST v1.1. The efficacy indicators are as follows:

[0547] 1) Objective response rate (ORR): The proportion of subjects who achieved a complete response (CR) or partial response (PR) during the study period, according to RECIST v1.1 criteria.

[0548] 2) Duration of response (DOR): The time from the first observed objective response (CR or PR) to disease progression (PD) or death from any cause (whichever comes first).

[0549] 3) Clinical benefit rate (CBR): The proportion of subjects who achieved complete remission (CR), partial remission (PR), or stable disease (SD) during the study period, according to RECIST v1.1 criteria.

[0550] 4) Disease control rate (DCR): The proportion of subjects who achieved the best overall response of complete remission (CR), partial remission (PR), or stable disease (SD) during the study period, according to RECIST 1.1 criteria.

[0551] 5) Progression-free survival (PFS): The time from the date of first administration of the study drug to disease progression or death from any cause (whichever comes first).

[0552] 6) Overall survival (OS): The time from the date of first administration of the study drug to death from any cause.

[0553] Safety assessment

[0554] All subjects underwent safety checks before each dose during the treatment period. Adverse events (AEs) and serious adverse events (SAEs) occurring throughout the study were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Indicators included vital signs, physical examination, ECOG performance status, 12-lead electrocardiogram, ophthalmological examination, clinical laboratory test results, AEs, and SAEs.

[0555] Pharmacokinetic evaluation

[0556] At each predetermined time point, venous blood samples were collected for drug concentration assays, including: TAb (only applicable to subjects with intensive PK sampling), ADC concentration, and free MMAE concentration. Pharmacokinetic characteristics: PK parameters include, but are not limited to, peak concentration (C). max Peak time (T) max ), area under the plasma concentration-time curve (AUC), elimination half-life (t) 1 / 2 ), clearance rate (CL), distribution volume (V), etc.

[0557] Immunogenicity evaluation

[0558] At each predetermined time point, venous blood was collected for ADA testing. If ADA was positive, neutralizing antibody testing was performed as appropriate. The positivity rate and titer of anti-drug antibody (ADA) in subjects receiving anti-Nectin-4-ADC treatment were assessed, as well as the occurrence of neutralizing antibody (NAb).

[0559] Biomarker evaluation

[0560] Tumor tissue samples were collected during the screening period to explore the relationship between the expression level of the biomarker Nectin-4 in tumor tissue and the therapeutic effect.

[0561] 6.5 Research Results

[0562] In the 1.5 mg / kg regimen, administered once every 21 days (once on days 1 and 8 of each cycle), all patients had previously received taxane-based chemotherapy and antibody-drug conjugates loaded with topoisomerase inhibitors. In the 1.5 mg / kg dose group, 3 subjects completed at least one efficacy assessment; 2 were assessed as PR (partial response), and 1 as PD (progressive disease). The ORR (objective response rate) was 67%, and the DCR (disease control rate) was 67%, demonstrating excellent treatment efficacy.

[0563] In terms of safety, the anti-Nectin-4-ADC treatment for triple-negative breast cancer is safe and manageable. Common adverse events are easily resolved with symptomatic treatment, and there have been no cases of discontinuation of the drug due to adverse events.

[0564] Example 7: Clinical study of anti-Nectin-4-ADC monotherapy or in combination with other antitumor drugs in patients with advanced solid tumors.

[0565] 7.1 Research Design

[0566] This example is an open-label, multicenter, phase Ib / II clinical study designed to evaluate the safety, tolerability, efficacy, pharmacokinetics, and immunogenicity of anti-Nectin-4 ADC monotherapy or in combination with other antitumor drugs in patients with advanced solid tumors.

[0567] The study comprises two phases: a phase Ib safety introductory phase and a phase II cohort expansion phase. Phase Ib will enroll patients with locally advanced or metastatic esophageal squamous cell carcinoma who have failed first-line standard therapy, or other advanced solid tumors who have failed first-line standard therapy. The phase II cohort expansion phase will enroll patients with locally advanced or metastatic esophageal squamous cell carcinoma who have not received systemic therapy or have failed first-line systemic therapy, or other advanced solid tumors who have not received systemic therapy or have failed first-line systemic therapy. All participants must provide archived tumor tissue samples or fresh tumor samples during the screening period for testing the expression levels of Nectin-4 and PD-L1, and Nectin-4 amplification.

[0568] The study is divided into a screening period, a treatment period, and a follow-up period. After signing an informed consent form, participants enter the screening period. Qualified participants will receive anti-Nectin-4 ADC monotherapy or in combination with other anti-tumor drugs.

[0569] 7.2 Subject Selection

[0570] To be eligible for this study, participants must meet all of the following inclusion criteria: age 18-75 years, gender not limited; pathologically confirmed esophageal cancer (including gastroesophageal junction), locally advanced and unresectable or with distant metastasis, having previously received first-line platinum-based standard therapy or having not previously received systemic therapy; and having at least one measurable lesion during the screening period according to RECIST 1.1 criteria.

