Use of antibody-drug conjugate targeting nectin-4

Abstract

Provided is the use of an antibody-drug conjugate targeting Nectin-4 in the preparation of a drug for treating tumors; also provided are a tumor treatment therapeutic regimen and a safe effective dose of the drug.

Description

Use of antibody-drug conjugates targeting nectin-4

[0001] Citation of Related Applications

[0002] This application claims priority to Chinese Patent Application No. 202410087558.1 filed on January 22, 2024, the entire contents of which are incorporated herein by reference in their entirety and for all purposes. Technical Field

[0003] The present application relates to the field of biopharmaceuticals, and more specifically, to the use and treatment of antibody-drug conjugates targeting nectin-4. Background Art

[0004] Nectin is a new type of cell adhesion molecule (CAMs) belonging to the immunoglobulin superfamily (Ig SF) that can be used independently of Ca 2+ It participates in cell-to-cell interactions and forms cell-to-cell adhesion junctions (AJs). The nectin protein family has four members, namely nectin-1, nectin-2, nectin-3 and nectin-4. Nectin1-3 is widely expressed in normal human tissues, among which nectin1-2 is common in immune organs (bone marrow, thymus, spleen and lymph nodes), and nectin-3 is mainly expressed in the testis and placenta. Unlike other nectin family members that are widely expressed in normal human tissues, nectin-4 is highly expressed in normal embryonic and fetal tissues and very low in healthy adult tissues. The abnormally high expression of nectin-4 can be detected in a variety of cancer samples, so nectin-4 is a reliable marker for a variety of cancers, especially in urothelial carcinoma, cervical cancer, breast cancer, lung cancer and pancreatic cancer.

[0005] As a member of the nectin protein family, nectin-4 is a type I transmembrane immunoglobulin-like intercellular adhesion molecule that participates in the formation of intercellular adherens junctions, mediates intercellular connections, and regulates physiological processes such as cell proliferation, differentiation, and migration. Although the precise molecular mechanisms underlying tumorigenesis and progression remain unclear, multiple studies have demonstrated that nectin-4 can induce angiogenesis, promote cancer cell proliferation and migration, and induce epithelial-mesenchymal transition (EMT), implicating it in the progression of various cancers.

[0006] Considering the expression pattern and level of Nectin-4, Nectin-4 has become an attractive target for the treatment of various tumor diseases. So far, the drug development targeting Nectin-4 mainly includes Antibody Drug Conjugate (ADC), Bicycle Toxin Conjugate (BTC), Bicyclic peptide, monoclonal antibody and Chimeric Antigen Receptor T-Cell Immunotherapy (CAR-T). Currently, the drug targeting Nectin-4 with the fastest progress is Enfortumab vedotin (product name: ), an ADC drug composed of enfortumab, a monoclonal antibody targeting nectin-4, and MMAE, a microtubule disruptor, connected by a cleavable dipeptide linker. The drug was approved for marketing by the FDA in 2019 and is mainly used to treat locally advanced or metastatic urothelial carcinoma. Summary of the Invention

[0007] In a first aspect, the present application provides a use of an antibody-drug conjugate targeting nectin-4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating tumors (including cancers), wherein the tumor is preferably a nectin-4-positive tumor, and the antibody-drug conjugate is conjugated with a drug-linker represented by Formula I and an antibody or antigen-binding fragment thereof targeting nectin-4:

[0008] In a second aspect, the present application provides a method for treating tumors, comprising administering a therapeutically effective amount of an antibody-drug conjugate or a pharmaceutically acceptable salt thereof to a subject or patient in need thereof, wherein the tumor is preferably a nectin-4-positive tumor, and the antibody-drug conjugate is conjugated with a drug-linker represented by Formula I and an antibody or antigen-binding fragment thereof that targets nectin-4:

[0009] In a third aspect, the present application provides a pharmaceutical composition comprising (i) an antibody-drug conjugate targeting nectin-4 or a pharmaceutically acceptable salt thereof and (ii) a pharmaceutically acceptable carrier, for treating tumors (including cancers), wherein the tumor is preferably a nectin-4-positive tumor, and the antibody-drug conjugate is conjugated with a drug-linker represented by Formula I and an antibody or antigen-binding fragment thereof targeting nectin-4: BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 shows a schematic structural diagram of the antibody-drug conjugate of the present application, where LND1002 represents the linker + drug molecule (Drug) portion, and the circled portion represents the amide bond connection between the linker and the antibody in the L&D. The Nectin-4 ADC shown in this figure is a site-specific antibody-drug conjugate. Each molecule consists of an anti-nectin-4 monoclonal antibody coupled to one MMAE molecule at amino acid position Q295 of each heavy chain by Kabat numbering via a linker (NH2-(CH2-CH2-O)3-CH2-C(=O)-Val-Cit-pABC). The antibody and linker are connected via a stable amide bond (isopeptide bond), and the average drug-antibody ratio (DAR) of the drug molecule to the antibody is 2.0.

[0011] FIG2 shows the best overall response assessment target lesion change rate in Example 1 of the present application.

[0012] FIG3 shows a Bayesian Optimal Interval (BOIN) design decision diagram adopted in an embodiment of the present application.

[0013] FIG4 shows a design dose escalation decision diagram used in an embodiment of the present application. DETAILED DESCRIPTION

[0014] The following specific embodiments and examples are intended to better illustrate the contents of this application, but the contents of this application are not limited to the specific embodiments and examples. Those skilled in the art may make non-essential improvements and adjustments to the embodiments based on the above invention, which still fall within the scope of protection of this application.

[0015] Definition of terms

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as understood by one of ordinary skill in the art.The abbreviations for amino acid residues are the standard three-letter and / or one-letter codes used in the art to refer to one of the 20 common L-amino acids.

[0017] Although the numerical ranges and parameter approximations shown in the broad scope of this application, the numerical values ​​shown in the specific embodiments are recorded as accurately as possible. However, any numerical value is necessarily contained in a certain error, which is caused by the standard deviation present in their respective measurements. In addition, all ranges disclosed herein should be understood to cover any and all sub-ranges contained therein. For example, a range of "1 to 10" recorded should be considered to include any and all sub-ranges between a minimum of 1 and a maximum of 10 (including endpoints); that is, all sub-ranges starting with a minimum of 1 or greater, such as 1 to 6.1, and sub-ranges terminating with a maximum of 10 or less, such as 5.5 to 10. In addition, any reference referred to as "incorporated herein" should be understood to be incorporated in its entirety.

[0018] As used herein, the term "pharmaceutical composition" refers to a combination of at least one drug and, optionally, a pharmaceutically acceptable carrier or excipient, combined to achieve a specific purpose. The type of pharmaceutically acceptable carrier is not particularly limited, and suitable buffers, stabilizers, surfactants, and the like may be added based on the state of the art in ADC pharmaceutical formulation. The type of pharmaceutically acceptable carrier used depends, among other things, on whether the composition of the present application is formulated for oral, nasal, intradermal, subcutaneous, intramuscular, or intravenous administration.

[0019] In a broad sense, "antibody" can refer to an immunoglobulin molecule that can specifically bind to a target via at least one antigen recognition site located in the variable region of the immunoglobulin molecule, and thus encompasses intact antibodies / full-length antibodies, single antibody chains, or any antigen-binding fragment of an antibody (also referred to as "antigen-binding portion"). When "antibody" and "antigen-binding fragment" appear in the same context, "antibody" can be understood as the intact body relative to the "antigen-binding fragment", and the two together correspond to the broad concept of antibody.

[0020] A "full-length / intact antibody" refers to a protein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain comprises a heavy chain variable region (abbreviated as VH) and a heavy chain constant region, which consists of three domains: CH1, CH2, and CH3. Each light chain comprises a light chain variable region (abbreviated as VL) and a light chain constant region, which consists of one domain: CL. The VH and VL regions are further subdivided into highly variable regions known as complementarity determining regions (CDRs), interspersed with more conserved regions known as framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. These variable regions of the heavy and light chains contain the binding domain that interacts with the antigen. The constant region of an antibody can mediate the binding of an immunoglobulin to the host's tissue or factors, including various cells of the immune system (such as effector cells) and the first component (C1q) of the classical complement system. Chimeric or humanized antibodies are also encompassed in antibodies according to the present application. Full-length / complete antibodies can be antibodies of any type, such as IgD, IgE, IgG, IgA or IgM (or the subclasses described above), but antibodies do not need to belong to any specific class. According to the antibody amino acid sequence of the constant domain of the heavy chain, immunoglobulins can be designated as different classes. Typically, immunoglobulins have five main classes: IgA, IgD, IgE, IgG and IgM, and several of these classes can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. The heavy chain constant domains corresponding to different immunoglobulin classes are referred to as ɑ, δ, ε, γ and μ, respectively. The subunit structure and three-dimensional structure of different classes of immunoglobulins are well known.

