Use of Anti-nectin-4 antibody-drug conjugate for treating tumor

Abstract

A method and medical use of an anti-Nectin-4 antibody-drug conjugate for treating tumor, and a method and medical use of an anti-Nectin-4 antibody-drug conjugate in combination with other therapeutic agents for treating tumor.

Description

Use of anti-nectin-4 antibody drug conjugate in treating tumor

[0001] The present disclosure claims priority to the following patent applications: Chinese patent application No. 202410730228.X, filed on June 6, 2024; Chinese patent application No. 202410769468.0, filed on June 14, 2024; Chinese patent application No. 202411169353.4, filed on August 24, 2024; Chinese patent application No. 202411251599.6, filed on September 8, 2024; Chinese patent application No. 202411251596.2, filed on September 8, 2024; Chinese patent application No. 202411251591.X, filed on September 8, 2024; Chinese patent application No. 202510515473.3, filed on April 23, 2024; Chinese patent application No. 202510718264.9, filed on May 30, 2024. The entire contents of the foregoing patent applications are hereby incorporated by reference into the present disclosure. TECHNICAL FIELD

[0002] The present disclosure belongs to the field of medicine, and relates to anti-nectin-4 antibody drug conjugate and methods and medical uses of the anti-nectin-4 antibody drug conjugate in combination with other therapeutic agents in treating tumor. BACKGROUND

[0003] Nectin-4 (gene name PVRL4, poliovirus receptor 4) protein is a member of the Nectin family belonging to the immunoglobulin superfamily. The Nectin family, which works together with cadherins, has a significant impact on the generation and maintenance of adherens junctions (AJs) and tight junctions (TJs), and they regulate a variety of cellular behaviors, including cell adhesion, growth, differentiation, migration, and apoptosis. Unlike Nectin 1-3, which is widely expressed in normal adult tissues, Nectin-4 protein is specifically expressed in embryos and placenta, expressed in a few normal adult tissues (including skin), and overexpressed in tumor tissues (in addition to AJs, also distributed at the top of the cell and free to plasma). Nectin-4 is specifically highly expressed in tumor tissues and is closely related to the prognosis of tumors. The potential mechanisms by which Nectin-4 promotes tumor occurrence and metastasis include: 1) promoting tumor angiogenesis: by activating the PI3K / AKT signaling pathway; 2) promoting tumor cell growth, proliferation, and migration: by activating the Ras-related C3 botulinum toxin substrate 1 (Rac1) signaling pathway; 3) promoting epithelial-mesenchymal transition (EMT): Nectin-4 can regulate intercellular adhesion, remodel the actin cytoskeleton, enhance the driving force for pseudopod extension in tumor cells, and ultimately lead to tumor development and spread.

[0004] An antibody drug conjugate (ADC) is a small molecule drug with cytotoxicity covalently linked to an antibody through a chemical linker, which uses the antibody as a carrier to target the small molecule drug to the target cell. It combines the high targeting of antibodies and the strong killing power of cytotoxic drugs on target cells, and is considered a new generation of antibody targeted therapy drugs. The antibody in the Nectin-4 ADC specifically recognizes and binds to the Nectin-4 receptor on the surface of the target cell, then enters the target cell through endocytosis, and releases the cytotoxic drug intracellularly. Finally, the cytotoxic drug destroys DNA or acts on microtubules, preventing cell division and causing cell apoptosis, thereby exerting an anti-tumor effect.

[0005] Currently, for the Nectin-4 target, there is a need in the art to develop safe and effective drug treatment regimens. SUMMARY

[0006] The present disclosure provides methods and medical uses of anti-Nectin-4 antibody drug conjugates for treating tumors.

[0007] In some embodiments, the present disclosure provides uses as shown in any of the following:

[0008] (1) use of an anti-Nectin-4 antibody drug conjugate in the preparation of a medicament for treating tumors;

[0009] (2) Use of the anti-Nectin-4 antibody drug conjugate combined with an immunotherapeutic agent in the preparation of a drug for treating tumors;

[0010] (3) Use of the anti-Nectin-4 antibody drug conjugate combined with an immunotherapeutic agent and a VEGF signaling pathway inhibitor in the preparation of a drug for treating tumors;

[0011] (4) Use of the anti-Nectin-4 antibody drug conjugate combined with an immunotherapeutic agent and a platinum drug in the preparation of a drug for treating tumors; (5) Use of the combination of the anti-Nectin-4 antibody drug conjugate and an immunotherapeutic agent in the preparation of a drug for treating tumors;

[0012] (5) Use of the combination of the anti-Nectin-4 antibody drug conjugate, an immunotherapeutic agent and a VEGF signaling pathway inhibitor in the preparation of a drug for treating tumors;

[0013] (6) Use of the anti-Nectin-4 antibody drug conjugate combined with an immunotherapeutic agent and a platinum drug in the preparation of a drug for treating tumors;

[0014] (7) The anti-Nectin-4 antibody drug conjugate for use in treating tumors;

[0015] (8) The anti-Nectin-4 antibody drug conjugate combined with an immunotherapeutic agent for use in treating tumors;

[0016] (9) The anti-Nectin-4 antibody drug conjugate combined with an immunotherapeutic agent and a VEGF signaling pathway inhibitor for use in treating tumors;

[0017] (10) Use of the anti-Nectin-4 antibody drug conjugate combined with an immunotherapeutic agent and a platinum drug in the preparation of a drug for treating tumors;

[0018] (11) The anti-Nectin-4 antibody drug conjugate for use in treating tumors, wherein the anti-Nectin-4 antibody drug conjugate is administered to a subject in combination with an immunotherapeutic agent;

[0019] (12) The immunotherapeutic agent for use in treating tumors, wherein the immunotherapeutic agent is administered to a subject in combination with an anti-Nectin-4 antibody drug conjugate;

[0020] (13) The anti-Nectin-4 antibody drug conjugate for use in treating tumors, wherein the anti-Nectin-4 antibody drug conjugate is administered to a subject in combination with an immunotherapeutic agent and a VEGF signaling pathway inhibitor;

[0021] (14) The immunotherapeutic agent for use in treating tumors, wherein the immunotherapeutic agent is administered to a subject in combination with an anti-Nectin-4 antibody drug conjugate and a VEGF signaling pathway inhibitor;

[0022] (15) a VEGF signaling pathway inhibitor, wherein the VEGF signaling pathway inhibitor is administered to the subject in combination with the immunotherapeutic agent and the anti-Nectin-4 antibody drug conjugate;

[0023] (16) an anti-Nectin-4 antibody drug conjugate for use in treating a tumor, wherein the anti-Nectin-4 antibody drug conjugate is administered to the subject in combination with the immunotherapeutic agent and the platinum drug;

[0024] (17) an immunotherapeutic agent for use in treating a tumor, wherein the immunotherapeutic agent is administered to the subject in combination with the anti-Nectin-4 antibody drug conjugate and the platinum drug;

[0025] (18) a platinum drug, wherein the platinum drug is administered to the subject in combination with the immunotherapeutic agent and the anti-Nectin-4 antibody drug conjugate;

[0026] (19) an anti-Nectin-4 antibody drug conjugate for use in treating a tumor, wherein the anti-Nectin-4 antibody drug conjugate is administered to the subject;

[0027] (20) a pharmaceutical composition, a kit or an article of manufacture for use in treating a tumor, wherein the pharmaceutical composition, the kit or the article of manufacture comprises an anti-Nectin-4 antibody drug conjugate;

[0028] (21) a pharmaceutical composition, a kit or an article of manufacture for use in treating a tumor, wherein the pharmaceutical composition, the kit or the article of manufacture comprises an anti-Nectin-4 antibody drug conjugate and an immunotherapeutic agent;

[0029] (22) a pharmaceutical composition, a kit or an article of manufacture for use in treating a tumor, wherein the pharmaceutical composition, the kit or the article of manufacture comprises an anti-Nectin-4 antibody drug conjugate, an immunotherapeutic agent and a VEGF signaling pathway inhibitor;

[0030] (23) a pharmaceutical composition, a kit or an article of manufacture for use in treating a tumor, wherein the pharmaceutical composition, the kit or the article of manufacture comprises an anti-Nectin-4 antibody drug conjugate, an immunotherapeutic agent and a platinum drug;

[0031] (24) use of a pharmaceutical composition, a kit or an article of manufacture in the manufacture of a medicament for treating a tumor, wherein the pharmaceutical composition, the kit or the article of manufacture comprises an anti-Nectin-4 antibody drug conjugate;

[0032] (25) use of a pharmaceutical composition, a kit or an article of manufacture in the manufacture of a medicament for treating a tumor, wherein the pharmaceutical composition, the kit or the article of manufacture comprises an anti-Nectin-4 antibody drug conjugate and an immunotherapeutic agent;

[0033] (26) Use of a pharmaceutical composition, a kit or an article of manufacture in the preparation of a medicament for treating a tumor, wherein the pharmaceutical composition, the kit or the article of manufacture comprises an anti-Nectin-4 antibody drug conjugate, an immunotherapeutic agent and a VEGF signaling pathway inhibitor;

[0034] (27) Use of a pharmaceutical composition, a kit or an article of manufacture in the preparation of a medicament for treating a tumor, wherein the pharmaceutical composition, the kit or the article of manufacture comprises an anti-Nectin-4 antibody drug conjugate, an immunotherapeutic agent and a platinum drug.

[0035] In some embodiments, the present disclosure provides a method as shown in any one of the following:

[0036] (1) A method of treating a tumor, comprising administering to a subject in need thereof a therapeutically effective amount of an anti-Nectin-4 antibody drug conjugate;

[0037] (2) A method of treating a tumor, comprising administering to a subject in need thereof a therapeutically effective amount of an anti-Nectin-4 antibody drug conjugate and an immunotherapeutic agent;

[0038] (3) A method of treating a tumor, comprising administering to a subject in need thereof a therapeutically effective amount of an anti-Nectin-4 antibody drug conjugate, an immunotherapeutic agent and a VEGF signaling pathway inhibitor;

[0039] (4) A method of treating a tumor, comprising administering to a subject in need thereof a therapeutically effective amount of an anti-Nectin-4 antibody drug conjugate, an immunotherapeutic agent and a platinum drug.

[0040] (5) A method of treating a tumor, comprising administering to a subject in need thereof a pharmaceutical composition, a kit or an article of manufacture; wherein the pharmaceutical composition, the kit or the article of manufacture comprises an anti-Nectin-4 antibody drug conjugate.

[0041] (6) A method of treating a tumor, comprising administering to a subject in need thereof a pharmaceutical composition, a kit or an article of manufacture; wherein the pharmaceutical composition, the kit or the article of manufacture comprises an anti-Nectin-4 antibody drug conjugate and an immunotherapeutic agent.

[0042] (7) A method of treating a tumor, comprising administering to a subject in need thereof a pharmaceutical composition, a kit or an article of manufacture; wherein the pharmaceutical composition, the kit or the article of manufacture comprises an anti-Nectin-4 antibody drug conjugate and an immunotherapeutic agent and a VEGF signaling pathway inhibitor.

[0043] (8) A method of treating a tumor, comprising administering to a subject in need thereof a pharmaceutical composition, a kit or an article of manufacture; wherein the pharmaceutical composition, the kit or the article of manufacture comprises an anti-Nectin-4 antibody drug conjugate and an immunotherapeutic agent and a platinum drug.

[0044] In some embodiments, the present disclosure provides a product as shown in any one of the following:

[0045] (1) A pharmaceutical composition comprising an anti-Nectin-4 antibody drug conjugate;

[0046] (2) A kit comprising an anti-Nectin-4 antibody drug conjugate;

[0047] (3) An article of manufacture comprising an anti-Nectin-4 antibody drug conjugate;

[0048] (4) A pharmaceutical composition comprising an anti-Nectin-4 antibody drug conjugate and an immunotherapeutic agent;

[0049] (5) A kit comprising an anti-Nectin-4 antibody drug conjugate and an immunotherapeutic agent;

[0050] (6) An article of manufacture comprising an anti-Nectin-4 antibody drug conjugate and an immunotherapeutic agent;

[0051] (7) A pharmaceutical composition comprising an anti-Nectin-4 antibody drug conjugate, an immunotherapeutic agent and a VEGF signaling pathway inhibitor;

[0052] (8) A kit comprising an anti-Nectin-4 antibody drug conjugate, an immunotherapeutic agent and a VEGF signaling pathway inhibitor;

[0053] (9) An article of manufacture comprising an anti-Nectin-4 antibody drug conjugate, an immunotherapeutic agent and a platinum drug;

[0054] (10) A pharmaceutical composition comprising an anti-Nectin-4 antibody drug conjugate, an immunotherapeutic agent and a platinum drug;

[0055] (11) A kit comprising an anti-Nectin-4 antibody drug conjugate, an immunotherapeutic agent and a platinum drug;

[0056] (12) An article of manufacture comprising an anti-Nectin-4 antibody drug conjugate, an immunotherapeutic agent and a platinum drug.

[0057] In some embodiments, the kit or article of manufacture further comprises one or more containers each independently comprising an anti-Nectin-4 antibody drug conjugate. In some embodiments, the kit or article of manufacture further comprises one or more containers each independently comprising an anti-Nectin-4 antibody drug conjugate and an immunotherapeutic agent. In some embodiments, the kit or article of manufacture further comprises one or more containers each independently comprising an anti-Nectin-4 antibody drug conjugate, an immunotherapeutic agent, and a VEGF signaling pathway inhibitor. In some embodiments, the kit or article of manufacture further comprises one or more containers each independently comprising an anti-Nectin-4 antibody drug conjugate, an immunotherapeutic agent, and a platinum-based drug.

[0058] In some embodiments, the pharmaceutical composition comprises an anti-Nectin-4 antibody drug conjugate in a stand-alone packaged form. In some embodiments, the pharmaceutical composition comprises an anti-Nectin-4 antibody drug conjugate and an immunotherapeutic agent in a stand-alone packaged form. In some embodiments, the pharmaceutical composition comprises an anti-Nectin-4 antibody drug conjugate, an immunotherapeutic agent, and a VEGF signaling pathway inhibitor in a stand-alone packaged form. In some embodiments, the pharmaceutical composition comprises an anti-Nectin-4 antibody drug conjugate, an immunotherapeutic agent, and a platinum-based drug in a stand-alone packaged form.

[0059] In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor is an advanced solid tumor.

[0060] In some embodiments, the tumor is a non-small cell lung cancer. In some embodiments, the tumor is an advanced non-small cell lung cancer. In some embodiments, the tumor is a locally advanced or metastatic non-small cell lung cancer. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-small cell lung cancer.

[0061] In some embodiments, the tumor is a squamous or non-squamous non-small cell lung cancer.

[0062] In some embodiments, the tumor is a squamous non-small cell lung cancer. In some embodiments, the tumor is an advanced squamous non-small cell lung cancer. In some embodiments, the tumor is a locally advanced or metastatic squamous non-small cell lung cancer. In some embodiments, the tumor is a locally advanced unresectable or metastatic squamous non-small cell lung cancer.

[0063] In some embodiments, the tumor is non-squamous non-small cell lung cancer. In some embodiments, the tumor is advanced non-squamous non-small cell lung cancer. In some embodiments, the tumor is locally advanced or metastatic non-squamous non-small cell lung cancer. In some embodiments, the tumor is locally advanced unresectable or metastatic non-squamous non-small cell lung cancer.

[0064] In some embodiments, the tumor is driver gene positive non-small cell lung cancer. In some embodiments, the tumor is driver gene positive advanced non-small cell lung cancer. In some embodiments, the tumor is driver gene positive locally advanced or metastatic non-small cell lung cancer. In some embodiments, the tumor is driver gene positive locally advanced unresectable or metastatic non-small cell lung cancer.

[0065] In some embodiments, the tumor is EGFR mutant non-small cell lung cancer. In some embodiments, the tumor is EGFR mutant advanced non-small cell lung cancer. In some embodiments, the tumor is EGFR mutant locally advanced or metastatic non-small cell lung cancer. In some embodiments, the tumor is EGFR mutant locally advanced unresectable or metastatic non-small cell lung cancer.

[0066] In some embodiments, the tumor is driver gene positive non-squamous non-small cell lung cancer. In some embodiments, the tumor is driver gene positive advanced non-squamous non-small cell lung cancer. In some embodiments, the tumor is driver gene positive locally advanced or metastatic non-squamous non-small cell lung cancer. In some embodiments, the tumor is driver gene positive locally advanced unresectable or metastatic non-squamous non-small cell lung cancer.

[0067] In some embodiments, the tumor is EGFR mutant non-squamous non-small cell lung cancer. In some embodiments, the tumor is EGFR mutant advanced non-squamous non-small cell lung cancer. In some embodiments, the tumor is EGFR mutant locally advanced or metastatic non-squamous non-small cell lung cancer. In some embodiments, the tumor is EGFR mutant locally advanced unresectable or metastatic non-squamous non-small cell lung cancer.

[0068] In some embodiments, the tumor is an EGFR driver gene negative (also referred to as“EGFR wild type,” including driver gene negative and other driver gene positive than EGFR) non-squamous non-small cell lung cancer. In some embodiments, the tumor is an EGFR driver gene negative (EGFR wild type) advanced non-squamous non-small cell lung cancer. In some embodiments, the tumor is an EGFR driver gene negative (EGFR wild type) locally advanced or metastatic non-squamous non-small cell lung cancer. In some embodiments, the tumor is an EGFR driver gene negative (EGFR wild type) locally advanced unresectable or metastatic non-squamous non-small cell lung cancer.