[0571] 7.3 Research Intervention

[0572] test drug

[0573] Appearance: White or slightly yellow loose material.

[0574] Dosage form: Injection (lyophilized powder for injection).

[0575] Specification: 20mg / bottle.

[0576] Validity period: tentatively 24 months.

[0577] Storage conditions: Store at 2-8℃, away from light.

[0578] Implementation of research intervention

[0579] The enrolled participants will receive the following treatments:

[0580] ■Arm1 * :

[0581] ◆Anti-Nectin-4 ADC: 1.25 mg / kg, one treatment cycle is 21 days, intravenous infusion on days 1 and 8 of each cycle;

[0582] ◆Toripalimab injection: 240mg, every 21 days is one treatment cycle, intravenous infusion on day 1 of each cycle.

[0583] ■Arm2 * :

[0584] ◆Anti-Nectin-4 ADC: 1.5 mg / kg, every 21 days is one treatment cycle, intravenous infusion on days 1 and 8 of each cycle;

[0585] ◆Toripalimab injection: 240mg, every 21 days is one treatment cycle, intravenous infusion on day 1 of each cycle.

[0586] Qualified subjects will enter the treatment period and receive anti-Nectin-4 ADC monotherapy or in combination with different drugs until the treatment termination criteria specified in the protocol are met.

[0587] 7.4 Evaluation Indicators

[0588] Validity evaluation

[0589] All subjects underwent tumor assessment every 6 weeks (or every 12 weeks after 48 weeks from the first dose), and efficacy was assessed according to RECIST v1.1. The efficacy indicators are as follows:

[0590] • Objective response rate (ORR): The proportion of subjects whose best overall response during the study period was confirmed as a complete response (CR) or partial response (PR).

[0591] • Duration of Remission (DOR): Defined as the time from the first observed confirmed objective response (CR or PR) to disease progression (PD) or death from any cause.

[0592] • Time to Treatment Onset (TTR): Defined as the time between the date of first administration of the study drug and the first observed complete response (CR) or partial response (PR).

[0593] • Disease control rate (DCR): The proportion of subjects whose best overall response during the study period was confirmed as complete remission (CR), partial remission (PR), or stable disease (SD).

[0594] • Progression-free survival (PFS): defined as the time from the date of first administration of the study drug to disease progression or death from any cause (whichever comes first).

[0595] • Overall survival (OS): defined as the time from the date of first administration of the study drug to death from any cause.

[0596] Safety assessment

[0597] According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, adverse events (AEs) and serious adverse events (SAEs) that occurred throughout the study period were evaluated.

[0598] The indicators include vital signs, physical examination, ECOG fitness score, 12-lead electrocardiogram, ophthalmological examination, clinical laboratory test indicators, AE and SAE, etc.

[0599] Pharmacokinetic evaluation

[0600] PK parameters (applicable to subjects undergoing PK intensive sampling) include, but are not limited to, area under the plasma concentration-time curve (AUC), time to reach maximum plasma concentration (Tmax), maximum plasma concentration (Cmax), half-life (t1 / 2), apparent volume of distribution (V), clearance rate (CL), etc.

[0601] Distribution of drug concentrations in the blood of the subjects.

[0602] Immunogenicity evaluation

[0603] Based on ADAAS, the occurrence of ADA and NAb in each visit was statistically analyzed. The immunogenicity of anti-Nectin-4 ADC was assessed by summarizing the number and percentage of subjects with detectable ADA (anti-Nectin-4 ADC antibody) and NAb.

[0604] Biomarker evaluation

[0605] This study aims to analyze the expression level and amplification of the biomarker Nectin-4 in tumor tissue and their relationship with treatment efficacy and prognosis. The decision to test for Nectin-4 amplification can be made based on clinical circumstances (e.g., the number of tissue sections).

[0606] For subjects receiving the combination therapy with toripalimab, the relationship between PD-L1 biomarker expression and efficacy or prognosis was analyzed.

[0607] 7.5 Research Results

[0608] In a treatment regimen consisting of anti-Nectin-4 ADC 1.25 mg / kg, administered once on days 1 and 8 of each 21-day cycle, combined with toripalimab 240 mg, administered on day 1 of each 21-day cycle, five esophageal cancer patients who had received first-line standard therapy completed at least one efficacy assessment. The ORR was 40% and the DCR was 100%.

[0609] In terms of safety, the combination of anti-Nectin-4-ADC and toripalimab for the treatment of solid tumors is safe and manageable. Common adverse events are easily resolved with symptomatic treatment, and there have been no cases of discontinuation of the drug due to adverse events.

[0610] Example 8: Clinical study of anti-Nectin-4-ADC in combination with other anti-tumor drugs in patients with advanced gynecologic tumors.

[0611] 8.1 Research Design

[0612] This embodiment is an open-label, multicenter, phase Ib / II clinical study designed to evaluate the safety, tolerability, efficacy, pharmacokinetics, and immunogenicity of anti-Nectin-4 ADC in combination with other antitumor drugs in patients with advanced gynecologic tumors.