[0021] As used herein, the term "antigen-binding fragment" refers to an antibody fragment such as Fv, Fab, F(ab')2, or Fab', or any fragment whose half-life can be increased by chemical modification, such as the addition of a poly(alkylene) glycol, such as polyethylene glycol ("PEGylation") (PEGylated fragments referred to as Fv-PEG, scFv-PEG, Fab-PEG, F(ab')2-PEG, or Fab'-PEG) ("PEG" is polyethylene glycol), or by incorporation into liposomes, wherein the fragment has nectin-4 binding activity. Preferably, the antigen-binding fragment will be composed of or comprise a portion of the heavy chain or light chain variable region of the antibody from which it is derived, the portion of which is sufficient to retain the same binding specificity and sufficient affinity as the antibody from which it is derived. Such a functional fragment will contain a minimum of 5 amino acids, preferably 10, 15, 25, 50, or 100 consecutive amino acids of the antibody sequence from which it is derived. Examples of antigen-binding fragments include, but are not limited to: (1) a Fab fragment, which can be a monovalent fragment having a VL-CL chain and a VH-CH1 chain; (2) a F(ab')2 fragment, which can be a bivalent fragment having two Fab' fragments connected by a disulfide bridge at the hinge region (i.e., a dimer of Fab'); and (3) an Fv fragment having the VL and VH domains of a single arm of an antibody.

[0022] The complementarity determining regions (CDRs, typically CDR1, CDR2, and CDR3) are the regions in the variable region that have the greatest impact on the affinity and specificity of an antibody. There are several common definitions for VH or VL CDR sequences, including the IMGT, Chothia, and Kabat definitions. For a given antibody variable region sequence, the CDR sequences in the VH and VL sequences can be determined according to the IMGT, Chothia, or Kabat definitions. The CDR definition used in this application adopts the IMGT definition.

[0023] The term "humanized antibody" means an antibody obtained by grafting CDR sequences derived from another mammalian species, such as a mouse germline, onto human framework sequences. In order to retain binding affinity, some residues of the backbone (called FR) segment may be modified. Humanized antibodies or fragments thereof according to the present application may be prepared by techniques known to those skilled in the art.

[0024] The term "unit preparation" in this application refers to the smallest sub-package of each pharmaceutical preparation containing an appropriate amount of active compound, such as a unit preparation in a capsule refers to a capsule, a unit preparation in a tablet refers to a tablet, a unit preparation in an injection refers to an injection, and so on for other types of preparations.

[0025] The term "therapeutically effective amount" as used herein refers to an amount that brings about a therapeutic effect on a subject, for example, in a subject to which this amount is administered, the symptoms or state of the disease are alleviated, reduced, or eliminated, or the development of the symptoms or state of the disease is delayed or inhibited, compared to a subject not administered this amount.

[0026] In this application, according to the Solid Tumor Response Evaluation Criteria (RECIST) v1.1, the term "best overall response" is defined as the best overall response among all time points. When complete response (CR) / partial response (PR) does not require confirmation: a patient is evaluated as stable disease (SD) in the first cycle, partial response (PR) in the second cycle, and progressive disease (PD) in the last cycle, and his best overall response is evaluated as PR. When the best overall response is evaluated as SD, it must meet the minimum time from the baseline level specified in the protocol. If the minimum time standard is not met, even if the best overall response is evaluated as SD, it is not recognized, and the patient's best overall response will be determined based on subsequent evaluations. For example: a patient is evaluated as SD in the first cycle and PD in the second cycle, but he does not meet the shortest time requirement for SD, and his best overall response is evaluated as PD. The same patient who is lost to follow-up after being assessed as SD in the first cycle will be considered unevaluable; when complete remission (CR) / partial remission (PR) needs to be confirmed: complete or partial remission can only be confirmed if the patient meets the partial or complete remission criteria and the efficacy is reconfirmed at a subsequent time point (usually four weeks later).

[0027] As used herein, the terms "standard of care," "best practices," and "standard therapy" refer to treatments that are accepted by medical practitioners as suitable, appropriate, effective, and / or widely used for certain diseases. The standard of care for certain diseases depends on many different factors, including the biological effects of the treatment, region or location in the body, patient status (e.g., age, weight, sex, genetic risk, other disabilities, secondary conditions), toxicity, metabolism, bioaccumulation, therapeutic index, dosage, and other factors known in the art. Determining the standard of care for a disease also depends on establishing safety and effectiveness in clinical trials that are standardized by regulatory agencies such as the U.S. Food and Drug Administration, the International Committee for Harmonization, Health Canada, the European Medicines Agency, the Therapeutic Goods Administration, the Central Drug Standard Control Agency, the State Drug Administration, the Drug and Medical Device Administration, the Ministry of Food and Drug Safety, and the World Health Organization. The standard of care for a disease may include, but is not limited to, surgery, radiation, chemotherapy, targeted therapy, or immunotherapy.

[0028] The term "Nectin-4 positive tumor" in this application is understood in the conventional sense in the art, generally referring to at least a portion of tumor cells expressing Nectin-4. The degree of Nectin-4 positivity of a tumor can be qualitatively, quantitatively, or semi-quantitatively analyzed according to a variety of methods in the art. An exemplary method is to perform immunohistochemical analysis on a solid tumor sample (such as a biopsy or postoperative section), for example, using an H-score for semi-quantitative expression. The H-score can be expressed as the weighted sum of the cell staining percentages to indicate Nectin-4 expression in tumor cells: H-score = (3x the percentage of strongly stained cells) + (2x the percentage of moderately stained cells) + (1x the percentage of weakly stained cells).

[0029] In general, the present application provides the use of an antibody drug conjugate targeting Nectin-4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating tumors (including cancer), a method for treating tumors (including cancer) using an antibody drug conjugate targeting Nectin-4 or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising an antibody drug conjugate targeting Nectin-4 or a pharmaceutically acceptable salt thereof for treating tumors (including cancer). In some non-limiting examples, the antibody drug conjugate targeting Nectin-4 or a pharmaceutically acceptable salt thereof of the present application has lower free plasma MMAE and fewer treatment-related adverse events compared to treatment with PADCEV.

[0030] In a first aspect, the present application provides a use of an antibody-drug conjugate targeting nectin-4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating tumors (including cancers), wherein the tumor is preferably a nectin-4-positive tumor, and the antibody-drug conjugate is conjugated with a drug-linker represented by Formula I and an antibody or antigen-binding fragment thereof targeting nectin-4:

[0031] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain, wherein:

[0032] (i) the heavy chain comprises three CDR regions, namely, CDR1-H region, CDR2-H region and CDR3-H region, wherein the CDR1-H region, CDR2-H region and CDR3-H region have the amino acid sequences shown in SEQ ID NOs. 1, 2 and 3, respectively; and / or

[0033] (ii) The light chain comprises three CDR regions, namely CDR1-L region, CDR2-L region and CDR3-L region, and the CDR1-L region, CDR2-L region and CDR3-L region have the amino acid sequences shown in SEQ ID NO. 4, 5 and 6, respectively.

[0034] In some embodiments, the antibody is human or murine. In some embodiments, the antibody is a humanized antibody.

[0035] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO.7, and the light chain variable region is selected from an amino acid sequence shown in any one of SEQ ID NOs.8-10.

[0036] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region and a light chain constant region, wherein the heavy chain constant region has the amino acid sequence shown in SEQ ID NO.11 or SEQ ID NO.13, and the light chain constant region has the amino acid sequence shown in SEQ ID NO.12.

[0037] In some embodiments, the antibody-drug conjugate has the structure shown in Figure 1. In some embodiments, the drug-linker represented by Formula I is linked to the antibody or antigen-binding fragment thereof targeting nectin-4 via an amide bond, for example, via amino acid Q295 of the antibody heavy chain according to Kabat numbering. In some embodiments, the antibody-drug conjugate has an average drug-antibody ratio DAR of 1-8 (not limited to integers, but also decimals), preferably an integer from 1 to 8, preferably 2, 4, 6, 8, and more preferably 2.

[0038] In some embodiments, the tumor (including cancer) is selected from cervical cancer (such as cervical adenocarcinoma or cervical squamous cell carcinoma), urothelial cancer (such as bladder cancer, renal pelvis cancer, urethra cancer or ureteral cancer), and breast cancer.

[0039] In some embodiments, the tumor is an advanced tumor.

[0040] In some embodiments, the urothelial carcinoma is locally advanced or metastatic urothelial carcinoma.

[0041] In some embodiments, the tumor is one that has failed standard therapy or has failed a previous therapy.

[0042] In some embodiments, the tumor is a tumor that is intolerant to nectin-4 targeted therapy.

[0043] In some embodiments, the tumor is one that has not been previously treated with nectin-4 targeted therapy.

[0044] In some embodiments, the antibody drug conjugate or a pharmaceutically acceptable salt thereof is administered at a dose range of about 0.001 mg / kg to about 1000 mg / kg per administration. In a preferred embodiment, the antibody drug conjugate or a pharmaceutically acceptable salt thereof is administered at a dose range of about 0.01 mg / kg to about 100 mg / kg per administration. In a preferred embodiment, the antibody drug conjugate or a pharmaceutically acceptable salt thereof is administered at a dose range of about 0.02 mg / kg to about 50 mg / kg per administration.

[0045] In some embodiments, the antibody drug conjugate or a pharmaceutically acceptable salt thereof is administered in a single dose or divided doses.