[0069] In some embodiments, the tumor is a driver gene negative non-small cell lung cancer. In some embodiments, the tumor is a driver gene negative advanced non-small cell lung cancer. In some embodiments, the tumor is a driver gene negative locally advanced or metastatic non-small cell lung cancer. In some embodiments, the tumor is a driver gene negative locally advanced unresectable or metastatic non-small cell lung cancer.

[0070] In some embodiments, the tumor is a driver gene negative non-squamous non-small cell lung cancer. In some embodiments, the tumor is a driver gene negative advanced non-squamous non-small cell lung cancer. In some embodiments, the tumor is a driver gene negative locally advanced or metastatic non-squamous non-small cell lung cancer. In some embodiments, the tumor is a driver gene negative locally advanced unresectable or metastatic non-squamous non-small cell lung cancer.

[0071] In some embodiments, the tumor is an other driver gene positive (driver gene positive other than EGFR mutant) non-squamous non-small cell lung cancer. In some embodiments, the tumor is an other driver gene positive locally advanced or metastatic non-squamous non-small cell lung cancer. In some embodiments, the tumor is an other driver gene positive locally advanced unresectable or metastatic non-squamous non-small cell lung cancer.

[0072] In some embodiments, the tumor is a Nectin-4 positive non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive advanced non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive locally advanced or metastatic non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive locally advanced unresectable or metastatic non-small cell lung cancer.

[0073] In some embodiments, the tumor is a non-small cell lung cancer that is Nectin-4 negative. In some embodiments, the tumor is an advanced non-small cell lung cancer that is Nectin-4 negative. In some embodiments, the tumor is a locally advanced or metastatic non-small cell lung cancer that is Nectin-4 negative. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-small cell lung cancer that is Nectin-4 negative.

[0074] In some embodiments, the tumor is an esophageal cancer. In some embodiments, the tumor is an advanced esophageal cancer. In some embodiments, the tumor is a locally advanced or metastatic esophageal cancer. In some embodiments, the tumor is a locally advanced unresectable or metastatic esophageal cancer. In some embodiments, the tumor is an esophageal squamous cell carcinoma. In some embodiments, the tumor is an advanced esophageal squamous cell carcinoma. In some embodiments, the tumor is a locally advanced or metastatic esophageal squamous cell carcinoma. In some embodiments, the tumor is a locally advanced unresectable or metastatic esophageal squamous cell carcinoma.

[0075] In some embodiments, the subject having any one of the preceding non-small cell lung cancer or esophageal cancer has previously received an anti-tumor standard treatment selected from chemotherapy, immunotherapy, and / or targeted drug therapy, the chemotherapy comprising platinum-based chemotherapy.

[0076] In some embodiments, the subject having any one of the preceding driver gene-negative non-small cell lung cancer has previously received an anti-tumor standard treatment comprising immunotherapy and platinum-based chemotherapy. In some embodiments, the immunotherapy is a PD-1 / PD-L1 inhibitor treatment. In some embodiments, the subject has previously received ≤ 2 lines of chemotherapy (chemo). In some embodiments, the subject has previously received ≤ 2 lines of anti-tumor treatment.

[0077] In some embodiments, the subject having any one of the preceding driver gene-positive non-small cell lung cancer has previously received an anti-tumor standard treatment, if there is no approved targeted therapy drug for the driver gene, the anti-tumor standard treatment of the subject is referenced to the driver gene-negative subject. In some embodiments, the anti-tumor standard treatment comprises immunotherapy and platinum-based chemotherapy, the immunotherapy is a PD-1 / PD-L1 inhibitor treatment. In some embodiments, the subject has previously received ≤ 2 lines of chemotherapy (chemo). In some embodiments, the subject has previously received ≤ 2 lines of anti-tumor treatment.

[0078] In some embodiments, the subject having the esophageal cancer described in any one of the preceding embodiments has previously received an anti-tumor standard treatment comprising an immunotherapy and a platinum-based chemotherapy. In some embodiments, the immunotherapy is a PD-1 / PD-L1 inhibitor treatment. In some embodiments, the subject has previously received ≤ 2 lines of chemotherapy (chemo). In some embodiments, the subject has previously received ≤ 2 lines of anti-tumor treatment.

[0079] In some embodiments, the subject having the esophageal cancer described in any one of the preceding embodiments has previously received an anti-tumor standard treatment comprising an immunotherapy and a platinum-based chemotherapy. In some embodiments, the immunotherapy is a PD-1 / PD-L1 inhibitor treatment. In some embodiments, the subject has previously received ≤ 2 lines of chemotherapy (chemo). In some embodiments, the subject has previously received ≤ 2 lines of anti-tumor treatment.

[0080] In some embodiments, the subject having the non-small cell lung cancer or esophageal cancer described in any one of the preceding embodiments has previously failed or been intolerant to, has no standard treatment or has refused a standard anti-tumor treatment selected from a chemotherapy comprising a platinum-based chemotherapy, an immunotherapy, and / or a targeted drug therapy.

[0081] In some embodiments, the subject having the non-small cell lung cancer or esophageal cancer described in any one of the preceding embodiments has previously failed or been intolerant to, has no standard treatment or has refused a standard anti-tumor treatment comprising an immunotherapy and a platinum-based chemotherapy. In some embodiments, the immunotherapy is a PD-1 / PD-L1 inhibitor treatment. In some embodiments, the subject has previously received ≤ 2 lines of chemotherapy (chemo). In some embodiments, the subject has previously received ≤ 2 lines of anti-tumor treatment.

[0082] In some embodiments, the subject having the non-small cell lung cancer described in any one of the preceding embodiments has previously failed or been intolerant to, has no standard treatment or has refused a standard anti-tumor treatment, if there is no approved targeted therapy drug for the driver gene, the anti-tumor standard treatment of the subject is referenced to the subject with a driver gene-negative. In some embodiments, the anti-tumor standard treatment comprises an immunotherapy and a platinum-based chemotherapy, the immunotherapy is a PD-1 / PD-L1 inhibitor treatment. In some embodiments, the subject has previously received ≤ 2 lines of chemotherapy (chemo). In some embodiments, the subject has previously received ≤ 2 lines of anti-tumor treatment.

[0083] In some embodiments, the subject having the esophageal cancer described in any one of the preceding embodiments has failed or is intolerant to, has no standard treatment or refuses standard treatment of an anti-tumor standard treatment comprising an immunotherapy and a platinum-based chemotherapy. In some embodiments, the immunotherapy is a PD-1 / PD-L1 inhibitor treatment. In some embodiments, the subject has received ≤ 2 lines of chemotherapy (chemo) previously. In some embodiments, the subject has received ≤ 2 lines of anti-tumor treatment previously.

[0084] In some embodiments, the subject having the esophageal cancer described in any one of the preceding embodiments has failed or is intolerant to, has no standard treatment or refuses standard treatment of an anti-tumor standard treatment comprising an immunotherapy and a platinum-based chemotherapy. In some embodiments, the immunotherapy is a PD-1 / PD-L1 inhibitor treatment. In some embodiments, the subject has received ≤ 2 lines of chemotherapy (chemo) previously. In some embodiments, the subject has received ≤ 2 lines of anti-tumor treatment previously.

[0085] In some embodiments, the subject having the non-small cell lung cancer or esophageal cancer described in any one of the preceding embodiments has not been treated (has not received systemic anti-tumor treatment) previously. In some embodiments, the subject having the driver gene positive non-small cell lung cancer described in any one of the preceding embodiments has not been treated (has not received systemic anti-tumor treatment) previously and there is no approved targeted therapy drug for the driver gene.

[0086] In some embodiments, the subject having the non-small cell lung cancer described in any one of the preceding embodiments has not been treated (has not received systemic anti-tumor treatment) previously and there is a STK11 single mutation, a KEAP1 single mutation, or a STK11 / KEAP1 co-mutation.

[0087] In some embodiments, the driver gene positive includes, but is not limited to, an EGFR mutation, an ALK fusion, a ROS1 fusion, a BRAF V600E mutation, a NTRK fusion, a MET exon 14 skipping mutation, a RET fusion, a KRAS G12C mutation, a HER-2 mutation, an EGFR T790M mutation, and / or an EGFR exon 20 insertion. In some embodiments, the driver gene positive is an EGFR mutation or other driver gene positive.

[0088] In some embodiments, the tumor is a squamous non-small cell lung cancer that is driver gene negative. In some embodiments, the tumor is a locally advanced or metastatic squamous non-small cell lung cancer that is driver gene negative. In some embodiments, the tumor is a locally advanced unresectable or metastatic squamous non-small cell lung cancer that is driver gene negative. In some embodiments, the tumor is a squamous non-small cell lung cancer that is driver gene positive. In some embodiments, the tumor is a locally advanced or metastatic squamous non-small cell lung cancer that is driver gene positive. In some embodiments, the tumor is a locally advanced unresectable or metastatic squamous non-small cell lung cancer that is driver gene positive.

[0089] In some embodiments, the tumor is a non-squamous non-small cell lung cancer that is driver gene negative. In some embodiments, the tumor is a locally advanced or metastatic non-squamous non-small cell lung cancer that is driver gene negative. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-squamous non-small cell lung cancer that is driver gene negative.

[0090] In some embodiments, the tumor is a squamous or non-squamous non-small cell lung cancer that is Nectin-4 positive. In some embodiments, the tumor is a squamous non-small cell lung cancer that is Nectin-4 positive. In some embodiments, the tumor is a locally advanced or metastatic squamous non-small cell lung cancer that is Nectin-4 positive. In some embodiments, the tumor is a locally advanced unresectable or metastatic squamous non-small cell lung cancer that is Nectin-4 positive. In some embodiments, the tumor is a non-squamous non-small cell lung cancer that is Nectin-4 positive. In some embodiments, the tumor is a locally advanced or metastatic non-squamous non-small cell lung cancer that is Nectin-4 positive. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-squamous non-small cell lung cancer that is Nectin-4 positive.

[0091] In some embodiments, the tumor is a squamous or non-squamous non-small cell lung cancer that is Nectin-4 negative. In some embodiments, the tumor is a squamous non-small cell lung cancer that is Nectin-4 negative. In some embodiments, the tumor is a locally advanced or metastatic squamous non-small cell lung cancer that is Nectin-4 negative. In some embodiments, the tumor is a locally advanced unresectable or metastatic squamous non-small cell lung cancer that is Nectin-4 negative. In some embodiments, the tumor is a non-squamous non-small cell lung cancer that is Nectin-4 negative. In some embodiments, the tumor is a locally advanced or metastatic non-squamous non-small cell lung cancer that is Nectin-4 negative. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-squamous non-small cell lung cancer that is Nectin-4 negative.

[0092] In some embodiments, the tumor is a Nectin-4 positive and driver gene positive non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive and driver gene positive locally advanced or metastatic non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive and driver gene positive locally advanced unresectable or metastatic non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive and driver gene negative non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive and driver gene negative locally advanced or metastatic non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive and driver gene negative locally advanced unresectable or metastatic non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive and EGFR driver gene negative (EGFR wild type) non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive and EGFR driver gene negative locally advanced or metastatic non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive and EGFR driver gene negative locally advanced unresectable or metastatic non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 negative and driver gene positive non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 negative and driver gene positive locally advanced or metastatic non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 negative and driver gene positive locally advanced unresectable or metastatic non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 negative and driver gene negative non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 negative and driver gene negative locally advanced or metastatic non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 negative and driver gene negative locally advanced unresectable or metastatic non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 negative and EGFR driver gene negative non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 negative and EGFR driver gene negative locally advanced or metastatic non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 negative and EGFR driver gene negative locally advanced unresectable or metastatic non-small cell lung cancer.

[0093] In some embodiments, the tumor is a Nectin-4 positive and driver gene positive squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive and driver gene positive locally advanced or metastatic squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive and driver gene positive locally advanced unresectable or metastatic squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive and driver gene negative squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive and driver gene negative locally advanced or metastatic squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive and driver gene negative locally advanced unresectable or metastatic squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 negative and driver gene positive squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 negative and driver gene positive locally advanced or metastatic squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 negative and driver gene positive locally advanced unresectable or metastatic squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 negative and driver gene negative squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 negative and driver gene negative locally advanced or metastatic squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 negative and driver gene negative locally advanced unresectable or metastatic squamous non-small cell lung cancer.

[0094] In some embodiments, the tumor is a Nectin-4 positive and driver gene positive non-squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive and driver gene positive locally advanced or metastatic non-squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive and driver gene positive locally advanced unresectable or metastatic non-squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive and driver gene negative non-squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive and driver gene negative locally advanced or metastatic non-squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive and driver gene negative locally advanced unresectable or metastatic non-squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive and EGFR driver gene negative (EGFR wild type) non-squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive and EGFR driver gene negative locally advanced or metastatic non-squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive and EGFR driver gene negative locally advanced unresectable or metastatic non-squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 negative and driver gene positive non-squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 negative and driver gene positive locally advanced or metastatic non-squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 negative and driver gene positive locally advanced unresectable or metastatic non-squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 negative and driver gene negative non-squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 negative and driver gene negative locally advanced or metastatic non-squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 negative and driver gene negative locally advanced unresectable or metastatic non-squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 negative and EGFR driver gene negative non-squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 negative and EGFR driver gene negative locally advanced or metastatic non-squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 negative and EGFR driver gene negative locally advanced unresectable or metastatic non-squamous non-small cell lung cancer.

[0095] In some embodiments, the tumor is an EGFR-mutant squamous non-small cell lung cancer. In some embodiments, the tumor is an EGFR-mutant advanced squamous non-small cell lung cancer. In some embodiments, the tumor is an EGFR-mutant locally advanced or metastatic squamous non-small cell lung cancer. In some embodiments, the tumor is an EGFR-mutant locally advanced unresectable or metastatic squamous non-small cell lung cancer.

[0096] In some embodiments, the tumor is a Nectin-4 positive and EGFR mutation positive non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive and EGFR mutation positive locally advanced or metastatic non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive and EGFR mutation positive locally advanced unresectable or metastatic non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 negative and EGFR mutation positive non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 negative and EGFR mutation positive locally advanced or metastatic non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 negative and EGFR mutation positive locally advanced unresectable or metastatic non-small cell lung cancer.

[0097] In some embodiments, the tumor is a squamous non-small cell lung cancer that is Nectin-4 positive and EGFR mutation positive. In some embodiments, the tumor is a locally advanced or metastatic squamous non-small cell lung cancer that is Nectin-4 positive and EGFR mutation positive. In some embodiments, the tumor is a locally advanced unresectable or metastatic squamous non-small cell lung cancer that is Nectin-4 positive and EGFR mutation positive. In some embodiments, the tumor is a non-squamous non-small cell lung cancer that is Nectin-4 positive and EGFR mutation positive. In some embodiments, the tumor is a locally advanced or metastatic non-squamous non-small cell lung cancer that is Nectin-4 positive and EGFR mutation positive. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-squamous non-small cell lung cancer that is Nectin-4 positive and EGFR mutation positive. In some embodiments, the tumor is a squamous non-small cell lung cancer that is Nectin-4 negative and EGFR mutation positive. In some embodiments, the tumor is a locally advanced or metastatic squamous non-small cell lung cancer that is Nectin-4 negative and EGFR mutation positive. In some embodiments, the tumor is a locally advanced unresectable or metastatic squamous non-small cell lung cancer that is Nectin-4 negative and EGFR mutation positive. In some embodiments, the tumor is a non-squamous non-small cell lung cancer that is Nectin-4 negative and EGFR mutation positive. In some embodiments, the tumor is a locally advanced or metastatic non-squamous non-small cell lung cancer that is Nectin-4 negative and EGFR mutation positive. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-squamous non-small cell lung cancer that is Nectin-4 negative and EGFR mutation positive.

[0098] In some embodiments, the tumor is a non-small cell lung cancer that is positive for other driver genes (positive for driver genes other than EGFR mutation). In some embodiments, the tumor is an advanced non-small cell lung cancer that is positive for other driver genes. In some embodiments, the tumor is a locally advanced or metastatic non-small cell lung cancer that is positive for other driver genes. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-small cell lung cancer that is positive for other driver genes.

[0099] In some embodiments, the tumor is a squamous non-small cell lung cancer that is positive for other driver genes (positive for driver genes other than EGFR-mutant). In some embodiments, the tumor is a locally advanced or metastatic squamous non-small cell lung cancer that is positive for other driver genes. In some embodiments, the tumor is a locally advanced unresectable or metastatic squamous non-small cell lung cancer that is positive for other driver genes. In some embodiments, the tumor is a non-small cell lung cancer that is positive for Nectin-4 and positive for other driver genes. In some embodiments, the tumor is a locally advanced or metastatic non-small cell lung cancer that is positive for Nectin-4 and positive for other driver genes. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-small cell lung cancer that is positive for Nectin-4 and positive for other driver genes. In some embodiments, the tumor is a non-small cell lung cancer that is negative for Nectin-4 and positive for other driver genes. In some embodiments, the tumor is a locally advanced or metastatic non-small cell lung cancer that is negative for Nectin-4 and positive for other driver genes. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-small cell lung cancer that is negative for Nectin-4 and positive for other driver genes.