[0613] The study comprises two phases: a phase Ib safety introduction phase and a phase II cohort expansion phase. Phase Ib will include cervical cancer patients who have failed first-line standard therapy and platinum-sensitive ovarian cancer patients who have failed first-line standard therapy. The phase II cohort expansion phase will include patients with recurrent or metastatic cervical cancer who have not received systemic therapy, platinum-sensitive ovarian cancer patients who have failed first-line standard therapy, and patients with endometrial cancer who have not received systemic therapy. All participants must provide archived tumor tissue samples or fresh tumor samples during the screening period to measure Nectin-4 expression levels. For the cohort receiving combined immune checkpoint inhibitor therapy, PD-L1 expression levels in tumor samples will also be measured.

[0614] The study is divided into a screening period, a treatment period, and a follow-up period. After signing an informed consent form, participants enter the screening period. Qualified participants will receive anti-Nectin-4 ADC combined with other anti-tumor drugs.

[0615] 8.2 Subject Selection

[0616] To be eligible for this study, participants must meet all of the following inclusion criteria: female, aged 18–75 years; histopathologically confirmed recurrent or metastatic cervical cancer, untreatable surgical resection and / or radical radiotherapy, failure of first-line platinum-based doublet chemotherapy or no prior systemic therapy for recurrent or metastatic cervical cancer; histopathologically confirmed high-grade serous ovarian cancer, primary peritoneal cancer, or fallopian tube cancer; histologically confirmed stage III, IV, or recurrent endometrial cancer; and at least one measurable lesion during the screening period according to RECIST 1.1 criteria.

[0617] 8.3 Research Intervention

[0618] test drug

[0619] Appearance: White or slightly yellow loose material.

[0620] Dosage form: Injection (lyophilized powder for injection).

[0621] Specification: 20mg / bottle.

[0622] Validity period: tentatively 24 months.

[0623] Storage conditions: Store at 2-8℃, away from light.

[0624] Implementation of research intervention

[0625] The enrolled participants will receive the following treatments:

[0626] ■Arm 1:

[0627] ◆Anti-Nectin-4 ADC: 1.25 mg / kg, one treatment cycle is 21 days, intravenous infusion on days 1 and 8 of each cycle;

[0628] ◆Toripalimab injection: 240mg, every 21 days is one treatment cycle, intravenous infusion on day 1 of each cycle.

[0629] ■Arm 2:

[0630] ◆Anti-Nectin-4 ADC: 1.5 mg / kg, every 21 days is one treatment cycle, intravenous infusion on days 1 and 8 of each cycle;

[0631] ◆Toripalimab injection: 240mg, every 21 days is one treatment cycle, intravenous infusion on day 1 of each cycle.

[0632] Qualified subjects will enter the treatment period and receive anti-Nectin-4 ADC combined with different drugs until the treatment termination criteria specified in the protocol are met.

[0633] 8.4 Evaluation Indicators

[0634] Validity evaluation

[0635] All subjects underwent tumor assessment every 6 weeks (or every 12 weeks after 48 weeks from the first dose), and efficacy was assessed according to RECIST v1.1. The efficacy indicators are as follows:

[0636] • Objective response rate (ORR): The proportion of subjects whose best overall response during the study period was confirmed as a complete response (CR) or partial response (PR).

[0637] • Duration of Remission (DOR): Defined as the time from the first observed confirmed objective response (CR or PR) to disease progression (PD) or death from any cause.

[0638] • Time to Treatment Onset (TTR): Defined as the time between the date of first administration of the study drug and the first observed complete response (CR) or partial response (PR).

[0639] • Disease control rate (DCR): The proportion of subjects whose best overall response during the study period was confirmed as complete remission (CR), partial remission (PR), or stable disease (SD).

[0640] • Progression-free survival (PFS): defined as the time from the date of first administration of the study drug to disease progression or death from any cause (whichever comes first).

[0641] • Overall survival (OS): defined as the time from the date of first administration of the study drug to death from any cause.

[0642] Safety assessment

[0643] According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, adverse events (AEs) and serious adverse events (SAEs) that occurred throughout the study period were evaluated.

[0644] The indicators include vital signs, physical examination, ECOG fitness score, 12-lead electrocardiogram, ophthalmological examination, clinical laboratory test indicators, AE and SAE, etc.

[0645] Pharmacokinetic evaluation

[0646] Phase Ib security implementation phase:

[0647] PK parameters (applicable to subjects undergoing intensive PK sampling) include, but are not limited to, the area under the plasma concentration-time curve (AUC) and the time to reach maximum plasma concentration (T). max ), maximum blood concentration (C max ), half-life (t) 1 / 2 Apparent distribution volume (V), clearance rate (CL), etc.

[0648] Phase II:

[0649] Distribution of drug concentrations in the blood of the subjects.