[0046] In some embodiments, the antibody drug conjugate or a pharmaceutically acceptable salt thereof is administered at a dose range of about 0.03 mg / kg to about 20.0 mg / kg per administration, preferably about 1.0 mg / kg to about 10.0 mg / kg, more preferably about 2.0 mg / kg to about 8.0 mg / kg, for example, about 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2.0 mg / kg, 2.1 mg / kg, 2.2 mg / kg, 2.3 mg / kg, 2.4 mg / kg, 2.5 mg / kg, 2.6 mg / kg, 2.7 mg / kg, 2.8 mg / kg, 2.9 mg / kg, 3.0 mg / kg, 3.1 mg / kg, 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / kg, 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5.1 mg / kg, 5.2 mg / kg, 5. .1mg / kg, 2.2mg / kg, 2.3mg / kg, 2.4mg / kg, 2.5mg / kg, 2.6mg / kg, 2.7mg / kg, 2.8mg / kg, 2.9mg / kg, 3.0mg / kg, 3.1mg / kg, 3.2mg / kg, 3.3mg / kg, 3.4mg / kg, 3.5mg / kg, 3.6mg / kg, 3.7mg / kg, 3.8mg / kg, 3.9mg / kg, 4.0mg / kg, 4.5mg / kg, 5.0mg / kg, 5.5mg / kg or 6.0mg / kg, or a range formed by any two points. In some embodiments, the dose per administration ranges from about 1.8 mg / kg to about 4.5 mg / kg, about 1.8 mg / kg to about 2.5 mg / kg, about 2.5 mg / kg to about 3.0 mg / kg, about 3.0 mg / kg to about 3.5 mg / kg, about 3.5 mg / kg to about 4.0 mg / kg, or about 4.0 mg / kg to about 4.5 mg / kg.

[0047] In some embodiments, the antibody drug conjugate or a pharmaceutically acceptable salt thereof is administered at a frequency of QW (once a week), Q2W (once every 2 weeks), Q3W (once every 3 weeks), or Q4W (once every 4 weeks).

[0048] In some embodiments, the antibody drug conjugate or a pharmaceutically acceptable dosage regimen thereof is once every 3 weeks (Q3W), with 21 days as one treatment cycle.

[0049] In some embodiments, the antibody drug conjugate or a pharmaceutically acceptable dosage regimen thereof is once every four weeks (Q4W), with 28 days as one treatment cycle.

[0050] In some embodiments, the antibody drug conjugate or a pharmaceutically acceptable dosage regimen thereof is once every 2 weeks (Q2W), with 14 days or 28 days as a treatment cycle.

[0051] In some embodiments, the antibody drug conjugate or a pharmaceutically acceptable dosage regimen thereof is once a week (QW), administered for 3 consecutive weeks, and rested for one week, with 28 days as one treatment cycle.

[0052] In some embodiments, the antibody drug conjugate or a pharmaceutically acceptable dosage regimen thereof is once a week (QW), administered for 2 consecutive weeks and rested for one week, with 21 days as one treatment cycle.

[0053] In some embodiments, the antibody drug conjugate, or a pharmaceutically acceptable salt thereof, is administered for 1, 2, 3, or more treatment cycles.

[0054] In some embodiments, the medicament contains a therapeutically effective amount of an antibody drug conjugate or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 0.001 to about 1000 mg.

[0055] The administration method of the antibody drug conjugate or its pharmaceutically acceptable salt is not particularly limited. Representative administration methods can be oral administration, injection, topical administration, or in vitro administration. Accordingly, the drug is prepared using conventional excipients and processes into clinically accepted formulations, such as oral formulations, injection formulations, topical formulations, and external preparations. In some embodiments, the injection formulation is preferably a powder injection. These preparations can be prepared using preparation techniques known to those skilled in the art.

[0056] In some embodiments, based on the antibody drug conjugate, the unit preparation of the drug contains about 0.001 mg to about 1000 mg of the antibody drug conjugate or a pharmaceutically acceptable salt thereof, preferably about 1 mg to about 500 mg, or about 5 mg to about 400 mg, or about 10 mg to about 300 mg, or about 10 mg to about 250 mg, or about 10 mg to about 200 mg, or about 20 mg to about 200 mg, more preferably about 10 mg to about 160 mg, or about 20 mg to about 160 mg, or about 80 mg to about 160 mg; or about 1 20 mg to about 240 mg; or about 160 mg to about 220 mg; for example, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, more preferably about 10 mg, about 20 mg, about 40 mg, about 80 mg, about 120 mg or about 160 mg, even more preferably about 20 mg, about 40 mg, about 80 mg, about 120 mg, about 160 mg or about 240 mg, or even more preferably about 10 mg or about 40 mg.

[0057] In some embodiments, the unit preparation of the drug contains about 0.001 mg to about 1000 mg of the antibody drug conjugate or a pharmaceutically acceptable salt thereof, preferably about 90 mg to 350 mg, for example, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg. , about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 320 mg, about 333 mg about 340 mg or about 350 mg.

[0058] In a second aspect, the present application provides a method for treating tumors (including cancer), comprising administering to a subject or patient a therapeutically effective amount of an antibody-drug conjugate targeting nectin-4 or a pharmaceutically acceptable salt thereof, wherein the tumor is preferably a nectin-4-positive tumor, and the antibody-drug conjugate is conjugated to a drug-linker represented by Formula I and an antibody or antigen-binding fragment thereof targeting nectin-4:

[0059] The embodiments and technical features described in the first aspect regarding antibodies or antigen-binding fragments thereof, antibody drug conjugates, tumors, pharmaceutical dosage forms, pharmaceutical dosages, and dosing regimens are also applicable to the second aspect unless they conflict. In some embodiments, the subject or patient is a subject or patient who has failed standard treatment or a previous treatment.

[0060] In some embodiments, the subject or patient is a subject or patient who is intolerant to a nectin-4 targeted therapy.

[0061] In some embodiments, the subject or patient is a subject or patient who has not previously received a nectin-4 targeted therapy.

[0062] In some embodiments, the antibody drug conjugate or a pharmaceutically acceptable salt thereof is administered at a dose range of about 0.03 mg / kg to about 20.0 mg / kg per administration, preferably about 1.0 mg / kg to about 10.0 mg / kg, more preferably about 2.0 mg / kg to about 8.0 mg / kg, for example, about 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2.0 mg / kg, g / kg, 2.1mg / kg, 2.2mg / kg, 2.3mg / kg, 2.4mg / kg, 2.5mg / kg, 2.6mg / kg, 2.7mg / kg, 2.8mg / kg, 2.9mg / kg, 3.0mg / kg, 3.1mg / kg, 3.2mg / kg, 3.3mg / kg, 3.4mg / kg, 3.5mg / kg, 3.6mg / kg, 3.7mg / kg, 3.8mg / kg, 3.9mg / kg, 4.0mg / kg, 4.5mg / kg, 5.0mg / kg, 5.5mg / kg or 6.0mg / kg.

[0063] In some embodiments, the antibody drug conjugate or a pharmaceutically acceptable salt thereof is administered at a frequency of QW, Q2W, Q3W, or Q4W.

[0064] In some embodiments, the antibody drug conjugate or a pharmaceutically acceptable salt thereof is administered in a single dose or divided doses.

[0065] In some embodiments, the antibody drug conjugate or a pharmaceutically acceptable salt thereof is administered at a frequency of QW, and the antibody drug conjugate or a pharmaceutically acceptable salt thereof is administered at a dose range of about 0.03 mg / kg to about 20.0 mg / kg per administration, based on the weight of the antibody drug conjugate, preferably about 1.0 mg / kg to about 10.0 mg / kg, more preferably about 2.0 mg / kg to about 8.0 mg / kg, for example, about 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg. / kg, 2.0mg / kg, 2.1mg / kg, 2.2mg / kg, 2.3mg / kg, 2.4mg / kg, 2.5mg / kg, 2.6mg / kg, 2.7mg / kg, 2.8mg / kg, 2.9mg / kg, 3.0mg / kg, 3.1mg / kg, 3.2mg / kg, 3.3mg / kg, 3.4mg / kg, 3.5mg / kg, 3.6mg / kg, 3.7mg / kg, 3.8mg / kg, 3.9mg / kg, 4.0mg / kg, 4.5mg / kg, 5.0mg / kg, 5.5mg / kg or 6.0mg / kg, or a range formed by any two points. In some embodiments, the dose per administration ranges from about 1.8 mg / kg to about 4.5 mg / kg, about 1.8 mg / kg to about 2.5 mg / kg, about 2.5 mg / kg to about 3.0 mg / kg, about 3.0 mg / kg to about 3.5 mg / kg, about 3.5 mg / kg to about 4.0 mg / kg, or about 4.0 mg / kg to about 4.5 mg / kg.