[0100] In some embodiments, the tumor is a squamous non-small cell lung cancer that is Nectin-4 positive and other driver gene positive. In some embodiments, the tumor is a locally advanced or metastatic squamous non-small cell lung cancer that is Nectin-4 positive and other driver gene positive. In some embodiments, the tumor is a locally advanced unresectable or metastatic squamous non-small cell lung cancer that is Nectin-4 positive and other driver gene positive. In some embodiments, the tumor is a non-squamous non-small cell lung cancer that is Nectin-4 positive and other driver gene positive. In some embodiments, the tumor is a locally advanced or metastatic non-squamous non-small cell lung cancer that is Nectin-4 positive and other driver gene positive. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-squamous non-small cell lung cancer that is Nectin-4 positive and other driver gene positive. In some embodiments, the tumor is a squamous non-small cell lung cancer that is Nectin-4 negative and other driver gene positive. In some embodiments, the tumor is a locally advanced or metastatic squamous non-small cell lung cancer that is Nectin-4 negative and other driver gene positive. In some embodiments, the tumor is a locally advanced unresectable or metastatic squamous non-small cell lung cancer that is Nectin-4 negative and other driver gene positive. In some embodiments, the tumor is a non-squamous non-small cell lung cancer that is Nectin-4 negative and other driver gene positive. In some embodiments, the tumor is a locally advanced or metastatic non-squamous non-small cell lung cancer that is Nectin-4 negative and other driver gene positive. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-squamous non-small cell lung cancer that is Nectin-4 negative and other driver gene positive.

[0101] In some embodiments, the tumor is a subject who failed or was intolerant to standard treatment, who has no standard treatment, or who refused standard treatment, the standard treatment comprising: a subject who is driver gene negative, receiving immunotherapy and platinum chemotherapy; a subject who is driver gene positive, receiving targeted therapy and platinum chemotherapy.

[0102] In some embodiments, the tumor is a non-small cell lung cancer that is driver gene negative and failed immunotherapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic non-small cell lung cancer that is driver gene negative and failed immunotherapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-small cell lung cancer that is driver gene negative and failed immunotherapy and platinum chemotherapy.

[0103] In some embodiments, the tumor is a squamous non-small cell lung cancer that is driver gene negative and failed immunotherapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic squamous non-small cell lung cancer that is driver gene negative and failed immunotherapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic squamous non-small cell lung cancer that is driver gene negative and failed immunotherapy and platinum chemotherapy. In some embodiments, the tumor is a non-squamous non-small cell lung cancer that is driver gene negative and failed immunotherapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic non-squamous non-small cell lung cancer that is driver gene negative and failed immunotherapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-squamous non-small cell lung cancer that is driver gene negative and failed immunotherapy and platinum chemotherapy.

[0104] In some embodiments, the tumor is a non-small cell lung cancer that is Nectin-4 negative and driver gene negative and failed immunotherapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic non-small cell lung cancer that is Nectin-4 negative and driver gene negative and failed immunotherapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-small cell lung cancer that is Nectin-4 negative and driver gene negative and failed immunotherapy and platinum chemotherapy. In some embodiments, the tumor is a non-small cell lung cancer that is Nectin-4 positive and driver gene negative and failed immunotherapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic non-small cell lung cancer that is Nectin-4 positive and driver gene negative and failed immunotherapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-small cell lung cancer that is Nectin-4 positive and driver gene negative and failed immunotherapy and platinum chemotherapy.

[0105] In some embodiments, the tumor is a squamous non-small cell lung cancer that is Nectin-4 negative and driver gene negative, and failed immunotherapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic squamous non-small cell lung cancer that is Nectin-4 negative and driver gene negative, and failed immunotherapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic squamous non-small cell lung cancer that is Nectin-4 negative and driver gene negative, and failed immunotherapy and platinum chemotherapy. In some embodiments, the tumor is a squamous non-small cell lung cancer that is Nectin-4 positive and driver gene negative, and failed immunotherapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic squamous non-small cell lung cancer that is Nectin-4 positive and driver gene negative, and failed immunotherapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic squamous non-small cell lung cancer that is Nectin-4 positive and driver gene negative, and failed immunotherapy and platinum chemotherapy.

[0106] In some embodiments, the tumor is a non-squamous non-small cell lung cancer that is Nectin-4 negative and driver gene negative, and failed immunotherapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic non-squamous non-small cell lung cancer that is Nectin-4 negative and driver gene negative, and failed immunotherapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-squamous non-small cell lung cancer that is Nectin-4 negative and driver gene negative, and failed immunotherapy and platinum chemotherapy. In some embodiments, the tumor is a non-squamous non-small cell lung cancer that is Nectin-4 positive and driver gene negative, and failed immunotherapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic non-squamous non-small cell lung cancer that is Nectin-4 positive and driver gene negative, and failed immunotherapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-squamous non-small cell lung cancer that is Nectin-4 positive and driver gene negative, and failed immunotherapy and platinum chemotherapy.

[0107] In some embodiments, the tumor is a non-small cell lung cancer that is driver gene positive, and failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic non-small cell lung cancer that is driver gene positive, and failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-small cell lung cancer that is driver gene positive, and failed at least one targeted drug therapy and platinum chemotherapy.

[0108] In some embodiments, the tumor is a squamous non-small cell lung cancer that is driver gene positive and failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic squamous non-small cell lung cancer that is driver gene positive and failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic squamous non-small cell lung cancer that is driver gene positive and failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a non-squamous non-small cell lung cancer that is driver gene positive and failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic non-squamous non-small cell lung cancer that is driver gene positive and failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-squamous non-small cell lung cancer that is driver gene positive and failed at least one targeted drug therapy and platinum chemotherapy.

[0109] In some embodiments, the tumor is a non-small cell lung cancer that is Nectin-4 negative and driver gene positive and failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic non-small cell lung cancer that is Nectin-4 negative and driver gene positive and failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-small cell lung cancer that is Nectin-4 negative and driver gene positive and failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a non-small cell lung cancer that is Nectin-4 positive and driver gene positive and failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic non-small cell lung cancer that is Nectin-4 positive and driver gene positive and failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-small cell lung cancer that is Nectin-4 positive and driver gene positive and failed at least one targeted drug therapy and platinum chemotherapy.

[0110] In some embodiments, the tumor is a squamous non-small cell lung cancer that is Nectin-4 negative and driver gene positive, and failed at least one targeted agent therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic squamous non-small cell lung cancer that is Nectin-4 negative and driver gene positive, and failed at least one targeted agent therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic squamous non-small cell lung cancer that is Nectin-4 negative and driver gene positive, and failed at least one targeted agent therapy and platinum chemotherapy. In some embodiments, the tumor is a squamous non-small cell lung cancer that is Nectin-4 positive and driver gene positive, and failed at least one targeted agent therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic squamous non-small cell lung cancer that is Nectin-4 positive and driver gene positive, and failed at least one targeted agent therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic squamous non-small cell lung cancer that is Nectin-4 positive and driver gene positive, and failed at least one targeted agent therapy and platinum chemotherapy.

[0111] In some embodiments, the tumor is a non-squamous non-small cell lung cancer that is Nectin-4 negative and driver gene positive, and failed at least one targeted agent therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic non-squamous non-small cell lung cancer that is Nectin-4 negative and driver gene positive, and failed at least one targeted agent therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-squamous non-small cell lung cancer that is Nectin-4 negative and driver gene positive, and failed at least one targeted agent therapy and platinum chemotherapy. In some embodiments, the tumor is a non-squamous non-small cell lung cancer that is Nectin-4 positive and driver gene positive, and failed at least one targeted agent therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic non-squamous non-small cell lung cancer that is Nectin-4 positive and driver gene positive, and failed at least one targeted agent therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-squamous non-small cell lung cancer that is Nectin-4 positive and driver gene positive, and failed at least one targeted agent therapy and platinum chemotherapy.

[0112] In some embodiments, the tumor is a non-small cell lung cancer that is EGFR mutation positive and failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic non-small cell lung cancer that is EGFR mutation positive and failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-small cell lung cancer that is EGFR mutation positive and failed at least one targeted drug therapy and platinum chemotherapy.

[0113] In some embodiments, the tumor is a squamous non-small cell lung cancer that is EGFR mutation positive and failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic squamous non-small cell lung cancer that is EGFR mutation positive and failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic squamous non-small cell lung cancer that is EGFR mutation positive and failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a non-squamous non-small cell lung cancer that is EGFR mutation positive and failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic non-squamous non-small cell lung cancer that is EGFR mutation positive and failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-squamous non-small cell lung cancer that is EGFR mutation positive and failed at least one targeted drug therapy and platinum chemotherapy.

[0114] In some embodiments, the tumor is a non-small cell lung cancer that is Nectin-4 negative and EGFR mutation positive and failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic non-small cell lung cancer that is Nectin-4 negative and EGFR mutation positive and failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-small cell lung cancer that is Nectin-4 negative and EGFR mutation positive and failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a non-small cell lung cancer that is Nectin-4 positive and EGFR mutation positive and failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic non-small cell lung cancer that is Nectin-4 positive and EGFR mutation positive and failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-small cell lung cancer that is Nectin-4 positive and EGFR mutation positive and failed at least one targeted drug therapy and platinum chemotherapy.

[0115] In some embodiments, the tumor is a squamous non-small cell lung cancer that is Nectin-4 negative and EGFR mutation positive, and has failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic squamous non-small cell lung cancer that is Nectin-4 negative and EGFR mutation positive, and has failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic squamous non-small cell lung cancer that is Nectin-4 negative and EGFR mutation positive, and has failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a squamous non-small cell lung cancer that is Nectin-4 positive and EGFR mutation positive, and has failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic squamous non-small cell lung cancer that is Nectin-4 positive and EGFR mutation positive, and has failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic squamous non-small cell lung cancer that is Nectin-4 positive and EGFR mutation positive, and has failed at least one targeted drug therapy and platinum chemotherapy.

[0116] In some embodiments, the tumor is a non-squamous non-small cell lung cancer that is Nectin-4 negative and EGFR mutation positive, and has failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic non-squamous non-small cell lung cancer that is Nectin-4 negative and EGFR mutation positive, and has failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-squamous non-small cell lung cancer that is Nectin-4 negative and EGFR mutation positive, and has failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a non-squamous non-small cell lung cancer that is Nectin-4 positive and EGFR mutation positive, and has failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic non-squamous non-small cell lung cancer that is Nectin-4 positive and EGFR mutation positive, and has failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-squamous non-small cell lung cancer that is Nectin-4 positive and EGFR mutation positive, and has failed at least one targeted drug therapy and platinum chemotherapy.

[0117] In some embodiments, the tumor is non-small cell lung cancer that is positive for other driver genes (positive for driver genes other than EGFR mutation positive), and failed at least one targeted drug therapy and platinum-based chemotherapy. In some embodiments, the tumor is locally advanced or metastatic non-small cell lung cancer that is positive for other driver genes (positive for driver genes other than EGFR mutation positive), and failed at least one targeted drug therapy and platinum-based chemotherapy. In some embodiments, the tumor is locally advanced unresectable or metastatic non-small cell lung cancer that is positive for other driver genes (positive for driver genes other than EGFR mutation positive), and failed at least one targeted drug therapy and platinum-based chemotherapy.

[0118] In some embodiments, the tumor is squamous non-small cell lung cancer that is positive for other driver genes (positive for driver genes other than EGFR mutation positive), and failed at least one targeted drug therapy and platinum-based chemotherapy. In some embodiments, the tumor is locally advanced or metastatic squamous non-small cell lung cancer that is positive for other driver genes (positive for driver genes other than EGFR mutation positive), and failed at least one targeted drug therapy and platinum-based chemotherapy. In some embodiments, the tumor is locally advanced unresectable or metastatic squamous non-small cell lung cancer that is positive for other driver genes (positive for driver genes other than EGFR mutation positive), and failed at least one targeted drug therapy and platinum-based chemotherapy. In some embodiments, the tumor is non-squamous non-small cell lung cancer that is positive for other driver genes, and failed at least one targeted drug therapy and platinum-based chemotherapy. In some embodiments, the tumor is locally advanced or metastatic non-squamous non-small cell lung cancer that is positive for other driver genes (positive for driver genes other than EGFR mutation positive), and failed at least one targeted drug therapy and platinum-based chemotherapy. In some embodiments, the tumor is locally advanced unresectable or metastatic non-squamous non-small cell lung cancer that is positive for other driver genes (positive for driver genes other than EGFR mutation positive), and failed at least one targeted drug therapy and platinum-based chemotherapy.

[0119] In some embodiments, the tumor is a non-small cell lung cancer that is Nectin-4 negative and other driver gene positive (except EGFR mutation positive), and failed at least one targeted agent therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic non-small cell lung cancer that is Nectin-4 negative and other driver gene positive (except EGFR mutation positive), and failed at least one targeted agent therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-small cell lung cancer that is Nectin-4 negative and other driver gene positive (except EGFR mutation positive), and failed at least one targeted agent therapy and platinum chemotherapy. In some embodiments, the tumor is a non-small cell lung cancer that is Nectin-4 positive and other driver gene positive (except EGFR mutation positive), and failed at least one targeted agent therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic non-small cell lung cancer that is Nectin-4 positive and other driver gene positive (except EGFR mutation positive), and failed at least one targeted agent therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-small cell lung cancer that is Nectin-4 positive and other driver gene positive (except EGFR mutation positive), and failed at least one targeted agent therapy and platinum chemotherapy.

[0120] In some embodiments, the tumor is a squamous non-small cell lung cancer that is Nectin-4 negative and other driver gene positive (except EGFR mutation positive), and has failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic squamous non-small cell lung cancer that is Nectin-4 negative and other driver gene positive (except EGFR mutation positive), and has failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic squamous non-small cell lung cancer that is Nectin-4 negative and other driver gene positive (except EGFR mutation positive), and has failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a squamous non-small cell lung cancer that is Nectin-4 positive and other driver gene positive (except EGFR mutation positive), and has failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic squamous non-small cell lung cancer that is Nectin-4 positive and other driver gene positive (except EGFR mutation positive), and has failed at least one targeted drug therapy and platinum chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic squamous non-small cell lung cancer that is Nectin-4 positive and other driver gene positive (except EGFR mutation positive), and has failed at least one targeted drug therapy and platinum chemotherapy.

[0121] In some embodiments, the tumor is a non-squamous non-small cell lung cancer that is Nectin-4 negative and other driver gene positive (except EGFR mutation positive), and failed at least one targeted drug therapy and platinum-based chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic non-squamous non-small cell lung cancer that is Nectin-4 negative and other driver gene positive (except EGFR mutation positive), and failed at least one targeted drug therapy and platinum-based chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-squamous non-small cell lung cancer that is Nectin-4 negative and other driver gene positive (except EGFR mutation positive), and failed at least one targeted drug therapy and platinum-based chemotherapy. In some embodiments, the tumor is a non-squamous non-small cell lung cancer that is Nectin-4 positive and other driver gene positive (except EGFR mutation positive), and failed at least one targeted drug therapy and platinum-based chemotherapy. In some embodiments, the tumor is a locally advanced or metastatic non-squamous non-small cell lung cancer that is Nectin-4 positive and other driver gene positive (except EGFR mutation positive), and failed at least one targeted drug therapy and platinum-based chemotherapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic non-squamous non-small cell lung cancer that is Nectin-4 positive and other driver gene positive (except EGFR mutation positive), and failed at least one targeted drug therapy and platinum-based chemotherapy.

[0122] In some embodiments, the tumor is a non-small cell lung cancer subject who failed prior standard treatment or is intolerant to standard treatment. In some embodiments, the tumor is a non-small cell lung cancer subject who received ≤ 2 lines of systemic anti-neoplastic treatment prior. In some embodiments, the tumor is a non-squamous non-small cell lung cancer subject who is driver gene negative. In some embodiments, the tumor is a non-squamous non-small cell lung cancer subject who is driver gene negative and progressed after prior platinum-containing chemotherapy and PD-(L)1 treatment. In some embodiments, the tumor is a non-squamous non-small cell lung cancer subject who has a driver gene mutation and progressed after at least 1 targeted drug therapy against the driver gene mutation and progressed after platinum-containing chemotherapy.

[0123] In some embodiments, the tumor is a subject who has not received systemic anti-neoplastic treatment for non-small cell lung cancer prior. In some embodiments, the tumor is a subject who has not received systemic anti-neoplastic treatment for locally advanced or metastatic non-small cell lung cancer prior. In some embodiments, the tumor is a subject who has not received systemic anti-neoplastic treatment for locally advanced unresectable or metastatic non-small cell lung cancer prior.

[0124] In some embodiments, the tumor is a non-small cell lung cancer and the subject is not drive gene positive. In some embodiments, the tumor is a locally advanced or metastatic non-small cell lung cancer and the subject is not drive gene positive. In some embodiments, the tumor is a non-squamous non-small cell lung cancer and the subject is not drive gene positive. In some embodiments, the tumor is a locally advanced or metastatic non-squamous non-small cell lung cancer and the subject is not drive gene positive. In some embodiments, the drive gene positive includes, but is not limited to, EGFR mutation, ALK fusion, ROS1 fusion, BRAF V600E mutation, NTRK fusion, MET 14 exon skip mutation, RET fusion, KRAS G12C mutation, HER-2 mutation, EGFR T790M mutation, and / or EGFR 20 exon insertion. In some embodiments, the drive gene positive is EGFR mutation positive or other drive gene positive.