[0650] Immunogenicity evaluation

[0651] Based on ADAAS, the occurrence of ADA and NAb in each visit was statistically analyzed. The immunogenicity of anti-Nectin-4 ADC was assessed by summarizing the number and percentage of subjects with detectable ADA (anti-Nectin-4 ADC antibody) and NAb.

[0652] Biomarker evaluation

[0653] To analyze the relationship between the expression level of the biomarker Nectin-4 in tumor tissue and the efficacy or prognosis, and the relationship between the expression of the biomarker PD-L1 in subjects treated with combined immune checkpoint inhibitors and the efficacy or prognosis.

[0654] 8.5 Research Results

[0655] In a treatment regimen of anti-Nectin-4 ADC 1.25 mg / kg, administered once on days 1 and 8 of each 21-day cycle, combined with toripalimab 240 mg, administered on day 1 of each 21-day cycle, three cervical cancer patients who had received first-line standard therapy completed at least one efficacy assessment. The ORR was 67% and the DCR was 100%.

[0656] In terms of safety, the combination of anti-Nectin-4-ADC and toripalimab for the treatment of advanced gynecologic tumors is safe and manageable. Common adverse events are easily resolved with symptomatic treatment, and there have been no cases of discontinuation of the drug due to adverse events.

[0657] Example 9: Clinical study of anti-Nectin-4-ADC in combination with other anti-tumor drugs in patients with triple-negative breast cancer.

[0658] 9.1 Research Design

[0659] This embodiment is an open-label, multicenter phase II clinical trial designed to evaluate the efficacy and safety of anti-Nectin-4-ADC combined with toripalimab injection in patients with locally advanced or metastatic triple-negative breast cancer.

[0660] The study included patients with locally advanced or metastatic triple-negative breast cancer who had not previously received systemic therapy and received anti-Nectin-4-ADC combined with toripalimab injection.

[0661] The study was divided into a screening period, a treatment period, and a follow-up period. Participants in the screening period were evaluated within 28 days prior to their first dose to determine eligibility for the study. Eligible participants entered the treatment period and received anti-Nectin-4-ADC combined with toripalimab injection.

[0662] 9.2 Subject Selection

[0663] To be eligible for this study, participants must meet all of the following inclusion criteria: age 18–75 years, regardless of sex; histopathologically confirmed locally advanced or metastatic triple-negative breast cancer; at least one measurable extracranial lesion during the screening period according to RECIST 1.1 criteria; and no prior systemic therapy for locally advanced or metastatic triple-negative breast cancer.

[0664] 9.3 Research Intervention

[0665] test drug

[0666] Appearance: White or slightly yellow loose material.

[0667] Dosage form: Injection (lyophilized powder for injection).

[0668] Specification: 20mg / bottle.

[0669] Validity period: tentatively 24 months.

[0670] Storage conditions: Store at 2-8℃, away from light.

[0671] Dosing regimen

[0672] Anti-Nectin-4-ADC, 1.25 mg / kg, is administered intravenously on days 1 and 8 of each 21-day treatment cycle; toripalimab injection, 240 mg, is administered intravenously on day 1 of each 21-day treatment cycle. Subjects will receive anti-Nectin-4-ADC combined with toripalimab injection until disease progression, intolerable toxicity, death, withdrawal of informed consent, loss to follow-up, or completion of 2 years of treatment, whichever occurs first.

[0673] 9.4 Evaluation Indicators

[0674] Validity evaluation

[0675] All subjects underwent tumor assessment every 6 weeks (or every 12 weeks after 48 weeks from the first dose), and efficacy was assessed according to RECIST v1.1. The efficacy indicators are as follows:

[0676] 1) Objective response rate (ORR): The proportion of subjects who achieved a complete response (CR) or partial response (PR) during the study period, according to RECIST v1.1 criteria.

[0677] 2) Duration of response (DOR): The time from the first observed objective response (CR or PR) to disease progression (PD) or death from any cause (whichever comes first).

[0678] 3) Time to Remission (TTR): The time between the date of first administration of the study drug and the first observed objective response.

[0679] 4) Disease control rate (DCR): The proportion of subjects who achieved the best overall response of complete remission (CR), partial remission (PR), or stable disease (SD) during the study period, according to RECIST 1.1 criteria.

[0680] 5) Progression-free survival (PFS): The time from the date of first administration of the study drug to disease progression or death from any cause (whichever comes first).

[0681] 6) Overall survival (OS): The time from the date of first administration of the study drug to death from any cause.

[0682] Safety assessment

[0683] All subjects underwent safety checks before each dose during the treatment period. Adverse events (AEs) and serious adverse events (SAEs) occurring throughout the study were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Indicators included vital signs, physical examination, ECOG performance status, 12-lead electrocardiogram, ophthalmological examination, clinical laboratory test results, AEs, and SAEs.