[0066] In some embodiments, the antibody drug conjugate or a pharmaceutically acceptable salt thereof is administered at a frequency of Q2W, and the antibody drug conjugate or a pharmaceutically acceptable salt thereof is administered at a dose range of about 0.03 mg / kg to about 20.0 mg / kg per administration, based on the weight of the antibody drug conjugate, preferably about 1.0 mg / kg to about 10.0 mg / kg, more preferably about 2.0 mg / kg to about 8.0 mg / kg, for example, about 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg. / kg, 2.0mg / kg, 2.1mg / kg, 2.2mg / kg, 2.3mg / kg, 2.4mg / kg, 2.5mg / kg, 2.6mg / kg, 2.7mg / kg, 2.8mg / kg, 2.9mg / kg, 3.0mg / kg, 3.1mg / kg, 3.2mg / kg, 3.3mg / kg, 3.4mg / kg, 3.5mg / kg, 3.6mg / kg, 3.7mg / kg, 3.8mg / kg, 3.9mg / kg, 4.0mg / kg, 4.5mg / kg, 5.0mg / kg, 5.5mg / kg or 6.0mg / kg, or a range formed by any two values. In some embodiments, the dose per administration ranges from about 1.8 mg / kg to about 4.5 mg / kg, about 1.8 mg / kg to about 2.5 mg / kg, about 2.5 mg / kg to about 3.0 mg / kg, about 3.0 mg / kg to about 3.5 mg / kg, about 3.5 mg / kg to about 4.0 mg / kg, or about 4.0 mg / kg to about 4.5 mg / kg.

[0067] In some embodiments, the antibody drug conjugate or a pharmaceutically acceptable salt thereof is administered at a frequency of Q3W, and the antibody drug conjugate or a pharmaceutically acceptable salt thereof is administered at a dose range of about 0.03 mg / kg to about 20.0 mg / kg per administration, based on the weight of the antibody drug conjugate, preferably about 1.0 mg / kg to about 10.0 mg / kg, more preferably about 2.0 mg / kg to about 8.0 mg / kg, for example, about 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg. / kg, 2.0mg / kg, 2.1mg / kg, 2.2mg / kg, 2.3mg / kg, 2.4mg / kg, 2.5mg / kg, 2.6mg / kg, 2.7mg / kg, 2.8mg / kg, 2.9mg / kg, 3.0mg / kg, 3.1mg / kg, 3.2mg / kg, 3.3mg / kg, 3.4mg / kg, 3.5mg / kg, 3.6mg / kg, 3.7mg / kg, 3.8mg / kg, 3.9mg / kg, 4.0mg / kg, 4.5mg / kg, 5.0mg / kg, 5.5mg / kg or 6.0mg / kg, or a range formed by any two values. In some embodiments, the dose per administration ranges from about 1.8 mg / kg to about 4.5 mg / kg, about 1.8 mg / kg to about 2.5 mg / kg, about 2.5 mg / kg to about 3.0 mg / kg, about 3.0 mg / kg to about 3.5 mg / kg, about 3.5 mg / kg to about 4.0 mg / kg, or about 4.0 mg / kg to about 4.5 mg / kg.

[0068] In some embodiments, the antibody drug conjugate or a pharmaceutically acceptable salt thereof is administered at a frequency of Q4W, and the antibody drug conjugate or a pharmaceutically acceptable salt thereof is administered at a dose range of about 0.03 mg / kg to about 20.0 mg / kg per administration, based on the weight of the antibody drug conjugate, preferably about 1.0 mg / kg to about 10.0 mg / kg, more preferably about 2.0 mg / kg to about 8.0 mg / kg, for example, about 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg. / kg, 2.0mg / kg, 2.1mg / kg, 2.2mg / kg, 2.3mg / kg, 2.4mg / kg, 2.5mg / kg, 2.6mg / kg, 2.7mg / kg, 2.8mg / kg, 2.9mg / kg, 3.0mg / kg, 3.1mg / kg, 3.2mg / kg, 3.3mg / kg, 3.4mg / kg, 3.5mg / kg, 3.6mg / kg, 3.7mg / kg, 3.8mg / kg, 3.9mg / kg, 4.0mg / kg, 4.5mg / kg, 5.0mg / kg, 5.5mg / kg or 6.0mg / kg, or a range formed by any two points. In some embodiments, the dose per administration ranges from about 1.8 mg / kg to about 4.5 mg / kg, about 1.8 mg / kg to about 2.5 mg / kg, about 2.5 mg / kg to about 3.0 mg / kg, about 3.0 mg / kg to about 3.5 mg / kg, about 3.5 mg / kg to about 4.0 mg / kg, or about 4.0 mg / kg to about 4.5 mg / kg.

[0069] In some embodiments, the antibody drug conjugate or a pharmaceutically acceptable salt thereof is administered at a frequency of Q2W, and the antibody drug conjugate or a pharmaceutically acceptable salt thereof is administered at a dose range of about 2.0 mg / kg to 3.0 mg / kg per administration, based on the weight of the antibody drug conjugate, more preferably, about 2.4 mg / kg or about 2.7 mg / kg.

[0070] In some embodiments, the antibody drug conjugate or a pharmaceutically acceptable salt thereof is administered at a frequency of Q3W, and the antibody drug conjugate or a pharmaceutically acceptable salt thereof is administered at a dose range of about 2.0 mg / kg to 4.0 mg / kg per administration, based on the weight of the antibody drug conjugate, more preferably, about 2.4 mg / kg, 2.7 mg / kg, about 3.6 mg / kg or 4.5 mg / kg.

[0071] In some embodiments, the therapeutically effective amount of the antibody drug conjugate or a pharmaceutically acceptable salt thereof is about 1 mg to about 500 mg, preferably about 5 mg to about 400 mg, or about 10 mg to about 300 mg, or about 10 mg to about 250 mg, or about 10 mg to about 200 mg, or about 20 mg to about 200 mg, more preferably about 10 mg to about 160 mg, or about 20 mg to about 160 mg, or about 80 mg to about 160 mg; or about 120 mg to about or about 160 mg to about 220 mg; for example, about 10 mg, about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg or about 160 mg, more preferably about 10 mg, about 20 mg, about 40 mg, about 80 mg, about 120 mg or about 160 mg, even more preferably about 20 mg, about 40 mg, about 80 mg, about 120 mg, about 160 mg or about 240 mg, or even more preferably about 10 mg or about 40 mg.

[0072] In some embodiments, the therapeutically effective amount is about 90 mg to 350 mg, for example, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg g, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 320 mg, about 333 mg, about 340 mg or about 350 mg.

[0073] In some embodiments, the antibody drug conjugate or a pharmaceutically acceptable salt thereof is administered intravenously. In some embodiments, the antibody drug conjugate or a pharmaceutically acceptable salt thereof is infused intravenously for more than 60±5 minutes.

[0074] In a third aspect, the present application provides a pharmaceutical composition comprising (i) an antibody-drug conjugate targeting nectin-4 or a pharmaceutically acceptable salt thereof and (ii) a pharmaceutically acceptable carrier, for treating tumors (including cancers), wherein the tumor is preferably a nectin-4-positive tumor, and the antibody-drug conjugate is conjugated with a drug-linker represented by Formula I and an antibody or antigen-binding fragment thereof targeting nectin-4:

[0075] The embodiments and technical features described in the first and second aspects regarding antibodies or antigen-binding fragments thereof, antibody-drug conjugates, tumors, patients, drug dosage forms, drug doses, and dosing regimens are also applicable to the third aspect if there is no conflict.

[0076] In some embodiments, the pharmaceutical composition comprises (i) the antibody drug conjugate, (ii) a buffer, (iii) a stabilizer, and (iv) a surfactant. In some embodiments, the surfactant is polysorbate 20 or polysorbate 80, preferably polysorbate 20. In some embodiments, the stabilizer is sucrose or trehalose, preferably trehalose. In some embodiments, the buffer is histidine-histidine hydrochloride, succinic acid-sodium succinate or citric acid-sodium citrate, preferably histidine-histidine hydrochloride. In some specific embodiments, the pharmaceutical composition comprises: histidine-histidine hydrochloride: 5-30mM, polysorbate 20 or polysorbate 80: 0.02wt%~0.08wt%, trehalose: 4wt%~8wt%, and antibody drug conjugate: 5-50mg / ml, pH 5.0-6.5. In some specific embodiments, the pharmaceutical composition comprises: histidine-histidine hydrochloride: 10-30mM, polysorbate 20 or polysorbate 80: 0.02wt% to 0.04wt%, trehalose: 5wt% to 7wt%, and antibody drug conjugate: 10-20mg / ml, pH 5.0-6.0. In some specific embodiments, the pharmaceutical composition comprises: histidine-histidine hydrochloride: 20mM, polysorbate 20: 0.02wt%, trehalose: 5.5wt%, and antibody drug conjugate: 10mg / ml, pH 6.0. In some embodiments, the pharmaceutical composition further comprises water. In some embodiments, the pharmaceutical composition is a liquid preparation, a lyophilized preparation, or a powder injection preparation, preferably a liquid preparation or a lyophilized preparation. The embodiments and technical features described in this paragraph regarding the pharmaceutical composition also apply to the drugs described in the first aspect and the therapeutic drugs in the second aspect method.