[0125] In some embodiments, the tumor is a Nectin-4 positive, PD-L1 TPS < 50% non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive, PD-L1 TPS < 50% locally advanced or metastatic non-small cell lung cancer.

[0126] In some embodiments, the tumor is a Nectin-4 positive, PD-L1 TPS < 50% squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive, PD-L1 TPS < 50% non-squamous non-small cell lung cancer.

[0127] In some embodiments, the tumor is a Nectin-4 positive, PD-L1 TPS < 50% locally advanced or metastatic squamous non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive, PD-L1 TPS < 50% locally advanced or metastatic non-squamous non-small cell lung cancer.

[0128] In some embodiments, the tumor is a Nectin-4 positive and drive gene negative, PD-L1 TPS < 50% non-small cell lung cancer. In some embodiments, the tumor is a Nectin-4 positive and drive gene negative, PD-L1 TPS < 50% locally advanced or metastatic non-small cell lung cancer.

[0129] In some embodiments, the tumor is a squamous non-small cell lung cancer that is Nectin-4 positive and driver gene negative, PD-L1 TPS < 50%. In some embodiments, the tumor is a non-squamous non-small cell lung cancer that is Nectin-4 positive and driver gene negative, PD-L1 TPS < 50%.

[0130] In some embodiments, the tumor is a squamous non-small cell lung cancer that is Nectin-4 positive and driver gene negative, PD-L1 TPS < 50%. In some embodiments, the tumor is a non-squamous non-small cell lung cancer that is Nectin-4 positive and driver gene negative, PD-L1 TPS < 50%.

[0131] In some embodiments, the tumor is a subject who has failed a PD-1 / PD-L1 inhibitor and platinum-based chemotherapy and the number of prior treatment lines is ≤ 2 lines. In some embodiments, the tumor is a subject who has not received prior systemic anti-neoplastic treatment for locally advanced unresectable or metastatic esophageal cancer.

[0132] In some embodiments, the tumor is a Nectin-4 positive tumor. In some embodiments, the tumor is a Nectin-4 positive advanced solid tumor. In some embodiments, the tumor is a Nectin-4 positive esophageal cancer. In some embodiments, the tumor is a Nectin-4 positive locally advanced or metastatic esophageal cancer. In some embodiments, the tumor is a Nectin-4 positive esophageal squamous carcinoma. In some embodiments, the tumor is a Nectin-4 positive locally advanced or metastatic esophageal squamous carcinoma.

[0133] In the present disclosure, standard treatment, systemic anti-neoplastic treatment (including first-line treatment, second-line treatment, third-line treatment, fourth-line treatment) is a treatment regimen for non-small cell lung cancer (advanced non-small cell lung cancer) or esophageal cancer (advanced esophageal cancer) well known to those skilled in the art, for example, the treatment regimen disclosed in the regulatory department approved treatment guidelines; systemic treatment of clinical research drugs for solid tumor indications. For example, it includes but is not limited to the detailed and latest information on standard treatment regimens, systemic anti-neoplastic treatment regimens (including first-line treatment, second-line treatment, third-line treatment, fourth-line treatment) for various cancers provided in the NCCN guidelines, CSCO guidelines.

[0134] In some embodiments, the anti-Nectin-4 antibody drug conjugate provided by the present disclosure for treating non-small cell lung cancer patients who have failed standard treatment (≤2 lines of prior systemic anti-tumor therapy) can significantly improve the objective remission rate of patients' tumors and the progression-free survival time (ORR is 30.4%, DCR is 89.1%). Among them, the ORR for squamous non-small cell lung cancer patients is 25%, the DCR is 100%, and the mPFS under the 8 mg / kg dose is 6.0 months; the ORR for non-squamous non-small cell lung cancer patients is 36.7%, the DCR is 83.3%, and in particular for EGFR mutant non-squamous non-small cell lung cancer patients, under the 6 mg / kg dose, the ORR can reach 48.6% and the mPFS can reach 8.5 months, and under the 8 mg / kg dose, the ORR can reach 43.8% and the mPFS can reach 8.5 months; for EGFR wild-type (EGFR driver gene negative) non-squamous non-small cell lung cancer patients, the ORR is 25%, the DCR is 72.7%, and the mPFS under the 8 mg / kg dose is 5.7 months; for driver gene negative non-squamous non-small cell lung cancer patients, the ORR under the 8 mg / kg dose is 21.1%, the DCR is 68.4%, and the mPFS is 5.7 months; compared with other ADC drugs of the same target and other standard treatment regimens, it has a significant treatment advantage, providing a positive and effective clinical treatment regimen for non-small cell lung cancer patients who have failed treatment.

[0135] In some embodiments, the anti-Nectin-4 antibody drug conjugate provided by the present disclosure is administered as a single agent to solid tumor subjects, and 35.2% of all subjects experience ≥ grade 3 TRAE, demonstrating tolerable and controllable clinical safety.

[0136] In some embodiments, the anti-Nectin-4 antibody drug conjugate provided by the present disclosure in combination with an immunotherapeutic agent for treating non-small cell lung cancer patients who have failed standard treatment (≤2 lines of prior systemic anti-tumor therapy) can significantly improve the objective remission rate of patients' tumors. For example, under the dose level 1 (ADC-4, 6 mg / kg Q3W + anti-PD-L1 antibody, 1200 mg Q3W), the ORR is 30%, and the DCR is 80%; under the dose level 2 (ADC-4, 8 mg / kg Q3W + anti-PD-L1 antibody, 1200 mg Q3W), the ORR is 29.7%, and the DCR is 91.9%; compared with other ADC drugs of the same target and other standard treatment regimens, it has a significant treatment advantage, providing a positive and effective clinical treatment regimen for non-small cell lung cancer patients who have failed treatment.

[0137] In some embodiments, the anti-Nectin-4 ADCs of the present disclosure in combination with an immunotherapeutic agent for treating non-small cell lung cancer naive patients (no prior systemic anti-tumor therapy) can significantly improve the objective response rate of patients. For example, at the dose level of ADC-4 (8 mg / kg, Q3W) + anti-PD-L1 antibody (1200 mg, Q3W), the ORR can reach 69.4% and the DCR can reach 96.4%. Compared with other ADC drugs of the same target and other standard treatment regimens, the combination treatment has a significant therapeutic advantage and provides a positive and effective clinical treatment regimen for non-small cell lung cancer naive patients.

[0138] In some embodiments, the anti-Nectin-4 ADCs of the present disclosure in combination with an immunotherapeutic agent for treating non-small cell lung cancer naive patients (no prior systemic anti-tumor therapy) can significantly improve the objective response rate of patients. For example, at the dose level of ADC-4 (8 mg / kg, Q3W) + anti-PD-L1 antibody (1200 mg, Q3W), the ORR can reach 69.4% and the DCR can reach 96.4%. Compared with other ADC drugs of the same target and other standard treatment regimens, the combination treatment has a significant therapeutic advantage and provides a positive and effective clinical treatment regimen for non-small cell lung cancer naive patients.

[0139] In some embodiments, the anti-Nectin-4 ADCs of the present disclosure as a monotherapy for treating esophageal cancer patients who have failed standard treatment (≤2 lines of prior chemotherapy) can significantly improve the objective response rate and progression-free survival time of patients. The ORR is 20%, the DCR is 77.5%, the mPFS is 4.1 months, and the mOS is 9.1 months. Compared with other ADC drugs of the same target and other standard treatment regimens, the combination treatment has a significant therapeutic advantage and provides a positive and effective clinical treatment regimen for esophageal cancer patients who have failed standard treatment.

[0140] In some embodiments, the anti-Nectin-4 ADCs of the present disclosure in combination with an immunotherapeutic agent for treating esophageal cancer patients who have failed standard treatment (prior treatment line number ≤ 2 lines) can significantly improve the objective remission rate of patients. For example, the ORR at dose level 1 (ADC-4, 6 mg / kg Q3W + anti-PD-L1 antibody, 1200 mg Q3W) was 23.5%, and the DCR was 82.4%. The ORR at dose level 2 (ADC-4, 8 mg / kg Q3W + anti-PD-L1 antibody, 1200 mg Q3W) was 40.5%, and the DCR was 89.2%. In particular, for esophageal cancer patients who have failed standard treatment, the ORR at dose level 1 was 30%, and the DCR was 90%. The ORR at dose level 2 was 46.4%, and the DCR was 92.9%. Compared with the anti-Nectin-4 ADCs of the present disclosure as a single agent, other ADC drugs of the same target, and other standard treatment regimens, the combination therapy has a significant therapeutic advantage, providing a positive and effective clinical treatment regimen for esophageal cancer patients who have failed standard treatment.

[0141] In some embodiments, the anti-Nectin-4 ADCs of the present disclosure in combination with an immunotherapeutic agent for treating esophageal cancer patients who have failed standard treatment (prior treatment line number ≤ 2 lines) can significantly improve the objective remission rate of patients. For example, the ORR at dose level 1 (ADC-4, 6 mg / kg Q3W + anti-PD-L1 antibody, 1200 mg Q3W) was 23.5%, and the DCR was 82.4%. The ORR at dose level 2 (ADC-4, 8 mg / kg Q3W + anti-PD-L1 antibody, 1200 mg Q3W) was 40.5%, and the DCR was 89.2%. In particular, for esophageal cancer patients who have failed standard treatment, the ORR at dose level 1 was 30%, and the DCR was 90%. The ORR at dose level 2 was 46.4%, and the DCR was 92.9%. Compared with the anti-Nectin-4 ADCs of the present disclosure as a single agent, other ADC drugs of the same target, and other standard treatment regimens, the combination therapy has a significant therapeutic advantage, providing a positive and effective clinical treatment regimen for esophageal cancer patients who have failed standard treatment.

[0142] In some embodiments, the anti-Nectin-4 ADCs of the present disclosure in combination with an immunotherapeutic agent for treating esophageal cancer patients who have failed standard treatment (prior treatment line number ≤ 2 lines) can significantly improve the objective remission rate of patients. For example, the ORR at dose level 1 (ADC-4, 6 mg / kg Q3W + anti-PD-L1 antibody, 1200 mg Q3W) was 23.5%, and the DCR was 82.4%. The ORR at dose level 2 (ADC-4, 8 mg / kg Q3W + anti-PD-L1 antibody, 1200 mg Q3W) was 40.5%, and the DCR was 89.2%. In particular, for esophageal cancer patients who have failed standard treatment, the ORR at dose level 1 was 30%, and the DCR was 90%. The ORR at dose level 2 was 46.4%, and the DCR was 92.9%. Compared with the anti-Nectin-4 ADCs of the present disclosure as a single agent, other ADC drugs of the same target, and other standard treatment regimens, the combination therapy has a significant therapeutic advantage, providing a positive and effective clinical treatment regimen for esophageal cancer patients who have failed standard treatment.

[0143] < Anti-Nectin-4 ADCs >

[0144] In some embodiments, the anti-Nectin-4 antibody drug conjugate is derived from any of the antibody drug conjugates of WO2022228406A, WO2023221971A, the structure, preparation method, etc. of the immunoconjugate in the above-mentioned patents are incorporated into the present disclosure by reference.

[0145] In some embodiments, the anti-Nectin-4 antibody drug conjugate has a structure as shown in the following formula:

[0146] wherein n is 1 to 10, n is a decimal or an integer. In some embodiments, n is 1 to 8. For example, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or any decimal or integer between any two of the foregoing. In some embodiments, n is an integer or a decimal of 3 to 5, for example, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0. In some embodiments, n is 3.5 to 4.7.

[0147] In some embodiments, the anti-Nectin-4 antibody is derived from any of the anti-Nectin-4 antibodies or antigen binding fragments thereof in WO2022228406A, the antibody sequences, preparation methods, etc. in the above-mentioned patents are incorporated into the present disclosure by reference.

[0148] In some embodiments, the anti-Nectin-4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1-3, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4-6.

[0149] wherein each of the aforementioned CDR sequences is shown in Table 1 below:

[0150] Table 1. CDR sequences of anti-Nectin-4 antibodies (Kabat scheme)

[0151] In some embodiments, the anti-Nectin-4 antibody comprises any 1, or a combination of any 2, 3, 4, 5 or 6 of the aforementioned HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3.

[0152] In some embodiments, the anti-Nectin-4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1, HCDR2, and HCDR3 in the amino acid sequence set forth in SEQ ID NO: 7, and the VL comprises LCDR1, LCDR2, and LCDR3 in the amino acid sequence set forth in SEQ ID NO: 8. The CDRs described above are defined according to the Kabat, IMGT, Chothia, AbM, or Contact definition scheme. In some particular embodiments, the CDRs are defined according to the Kabat definition scheme.

[0153] In some embodiments, the anti-Nectin-4 antibody is a chimeric, humanized, fully human antibody, or an antigen binding fragment thereof.

[0154] In some embodiments, the anti-Nectin-4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises an amino acid sequence set forth in SEQ ID NO: 7 or at least 80%, 90% identical thereto, and the VL comprises an amino acid sequence set forth in SEQ ID NO: 8 or at least 80%, 90% identical thereto.

[0155] Heavy chain variable region:

[0156] Light chain variable region:

[0157] In some embodiments, the anti-Nectin-4 antibody comprises any one or both of the preceding VH, VL.

[0158] In some embodiments, the anti-Nectin-4 antibody further comprises a heavy chain constant region and / or a light chain constant region. The heavy chain constant region of the antibody can be selected from the constant region of human IgGl, IgG2, IgG3, IgG4, and variants thereof. In some embodiments, the light chain constant region can be selected from the light chain constant region of human kappa, lambda chain, or variants thereof.

[0159] In some embodiments, the anti-Nectin-4 antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 9 or at least 80%, at least 90% sequence identity thereto; and / or, a light chain comprising an amino acid sequence set forth in SEQ ID NO: 10 or at least 80%, at least 90% identity thereto.

[0160] In some embodiments, the anti-Nectin-4 antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 9, and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 10.

[0161] Heavy chain sequence of anti-Nectin-4 antibody:

[0162] Light chain sequence of anti-Nectin-4 antibody:

[0163] Note: The underlined part is the variable region sequence of antibody heavy chain or light chain, and the non-underlined part is the constant region sequence of antibody.

[0164] In the context of the present disclosure, “at least 80%, 90%” encompasses 80% and above, for example, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, and any numerical range between any two of them.

[0165] In the context of the present disclosure, “antibody” is used in the broadest sense, encompassing various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), full-length antibodies or antigen-binding fragments thereof (also known as “antigen-binding portions”) as long as they exhibit the desired antigen-binding activity. In some embodiments, the antibody is a full-length antibody or an antigen-binding fragment thereof

[0166] In some embodiments, the anti-Nectin-4 antibody drug conjugate is prepared according to Example 1.