[0684] Pharmacokinetic evaluation

[0685] At each predetermined time point, venous blood samples were collected for drug concentration assays, including: TAb (only applicable to subjects with intensive PK sampling), ADC concentration, and free MMAE concentration. Pharmacokinetic characteristics: PK parameters include, but are not limited to, peak concentration (C). max Peak time (T) max ), area under the plasma concentration-time curve (AUC), elimination half-life (t) 1 / 2 Clearance rate (CL), volume of distribution (V), etc. (applicable to subjects in intensive PK sampling); distribution of drug concentration in the blood of subjects (applicable to all subjects).

[0686] Immunogenicity evaluation

[0687] At each predetermined time point, venous blood was collected for ADA testing. If ADA was positive, neutralizing antibody testing was performed as appropriate. The positivity rate and titer of anti-drug antibody (ADA) in subjects receiving anti-Nectin-4-ADC treatment were assessed, as well as the occurrence of neutralizing antibody (NAb).

[0688] Biomarker evaluation

[0689] Tumor tissue samples were collected during the screening period to explore the expression level of the biomarker Nectin-4 in the tumor tissue and the relationship between PD-L1 and treatment efficacy.

Claims

1. A method for preventing or treating cancer, the method comprising: To eligible subjects, at approximately 0.33- The dose is 2.0 mg / kg, administered in cycles of 21 days or 28 days, and the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered at least twice (e.g., twice or three times) per cycle. The anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt has the molecular formula Ab-[L-CTD]m, where Ab represents an anti-Nectin-4 antibody or its antigen-binding fragment, L represents a linker, CTD represents a drug, and m represents the average number of drug linkages relative to each Ab molecule. Wherein, Ab includes a heavy chain variable region and a light chain variable region, and the heavy chain variable region includes HCDR1 shown in SEQ ID NO:1, HCDR2 shown in SEQ ID NO:2, and HCDR3 shown in SEQ ID NO:3; and the light chain variable region includes LCDR1 shown in SEQ ID NO:4, LCDR2 shown in SEQ ID NO:5, and LCDR3 shown in SEQ ID NO:

6.

2. The method of claim 1, wherein the cancer comprises a tumor that highly expresses Nectin-4, and / or a tumor that lowly expresses Nectin-4.

3. The method according to any one of claims 1-2, wherein the cancer is advanced cancer, recurrent cancer, or metastatic cancer.

4. The method according to any one of claims 1-3, wherein the cancer is a solid tumor or a hematologic malignancy.

5. The method according to any one of claims 1-4, wherein the cancer is an advanced solid tumor.

6. The method according to any one of claims 1-5, wherein the cancer is selected from any one of the following: urothelial carcinoma, bladder cancer, cervical cancer, esophageal cancer, breast cancer, ovarian cancer, pancreatic cancer, hepatocellular carcinoma, gastric cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, acute lymphoblastic leukemia, anaplastic large cell lymphoma, multiple myeloma, prostate cancer, non-small cell lung cancer, small cell lung cancer, malignant melanoma, squamous cell carcinoma, glioblastoma, renal cell carcinoma, gastrointestinal tumors, prostate cancer, rectal cancer, colon cancer, glioma, triple-negative breast cancer, HER-2 negative breast cancer, HR+ / HER2- breast cancer, mesothelioma, head and neck squamous cell carcinoma, malignant skin tumors, thyroid cancer, esophageal squamous cell carcinoma, endometrial cancer, fallopian tube cancer, primary peritoneal cancer, high-grade serous ovarian cancer, muscle-invasive bladder cancer, and upper urinary tract urothelial carcinoma.

7. The method according to any one of claims 1-6, wherein the cancer is selected from any one of: urothelial carcinoma, cervical cancer, esophageal cancer, breast cancer, and triple-negative breast cancer.

8. The method according to any one of claims 1-7, wherein the subject has received chemotherapy and / or immune checkpoint inhibitor treatment.

9. The method according to any one of claims 1-8, wherein the subject has received platinum-based chemotherapy.

10. The method according to any one of claims 1-9, wherein the subject has received taxane / anthracycline chemotherapy.

11. The method according to any one of claims 1-10, wherein the subject has received treatment with an antibody-drug conjugate loaded with a topoisomerase inhibitor.

12. The method according to any one of claims 1-11, wherein the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof is administered by intravenous infusion.

13. The method according to any one of claims 1-12, wherein the dose of the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof is about 0.33 to about 1.5 mg / kg.

14. The method according to any one of claims 1-13, wherein the dose of the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof is about 1.0 to about 1.5 mg / kg.

15. The method according to any one of claims 1-14, wherein the dose of the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof is about 1.25 to about 1.5 mg / kg.

16. The method according to any one of claims 1-15, wherein the dose of the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof is about 1.25 mg / kg, or about 1.5 mg / kg.

17. The method according to any one of claims 1-16, wherein the dose of the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof is about 2 mg / kg.

18. The method according to any one of claims 1-17, wherein the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof is administered at least on day 1 and day 8 of each cycle.

19. The method according to any one of claims 1-18, wherein the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 21-day cycle, and on day 1 and day 8 of each cycle.

20. The method according to any one of claims 1-19, wherein the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 28-day cycle, and on days 1, 8, and 15 of each cycle.