[0077] SWY2001-Ab3-LND1002 is a non-limiting example of the antibody drug conjugate of the present application, wherein the antibody portion is the humanized antibody 3SWY2001-Ab3, the heavy chain variable region of the antibody is SWY2001-Ab3-VH (SEQ ID NO.7), the light chain variable region is SWY2001-Ab3-VL (SEQ ID NO.10), the heavy chain constant region is HC1 (SEQ ID NO.11), and the light chain constant region is LC (SEQ ID NO.12). The structure of SWY2001-Ab3-LND1002 is shown in Figure 1 of the present application and the related description. The preparation method of the antibody and antibody drug conjugate in SWY2001-Ab3-LND1002 refers to the method described in WO 2023 / 025243A1, which is incorporated herein by reference in its entirety for all purposes. The preparation method of the SWY2001-Ab3-LND1002 test formulation refers to the method described in WO2024 / 179453A1, which is incorporated herein by reference in its entirety for all purposes.

[0078] Example 1: An open, single-arm, multicenter Phase I clinical trial to evaluate the safety, tolerability, pharmacokinetic characteristics and preliminary efficacy of SWY2001-Ab3-LND1002 in patients with advanced solid tumors

[0079] 1. Drug information and experimental plan

[0080] 1.1 Drug Information

[0081] Name of the experimental drug: SWY2001-Ab3-LND1002 (recombinant humanized anti-human nectin-4 monoclonal antibody-MMAE conjugate drug for injection).

[0082] Specification: 30mg / bottle.

[0083] Dosage form: powder injection.

[0084] Storage conditions: Store at 2-8°C in the dark. Avoid light and shaking before use.

[0085] 1.2 Experimental Purpose

[0086] Main Purpose:

[0087] To evaluate the safety and tolerability of SWY2001-Ab3-LND1002 in patients with advanced solid tumors, and to determine the maximum tolerated dose (MTD) (if any) and recommended dose (RP2D) of SWY2001-Ab3-LND1002 for Phase II clinical studies.

[0088] Secondary objectives:

[0089] To evaluate the pharmacokinetic (PK) characteristics of SWY2001-Ab3-LND1002 in patients with advanced solid tumors;

[0090] Evaluate the immunogenicity of SWY2001-Ab3-LND1002 in patients with advanced solid tumors;

[0091] To preliminarily evaluate the efficacy of SWY2001-Ab3-LND1002 in the treatment of advanced solid tumors with positive Nectin-4 expression.

[0092] 1.3 Overall experimental design

[0093] Sample size: The total sample size does not exceed 429 cases;

[0094] Dose escalation phase: no more than 36 patients will be enrolled.

[0095] PK expansion phase: Select 2-3 dose groups for PK expansion, and plan to expand each dose group to 8-12 subjects (including all subjects who completed PK blood sampling before the second cycle of administration in the same dose group during the dose escalation phase).

[0096] Cohort expansion phase: Cohort A will enroll 55-97 subjects, and Cohorts B-CE will enroll 20-50 subjects in each cohort based on exploratory research purposes.

[0097] Dose escalation and PK expansion phases for urothelial carcinoma with severe renal impairment: 6-12 subjects will be enrolled in the dose escalation phase, and up to 15 subjects will be enrolled in the expansion phase (including subjects in the escalation phase).

[0098] 1.4 Primary Study Endpoints

[0099] Primary endpoints: Safety endpoints: occurrence and frequency of adverse events (AEs), serious adverse events (SAEs), dose-limiting toxicities (DLTs); MTD (if any), RP2D.

[0100] Secondary endpoints: PK indicators: Plasma concentrations and / or PK parameters of toxin-bound antibodies, total antibodies, and free toxins MMAE and MMAE derivatives after single and continuous administration of SWY2001-Ab3-LND1002, including but not limited to AUC 0- t , AUC 0-∞ 、C max 、T max , t 1 / 2 , CL, V ss , MRT, C max,ss 、C min,ss 、T max,ss , AUCss 、R ac wait;

[0101] Immunogenicity: incidence of anti-SWY2001-Ab3-LND1002 antibodies (ADA);

[0102] Efficacy endpoints: objective response rate (ORR), duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

[0103] 1.5 Experimental Design

[0104] This study is an open, single-arm, multicenter Phase I clinical study, which is divided into four phases: dose escalation, PK expansion, cohort expansion, dose escalation and PK expansion for urothelial carcinoma with severe renal insufficiency.

[0105] 1.5.1 Dose escalation phase

[0106] The starting dose of SWY2001-Ab3-LND1002 is 0.2 mg / kg, administered by intravenous drip once every 3 weeks (Q3W), with a treatment cycle of 21 days.

[0107] This study used a BOIN design (Bayesian Optimal Interval Design) with accelerated titration for dose escalation.

[0108] BOIN design phase: Six dose groups (0.2mg / kg, 0.6mg / kg, 1.2mg / kg, 1.8mg / kg, 2.7mg / kg and 3.6mg / kg) are preset, of which the 0.2mg / kg group is the accelerated titration dose group. The target toxicity rate is 0.3, and the maximum sample size of the "BOIN" design is 36. The subjects are enrolled in each group with 3 cases for treatment. The first cycle of administration (C1) is used as the observation window for DLT, and the occurrence of DLT is used to make decisions such as dose increase or decrease. As shown in Figures 3 and 4, the BOIN design uses the following optimization rules for dose increase or decrease decisions:

[0109] 1. If the estimated dose-limiting toxicity (DLT) rate at the current dose is ≤ 0.236, escalate the dose to the next higher dose level. The estimated DLT rate at the current dose is equal to the ratio of the number of subjects who experienced a DLT at the current dose level to the number of subjects treated at the current dose.

[0110] 2. If the estimated DLT rate at the current dose is > 0.359, reduce the dose to the next lower dose level.

[0111] 3. Otherwise, maintain current dose.

[0112] The specific steps for conducting a clinical trial using BOIN design are as follows:

[0113] 1. Perform accelerated titration at the accelerated titration dose cohort (0.2 mg / kg) as follows: Assign the first subject to this dose level. If the subject does not experience dose-limiting toxicity (DLT), complete the accelerated titration and enroll subsequent subjects in the 0.6 mg / kg dose cohort according to steps 2 and 3, with a total of three subjects per cohort. If the subject experiences DLT, treat two additional subjects at the current dose. Thereafter, enroll subsequent subjects in steps 2 and 3, with a total of three subjects per cohort.

[0114] 2. Assign doses to the next group of subjects according to the dose escalation rule shown in the table below. This rule is a tabular form of the above rule. When using the table below, please note the following:

[0115] Table 1: Bayesian Optimal Interval (BOIN) design dose escalation decision table

[0116] a. "Remove" means removing the current and higher doses from the trial. The removed dose is considered overly toxic and will not be used to treat any new subjects.

[0117] b. If the current dose is eliminated, the dose will be automatically reduced to the next lower level for the subject. If the lowest dose is eliminated, the trial will be terminated early to ensure subject safety. In this case, the maximum tolerated dose (MTD) cannot be determined.

[0118] c. If none of the decision criteria (i.e., dose escalation, reduction, or elimination) are met, continue to treat the next cohort of subjects using the current dose.

[0119] d. If the current dose is the lowest dose but the dose still needs to be reduced according to the regulations, new subjects will be treated at the current lowest dose. If the number of subjects experiencing DLT reaches the exclusion threshold, the trial will be terminated early to ensure subject safety.

[0120] e. If the current dose is the highest dose but the dose still needs to be increased according to the rules, the newly enrolled subjects will still be treated with the current highest dose, or the SMC will decide whether to explore a higher dose.

[0121] 3. Repeat step 2 until the set maximum sample size of 36 is reached, or terminate the trial early when the number of subjects treated at the current dose is ≥ 12 and the current decision based on the escalation rule is to maintain the current dose.

[0122] After the trial is completed, the maximum tolerated dose (MTD) will be determined based on the data of all enrolled subjects using ordinal regression. In order to better find the MTD, one or more dose groups may be added between the highest ascending dose group and the next lower dose group for DLT assessment. If necessary, the principal investigator and the sponsor will jointly discuss and decide whether to add other SWY2001-Ab3-LND1002 dose groups (such as adding one or more dose groups between the highest ascending dose group and the next lower dose group) and / or adjust the dosing frequency (such as once every two weeks, Q2W) based on the safety, tolerability, PK, immunogenicity data and efficacy information obtained.

[0123] Dose Expansion Phase

[0124] Based on the safety, tolerability, and PK data of different dose groups during the dose escalation phase, 2-3 dose groups will be selected for PK expansion. Each dose group is planned to be expanded to 8-12 subjects (including all subjects in the same dose group during the dose escalation phase who have completed PK blood sampling before the second cycle of dosing). At the same time, if the safety assessment of a dose group during the dose escalation phase is completed and the patient is tolerable, the PK expansion subjects can be enrolled in that dose group simultaneously.

[0125] 1.5.3 Queue Expansion Phase

[0126] The cohort expansion phase will be divided into three cohorts based on tumor type, namely:

[0127] Cohort A: urothelial carcinoma;

[0128] Cohort B: cervical cancer;

[0129] Cohort C: Others.

[0130] This phase adopts the recommended dose of SWY2001-Ab3-LND1002 determined in the dose escalation and PK expansion phases. Cohort A is planned to enroll 55-97 subjects, and cohort BE is planned to enroll 20-50 subjects in each cohort based on the exploratory research purpose.