[0167] In some embodiments, the anti-Nectin-4 antibody drug conjugate can be administered at a dose selected from the group consisting of about 0.1 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 40 mg / kg, about 0.1 mg / kg to about 30 mg / kg, about 0.1 mg / kg to about 20 mg / kg, about 1.0 mg / kg to about 20 mg / kg, about 1.0 mg / kg to about 19 mg / kg, about 1.0 mg / kg to about 18 mg / kg, about 1.0 mg / kg to about 17 mg / kg, about 1.0 mg / kg to about 16 mg / kg, about 1.0 mg / kg to about 15 mg / kg, about 1.0 mg / kg to about 14 mg / kg, about 1.0 mg / kg to about 13 mg / kg, about 1.0 mg / kg to about 12 mg / kg, about 1.0 mg / kg to about 11 mg / kg, about 1.0 mg / kg to about 10.5 mg / kg, about 1.0 mg / kg to about 10 mg / kg, about 1.0 mg / kg to about 9 mg / kg, about 2 mg / kg to about 15 mg, about 2 mg / kg to about 14 mg, about 2 mg / kg to about 13 mg / kg, about 2 mg / kg to about 12 mg / kg, about 2 mg / kg to about 11 mg / kg, about 2 mg / kg to about 10 mg / kg, about 2 mg / kg to about 9 mg / kg, about 3 mg / kg to about 15 mg, about 3 mg / kg to about 14 mg, about 3 mg / kg to about 13 mg / kg, about 3 mg / kg to about 12 mg / kg, about 3 mg / kg to about 11 mg / kg, about 3 mg / kg to about 10 mg / kg, about 3.0 mg / kg to about 9.0 mg / kg; about 4 mg / kg to about 15 mg, about 4 mg / kg to about 14 mg, about 4 mg / kg to about 13 mg / kg, about 4 mg / kg to about 12 mg / kg, about 4 mg / kg to about 11 mg / kg, about 4 mg / kg to about 10 mg / kg, about 4.0 mg / kg to about 9.0 mg / kg; about 4.5 mg / kg to about 15 mg, about 4.5 mg / kg to about 14 mg, about 4.5 mg / kg to about 13 mg / kg, about 4.5 mg / kg to about 12 mg / kg, about 4.5 mg / kg to about 11 mg / kg, about 4.5 mg / kg to about 10 mg / kg, about 4.5 mg / kg to about 9.0 mg / kg; about 5 mg / kg to about 15 mg, about 5 mg / kg to about 14 mg, about 5 mg / kg to about 13 mg / kg, about 5 mg / kg to about 12 mg / kg, about 5 mg / kg to about 11 mg / kg, about 5 mg / kg to about 10 mg / kg, about 5 mg / kg to about 9.0 mg / kg; about 6 mg / kg to about 15 mg, about 6 mg / kg to about 14 mg, about 6 mg / kg to about 13 mg / kg, about 6 mg / kg to about 12 mg / kg, about 6 mg / kg to about 11 mg / kg, about 6 mg / kg to about 10 mg / kg, about 6 mg / kg to about 9.0 mg / kg; about 7 mg / kg to about 15 mg, about 7 mg / kg to about 14 mg, about 7 mg / kg to about 13 mg / kg, about 7 mg / kg to about 12 mg / kg, about 7 mg / kg to about 11 mg / kg, about 7 mg / kg to about 10 mg / kg, about 7 mg / kg to about 9.0 mg / kg; about 8 mg / kg to about 15 mg, about 8 mg / kg to about 14 mg, about 8 mg / kg to about 13 mg / kg, about 8 mg / kg to about 12 mg / kg, about 8 mg / kg to about 11 mg / kg, about 8 mg / kg to about 10 mg / kg, about 8 mg / kg to about 9.0 mg / kg; about 9 mg / kg to about 15 mg, about 9 mg / kg to about 14 mg, about 9 mg / kg to about 13 mg / kg, about 9 mg / kg to about 12 mg / kg, about 9 mg / kg to about 11 mg / kg, about 9 mg / kg to about 10 mg / kg; about 10 mg / kg to about 15 mg, about 10 mg / kg to about 14 mg, about 10 mg / kg to about 13 mg / kg, about 10 mg / kg to about 12 mg / kg, about 10 mg / kg to about 11 mg / kg; about 11 mg / kg to about 15 mg, about 11 mg / kg to about 14 mg, about 11 mg / kg to about 13 mg / kg, about 11 mg / kg to about 12 mg / kg; about 12 mg / kg to about 15 mg, about 12 mg / kg to about 14 mg, about 12 mg / kg to about 13 mg / kg; about 13 mg / kg to about 15 mg, about 13 mg / kg to about 14 mg; about 14 mg / kg to about 15 mg; about 15 mg / kg.0 mg / kg; about 6 mg / kg to about 15 mg, about 6 mg / kg to about 14 mg, about 6 mg / kg to about 13 mg / kg, about 6 mg / kg to about 12 mg / kg, about 6 mg / kg to about 11 mg / kg, about 6 mg / kg to about 10 mg / kg, about 6.0 mg / kg to about 9.0 mg / kg, about 6.0 mg / kg to about 8.0 mg / kg, about 5.0 mg / kg to about 10 mg / kg, about 5.0 mg / kg to about 9.0 mg / kg, about 5.0 mg / kg to about 8.0 mg / kg, about 4.0 mg / kg to about 10.0 mg / kg, about 4.0 mg / kg to about 9.0 mg / kg, about 4.0 mg / kg to about 8.0 mg / kg, about 3 mg / kg to about 8 mg / kg, about 2 mg / kg to about 8 mg / kg, about 2 mg / kg to about 7 mg / kg, about 2 mg / kg to about 6 mg / kg, about 3 mg / kg to about 7 mg / kg, about 4 mg / kg to about 7 mg / kg, or any range between these point values.

[0168] In some embodiments, the anti-Nectin-4 antibody drug conjugate is administered at a dose selected from about 1.0 mg / kg, about 1.1 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2.0 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3.0 mg / kg, about 3.1 mg / kg, about 3.2 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.7 mg / kg, about 3.8 mg / kg, about 3.9 mg / kg, about 4.0 mg / kg, about 4.1 mg / kg, about 4.2 mg / kg, about 4.3 mg / kg, about 4.4 mg / kg, about 4.5 mg / kg, about 4.6 mg / kg, about 4.7 mg / kg, about 4.8 mg / kg, about 4.9 mg / kg, about 5.0 mg / kg, about 5.1 mg / kg, about 5.2 mg / kg, about 5.3 mg / kg, about 5.4 mg / kg, about 5.5 mg / kg, about 5.6 mg / kg, about 5.7 mg / kg, about 5.8 mg / kg, about 5.9 mg / kg, about 6.0 mg / kg, about 6.1 mg / kg, about 6.2 mg / kg, about 6.3 mg / kg, about 6.4 mg / kg, about 6.5 mg / kg, about 6.6 mg / kg, about 6.7 mg / kg, about 6.8 mg / kg, about 6.9 mg / kg, about 7.0 mg / kg, about 7.1 mg / kg, about 7.2 mg / kg, about 7.3 mg / kg, about 7.4 mg / kg, about 7.5 mg / kg, about 7.6 mg / kg, about 7.7 mg / kg, about 7.8 mg / kg, about 7.9 mg / kg, about 8.0 mg / kg, about 8.1 mg / kg, about 8.2 mg / kg, about 8.3 mg / kg, about 8.4 mg / kg, about 8.5 mg / kg, about 8.6 mg / kg, about 8.7 mg / kg, about 8.8 mg / kg, about 8.9 mg / kg, about 9.0 mg / kg, about 9.1 mg / kg, about 9.2 mg / kg, about 9.3 mg / kg, about 9.4 mg / kg, about 9.5 mg / kg, about 9.6 mg / kg, about 9.7 mg / kg, about 9.8 mg / kg, about 9.9 mg / kg, about 10.0 mg / kg, about 10.5 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.5 mg / kg, about 13 mg / kg, about 13.5 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 50 mg / kg, or any range between these point values.

[0169] In some embodiments, the anti-Nectin-4 antibody drug conjugate is administered at a dose selected from 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, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / kg, 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5.0 mg / kg, 5.1 mg / kg, 5.2 mg / kg, 5.3 mg / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7 mg / kg, 5.8 mg / kg, 5.9 mg / kg, 6.0 mg / kg, 6.1 mg / kg, 6.2 mg / kg, 6.3 mg / kg, 6.4 mg / kg, 6.5 mg / kg, 6.6 mg / kg, 6.7 mg / kg, 6.8 mg / kg, 6.9 mg / kg, 7.0 mg / kg, 7.1 mg / kg, 7.2 mg / kg, 7.3 mg / kg, 7.4 mg / kg, 7.5 mg / kg, 7.6 mg / kg, 7.7 mg / kg, 7.8 mg / kg, 7.9 mg / kg, 8.0 mg / kg, 8.1 mg / kg, 8.2 mg / kg, 8.3 mg / kg, 8.4 mg / kg, 8.5 mg / kg, 8.6 mg / kg, 8.7 mg / kg, 8.8 mg / kg, 8.9 mg / kg, 9.0 mg / kg, 9.1 mg / kg, 9.2 mg / kg, 9.3 mg / kg, 9.4 mg / kg, 9.5 mg / kg, 9.6 mg / kg, 9.7 mg / kg, 9.8 mg / kg, 9.9 mg / kg, 10.0 mg / kg, 10.5 mg / kg, 11 mg / kg, 12 mg / kg, 12.5 mg / kg, 13 mg / kg, 13.5 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 50 mg / kg, or any range between these point values.

[0170] In some embodiments, the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg, and at a frequency of once every 3 weeks. In some embodiments, the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, or about 4 mg / kg, and at a frequency of twice every 3 weeks. In some embodiments, the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 4 mg / kg, and at a frequency of twice every 3 weeks. In some embodiments, the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, or about 4 mg / kg, and at a frequency of twice every 3 weeks, administered on D1, D8 days of each cycle. In some embodiments, the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 4 mg / kg, and at a frequency of twice every 3 weeks, administered on D1, D8 days of each cycle. In some embodiments, the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 6 mg / kg or about 8 mg / kg, and at a frequency of once every 3 weeks.

[0171] In some embodiments, the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg, and at a frequency of once every 3 weeks. In some embodiments, the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, or about 4 mg / kg, and at a frequency of twice every 3 weeks. In some embodiments, the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 4 mg / kg, and at a frequency of twice every 3 weeks. In some embodiments, the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, or about 4 mg / kg, and at a frequency of twice every 3 weeks, administered on D1, D8 days of each cycle. In some embodiments, the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 4 mg / kg, and at a frequency of twice every 3 weeks, administered on D1, D8 days of each cycle. In some embodiments, the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 6 mg / kg or about 8 mg / kg, and at a frequency of once every 3 weeks.

[0172] In some embodiments, the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg, and at a frequency of once every 3 weeks. In some embodiments, the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, or about 4 mg / kg, and at a frequency of twice every 3 weeks. In some embodiments, the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 4 mg / kg, and at a frequency of twice every 3 weeks. In some embodiments, the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, or about 4 mg / kg, and at a frequency of twice every 3 weeks, administered on D1, D8 days of each cycle. In some embodiments, the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 4 mg / kg, and at a frequency of twice every 3 weeks, administered on D1, D8 days of each cycle. In some embodiments, the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 6 mg / kg or about 8 mg / kg, and at a frequency of once every 3 weeks.

[0173] In some embodiments, the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg, and at a frequency of once every 3 weeks. In some embodiments, the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, or about 4 mg / kg, and at a frequency of twice every 3 weeks. In some embodiments, the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 4 mg / kg, and at a frequency of twice every 3 weeks. In some embodiments, the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, or about 4 mg / kg, and at a frequency of twice every 3 weeks, administered on D1, D8 days of each cycle. In some embodiments, the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 4 mg / kg, and at a frequency of twice every 3 weeks, administered on D1, D8 days of each cycle. In some embodiments, the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 6 mg / kg or about 8 mg / kg, and at a frequency of once every 3 weeks.

[0174] immunotherapeutic agent

[0175] In some embodiments, the immunotherapeutic agent comprises any one or a combination of an anti-PD-L1 antibody and an anti-CTLA-4 antibody.

[0176] In some embodiments, the immunotherapeutic agent comprises any one of an anti-PD-L1 antibody, an anti-CTLA-4 antibody, or a combination of an anti-PD-L1 antibody and an anti-CTLA-4 antibody.

[0177] <anti-PD-L1 antibody>

[0178] In some embodiments, the anti-PD-L1 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3 as set forth in SEQ ID NOs: 11-13, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3 as set forth in SEQ ID NOs: 14-16.

[0179] wherein each of the aforementioned CDR sequences is set forth in Table 2 below:

[0180] Table 2. CDR sequences of anti-PD-L1 antibody (Kabat scheme)

[0181] In some embodiments, the anti-PD-L1 antibody comprises any 1, or any combination of 2, 3, 4, 5, or 6 of the aforementioned HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3.

[0182] In some embodiments, the anti-PD-L1 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1, HCDR2, and HCDR3 in the amino acid sequence set forth in SEQ ID NO: 17, and the VL comprises LCDR1, LCDR2, and LCDR3 in the amino acid sequence set forth in SEQ ID NO: 18. The aforementioned CDRs are defined according to the Kabat, IMGT, Chothia, AbM, or Contact definition scheme. In some particular embodiments, the CDRs are defined according to the Kabat definition scheme.

[0183] In some embodiments, the anti-PD-L1 antibody is a chimeric, humanized, fully human antibody, or an antigen-binding fragment thereof.

[0184] In some embodiments, the anti-PD-L1 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises an amino acid sequence as set forth in SEQ ID NO: 17 or at least 80%, 90% identical thereto, and the VL comprises an amino acid sequence as set forth in SEQ ID NO: 18 or at least 80%, 90% identical thereto.

[0185] Heavy chain variable region:

[0186] Light chain variable region:

[0187] Note: underlined part is CDR region determined according to Kabat numbering rule.

[0188] In some embodiments, the anti-PD-L1 antibody comprises any one or both of the preceding VH, VL.

[0189] In some embodiments, the anti-PD-L1 antibody further comprises a heavy chain constant region and / or a light chain constant region. The heavy chain constant region of the antibody can be selected from the constant region of human IgGl, IgG2, IgG3, IgG4 and variants thereof. In some embodiments, the anti-PD-L1 antibody comprises a human IgG2 or IgG4 heavy chain constant region. In some embodiments, the anti-PD-L1 antibody comprises an IgG4 heavy chain constant region with F234A and L235A mutations introduced. The light chain constant region can be selected from the light chain constant region of human kappa, lambda chain or variants thereof.

[0190] In some embodiments, the anti-PD-L1 antibody comprises a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 19 or at least 80%, at least 90% sequence identity thereto; and / or a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 20 or at least 80%, at least 90% identity thereto.

[0191] In some embodiments, the anti-PD-L1 antibody comprises a heavy chain of an amino acid sequence as set forth in SEQ ID NO: 19, and a light chain of an amino acid sequence as set forth in SEQ ID NO: 20.

[0192] Heavy chain sequence of anti-PD-L1 antibody:

[0193] Light chain sequence of anti-PD-L1 antibody:

[0194] Note: underlined part is variable region sequence of antibody heavy chain or light chain, and non-underlined part is constant region sequence of antibody.

[0195] In some embodiments, the preparation of the above-mentioned anti-PD-L1 antibody or antigen binding fragment thereof can refer to WO2017084495A1, WO2018210230A1, the relevant contents of the antibody sequences, preparation methods, compositions in WO2017084495A1, WO2018210230A1 are incorporated into the present disclosure by reference.

[0196] In the context of the present disclosure, "at least 80%, 90%" encompasses 80% and above, for example, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, and any numerical range between any two of them.

[0197] In some embodiments, the anti-PD-L1 antibody can be administered at a dose of about 5 mg to about 5000 mg, about 50 mg to about 5000 mg, about 100 mg to about 5000 mg, about 100 mg to about 4500 mg, about 100 mg to about 4000 mg, about 100 mg to about 3500 mg, about 100 mg to about 3000 mg, about 100 mg to about 2500 mg, about 100 mg to about 2000 mg, about 100 mg to about 1500 mg, about 500 mg to about 3500 mg, about 500 mg to about 3000 mg, about 500 mg to about 2500 mg, about 500 mg to about 2000 mg, about 500 mg to about 1500 mg, about 800 mg to about 3500 mg, about 800 mg to about 3000 mg, about 800 mg to about 2500 mg, about 800 mg to about 2000 mg, about 800 mg to about 1500 mg, or about 1000 mg to about 1500 mg; and any numerical range between any two of them.

[0198] In some embodiments, the anti-PD-Ll antibody is administered at a dose of about 5 mg, about 25 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, 225 mg, about 250 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 550 mg, about 600 mg, 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, about 2400 mg, 2450 mg, about 2500 mg, about 2550 mg, about 2600 mg, about 2650 mg, about 2700 mg, about 2750 mg, about 2800 mg, about 2850 mg, 2900 mg, about 2950 mg, about 3000 mg, about 3050 mg, about 3100 mg, about 3150 mg, about 3200 mg, about 3250 mg, about 3300 mg, about 3350 mg, about 3400 mg, 3450 mg, about 3500 mg, about 3550 mg, about 3600 mg, about 3650 mg, about 3700 mg, about 3750 mg, about 3800 mg, about 3850 mg, 3900 mg, about 3950 mg, about 4000 mg, about 4500 mg, or about 5000 mg; and any range of values between any two of these values.

[0199] In some embodiments, the anti-PD-Ll antibody is administered at a dose of 5 mg, 25 mg, 50 mg, 60 mg, 70 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, 3050 mg, 3100 mg, 3150 mg, 3200 mg, 3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, 3600 mg, 3650 mg, 3700 mg, 3750 mg, 3800 mg, 3850 mg, 3900 mg, 3950 mg, 4000 mg, 4500 mg, or 5000 mg; and any range of values therein.

[0200] In some embodiments, the anti-PD-Ll antibody is administered at a dose of about 1200 mg.

[0201] In some embodiments, the anti-PD-Ll antibody is administered at a frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks. In some particular embodiments, the anti-PD-Ll antibody is administered at a frequency of once every 3 weeks.

[0202] In some embodiments, the anti-PD-Ll antibody is administered at a dose of about 1200 mg at a frequency of once every 3 weeks.

[0203] In some embodiments, the anti-PD-Ll antibody is administered via oral administration, parenteral administration, transdermal administration; the parenteral administration includes, but is not limited to, intravenous injection, subcutaneous injection, intramuscular injection. In some embodiments, the anti-PD-Ll antibody is administered via intravenous injection.

[0204] <Anti-CTLA-4 antibody>

[0205] In some embodiments, the anti-CTLA-4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NOs: 21-23, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NOs: 24-26.

[0206] In some embodiments, the anti-CTLA-4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NOs: 21-23, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NOs: 24-26.

[0207] Table 3. CDR sequences of anti-CTLA-4 antibody

[0208] In some embodiments, the anti-CTLA-4 antibody comprises any 1, or any combination of 2, 3, 4, 5 or 6 of the aforementioned HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3.

[0209] In some embodiments, the anti-CTLA-4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1, HCDR2 and HCDR3 in the amino acid sequence of SEQ ID NO: 27, and the VL comprises LCDR1, LCDR2 and LCDR3 in the amino acid sequence of SEQ ID NO: 28. The aforementioned CDRs are defined according to the Kabat, IMGT, Chothia, AbM or Contact definition scheme. In some specific embodiments, the CDRs are defined according to the Kabat definition scheme.

[0210] In some embodiments, the anti-CTLA-4 antibody is a chimeric, humanized, fully human antibody or antigen binding fragment thereof.