21. The method according to any one of claims 1-20, wherein the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a cycle of 28 days, and on days 1 and 15 of each cycle.

22. The method according to any one of claims 1-21, wherein the cancer is breast cancer, and the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg or 1.5 mg / kg.

23. The method according to any one of claims 1-21, wherein the cancer is breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg or 1.5 mg / kg, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 21-day cycle, and on day 1 and day 8 of each cycle.

24. The method according to any one of claims 1-21, wherein the cancer is breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg or 1.5 mg / kg, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 28-day cycle, and on days 1, 8 and 15 of each cycle.

25. The method according to any one of claims 1-21, wherein the cancer is breast cancer, the cancer is advanced cancer, recurrent or metastatic cancer, and the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg or 1.5 mg / kg.

26. The method according to any one of claims 1-21, wherein the cancer is breast cancer, the cancer is advanced cancer, recurrent or metastatic cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg or 1.5 mg / kg, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 21-day cycle, and on day 1 and day 8 of each cycle.

27. The method according to any one of claims 1-21, wherein the cancer is breast cancer, the cancer is advanced cancer, recurrent or metastatic cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg or 1.5 mg / kg, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 28-day cycle, and on days 1, 8 and 15 of each cycle.

28. The method according to any one of claims 1-21, wherein the cancer is triple-negative breast cancer, and the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg or 1.5 mg / kg.

29. The method according to any one of claims 1-21, wherein the cancer is triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg or 1.5 mg / kg, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 21-day cycle, and on day 1 and day 8 of each cycle.

30. The method according to any one of claims 1-21, wherein the cancer is triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg or 1.5 mg / kg, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 28-day cycle, and on days 1, 8 and 15 of each cycle.

31. The method according to any one of claims 1-21, wherein the cancer is triple-negative breast cancer, the cancer is advanced cancer, recurrent or metastatic cancer, and the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg or 1.5 mg / kg.

32. The method according to any one of claims 1-21, wherein the cancer is triple-negative breast cancer, the cancer is advanced cancer, recurrent or metastatic cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg or 1.5 mg / kg, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 21-day cycle, and on day 1 and day 8 of each cycle.

33. The method according to any one of claims 1-21, wherein the cancer is triple-negative breast cancer, the cancer is advanced cancer, recurrent or metastatic cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg or 1.5 mg / kg, the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 28-day cycle, and on days 1, 8 and 15 of each cycle.

34. The method according to any one of claims 1-21, wherein the cancer is esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg, wherein the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 21-day cycle, and on day 1 and day 8 of each cycle.

35. The method according to any one of claims 1-21, wherein the cancer is esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg, wherein the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 28-day cycle, and on days 1, 8 and 15 of each cycle.

36. The method according to any one of claims 1-21, wherein the cancer is esophageal cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.5 mg / kg, wherein the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 21-day cycle, and on day 1 and day 8 of each cycle.

37. The method according to any one of claims 1-21, wherein the cancer is urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg, wherein the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 21-day cycle, and on day 1 and day 8 of each cycle.

38. The method according to any one of claims 1-21, wherein the cancer is urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof is 1.25 mg / kg, wherein the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof is administered in a 28-day cycle, and on days 1, 8 and 15 of each cycle.

39. The method according to any one of claims 1-21, wherein the cancer is cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg, wherein the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 21-day cycle, and on day 1 and day 8 of each cycle.

40. The method according to any one of claims 1-21, wherein the cancer is cervical cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is 1.25 mg / kg, wherein the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 28-day cycle, and on days 1, 8 and 15 of each cycle.

41. The method according to any one of claims 1-40, wherein, The heavy chain variable region comprises the sequence shown in SEQ ID NO:7 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it, and the light chain variable region comprises the sequence shown in SEQ ID NO:8 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it.

42. The method according to any one of claims 1-41, wherein, The heavy chain variable region contains the amino acid sequence shown in SEQ ID NO:7 or SEQ ID NO:9, and the light chain variable region contains the amino acid sequence shown in SEQ ID NO:8 or SEQ ID NO:

10.

43. The method according to any one of claims 1-42, wherein the Ab comprises: 1) The amino acid sequence of the heavy chain variable region shown in SEQ ID NO:7; and the amino acid sequence of the light chain variable region shown in SEQ ID NO:8; or, 2) The amino acid sequence of the heavy chain variable region shown in SEQ ID NO:9; and the amino acid sequence of the light chain variable region shown in SEQ ID NO:

10.

44. The method according to any one of claims 1-43, wherein the Ab is an IgG antibody.

45. The method of claim 44, wherein the IgG antibody is a human IgG antibody.

46. ​​The method according to any one of claims 44-45, wherein the IgG antibody is a human IgG1 or human IgG4 antibody.

47. The method according to any one of claims 1-46, wherein the antigen-binding fragment is Fab, Fab', F(ab')2, Fv, single-chain Fv, or single-chain Fab.