[0131] Based on the results of previous studies and the sponsor's R&D strategy, the cohort may be adjusted (such as adding or removing cohorts) during the study after discussion between the sponsor and the researchers.

[0132] 1.5.4 Dose-escalation and PK expansion phase for urothelial carcinoma with severe renal impairment

[0133] The subjects enrolled in this phase are patients with urothelial carcinoma and severe renal insufficiency. Severe renal insufficiency is defined as creatinine clearance ≥15mL / min and <30mL / min, calculated based on the Cockcroft-Gault formula (i.e., creatinine clearance = {(140-age [years]) × body weight [kg] / (72 × serum creatinine [mg / dL])} × 0.85 [if female]) or 24-hour urine test. The subjects will first undergo dose escalation (using a 3+3 design), with the starting dose being the lower dose of the recommended dose of SWY2001-Ab3-LND1002 determined in the previous dose escalation and PK expansion phases. After completing the safety assessment of the DLT observation period (i.e., the first cycle of study dosing), the decision on whether to enroll the next group of subjects will be made based on the 3+3 design dose escalation rules. The 3+3 dose escalation will follow the following principles (see Figure 3 for details):

[0134] The highest escalating dose in this phase is no higher than the recommended dose of SWY2001-Ab3-LND1002 determined in the previous dose-escalation and PK expansion phases. Following the completion of the dose-escalation trial, the highest tolerated dose will be selected for the expansion phase (with a maximum enrollment of 15 patients in the dose-escalation and expansion phases) to further evaluate the safety and PK of SWY2001-Ab3-LND1002 in patients with urothelial carcinoma and severe renal insufficiency.

[0135] All subjects in this study underwent safety assessments according to the protocol after receiving the first study treatment, and PK and immunogenicity blood samples were collected after a single dose and during continuous treatment. In addition, according to the Response Evaluation Criteria in Solid Tumors v1.1, subjects underwent tumor imaging assessments every 6 weeks for the first 24 weeks after the start of study treatment, every 9 weeks after 24 weeks, and at the end of treatment or withdrawal (if no tumor imaging assessment was performed within the previous 4 weeks). All subjects received SWY2001-Ab3-LND1002 treatment continuously (Q3W) until the end of treatment criteria specified in the protocol, and then entered the follow-up period.

[0136] Throughout the study, SMC will continue to review the safety of the investigational drug and make decisions on study-related issues such as study enrollment, dose escalation, dose group adjustment, expansion initiation time, and expansion dose recommendations.

[0137] 2. Inclusion and Exclusion Criteria

[0138] 2.1 Inclusion Criteria

[0139] Subjects must meet all of the following inclusion criteria to be included in this study:

[0140] 1. Age ≥ 18 years old, regardless of gender;

[0141] 2. Patients with pathologically confirmed advanced solid tumors who have failed or are intolerant to standard treatment, have no standard treatment, or refuse standard treatment;

[0142] 3. Ability to provide preserved or fresh tumor tissue, and tumor tissue positive for Nectin-4 expression (based on immunohistochemistry (IHC) testing performed by a central laboratory). Nectin-4 expression status is not limited for patients with urothelial carcinoma, but tumor tissue must be provided;

[0143] 4. According to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, there is at least one measurable lesion confirmed by CT or MRI;

[0144] 5. Eastern Cooperative Oncology Group (ECOG) performance status score 0-1;

[0145] 6. Expected survival time ≥ 3 months;

[0146] 7. Major organ function within 7 days before treatment meets the criteria described in Table 2 below:

[0147] Table 2.

[0148] 8. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days before the first use of the trial drug. The patient and her spouse must agree to take adequate contraceptive measures from the time the informed consent is signed until 6 months after the last dose. During this period, women should not be breastfeeding and men should avoid sperm donation;

[0149] 9. Voluntarily participate in this clinical study, understand the study procedures and be able to sign the written informed consent.

[0150] 2.2 Exclusion criteria

[0151] 1. Active central nervous system metastases and / or leptomeningeal metastases. Active central nervous system metastases include those with symptoms (past or new) and those without symptoms (past or new) but requiring treatment. If the central nervous system metastases are limited to the supratentorial and / or cerebellum (i.e., no midbrain, pons, medulla oblongata, or spinal cord metastases) and have received local treatment, and the neurological symptoms can be stabilized for at least 2 weeks before the first use of the trial drug, and no hormone treatment is required or ≤10 mg / day of prednisone (or equivalent hormones) is received, then the patient can participate in the study;

[0152] 2. Patients who have received Nectin-4 ADC drug treatment containing MMAE toxin before;

[0153] 3. According to NCI-CTCAE v5.0, adverse events caused by previous anti-tumor therapy have not recovered to ≤ Grade 1 (except for alopecia; based on the investigator's judgment, some tolerable chronic Grade 2 toxicities may be excluded after consultation with the sponsor);

[0154] 4. Any serious and / or uncontrolled comorbidities that may prevent the patient from participating in the study:

[0155] (1) A history of severe cardiovascular disease within 6 months before the first use of the investigational drug, including but not limited to:

[0156] 1) Severe cardiac rhythm or conduction abnormalities, such as ventricular arrhythmias requiring clinical intervention, third-degree atrioventricular block, etc.; Fridericia-corrected QT interval > 480ms (Fridericia formula: QTcF = QT / RR) 0.33 ,

[0157] RR = 60 / heart rate);

[0158] 2) history of myocardial infarction, unstable angina, angioplasty, or coronary artery bypass surgery;

[0159] 3) New York Heart Association (NYHA) grade III or above heart failure; screening examination showed left ventricular ejection fraction (LVEF) < 50%.

[0160] (2) Other clinically significant diseases:

[0161] 1) HbA1C ≥ 8%;

[0162] 2) Patients with active keratitis and corneal ulcer;

[0163] 3) neuropathy of grade 2 or higher before the first use of the trial drug;

[0164] 4) Severe infection within 4 weeks before the first use of the study drug, including but not limited to bacteremia and severe pneumonia requiring hospitalization; active infection of CTCAE v5.0 ≥ 2 requiring systemic antibiotics, antiviral or antifungal treatment within 2 weeks before the first use of the study drug;

[0165] 5) Active HBV or HCV infection (HBV-DNA ≥ 2000 IU / mL, HCV antibody positive, and HCV RNA above the detection limit of the analytical method);

[0166] 6) History of immunodeficiency (including HIV positive test, other acquired or congenital immunodeficiency diseases) or organ transplantation;

[0167] 7) Suffering from any other malignant tumor within 5 years before the first use of the investigational drug, excluding basal cell carcinoma of the skin and carcinoma in situ of the cervix that have been radically cured by surgery.

[0168] 5. Previous treatment:

[0169] (1) Patients have received other unlisted clinical trial drugs or treatments within 4 weeks before the first use of the study drug;

[0170] (2) The time interval between the last anti-tumor treatment and the first use of the trial drug meets the following requirements: chemotherapy, radiotherapy, targeted therapy, immunotherapy and other clinical trial drugs and other anti-tumor treatments within 4 weeks before the first use of the trial drug; oral fluorouracil, small molecule targeted drugs and traditional Chinese medicine with anti-tumor indications within 2 weeks before the first use of the trial drug; palliative radiotherapy or local treatment within 2 weeks before the first use of the trial drug;

[0171] (3) Major surgery within 4 weeks before the first use of the study drug.

[0172] 6. Received strong CYP3A4 inhibitors or inducers, or P-gp inhibitors or inducers within 14 days before the first use of the trial drug;

[0173] 7. Known allergy to any component of the SWY2001-Ab3-LND1002 product (antibody-conjugated toxin, antibody, toxin MMAE, etc.), or allergy to humanized monoclonal antibody products;

[0174] According to the investigator's judgment, there are concomitant diseases (such as poorly controlled hypertension and mental illness) or any other conditions that seriously endanger the patient's safety or affect the patient's completion of this study.

[0175] 2.3 Dose escalation regimen

[0176] The starting dose of SWY2001-Ab3-LND1002 is 0.2 mg / kg, with a pre-defined maximum escalation dose of 3.6 mg / kg. If safety and tolerability remain good at the pre-defined highest dose, the investigator and sponsor will jointly decide whether to add one or more dose cohorts between the highest escalation dose and the next lower dose for dose-finding. Specific doses are shown in Table 3 below:

[0177] Table 3 Dose escalation group settings

[0178] 2.4 Experimental Results

[0179] 2.4.1 Efficacy in the Dose-Escalation Phase

[0180] Nine subjects completed at least one efficacy assessment, with the best overall response assessment results including 1 PD, 5 SD, and 3 PR. PR was observed in urothelial carcinoma at 1.2 mg / kg and 2.7 mg / kg, and in cervical cancer at 3.6 mg / kg. 3.6 mg / kg is the potential target effective dose of SWY2001-Ab3-LND1002. The results are shown in Table 4 and Figure 2.

[0181] 2.4.2 Security

[0182] No DLT events were observed in the 0.2-3.6 mg / kg dose groups. Anemia, dry eyes, and corneal epithelial lesions were the most common TRAEs (treatment-related adverse events) associated with SWY2001-Ab3-LND1002. Other common (incidence ≥ 20%) TRAEs included proteinuria, lymphopenia, hypoalbuminemia, etc.