[0211] In some embodiments, the anti-CTLA-4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises an amino acid sequence as shown in SEQ ID NO: 27 or having at least 80%, 90% identity thereto, and the VL comprises an amino acid sequence as shown in SEQ ID NO: 28 or having at least 80%, 90% identity thereto. In some embodiments, the anti-CTLA-4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises an amino acid sequence as shown in SEQ ID NO: 27 or having at least 80%, 90% identity thereto, and the VL comprises an amino acid sequence as shown in SEQ ID NO: 28 or having at least 80%, 90% identity thereto.

[0212] Heavy chain variable region:

[0213] Light chain variable region:

[0214] In some embodiments, the anti-CTLA-4 antibody comprises any one or both of the preceding VH, VL.

[0215] In some embodiments, the anti-CTLA-4 antibody further comprises a heavy chain constant region and / or a light chain constant region. Wherein, the heavy chain constant region of the antibody can be selected from the constant region of human IgGl, IgG2, IgG3, IgG4 and variants thereof. In some embodiments, the light chain constant region can be selected from the light chain constant region of human kappa, lambda chain or variants thereof.

[0216] In some embodiments, the anti-CTLA-4 antibody comprises a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 29 or having at least 80%, at least 90% sequence identity thereto; and / or, a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 30 or having at least 80%, at least 90% identity thereto.

[0217] In some embodiments, the anti-CTLA-4 antibody comprises a heavy chain of an amino acid sequence as set forth in SEQ ID NO: 29, and a light chain of an amino acid sequence as set forth in SEQ ID NO: 30.

[0218] Heavy chain sequence of the anti-CTLA-4 antibody:

[0219] Light chain sequence of the anti-CTLA-4 antibody:

[0220] Note: The underlined part is the variable region sequence of the heavy chain or light chain of the antibody, and the non-underlined part is the constant region sequence of the antibody.

[0221] In the context of the present disclosure, “at least 80%, 90%” encompasses 80% and above, for example, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, and any numerical range between any two of the values.

[0222] In some embodiments, the anti-CTLA-4 antibody can be administered at a dose of about 0.1 mg / kg to about 100 mg / kg, 0.1 mg / kg to about 50 mg / kg, 0.1 mg / kg to about 20 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 9 mg / kg, about 0.1 mg / kg to about 8 mg / kg, about 0.1 mg / kg to about 7 mg / kg, about 0.1 mg / kg to about 6 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.5 mg / kg to about 50 mg / kg, about 0.5 mg / kg to about 20 mg / kg, about 0.5 mg / kg to about 10 mg / kg, about 0.5 mg / kg to about 9 mg / kg, about 0.5 mg / kg to about 8 mg / kg, about 0.5 mg / kg to about 7 mg / kg, about 0.5 mg / kg to about 6 mg / kg, about 0.5 mg / kg to about 5 mg / kg, about 1 mg / kg to about 50 mg / kg, about 1 mg / kg to about 20 mg / kg, about 1 mg / kg to about 10 mg / kg, about 1 mg / kg to about 9 mg / kg, about 1 mg / kg to about 8 mg / kg, about 1 mg / kg to about 7 mg / kg, about 1 mg / kg to about 6 mg / kg, about 1 mg / kg to about 5 mg / kg, about 2 mg / kg to about 10 mg / kg, about 2 mg / kg to about 9 mg / kg, about 2 mg / kg to about 8 mg / kg, about 2 mg / kg to about 7 mg / kg, about 2 mg / kg to about 6 mg / kg, about 2 mg / kg to about 5 mg / kg, about 3 mg / kg to about 10 mg / kg, about 3 mg / kg to about 9 mg / kg, about 3 mg / kg to about 8 mg / kg, about 3 mg / kg to about 7 mg / kg, about 3 mg / kg to about 6 mg / kg, about 3 mg / kg to about 5 mg / kg, or any range between these point values.

[0223] In some embodiments, the dosage of the anti-CTLA-4 antibody is about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 1.1 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2.0 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, and about 2 mg / kg. 3 mg / kg, approximately 2.4 mg / kg, approximately 2.5 mg / kg, approximately 2.6 mg / kg, approximately 2.7 mg / kg, approximately 2.8 mg / kg, approximately 2.9 mg / kg, approximately 3.0 mg / kg, approximately 3.1 mg / kg, approximately 3.2 mg / kg, approximately 3.3 mg / kg, approximately 3.4 mg / kg, approximately 3.5 mg / kg, approximately 3.6 mg / kg, approximately 3.7 mg / kg, approximately 3.8 mg / kg, approximately 3.9 mg / kg, approximately 4.0 mg / kg, approximately 4.1 mg / kg, approximately 4.2 mg / kg, approximately 4.3 mg / kg, approximately 4.4 mg / kg, approximately 4.5 mg / kg, approximately 4.6 mg / kg, approximately 4.7 mg / kg, approximately 4. 8 mg / kg, approximately 4.9 mg / kg, approximately 5.0 mg / kg, approximately 5.1 mg / kg, approximately 5.2 mg / kg, approximately 5.3 mg / kg, approximately 5.4 mg / kg, approximately 5.5 mg / kg, approximately 5.6 mg / kg, approximately 5.7 mg / kg, approximately 5.8 mg / kg, approximately 5.9 mg / kg, approximately 6.0 mg / kg, approximately 6.1 mg / kg, approximately 6.2 mg / kg, approximately 6.3 mg / kg, approximately 6.4 mg / kg, approximately 6.5 mg / kg, approximately 6.6 mg / kg, approximately 6.7 mg / kg, approximately 6.8 mg / kg, approximately 6.9 mg / kg, approximately 7.0 mg / kg, approximately 7.1 mg / kg, approximately 7.2 mg / kg, approximately 7. 3 mg / kg, approximately 7.4 mg / kg, approximately 7.5 mg / kg, approximately 7.6 mg / kg, approximately 7.7 mg / kg, approximately 7.8 mg / kg, approximately 7.9 mg / kg, approximately 8.0 mg / kg, approximately 8.1 mg / kg, approximately 8.2 mg / kg, approximately 8.3 mg / kg, approximately 8.4 mg / kg, approximately 8.5 mg / kg, approximately 8.6 mg / kg, approximately 8.7 mg / kg, approximately 8.8 mg / kg, approximately 8.9 mg / kg, approximately 9.0 mg / kg, approximately 9.1 mg / kg, approximately 9.2 mg / kg, approximately 9.3 mg / kg, approximately 9.4 mg / kg, approximately 9.5 mg / kg, approximately 9.6 mg / kg, approximately 9.7 mg / kg, approximately 9.8 mg / kg, about 9.9 mg / kg, about 10.0 mg / kg, about 10.5 mg / kg, about 11 mg / kg, about 11.5 mg / kg, about 12 mg / kg, about 12.5 mg / kg, about 13 mg / kg, about 13.5 mg / kg, about 14 mg / kg, about 14.5 mg / kg, about 15 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 100 mg / kg, or any range of values therein.

[0224] In some embodiments, the anti-CTLA-4 antibody is administered at a dose of 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2.0 mg / kg, 2.1 mg / kg, 2.2 mg / kg, 2.3 mg / kg, 2.4 mg / kg, 2.5 mg / kg, 2.6 mg / kg, 2.7 mg / kg, 2.8 mg / kg, 2.9 mg / kg, 3.0 mg / kg, 3.1 mg / kg, 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / kg, 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5.0 mg / kg, 5.1 mg / kg, 5.2 mg / kg, 5.3 mg / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7 mg / kg, 5.8 mg / kg, 5.9 mg / kg, 6.0 mg / kg, 6.1 mg / kg, 6.2 mg / kg, 6.3 mg / kg, 6.4 mg / kg, 6.5 mg / kg, 6.6 mg / kg, 6.7 mg / kg, 6.8 mg / kg, 6.9 mg / kg, 7.0 mg / kg, 7.1 mg / kg, 7.2 mg / kg, 7.3 mg / kg, 7.4 mg / kg, 7.5 mg / kg, 7.6 mg / kg, 7.7 mg / kg, 7.8 mg / kg, 7.9 mg / kg, 8.0 mg / kg, 8.1 mg / kg, 8.2 mg / kg, 8.3 mg / kg, 8.4 mg / kg, 8.5 mg / kg, 8.6 mg / kg, 8.7 mg / kg, 8.8 mg / kg, 8.9 mg / kg, 9.0 mg / kg, 9.1 mg / kg, 9.2 mg / kg, 9.3 mg / kg, 9.4 mg / kg, 9.5 mg / kg, 9.6 mg / kg, 9.7 mg / kg, 9.8 mg / kg, 9.9 mg / kg, 10.0 mg / kg, 10.5 mg / kg, 11 mg / kg, 11.5 mg / kg, 12 mg / kg, 12.5 mg / kg, 13 mg / kg, 13.5 mg / kg, 14 mg / kg, 14.5 mg / kg, 15 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 100 mg / kg, or any range of values therein.

[0225] In some embodiments, the anti-CTLA-4 antibody is administered at a dose of about 4.0 mg / kg.

[0226] In some embodiments, the anti-CTLA-4 antibody is administered at a dose of about 4.0 mg / kg.

[0227] In some embodiments, the anti-CTLA-4 antibody is administered at a dose of about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 180 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, or any range between these point values.

[0228] In some embodiments, the anti-CTLA-4 antibody is administered at a dose of 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 180 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, or any range between these point values.

[0229] In some embodiments, the anti-CTLA-4 antibody is administered at a dose of about 70 mg.

[0230] In some embodiments, the anti-CTLA-4 antibody is administered at a dose of about 280 mg or 210 mg.

[0231] In some embodiments, the anti-CTLA-4 antibody is administered at a frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, once every 12 weeks, once every 14 weeks, once every 16 weeks, or as a single administration. In some embodiments, the anti-CTLA-4 antibody is administered at a frequency of once every 12 weeks.

[0232] In some embodiments, the anti-CTLA-4 antibody is administered once every 6 weeks or a single administration. In some embodiments, the anti-CTLA-4 antibody is administered once at a dose of about 280 mg in the first week, no administration in the second to twelfth weeks, and administration at a dose of about 70 mg once every 6 weeks starting from the thirteenth week.

[0233] In some embodiments, 280 mg or 210 mg is administered once on day 1 of the first cycle, no administration in the second to fourth cycles, and administration at a frequency of 70 mg once every 6 weeks starting from day 1 of the fifth cycle (C1D1 280 mg or 210 mg once, C2-C4 no administration, C5 and subsequent cycles 70 mg Q6W) in a 21-day cycle.

[0234] In some embodiments, the anti-CTLA-4 antibody is administered orally, parenterally, transdermally; the parenteral administration includes but is not limited to intravenous injection, subcutaneous injection, intramuscular injection. In some embodiments, the anti-CTLA-4 antibody is administered by intravenous injection.

[0235] <VEGF signaling pathway inhibitor>

[0236] In some embodiments, the VEGF signaling pathway inhibitor is an anti-VEGF antibody.

[0237] In some embodiments, the anti-VEGF antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 31-33, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 34-36.

[0238] In some embodiments, the anti-VEGF antibody as described in any one of the above comprises a heavy chain variable region and a light chain variable region, the amino acid sequence of HCDR1 of the heavy chain variable region is as shown in SEQ ID NO: 31, the amino acid sequence of HCDR2 is as shown in SEQ ID NO: 32, and the amino acid sequence of HCDR3 is as shown in SEQ ID NO: 33, and the amino acid sequence of LCDR1 of the light chain variable region is as shown in SEQ ID NO: 34, the amino acid sequence of LCDR2 is as shown in SEQ ID NO: 35, and the amino acid sequence of LCDR3 is as shown in SEQ ID NO: 36. Wherein, each of the CDR sequences described above is shown in Table 4 as follows:

[0239] Table 4. CDR sequences of anti-VEGF antibody

[0240] The CDRs described above are defined according to the Kabat definition scheme.

[0241] In some embodiments, the anti-VEGF antibody of any of the above comprises any 1, or a combination of any 2, 3, 4, 5, or 6 of the preceding HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3.

[0242] In some embodiments, the anti-VEGF antibody of any of the above comprises a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3 in the amino acid sequence set forth in SEQ ID NO: 37, and a light chain variable region comprising LCDR1, LCDR2, and LCDR3 in the amino acid sequence set forth in SEQ ID NO: 38.

[0243] In some embodiments, the anti-VEGF antibody of any of the above, wherein the HCDR1, HCDR2, and HCDR3 of the heavy chain variable region and the LCDR1, LCDR2, and LCDR3 of the light chain variable region are defined according to a numbering scheme selected from Kabat, IMGT, Chothia, AbM, and Contact.

[0244] In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof is a chimeric, humanized, fully human antibody or antigen-binding fragment thereof.

[0245] In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof, the heavy chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 37, or an amino acid sequence having at least 80%, 90% sequence identity thereto; and the light chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 38, or an amino acid sequence having at least 80%, 90% sequence identity thereto.

[0246] Anti-VEGF antibody heavy chain variable region:

[0247] Anti-VEGF antibody heavy chain variable region:

[0248] In some embodiments, the anti-VEGF antibody comprises a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 37, or an amino acid sequence having at least 80% identity thereto, and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 38, or an amino acid sequence having at least 80% identity thereto.

[0249] In some embodiments, the anti-VEGF antibody further comprises a heavy chain constant region and / or a light chain constant region, for example, the heavy chain constant region of the antibody constant region is selected from the group consisting of human IgGl, IgG2, IgG3 and IgG4 constant regions and variants thereof; the light chain constant region of the antibody constant region is selected from the group consisting of human antibody kappa and lambda chain constant regions and variants thereof.

[0250] In some embodiments, the anti-VEGF antibody comprises a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 19 or having at least 80% sequence identity thereto; and / or, a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 20 or having at least 80% identity thereto.

[0251] In some embodiments, the anti-VEGF antibody comprises a heavy chain of an amino acid sequence as set forth in SEQ ID NO: 39, and a light chain of an amino acid sequence as set forth in SEQ ID NO: 40.

[0252] Heavy chain sequence of the anti-VEGF antibody:

[0253] Light chain sequence of the anti-VEGF antibody:

[0254] Note: the underlined part is the variable region sequence of the antibody heavy chain or light chain, and the non-underlined part is the antibody constant region sequence.

[0255] In some embodiments, the dosage of the anti-VEGF antibody may be selected from about 1.0 mg / kg to about 30 mg / kg, about 1 mg / kg to about 25 mg / kg; about 1.0 mg / kg to about 20 mg / kg, about 1.0 mg / kg to about 19 mg / kg, about 1.0 mg / kg to about 18 mg / kg, about 1.0 mg / kg to about 17 mg / kg, about 1.0 mg / kg to about 16 mg / kg, about 1.0 mg / kg to about 15 mg / kg, about 1.0 mg / kg to about 14 mg / kg, about 1.0 mg / kg to about 13 mg / kg, about 1.0 mg / kg to about 12 mg / kg, or about 1.0 mg / kg to about 11 mg / kg. kg, about 1.0 mg / kg to about 10 mg / kg, about 2 mg / kg to about 25 mg / kg; about 2.0 mg / kg to about 20 mg / kg, about 2.0 mg / kg to about 19 mg / kg, about 2.0 mg / kg to about 18 mg / kg, about 2.0 mg / kg to about 17 mg / kg, about 2.0 mg / kg to about 16 mg / kg, about 2.0 mg / kg to about 15 mg / kg, about 2.0 mg / kg to about 14 mg / kg, about 2.0 mg / kg to about 13 mg / kg, about 2.0 mg / kg to about 12 mg / kg, about 2.0 mg / kg to about 11 mg / kg, about 2.0 mg / kg to about 10 mg / kg, Approximately 3.0 mg / kg to approximately 25 mg / kg, approximately 3.0 mg / kg to approximately 20 mg / kg, approximately 3.0 mg / kg to approximately 19 mg / kg, approximately 3.0 mg / kg to approximately 18 mg / kg, approximately 3.0 mg / kg to approximately 17 mg / kg, approximately 3.0 mg / kg to approximately 16 mg / kg, approximately 3.0 mg / kg to approximately 15 mg / kg, approximately 3.0 mg / kg to approximately 14 mg / kg, approximately 3.0 mg / kg to approximately 13 mg / kg, approximately 3.0 mg / kg to approximately 12 mg / kg, approximately 3.0 mg / kg to approximately 11 mg / kg, approximately 3.0 mg / kg to approximately 10 mg / kg, approximately 4.0 mg / kg to approximately 25 mg / kg, approximately 4.0 mg / kg to about 20 mg / kg, about 4.0 mg / kg to about 19 mg / kg, about 4.0 mg / kg to about 18 mg / kg, about 4.0 mg / kg to about 17 mg / kg, about 4.0 mg / kg to about 16 mg / kg, about 4.0 mg / kg to about 15 mg / kg, about 4.0 mg / kg to about 14 mg / kg, about 4.0 mg / kg to about 13 mg / kg, about 4.0 mg / kg to about 12 mg / kg, about 4.0 mg / kg to about 11 mg / kg, about 4.0 mg / kg to about 10 mg / kg, about 5.0 mg / kg to about 25 mg / kg, about 5.0 mg / kg to about 20 mg / kg, about 5.0 mg / kg to about 19 mg / kg, about 5.0 mg / kg to about 18 mg / kg, about 5.0 mg / kg to about 17 mg / kg, about 5.0 mg / kg to about 16 mg / kg, about 5.0 mg / kg to about 15 mg / kg, about 5.0 mg / kg to about 14 mg / kg, about 5.0 mg / kg to about 13 mg / kg, about 5.0 mg / kg to about 12 mg / kg, about 5.0 mg / kg to about 11 mg / kg, about 5.0 mg / kg to about 10 mg / kg, about 6.0 mg / kg to about 25 mg / kg, about 6.0 mg / kg to about 20 mg / kg, about 6.0 mg / kg to about 19 mg / kg, about 6.0 mg / kg to about 18 mg / kg, about 6.0 mg / kg to about 17 mg / kg, about 6.0 mg / kg to about 16 mg / kg, about 6.0 mg / kg to about 15 mg / kg, about 6.0 mg / kg to about 14 mg / kg, about 6.0 mg / kg to about 13 mg / kg, about 6.0 mg / kg to about 12 mg / kg, about 6.0 mg / kg to about 11 mg / kg, about 6.0 mg / kg to about 10 mg / kg, about 7.0 mg / kg to about 25 mg / kg, about 7.0 mg / kg to about 23 mg / kg, about 7.0 mg / kg to about 20 mg / kg, about 7.0 mg / kg to about 19 mg / kg, about 7.0 mg / kg to about 18 mg / kg, about 7.0 mg / kg to about 17 mg / kg, about 7.0 mg / kg to about 16 mg / kg, about 7.0 mg / kg to about 15 mg / kg, about 7.0 mg / kg to about 14 mg / kg, about 7.0 mg / kg to about 13 mg / kg, about 7.0 mg / kg to about 12 mg / kg, about 7.0 mg / kg to about 11 mg / kg, about 7.0 mg / kg to about 10 mg / kg, about 8 mg / kg to about 20 mg / kg, about 8 mg / kg to about 19 mg / kg, about 8 mg / kg to about 18 mg / kg, about 8 mg / kg to about 17 mg / kg, about 8 mg / kg to about 16 mg / kg, about 8 mg / kg to about 15 mg / kg; about 8 mg / kg to about 15 g / kg, about 9 mg / kg to about 21 mg / kg, about 10 mg / kg to about 20 mg / kg, about 10 mg / kg to about 19 mg / kg, about 10 mg / kg to about 18 mg / kg, about 10 mg / kg to about 17 mg / kg, about 10 mg / kg to about 16 mg / kg, about 10 mg / kg to about 15 mg / kg, about 11 mg / kg to about 19 mg / kg, about 12 mg / kg to about 18 mg / kg, about 13 mg / kg to about 17 mg / kg, about 14 mg / kg to about 16 mg / kg, about 1 mg / kg to about 9 mg / kg, about 2 mg / kg to about 9 mg / kg, about 3 mg / kg to about 9 mg / kg, about 4 mg / kg to about 9 mg / kg, about 5 mg / kg to about 9 mg / kg, about 6 mg / kg to about 9 mg / kg, about 1 mg / kg to about 8 mg / kg, about 2 mg / kg to about 8 mg / kg, about 3 mg / kg to about 8 mg / kg, about 4 mg / kg to about 8 mg / kg, about 5 mg / kg to about 8 mg / kg, about 6 mg / kg to about 8 mg / kg, about 7 mg / kg to about 8 mg / kg.