48. The method according to any one of claims 1-47, wherein the CTD is a cytotoxic drug.

49. The method according to any one of claims 1-48, wherein the CTD is selected from one or more of the following: microtubule inhibitors MMAE, DM1, DM4, Tublysin, muscarinic acid, chalcogenide, eribulin and derivatives thereof; topoisomerase inhibitors SN38, eczema and derivatives thereof; DNA binders PBD, doxorubicin and derivatives thereof.

50. The method according to any one of claims 1-49, wherein m is 1.0-5.

0.

51. The method according to any one of claims 1-50, wherein m is 3.0-4.

2.

52. The method according to any one of claims 1-51, wherein m is 4.

0.

53. The method according to any one of claims 1-52, wherein the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof has a structure as shown in formula Ia and / or Ib: And / or, in, Ab is the anti-Nectin-4 antibody or its antigen-binding fragment as described in any one of claims 1-40; Ar' is selected from any of the following: substituted or unsubstituted C6-C10 arylene and substituted or unsubstituted 5-12 heteroarylene, wherein the substitution refers to the hydrogen atom on the group being replaced by one or more substituents, wherein the substituents are selected from any of the following: halogen, haloalkyl and alkoxy. L1 is -O(CH2CH2O)n- attached to the Ar' group, where n is selected from any integer from 1 to 24; L2 is the enzyme digestion fragment.

54. The method according to claim 53, wherein the halogen is F, Cl, Br or I; the haloalkyl is a C1-C6 haloalkyl; the alkoxy is a C1-C6 alkoxy; n is any integer from 1 to 10; and / or, L2 is a polypeptide fragment consisting of 2-4 amino acids or a combination thereof with a self-releasing structural fragment.

55. The method according to any one of claims 53-54, wherein the haloalkyl group is a C1-C4 haloalkyl group; the alkoxy group is a C1-C4 alkoxy group; n is any integer from 3 to 5; and / or, L2 is Val-Ala, Val-Ala-PAB, Val-Cit, Val-Cit-PAB, Phe-Lys-PAB, Ala-Ala-Ala, Gly-Gly-Phe-Gly (GGFG), or MAC glucuronide phenol.

56. The method according to any one of claims 53-55, wherein the haloalkyl group is trifluoromethyl; and / or, the alkoxy group is methoxy.

57. The method according to any one of claims 53-56, wherein the L2-CTD is VcMMAE, GGFG-Dxd, or VC-seco-DUBA.

58. The method according to any one of claims 53-57, wherein when Ar' is a substituted or unsubstituted 5-12-membered heteroarylene, the heteroatom is N; or, Ar' is a substituted or unsubstituted C6-membered heteroarylene or a substituted or unsubstituted 6-membered heteroarylene.

59. The method according to any one of claims 1-58, wherein the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof has the following structure: Coupler ADC-1a: Coupler ADC-1b: Coupler ADC-2a: Coupler ADC-2b: Coupler ADC-3a: Coupler ADC-3b: Coupler ADC-4a: Coupler ADC-4b: Coupler ADC-5a: Coupler ADC-5b: Coupler ADC-6a: Coupler ADC-6b: Alternatively, the coupling ADC-7a: Coupler ADC-7b:

60. The method of claim 59, wherein the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof is as follows: And / or, in, The anti-Nectin-4 antibody is any one of the anti-Nectin-4 antibodies or antigen-binding fragments thereof according to claims 1-59, where N represents the average number of drug linkages per molecule of anti-Nectin-4 antibody, which is about 1.0 to about 5.

0.

61. The method according to any one of claims 1-60, wherein the method further comprises the following step: Immune checkpoint inhibitors were administered to the subjects.

62. The method according to any one of claims 1-61, wherein the immune checkpoint inhibitor is an antibody or an antigen-binding fragment thereof.

63. The method according to any one of claims 61-62, wherein the immune checkpoint inhibitor specifically binds to PD-1.

64. The method according to any one of claims 61-63, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or its antigen-binding fragment.

65. The method of claim 64, wherein the anti-PD-1 antibody or its antigen-binding fragment comprises: 1) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1 shown in SEQ ID NO:11, HCDR2 shown in SEQ ID NO:12, and HCDR3 shown in SEQ ID NO:13; and the light chain variable region comprises LCDR1 shown in SEQ ID NO:14, LCDR2 shown in SEQ ID NO:15, and LCDR3 shown in SEQ ID NO:16; or, 2) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region includes HCDR1 shown in SEQ ID NO:21, HCDR2 shown in SEQ ID NO:22, and HCDR3 shown in SEQ ID NO:23; and the light chain variable region includes LCDR1 shown in SEQ ID NO:24, LCDR2 shown in SEQ ID NO:25, and LCDR3 shown in SEQ ID NO:

26.

66. The method according to any one of claims 64-65, wherein the anti-PD-1 antibody or its antigen-binding fragment comprises: 1) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence shown in SEQ ID NO:17 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it, and the light chain variable region comprises the sequence shown in SEQ ID NO:18 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it; or, 2) Heavy chain variable region and light chain variable region, wherein the heavy chain variable region contains the sequence shown in SEQ ID NO:27 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with it, and the light chain variable region contains the sequence shown in SEQ ID NO:28 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with it.