[0183] Adverse reactions primarily occurred in all dose groups, with CTCAE (Common Criteria for Adverse Events) Grade 1 and 2, and no CTCAE Grade 4 adverse reactions occurred. One patient in the 1.8 mg / kg dose group developed a pulmonary infection (CTCAE Grade 3) that may have been related to the drug, but recovered after treatment. Dosing was discontinued due to interstitial lung disease (CTCAE Grade 3) that may have been related to the drug.

[0184] 2.4.3PK

[0185] After a single dose of SWY2001-Ab3-LND1002 in the dose range of 0.2-3.6 mg / kg, the in vivo exposure of total antibody, ADC, and MMAE generally increased with increasing dose. ADC exposure in each dose group was lower than total antibody, approximately 60-80% of total antibody; MMAE exposure was significantly lower than total antibody and ADC exposure, less than 5% of total antibody and ADC exposure.

[0186] The elimination half-lives of total antibody, ADC and MMAE are approximately 4-6 days, 4-5 days and 5-10 days, respectively; MMAE reaches its peak approximately 3-7 days after administration; no obvious drug accumulation is observed after three doses of Q3W administration.

[0187] At equivalent doses, the in vivo elimination of SWY2001-Ab3-LND1002 and MMAE was slower than that of PADCEV. The Cmax of SWY2001-Ab3-LND1002 was slightly lower than that of PADCEV, while the trough concentration and AUC21d were comparable to those of PADCEV. The exposure to MMAE was significantly lower (more than 50% lower).

[0188] Example 2: Update on the cohort and results of the Phase I clinical trial of Example 1

[0189] Example 1 presents the progress and results of the Phase I clinical trial prior to the filing of the priority application for this application. Example 2 presents additional data from the clinical trial in Example 1, with the addition of a 2.4 mg / kg Q2W dose group. Efficacy data for selected subjects are shown in Table 5. A total of eight dose groups were enrolled (including 2.4 mg / kg Q2W and 3.6 mg / kg Q3W).

[0190] In terms of effectiveness: As of November 27, 2024, the study successfully screened 183 cases, and a total of 173 subjects received drug treatment, of which 135 subjects completed at least one tumor assessment. The overall ORR was 31.9%, including 1 CR, 42 PR, 58 SD, and 34 PD; DCR: 74.8%; median PFS: 4.14 months; median DoR: 6.11 months.

[0191] The efficacy of the three dose groups in PK expansion is as follows: the ORR of the 2.4 mg / kg Q2W dose group was 31.6%, the DCR was 78.9%, and the median PFS has not yet been reached; the ORR of the 2.7 mg / kg Q3W group was 20%; the DCR was 66.7%, and the PFS was 2.76 months; the ORR of the 3.6 mg / kg Q3W group was 34.9%; the DCR was 76.7%, and the median PFS was 4.07 months.

[0192] The primary tumor types enrolled were 68 urothelial carcinoma and 58 cervical cancer patients; 53 and 47 subjects, respectively, completed at least one tumor assessment. The overall ORR for urothelial carcinoma was 37.7%, with 20 partial responses, 19 partial responses, and 14 partial responses. The ORR for urothelial carcinoma was 40% and the DCR was 70% in the 3.6 mg / kg Q3W dose group. The overall ORR for cervical cancer was 36.2%, with 1 complete response, 16 partial responses, 22 partial responses, and 8 partial responses. The ORR for cervical cancer was 38.9% and the DCR was 83.3% in the 3.6 mg / kg Q3W dose group.

[0193] Safety: SWY2001-Ab3-LND1002 demonstrated a favorable safety profile overall and in the 3.6 mg / kg dose group. Among the 173 participants, TRAEs were primarily Grade 1-2, with only 22% experiencing Grade ≥3 TRAEs and no Grade 5 TRAEs. Safety profiles across dose groups, including the 3.6 mg / kg dose group every three weeks, were similar to the overall safety profile, with predominantly Grade 1-2 TRAEs and no Grade 5 TRAEs. Common TRAEs occurring in ≥20% of patients included corneal disease, dry eye, anemia, elevated AST, and hypertriglyceridemia. Common TRAEs across dose groups, including the 3.6 mg / kg dose group every three weeks, were consistent with those in the overall population.

[0194] Corneal disease, the most common AE with a high incidence and leading to dosing suspension, was primarily Grade 1-2. It resolved after dosing suspension and symptomatic supportive treatment and did not lead to permanent discontinuation. Compared with the marketed similar drug, enfortumab vedotin, SWY2001-Ab3-LND1002 demonstrated significantly lower incidence and severity of peripheral neuropathy, skin toxicity, hyperglycemia, and hematologic toxicity (decreased neutrophil count, white blood cell count, and platelet count). The overall dose and the 3.6 mg / kg dose group were safe and well-tolerated.

[0195] PK analysis: SWY2001-Ab3-LND1002 exhibited dose-dependent increases in total antibody and ADC exposure over a dose range of 0.2-4.5 mg / kg via intravenous infusion, demonstrating a nearly linear pharmacokinetic profile. Elimination was slow, with mean half-lives of approximately 4-12 days for total antibody and 4-9 days for ADC. Plasma exposure to the free toxin MMAE was low, less than 5% of total antibody and ADC exposure, suggesting that SWY2001-Ab3-LND1002 is relatively stable in the systemic circulation. Following multiple dosing of SWY2001-Ab3-LND1002 every three weeks or every two weeks, there was minimal or no significant accumulation of total antibody, ADC, or free toxin.

[0196] Based on the aforementioned safety, efficacy, and PK characteristics, the 3.6 mg / kg Q3W dose group was safe and tolerable. SWY2001-AB3-LND1002 demonstrated superior efficacy in the treatment of urothelial carcinoma and cervical cancer, demonstrating greater potential for development in these disease areas.

[0197] Table 6. Sequence information of antibodies and their components involved in this application

Claims

1. Use of an antibody-drug conjugate targeting nectin-4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating tumors, wherein the tumor is preferably a nectin-4-positive tumor, and the antibody-drug conjugate is conjugated with a drug-linker represented by Formula I and an antibody or antigen-binding fragment thereof targeting nectin-4:

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

3. The application according to claim 1 or 2, wherein the antibody or its antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region has the amino acid sequence shown in SEQ ID NO.7, and the light chain variable region is selected from the amino acid sequences shown in any one of SEQ ID NO.8-10.

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

12.

5. The application according to any one of claims 1-4, wherein the tumor is selected from cervical cancer (such as cervical adenocarcinoma or cervical squamous cell carcinoma), urothelial carcinoma (such as bladder cancer, renal pelvic cancer, urethral cancer or ureteral cancer), breast cancer.

6. The application according to any one of claims 1-5, wherein the antibody-drug conjugate or its pharmaceutically acceptable salt is administered at a per-dose range of about 0.03 mg / kg to about 20.0 mg / kg, preferably about 1.0 mg / kg to about 10.0 mg / kg, more preferably about 2.0 mg / kg to about 8.0 mg / kg, by weight of the antibody-drug conjugate, for example: about 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2.0 mg / kg, 2.1 mg / kg, 2.2 mg / kg, 2.3 mg / kg, 2.4 mg / kg, 2.5 mg / kg, 2.6 mg / kg, 2.7 mg / kg, 2.8 mg / kg, 2.9 mg / kg, 3.0 mg / kg, 3.1 mg / kg, 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, 4.0 mg / kg, 4.5 mg / kg, 5.0 mg / kg, 5.5 mg / kg or 6.0 mg / kg.

7. The use according to any one of claims 1-6, wherein the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is administered at a frequency of once a week (QW), once every 2 weeks (Q2W), once every 3 weeks (Q3W) or once every 4 weeks (Q4W).

8. The use according to any one of claims 1-7, wherein, based on the weight of the antibody-drug conjugate, the unit dosage form of the drug contains about 1 mg - about 500 mg of the antibody-drug conjugate or a pharmaceutically acceptable salt thereof, preferably about 5 mg - about 400 mg, or about 10 mg - about 300 mg, or about 10 mg - about 250 mg, or about 10 mg - about 200 mg, or about 20 mg - about 200 mg, more preferably about 10 mg - about 160 mg, or about 20 mg - about 160 mg, or about 80 mg - about 160 mg; or about 120 mg - about 240 mg; or about 160 mg - about 220 mg; such as about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg or about 160 mg, more preferably about 10 mg, about 20 mg, about 40 mg, about 80 mg, about 120 mg or about 160 mg, still more preferably about 20 mg, about 40 mg, about 80 mg, about 120 mg, about 160 mg or about 240 mg, still more preferably about 10 mg or about 40 mg.

9. The use according to claim 8, wherein, based on the weight of the antibody-drug conjugate, the unit dosage form contains 120 mg - 300 mg of the antibody-drug conjugate or a pharmaceutically acceptable salt thereof, preferably about 120 mg, about 130 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg or about 300 mg.

10. The use according to any one of claims 1-9, wherein the drug is formulated into a clinically acceptable formulation, such as an oral formulation, an injection formulation, a topical administration formulation, a topical preparation.