[0256] In some embodiments, the anti-VEGF antibody is administered at a dose of about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 6.5 mg / kg, about 7.0 mg / kg, about 7.5 mg / kg, 8.0 mg / kg, 8.5 mg / kg, about 9.0 mg / kg, about 9.5 mg / kg, about 10.0 mg / kg, about 10.5 mg / kg, about 11.0 mg / kg, about 11.5 mg / kg, about 12.0 mg / kg, about 12.5 mg / kg, about 13.0 mg / kg, about 13.5 mg / kg, about 14.0 mg / kg, about 14.5 mg / kg, about 15.0 mg / kg, about 15.5 mg / kg, about 16.0 mg / kg, about 16.5 mg / kg, about 17.0 mg / kg, about 18.0 mg / kg, about 19.0 mg / kg, about 20.0 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, about 25.0 mg / kg, about 30.0 mg / kg, or any range between these point values. In some embodiments, the anti-VEGF antibody is administered at a dose of 2.0 mg / kg, 3.0 mg / kg, 4.0 mg / kg, 5.0 mg / kg, 6.0 mg / kg, 6.5 mg / kg, 7.0 mg / kg, 7.5 mg / kg, 8.0 mg / kg, 8.5 mg / kg, 9.0 mg / kg, 9.5 mg / kg, 10.0 mg / kg, 10.5 mg / kg, 11.0 mg / kg, 11.5 mg / kg, 12.0 mg / kg, 12.5 mg / kg, 13.0 mg / kg, 13.5 mg / kg, 14.0 mg / kg, 14.5 mg / kg, 15.0 mg / kg, 15.5 mg / kg, 16.0 mg / kg, 16.5 mg / kg, 17.0 mg / kg, 18.0 mg / kg, 19.0 mg / kg, 20.0 mg / kg, 21.0 mg / kg, 22.0 mg / kg, 23.0 mg / kg, 24.0 mg / kg, 25.0 mg / kg, 30.0 mg / kg, or any range between these point values.

[0257] In some embodiments, the anti-VEGF antibody is administered at a frequency of once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks. In some particular embodiments, the anti-VEGF antibody is administered at a frequency of once every 3 weeks.

[0258] In some embodiments, the dosing regimen of the anti-VEGF antibody is selected from any one of:

[0259] the anti-VEGF antibody is administered at a dose of about 1.0 mg / kg to about 30 mg / kg once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks;

[0260] the anti-VEGF antibody is administered at a dose of about 1.0 mg / kg to about 25 mg / kg once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks;

[0261] the anti-VEGF antibody is administered at a dose of about 2.0 mg / kg to about 25 mg / kg once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks;

[0262] the anti-VEGF antibody is administered at a dose of about 7.0 mg / kg to about 23 mg / kg once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks;

[0263] the anti-VEGF antibody is administered at a dose of about 2.0 mg / kg to about 20 mg / kg once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks;

[0264] the anti-VEGF antibody is administered at a dose of about 5.0 mg / kg to about 20 mg / kg once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks;

[0265] the anti-VEGF antibody is administered at a dose of about 7.0 mg / kg to about 20 mg / kg once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks;

[0266] the anti-VEGF antibody is administered at a dose of about 8.0 mg / kg to about 20 mg / kg once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks;

[0267] about 9.0 mg / kg to about 20 mg / kg, with a dosing frequency of once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks;

[0268] about 10 mg / kg to about 20 mg / kg, with a dosing frequency of once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks;

[0269] about 11 mg / kg to about 19 mg / kg, with a dosing frequency of once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks;

[0270] about 12 mg / kg to about 18 mg / kg, with a dosing frequency of once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks;

[0271] about 13 mg / kg to about 17 mg / kg, with a dosing frequency of once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks;

[0272] about 14 mg / kg to about 16 mg / kg, with a dosing frequency of once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks;

[0273] about 14 mg / kg to about 16 mg / kg, with a dosing frequency of once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks;

[0274] about 1 mg / kg to about 15 mg / kg, with a dosing frequency of once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks;

[0275] about 2 mg / kg to about 14 mg / kg, with a dosing frequency of once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks;

[0276] about 2 mg / kg to about 13 mg / kg, with a dosing frequency of once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks;

[0277] about 3 mg / kg to about 12 mg / kg, with a dosing frequency of once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks;

[0278] about 4 mg / kg to about 11 mg / kg, with a dosing frequency of once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks;

[0279] about 5 mg / kg to about 10 mg / kg, with a dosing frequency of once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks;

[0280] about 6 mg / kg to about 9 mg / kg, with a dosing frequency of once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks;

[0281] about 7 mg / kg to about 8 mg / kg, with a dosing frequency of once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks;

[0282] The anti-VEGF antibody is administered at a dose of about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 6.5 mg / kg, about 7.0 mg / kg, about 7.5 mg / kg, 8.0 mg / kg, 8.5 mg / kg, about 9.0 mg / kg, about 9.5 mg / kg, about 10.0 mg / kg, about 10.5 mg / kg, about 11.0 mg / kg, about 11.5 mg / kg, about 12.0 mg / kg, about 12.5 mg / kg, about 13.0 mg / kg, about 13.5 mg / kg, about 14.0 mg / kg, about 14.5 mg / kg, about 15.0 mg / kg, about 15.5 mg / kg, about 16.0 mg / kg, about 16.5 mg / kg, about 17.0 mg / kg, about 18.0 mg / kg, about 19.0 mg / kg, about 20.0 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, about 25.0 mg / kg, about 30.0 mg / kg; and the frequency of administration is once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks;

[0283] The anti-VEGF antibody is administered at a dose of about 5.0 mg / kg with a frequency of administration of once every 3 weeks;

[0284] The anti-VEGF antibody is administered at a dose of about 5.5 mg / kg with a frequency of administration of once every 3 weeks;

[0285] The anti-VEGF antibody is administered at a dose of about 6.0 mg / kg with a frequency of administration of once every 3 weeks;

[0286] The anti-VEGF antibody is administered at a dose of about 6.5 mg / kg with a frequency of administration of once every 3 weeks;

[0287] The anti-VEGF antibody is administered at a dose of about 7.0 mg / kg with a frequency of administration of once every 3 weeks;

[0288] The anti-VEGF antibody is administered at a dose of about 7.5 mg / kg with a frequency of administration of once every 3 weeks;

[0289] The anti-VEGF antibody is administered at a dose of about 8.0 mg / kg with a frequency of administration of once every 3 weeks;

[0290] The anti-VEGF antibody is administered at a dose of about 8.5 mg / kg with a frequency of administration of once every 3 weeks;

[0291] about 9.0 mg / kg with a dosing frequency of once every 3 weeks;

[0292] about 9.5 mg / kg with a dosing frequency of once every 3 weeks;

[0293] about 10.0 mg / kg with a dosing frequency of once every 3 weeks;

[0294] about 10.5 mg / kg with a dosing frequency of once every 3 weeks;

[0295] about 11.0 mg / kg with a dosing frequency of once every 3 weeks;

[0296] about 11.5 mg / kg with a dosing frequency of once every 3 weeks;

[0297] about 12.0 mg / kg with a dosing frequency of once every 3 weeks;

[0298] about 12.5 mg / kg with a dosing frequency of once every 3 weeks;

[0299] about 13.0 mg / kg with a dosing frequency of once every 3 weeks;

[0300] about 13.5 mg / kg with a dosing frequency of once every 3 weeks;

[0301] about 14.0 mg / kg with a dosing frequency of once every 3 weeks;

[0302] about 14.5 mg / kg with a dosing frequency of once every 3 weeks;

[0303] about 15.0 mg / kg with a dosing frequency of once every 3 weeks;

[0304] about 15.5 mg / kg with a dosing frequency of once every 3 weeks;

[0305] about 16.0 mg / kg with a dosing frequency of once every 3 weeks;

[0306] about 16.5 mg / kg with a dosing frequency of once every 3 weeks;

[0307] the anti-VEGF antibody is administered at a dose of about 17.0 mg / kg with a dosing frequency of once every 3 weeks;

[0308] the anti-VEGF antibody is administered at a dose of about 17.5 mg / kg with a dosing frequency of once every 3 weeks;

[0309] the anti-VEGF antibody is administered at a dose of about 18.0 mg / kg with a dosing frequency of once every 3 weeks;

[0310] the anti-VEGF antibody is administered at a dose of about 18.5 mg / kg with a dosing frequency of once every 3 weeks;

[0311] the anti-VEGF antibody is administered at a dose of about 19.0 mg / kg with a dosing frequency of once every 3 weeks;

[0312] the anti-VEGF antibody is administered at a dose of about 19.5 mg / kg with a dosing frequency of once every 3 weeks;

[0313] the anti-VEGF antibody is administered at a dose of about 20.0 mg / kg with a dosing frequency of once every 3 weeks;

[0314] the anti-VEGF antibody is administered at a dose of about 21.5 mg / kg with a dosing frequency of once every 3 weeks;

[0315] the anti-VEGF antibody is administered at a dose of about 22.0 mg / kg with a dosing frequency of once every 3 weeks;

[0316] the anti-VEGF antibody is administered at a dose of about 22.5 mg / kg with a dosing frequency of once every 3 weeks;

[0317] the anti-VEGF antibody is administered at a dose of about 23.0 mg / kg with a dosing frequency of once every 3 weeks;

[0318] the anti-VEGF antibody is administered at a dose of about 23.5 mg / kg with a dosing frequency of once every 3 weeks;

[0319] the anti-VEGF antibody is administered at a dose of about 24.0 mg / kg with a dosing frequency of once every 3 weeks;

[0320] the anti-VEGF antibody is administered at a dose of about 24.5 mg / kg with a dosing frequency of once every 3 weeks;

[0321] the anti-VEGF antibody is administered at a dose of about 25.0 mg / kg with a dosing frequency of once every 3 weeks.

[0322] In some embodiments, in any of the dosing regimens described above, the anti-VEGF antibody is administered with a dosing frequency of once every 3 weeks.

[0323] In some embodiments, in any of the dosing regimens described above, the route of administration of the anti-VEGF antibody can be oral administration, parenteral administration, transdermal administration, the parenteral administration including but not limited to intravenous injection, subcutaneous injection, intramuscular injection. In some embodiments, the route of administration of the anti-VEGF antibody is intravenous infusion administration.

[0324] In some embodiments, the anti-VEGF antibody is configured in an injectable form. Illustratively, the injectable form of the anti-VEGF antibody is an injection solution or a lyophilized powder, which comprises the anti-VEGF antibody and one or more pharmaceutically acceptable excipients.

[0325] <Platinum drug>

[0326] In some embodiments, the platinum drug is carboplatin or cisplatin.

[0327] In some embodiments, the platinum drug is cisplatin, and the dosage of the cisplatin is about 1 mg / m 2 to about 500 mg / m 2 , or about 50 mg / m 2 to about 150 mg / m 2 ; for example, about 1 mg / m 2 to about 200 mg / m 2 , about 1 mg / m 2 to about 150 mg / m 2 , about 1 mg / m 2 to about 100 mg / m 2 , about 15 mg / m 2 to about 150 mg / m 2 , about 20 mg / m 2 to about 150 mg / m 2 , about 30 mg / m 2 to about 150 mg / m 2 , about 30 mg / m 2 to about 100 mg / m 2 , about 30 mg / m 2 to about 85 mg / m 2 , about 45 mg / m 2 to about 85 mg / m 2 , about 50 mg / m 2 to about 150 mg / m 2 , about 55 mg / m 2 to about 100 mg / m 2 , about 55 mg / m 2 to about 85 mg / m 2 , about 60 mg / m 2about 100 mg / m 2 about 60 mg / m 2 about 85 mg / m 2 about 65 mg / m 2 about 85 mg / m 2 about 70 mg / m 2 about 85 mg / m 2 or any range between any two of the foregoing.

[0328] Illustratively, the cisplatin is administered at a dosage of about 1 mg / m 2 about 5 mg / m 2 about 15 mg / m 2 about 20 mg / m 2 about 25 mg / m 2 about 30 mg / m 2 about 35 mg / m 2 about 40 mg / m 2 about 45 mg / m 2 about 50 mg / m 2 about 51 mg / m 2 about 52 mg / m 2 about 53 mg / m 2 about 55 mg / m 2 about 57 mg / m 2 about 58 mg / m 2 about 60 mg / m 2 about 61 mg / m 2 about 62 mg / m 2 about 63 mg / m 2 about 64 mg / m 2 about 65 mg / m 2 about 66 mg / m 2 about 67 mg / m 2 about 68 mg / m 2 about 69 mg / m 2 about 70 mg / m 2 about 71 mg / m 2 about 72 mg / m 2 about 73 mg / m 2 about 74 mg / m 2 about 75 mg / m 2 about 76 mg / m 2 about 77 mg / m 2 about 78 mg / m 2 about 79 mg / m 2 about 80 mg / m 2 about 81 mg / m 2about 82 mg / m 2 about 83 mg / m 2 about 84 mg / m 2 about 85 mg / m 2 about 86 mg / m 2 about 87 mg / m 2 about 88 mg / m 2 about 89 mg / m 2 about 90 mg / m 2 about 95 mg / m 2 about 100 mg / m 2 about 105 mg / m 2 about 110 mg / m 2 about 115 mg / m 2 about 120 mg / m 2 about 130 mg / m 2 about 140 mg / m 2 about 150 mg / m 2 about 160 mg / m 2 about 170 mg / m 2 about 180 mg / m 2 about 190 mg / m 2 about 200 mg / m 2 about 220 mg / m 2 about 250 mg / m 2 about 280 mg / m 2 about 300 mg / m 2 ; or any range between any two of the foregoing.

[0329] In some embodiments, the cisplatin is administered at a frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks. In some particular embodiments, the cisplatin is administered at a frequency of once every 3 weeks.

[0330] In some embodiments, the cisplatin is administered at a dose of about 1 mg / m 2 to about 500 mg / m 2 at a frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks. In some particular embodiments, the cisplatin is administered at a dose of about 1 mg / m 2 to about 500 mg / m 2 at a frequency of once every 3 weeks.

[0331] In some embodiments, the cisplatin is administered at a dose of about 1 mg / m 2 to about 200 mg / m 2, at a dosing frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks. In some particular embodiments, the cisplatin is administered at a dose of about 1 mg / m 2 to about 200 mg / m 2 , at a dosing frequency of once every 3 weeks.