67. The method according to any one of claims 64-66, wherein the anti-PD-1 antibody or its antigen-binding fragment comprises: 1) A heavy chain sequence of SEQ ID NO:19 or having at least 90%, 95%, 98%, or 99% identity with it, and a light chain sequence of SEQ ID NO:20 or having at least 90%, 95%, 98%, or 99% identity with it; or, 2) SEQ ID NO:29 or a heavy chain sequence having at least 90%, 95%, 98% or 99% identity with it, and SEQ ID NO:30 or a light chain sequence having at least 90%, 95%, 98% or 99% identity with it.

68. The method according to any one of claims 64-67, wherein the anti-PD-1 antibody or its antigen-binding fragment is an IgG antibody.

69. The method of claim 68, wherein the IgG antibody is a human IgG antibody.

70. The method according to any one of claims 68-69, wherein the IgG antibody is a human IgG1 or human IgG4 antibody.

71. The method according to any one of claims 64-70, wherein the antigen-binding fragment is Fab, Fab', F(ab')2, Fv, single-chain Fv, or single-chain Fab.

72. The method according to any one of claims 64-71, wherein the anti-PD-1 antibody or its antigen-binding fragment is toripalimab or its antigen-binding fragment; or pembrolizumab or its antigen-binding fragment.

73. The method according to any one of claims 64-72, wherein the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 21-day cycle, and on day 1 and day 8 of each cycle.

74. The method according to any one of claims 64-73, wherein the cancer is urothelial carcinoma, the dose of the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof is about 1.25 mg / kg, wherein the anti-Nectin-4 antibody-drug conjugate or a pharmaceutically acceptable salt thereof is administered in a 21-day cycle, and on day 1 and day 8 of each cycle.

75. The method according to any one of claims 64-74, wherein the cancer is cervical cancer, esophageal cancer or triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is about 1.25 mg / kg, wherein the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 21-day cycle, and on day 1 and day 8 of each cycle.

76. The method according to any one of claims 64-75, wherein the cancer is cervical cancer, esophageal cancer or triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is about 1.5 mg / kg, wherein the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 21-day cycle, and on day 1 and day 8 of each cycle.

77. The method according to any one of claims 64-76, wherein the cancer is cervical cancer, esophageal cancer or triple-negative breast cancer, the dose of the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is about 2 mg / kg, wherein the anti-Nectin-4 antibody-drug conjugate or its pharmaceutically acceptable salt is administered in a 28-day cycle, and on day 1 and day 15 of each cycle.

78. The method according to any one of claims 64-77, wherein the anti-PD-1 antibody or its antigen-binding fragment is administered via intravenous infusion.

79. The method according to any one of claims 64-78, wherein the anti-PD-1 antibody or its antigen-binding fragment is administered in a 21-day cycle, and on day 1 of each cycle.

80. The method according to any one of claims 64-79, wherein the anti-PD-1 antibody or its antigen-binding fragment is administered in a 28-day cycle, and on day 1 and day 15 of each cycle.

81. The method according to any one of claims 64-80, wherein the dose of the anti-PD-1 antibody or its antigen-binding fragment is about 240 mg.

82. The method according to any one of claims 64-81, wherein the dose of the anti-PD-1 antibody or its antigen-binding fragment is about 3.0 mg / kg.

83. The method according to any one of claims 64-82, wherein the dose of the anti-PD-1 antibody or its antigen-binding fragment is about 240 mg, wherein the anti-PD-1 antibody or its antigen-binding fragment is administered in a cycle of 21 days, and on day 1 of each cycle.

84. The method according to any one of claims 64-83, wherein the dose of the anti-PD-1 antibody or its antigen-binding fragment is about 3.0 mg / kg, wherein the anti-PD-1 antibody or its antigen-binding fragment is administered in a cycle of 28 days, and on day 1 and day 15 of each cycle.

85. A method for preventing or treating cancer, the method comprising: To subjects in need, an anti-PD-1 antibody or its antigen-binding fragment shall be administered in cycles of 21 days or 28 days; wherein the anti-PD-1 antibody or its antigen-binding fragment comprises: 1) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1 shown in SEQ ID NO:11, HCDR2 shown in SEQ ID NO:12, and HCDR3 shown in SEQ ID NO:13; and the light chain variable region comprises LCDR1 shown in SEQ ID NO:14, LCDR2 shown in SEQ ID NO:15, and LCDR3 shown in SEQ ID NO:16; or, 2) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region includes HCDR1 shown in SEQ ID NO:21, HCDR2 shown in SEQ ID NO:22, and HCDR3 shown in SEQ ID NO:23; and the light chain variable region includes LCDR1 shown in SEQ ID NO:24, LCDR2 shown in SEQ ID NO:25, and LCDR3 shown in SEQ ID NO:26.

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