11. A method for treating tumors, the method comprising administering to a subject or patient in need thereof a therapeutically effective amount of an antibody-drug conjugate targeting Nectin-4 or a pharmaceutically acceptable salt thereof, wherein the tumor is preferably a Nectin-4 positive tumor, and the antibody-drug conjugate is formed by conjugating a drug-linker represented by Formula I with an antibody targeting Nectin-4 or an antigen-binding fragment thereof:

12. The method according to claim 11, wherein the antibody or an antigen-binding fragment thereof comprises a heavy chain and a light chain, wherein, (i) the heavy chain comprises three CDR regions, namely CDR1-H region, CDR2-H region and CDR3-H region, and the CDR1-H region, CDR2-H region and CDR3-H region have the amino acid sequences shown in SEQ ID NO.1, 2 and 3 respectively; and / or (ii) The light chain comprises three CDR regions, namely CDR1-L region, CDR2-L region and CDR3-L region, and the CDR1-L region, CDR2-L region and CDR3-L region have the amino acid sequences shown in SEQ ID NO.4, 5 and 6 respectively.

13. The method according to claim 11 or 12, wherein the antibody or its antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region has the amino acid sequence shown in SEQ ID NO.7, and the light chain variable region is selected from the amino acid sequences shown in any one of SEQ ID NO.8-10.

14. The method according to any one of claims 11-13, wherein the antibody or its antigen-binding fragment comprises a heavy chain constant region and a light chain constant region, the heavy chain constant region has the amino acid sequence shown in SEQ ID NO.11 or SEQ ID NO.13, and the light chain constant region has the amino acid sequence shown in SEQ ID NO.

12.

15. The method according to any one of claims 11-14, wherein the tumor is selected from cervical cancer (such as cervical adenocarcinoma or cervical squamous cell carcinoma), urothelial carcinoma (such as bladder cancer, renal pelvic cancer, urethral cancer or ureteral cancer), breast cancer.

16. The method according to any one of claims 11-15, wherein the antibody-drug conjugate or its pharmaceutically acceptable salt is administered at a per-dose range of about 0.03 mg / kg to about 20.0 mg / kg, preferably about 1.0 mg / kg to about 10.0 mg / kg, more preferably about 2.0 mg / kg to about 8.0 mg / kg, based on the weight of the antibody-drug conjugate, for example: about 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2.0 mg / kg, 2.1 mg / kg, 2.2 mg / kg, 2.3 mg / kg, 2.4 mg / kg, 2.5 mg / kg, 2.6 mg / kg, 2.7 mg / kg, 2.8 mg / kg, 2.9 mg / kg, 3.0 mg / kg, 3.1 mg / kg, 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, 4.0 mg / kg, 4.5 mg / kg, 5.0 mg / kg, 5.5 mg / kg or 6.0 mg / kg.

17. The method according to any one of claims 11-16, wherein the antibody-drug conjugate or its pharmaceutically acceptable salt is administered at a frequency of once a week (QW), once every 2 weeks (Q2W), once every 3 weeks (Q3W) or once every 4 weeks (Q4W).

18. The method according to any one of claims 11 - 17, wherein the therapeutically effective amount of the antibody - drug conjugate or a pharmaceutically acceptable salt thereof, based on the weight of the antibody - drug conjugate, is about 1 mg - about 500 mg, preferably about 5 mg - about 400 mg, or about 10 mg - about 300 mg, or about 10 mg - about 250 mg, or about 10 mg - about 200 mg, or about 20 mg - about 200 mg, more preferably about 10 mg - about 160 mg, or about 20 mg - about 160 mg, or about 80 mg - about 160 mg; or about 120 mg - about 240 mg; or about 160 mg - about 220 mg; such as about 10 mg, about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg or about 160 mg, more preferably about 10 mg, about 20 mg, about 40 mg, about 80 mg, about 120 mg or about 160 mg, even more preferably about 20 mg, about 40 mg, about 80 mg, about 120 mg, about 160 mg or about 240 mg, even more preferably about 10 mg or about 40 mg.

19. The method according to claim 18, wherein the therapeutically effective amount is about 90 mg - 350 mg, such as: about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 320 mg, about 333 mg, about 340 mg or about 350 mg.

20. The method according to any one of claims 11 - 19, wherein the antibody - drug conjugate or a pharmaceutically acceptable salt thereof is formulated into a clinically acceptable preparation, such as an oral preparation, an injection preparation, a topical administration preparation, or a topical preparation.

21. A pharmaceutical composition comprising (i) an antibody-drug conjugate targeting nectin-4 or a pharmaceutically acceptable salt thereof and (ii) a pharmaceutically acceptable carrier, for treating tumors (including cancers), wherein the tumor is preferably a nectin-4-positive tumor, and the antibody-drug conjugate is conjugated to an antibody or antigen-binding fragment thereof targeting nectin-4 using a drug-linker represented by Formula I:

22. The pharmaceutical composition for the use according to claim 21, wherein the antibody or an antigen - binding fragment thereof comprises a heavy chain and a light chain, wherein, (i) the heavy chain comprises three CDR regions, namely CDR1 - H region, CDR2 - H region and CDR3 - H region, and the CDR1 - H region, CDR2 - H region and CDR3 - H region have the amino acid sequences shown in SEQ ID NO.1, 2 and 3 respectively; and / or (ii) The light chain comprises three CDR regions, namely CDR1-L region, CDR2-L region and CDR3-L region, and the CDR1-L region, CDR2-L region and CDR3-L region have the amino acid sequences shown in SEQ ID NO. 4, 5 and 6, respectively.

23. The pharmaceutical composition for use according to claim 21 or 22, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region has the amino acid sequence shown in SEQ ID NO. 7, and the light chain variable region is selected from the group consisting of those having the amino acid sequence shown in any one of SEQ ID NOs. 8-10.

24. The pharmaceutical composition for use according to any one of claims 21 to 23, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain constant region and a light chain constant region, the heavy chain constant region has the amino acid sequence shown in SEQ ID NO. 11 or SEQ ID NO. 13, and the light chain constant region has the amino acid sequence shown in SEQ ID NO.

12.

25. The pharmaceutical composition for use according to any one of claims 21 to 24, wherein the tumor is selected from cervical cancer (such as cervical adenocarcinoma or cervical squamous cell carcinoma), urothelial cancer (such as bladder cancer, renal pelvis cancer, urethral cancer or ureteral cancer), and breast cancer.

26. The pharmaceutical composition for use according to any one of claims 21 to 25, wherein the antibody drug conjugate or a pharmaceutically acceptable salt thereof is administered at a dose range of about 0.03 mg / kg to about 20.0 mg / kg per administration, preferably about 1.0 mg / kg to about 10.0 mg / kg, more preferably about 2.0 mg / kg to about 8.0 mg / kg, for example, about 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2.0mg / kg, 2.1mg / kg, 2.2mg / kg, 2.3mg / kg, 2.4mg / kg, 2.5mg / kg, 2.6mg / kg, 2.7mg / kg, 2.8mg / kg, 2.9mg / kg, 3.0mg / kg, 3.1mg / kg, 3 .2mg / kg, 3.3mg / kg, 3.4mg / kg, 3.5mg / kg, 3.6mg / kg, 3.7mg / kg, 3.8mg / kg, 3.9mg / kg, 4.0mg / kg, 4.5mg / kg, 5.0mg / kg, 5.5mg / kg or 6.0mg / kg.

27. The pharmaceutical composition for use according to any one of claims 21 to 26, wherein the pharmaceutical composition is administered at a frequency of once a week (QW), once every 2 weeks (Q2W), once every 3 weeks (Q3W) or once every 4 weeks (Q4W).

28. A pharmaceutical composition for the use according to any one of claims 21 - 27, wherein the unit dosage form of the pharmaceutical composition contains about 1 mg - about 500 mg of the antibody - drug conjugate or a pharmaceutically acceptable salt thereof, preferably about 5 mg - about 400 mg, or about 10 mg - about 300 mg, or about 10 mg - about 250 mg, or about 10 mg - about 200 mg, or about 20 mg - about 200 mg, more preferably about 10 mg - about 160 mg, or about 20 mg - about 160 mg, or about 80 mg - about 160 mg; or about 120 mg - about 240 mg; or about 160 mg - about 220 mg; such as about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg or about 160 mg, more preferably about 10 mg, about 20 mg, about 40 mg, about 80 mg, about 120 mg or about 160 mg, further more preferably about 20 mg, about 40 mg, about 80 mg, about 120 mg, about 160 mg or about 240 mg, further more preferably about 10 mg or about 40 mg.

29. A pharmaceutical composition for the use according to claim 28, wherein the unit dosage form contains 120 mg - 300 mg of the antibody - drug conjugate or a pharmaceutically acceptable salt thereof, preferably about 120 mg, about 130 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg or about 300 mg, based on the weight of the antibody - drug conjugate.

30. A pharmaceutical composition for the use according to any one of claims 21 - 29, wherein the pharmaceutical composition is formulated into a clinically acceptable formulation, such as an oral formulation, an injection formulation, a topical administration formulation, or a topical preparation.

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