[0332] In some embodiments, the cisplatin is administered at a dose of about 5 mg / m 2 to about 100 mg / m 2 , at a dosing frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks. In some particular embodiments, the cisplatin is administered at a dose of about 5 mg / m 2 to about 100 mg / m 2 , at a dosing frequency of once every 3 weeks.

[0333] In some embodiments, the cisplatin is administered at a dose of about 50 mg / m 2 to about 100 mg / m 2 , at a dosing frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks. In some particular embodiments, the cisplatin is administered at a dose of about 50 mg / m 2 to about 100 mg / m 2 , at a dosing frequency of once every 3 weeks.

[0334] In some embodiments, the cisplatin is administered at a dose of about 60 mg / m 2 to about 85 mg / m 2 , at a dosing frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks. In some particular embodiments, the cisplatin is administered at a dose of about 60 mg / m 2 to about 85 mg / m 2 , at a dosing frequency of once every 3 weeks.

[0335] In some embodiments, the cisplatin is administered at a dose of about 70 mg / m 2 , at a dosing frequency of once every 3 weeks.

[0336] In some embodiments, the cisplatin is administered at a dose of about 71 mg / m 2 , at a dosing frequency of once every 3 weeks.

[0337] In some embodiments, the cisplatin is administered at a dose of about 72 mg / m 2 , at a dosing frequency of once every 3 weeks.

[0338] In some embodiments, the cisplatin is administered at a dose of about 73 mg / m2 at a dosage of about 75 mg / m2with a dosing frequency of once every 3 weeks.

[0339] In some embodiments, the cisplatin is administered at a dosage of about 74 mg / m 2 at a dosage of about 75 mg / m2with a dosing frequency of once every 3 weeks.

[0340] In some embodiments, the cisplatin is administered at a dosage of about 75 mg / m 2 at a dosage of about 75 mg / m2with a dosing frequency of once every 3 weeks.

[0341] In some embodiments, the cisplatin is administered at a dosage of about 76 mg / m 2 at a dosage of about 75 mg / m2with a dosing frequency of once every 3 weeks.

[0342] In some embodiments, the cisplatin is administered at a dosage of about 77 mg / m 2 at a dosage of about 75 mg / m2with a dosing frequency of once every 3 weeks.

[0343] In some embodiments, the cisplatin is administered at a dosage of about 78 mg / m 2 at a dosage of about 75 mg / m2with a dosing frequency of once every 3 weeks.

[0344] In some embodiments, the cisplatin is administered at a dosage of about 79 mg / m 2 at a dosage of about 75 mg / m2with a dosing frequency of once every 3 weeks.

[0345] In some embodiments, the cisplatin is administered at a dosage of about 80 mg / m 2 at a dosage of about 75 mg / m2with a dosing frequency of once every 3 weeks.

[0346] In some embodiments, the cisplatin is administered at a dosage of about 81 mg / m 2 at a dosage of about 75 mg / m2with a dosing frequency of once every 3 weeks.

[0347] In some embodiments, the cisplatin is administered at a dosage of about 82 mg / m 2 at a dosage of about 75 mg / m2with a dosing frequency of once every 3 weeks.

[0348] In some embodiments, the cisplatin is administered at a dosage of about 83 mg / m 2 at a dosage of about 75 mg / m2with a dosing frequency of once every 3 weeks.

[0349] In some embodiments, the cisplatin is administered at a dosage of about 84 mg / m 2 at a dosage of about 75 mg / m2with a dosing frequency of once every 3 weeks.

[0350] In some embodiments, the cisplatin is administered at a dosage of about 85 mg / m 2 at a dosage of about 75 mg / m2with a dosing frequency of once every 3 weeks.

[0351] In some embodiments, the route of administration of cisplatin can be oral administration, parenteral administration, including but not limited to intravenous injection, subcutaneous injection, intramuscular injection, transdermal administration. In some specific embodiments, the route of administration of cisplatin is intravenous injection. In some specific embodiments, the route of administration of cisplatin is intravenous infusion.

[0352] In some embodiments, the platinum-based drug is carboplatin, and the dose of carboplatin administered (in AUC) is about 0.1 mg / mL / min to about 50 mg / mL / min, for example, about 1 mg / mL / min to 20 mg / mL / min, about 1 mg / mL / min to 10 mg / mL / min, about 1 mg / mL / min to 8 mg / mL / min, about 1 mg / mL / min to 6 mg / mL / min, about 2 mg / mL / min to 10 mg / mL / min, about 2 mg / mL / min to about 8 mg / mL / min, about 2 mg / mL / min to about 6 mg / mL / min, about 3 mg / mL / min to about 8 mg / mL / min, about 3 mg / mL / min to 6 mg / mL / min, about 4 mg / mL / min to 6 mg / mL / min.

[0353] In some embodiments, the dose of carboplatin administered (in AUC) is about 0.1 mg / mL / min, about 0.5 mg / mL / min, about 0.6 mg / mL / min, about 0.7 mg / mL / min, about 0.8 mg / mL / min, about 0.9 mg / mL / min, about 1.0 mg / mL / min, about 1.1 mg / mL / min, about 1.2 mg / mL / min, about 1.3 mg / mL / min, about 1.4 mg / mL / min, about 1.5 mg / mL / min, about 1.6 mg / mL / min, about 1.7 mg / mL / min, about 1.8 mg / mL / min, about 1.9 mg / mL / min, about 2.0 mg / mL / min, about 2.1 mg / mL / min, about 2.2 mg / mL / min, about 2.3 mg / mL / min, about 2.4 mg / mL / min, about 2.5 mg / mL / min, about 2.6 mg / mL / min, about 2.7 mg / mL / min, about 2.8 mg / mL / min, about 2.9 mg / mL / min, about 3.0 mg / mL / min, about 3.1 mg / mL / min, about 3.2 mg / mL / min, about 3.3 mg / mL / min, about 3.4 mg / mL / min, about 3.5 mg / mL / min, about 3.6 mg / mL / min, about 3.7 mg / mL / min, about 3.8 mg / mL / min, about 3.9 mg / mL / min, about 4.0 mg / mL / min, about 4.1 mg / mL / min, about 4.2 mg / mL / min, about 4.3 mg / mL / min, about 4.4 mg / mL / min, about 4.5 mg / mL / min, about 4.6 mg / mL / min, about 4.7 mg / mL / min, about 4.8 mg / mL / min, about 4.9 mg / mL / min, about 5.0 mg / mL / min, about 5.1 mg / mL / min, about 5.2 mg / mL / min, about 5.3 mg / mL / min, about 5.4 mg / mL / min, about 5.5 mg / mL / min, about 5.6 mg / mL / min, about 5.7 mg / mL / min, about 5.8 mg / mL / min, about 5.9 mg / mL / min, about 6.0 mg / mL / min, about 6.1 mg / mL / min, about 6.2 mg / mL / min, about 6.3 mg / mL / min, about 6.4 mg / mL / min, about 6.5 mg / mL / min, about 6.6 mg / mL / min, about 6.7 mg / mL / min, about 6.8 mg / mL / min, about 6.9 mg / mL / min, about 7.0 mg / mL / min, about 7.1 mg / mL / min, about 7.2 mg / mL / min, about 7.3 mg / mL / min, about 7.4 mg / mL / min, about 7.5 mg / mL / min, about 7.6 mg / mL / min, about 7.7 mg / mL / min, about 7.8 mg / mL / min, about 7.9 mg / mL / min, about 8.0 mg / mL / min, about 8.1 mg / mL / min, about 8.2 mg / mL / min, about 8.3 mg / mL / min, about 8.4 mg / mL / min, about 8.5 mg / mL / min, about 8.6 mg / mL / min, about 8.7 mg / mL / min, about 8.8 mg / mL / min, about 8.9 mg / mL / min, about 9.0 mg / mL / min, about 9.2 mg / mL / min, about 9.5 mg / mL / min, about 9.8 mg / mL / min, about 10.0 mg / mL / min, about 15 mg / mL / min, about 20 mg / mL / min, about 25 mg / mL / min, about 30 mg / mL / min, about 35 mg / mL / min, about 40 mg / mL / min, about 45 mg / mL / min, about 50 mg / mL / min, or any range between any two of the foregoing.

[0354] In some embodiments, the carboplatin is administered at a frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks. In some particular embodiments, the carboplatin is administered at a frequency of once every 3 weeks.

[0355] In some embodiments, the carboplatin is administered at a dose (in AUC) of about 0.1 mg / mL / min to about 50 mg / mL / min at a frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks. In some embodiments, the carboplatin is administered at a dose (in AUC) of about 0.1 mg / mL / min to about 50 mg / mL / min at a frequency of once every 3 weeks.

[0356] In some embodiments, the carboplatin is administered at a dose (in AUC) of about 1 mg / mL / min to about 20 mg / mL / min at a frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks. In some embodiments, the carboplatin is administered at a dose (in AUC) of about 1 mg / mL / min to about 20 mg / mL / min at a frequency of once every 3 weeks.

[0357] In some embodiments, the carboplatin is administered at a dose (in AUC) of about 1 mg / mL / min to about 10 mg / mL / min at a frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks. In some embodiments, the carboplatin is administered at a dose (in AUC) of about 1 mg / mL / min to about 10 mg / mL / min at a frequency of once every 3 weeks.

[0358] In some embodiments, the carboplatin is administered at a dose (in AUC) of about 1 mg / mL / min to about 8 mg / mL / min at a frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks. In some embodiments, the carboplatin is administered at a dose (in AUC) of about 1 mg / mL / min to about 8 mg / mL / min at a frequency of once every 3 weeks.

[0359] In some embodiments, the carboplatin is administered at a dose (in AUC) of about 2 mg / mL / min to about 10 mg / mL / min at a frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks. In some embodiments, the carboplatin is administered at a dose (in AUC) of about 2 mg / mL / min to about 10 mg / mL / min at a frequency of once every 3 weeks.

[0360] In some embodiments, the carboplatin is administered at a dose (in AUC) of about 2 mg / mL / min to about 8 mg / mL / min at a frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks. In some embodiments, the carboplatin is administered at a dose (in AUC) of about 2 mg / mL / min to about 8 mg / mL / min at a frequency of once every 3 weeks.

[0361] In some specific embodiments, the carboplatin is administered at a dose (in AUC) of about 3 mg / mL / min to about 8 mg / mL / min at a frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks. In some specific embodiments, the carboplatin is administered at a dose (in AUC) of about 3 mg / mL / min to about 8 mg / mL / min at a frequency of once every 3 weeks.

[0362] In some specific embodiments, the carboplatin is administered at a dose (in AUC) of about 1 mg / mL / min to about 6 mg / mL / min at a frequency of once every 3 weeks.

[0363] In some embodiments, the dose of carboplatin administered (in AUC) is about 2 mg / mL / min to about 6 mg / mL / min, with a dosing frequency of once every 3 weeks.

[0364] In some embodiments, the dose of carboplatin administered (in AUC) is about 3 mg / mL / min to about 6 mg / mL / min, with a dosing frequency of once every 3 weeks.

[0365] In some embodiments, the dose of carboplatin administered (in AUC) is about 4 mg / mL / min to about 6 mg / mL / min, with a dosing frequency of once every 3 weeks.

[0366] In some embodiments, the dose of carboplatin administered (in AUC) is about 5 mg / mL / min to about 6 mg / mL / min, with a dosing frequency of once every 3 weeks.

[0367] In some embodiments, the dose of carboplatin administered (in AUC) is about 2 mg / mL / min, with a dosing frequency of once every 3 weeks.

[0368] In some embodiments, the dose of carboplatin administered (in AUC) is about 3 mg / mL / min, with a dosing frequency of once every 3 weeks.

[0369] In some embodiments, the dose of carboplatin administered (in AUC) is about 4 mg / mL / min, with a dosing frequency of once every 3 weeks.

[0370] In some embodiments, the dose of carboplatin administered (in AUC) is about 5 mg / mL / min, with a dosing frequency of once every 3 weeks.

[0371] In some embodiments, the dose of carboplatin administered (in AUC) is about 6 mg / mL / min, with a dosing frequency of once every 3 weeks.

[0372] In some embodiments, the dose of carboplatin administered (in AUC) is about 7 mg / mL / min, with a dosing frequency of once every 3 weeks.

[0373] In some embodiments, the dose of carboplatin administered (in AUC) is about 8 mg / mL / min, with a dosing frequency of once every 3 weeks.

[0374] In some embodiments, the route of administration of carboplatin can be oral administration, parenteral administration, transdermal administration, including but not limited to intravenous injection, subcutaneous injection, intramuscular injection. In some specific embodiments, the route of administration of carboplatin is intravenous injection. In some specific embodiments, the route of administration of carboplatin is intravenous infusion.

[0375] Dosing regimen

[0376] In some embodiments, the use, method or composition of any of the foregoing is selected from any one of the following drug dosing regimens:

[0377] (1) anti-Nectin-4 antibody drug conjugate monotherapy,

[0378] (2) anti-Nectin-4 antibody drug conjugate in combination with anti-PD-L1 antibody,

[0379] (3) anti-Nectin-4 antibody drug conjugate in combination with anti-CTLA-4 antibody,

[0380] (4) anti-Nectin-4 antibody drug conjugate in combination with anti-PD-L1 antibody and anti-CTLA-4 antibody,

[0381] (5) anti-Nectin-4 antibody drug conjugate in combination with anti-PD-L1 antibody and anti-VEGF antibody,

[0382] (6) anti-Nectin-4 antibody drug conjugate in combination with anti-PD-L1 antibody, anti-CTLA-4 antibody and anti-VEGF antibody

[0383] (7) anti-Nectin-4 antibody drug conjugate in combination with anti-PD-L1 antibody and carboplatin.

[0384] (8) anti-Nectin-4 antibody drug conjugate in combination with anti-PD-L1 antibody and cisplatin.

[0385] In some embodiments, the dosing regimen of anti-Nectin-4 antibody drug conjugate monotherapy is:

[0386] a) the dosing amount of anti-Nectin-4 antibody drug conjugate is 0.1-50 mg / kg, and the dosing frequency is at least once every 2 weeks, at least once every 3 weeks, at least once every 4 weeks, at least once every 6 weeks, or at least once every 8 weeks;

[0387] a) the dosing amount of anti-Nectin-4 antibody drug conjugate is 0.1-20 mg / kg, and the dosing frequency is at least once every 2 weeks, at least once every 3 weeks, at least once every 4 weeks, at least once every 6 weeks, or at least once every 8 weeks;

[0388] a) the dosing amount of anti-Nectin-4 antibody drug conjugate is 1-15 mg / kg, and the dosing frequency is once every 2 weeks, once every 3 weeks, twice every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks;

[0389] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, or about 10 mg / kg, and the frequency of administration is once every 2 weeks, once every 3 weeks, twice every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks;

[0390] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, or about 10 mg / kg, and the frequency of administration is once every 2 weeks, once every 3 weeks, twice every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks;

[0391] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, or about 10 mg / kg, and the frequency of administration is once every 3 weeks or twice every 3 weeks;

[0392] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg, and the frequency of administration is once every 3 weeks; or

[0393] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, and the frequency of administration is twice every 3 weeks.

[0394] In some embodiments, the dosing regimen for the anti-Nectin-4 antibody drug conjugate in combination with an anti-PD-L1 antibody is:

[0395] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 0.1-50 mg / kg, and the frequency of administration is at least once every 2 weeks, at least once every 3 weeks, at least once every 4 weeks, at least once every 6 weeks, or at least once every 8 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg, and the frequency of administration is once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks;

[0396] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 0.1-20 mg / kg, and the frequency of administration is once every 2 weeks, once every 3 weeks, twice every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg, and the frequency of administration is once every 3 weeks;

[0397] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 1-10 mg / kg with a dosing frequency of twice every 3 weeks or once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg with a dosing frequency of once every 3 weeks;

[0398] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, or about 10 mg / kg; with a dosing frequency of twice every 3 weeks or once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg with a dosing frequency of once every 3 weeks;

[0399] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg; with a dosing frequency of once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg with a dosing frequency of once every 3 weeks;

[0400] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 1 mg / kg, about 2 mg / kg, about 3 mg / kg, or about 4 mg / kg; with a dosing frequency of twice every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg with a dosing frequency of once every 3 weeks;

[0401] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 1-10 mg / kg with a dosing frequency of twice every 3 weeks or once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 100 mg, about 500 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, about 2500 mg, about 3000 mg, with a dosing frequency of once every 3 weeks;

[0402] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg, with a dosing frequency of twice every 3 weeks or once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 100 mg, about 500 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, about 2500 mg, about 3000 mg, with a dosing frequency of once every 3 weeks;

[0403] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 3 mg / kg, or about 4 mg / kg, with a dosing frequency of twice every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 100 mg, about 500 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, about 2500 mg, about 3000 mg, with a dosing frequency of once every 3 weeks;

[0404] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 3 mg / kg, or about 4 mg / kg, with a dosing frequency of twice every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 1200 mg, with a dosing frequency of once every 3 weeks;

[0405] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg, with a dosing frequency of once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 100 mg, about 500 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, about 2500 mg, about 3000 mg, with a dosing frequency of once every 3 weeks;

[0406] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg with a dosing frequency of once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 1200 mg with a dosing frequency of once every 3 weeks;

[0407] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 4 mg / kg with a dosing frequency of twice every 3 weeks, dosed on D1, D8 of each cycle; b1) the anti-PD-L1 antibody is administered at a dose of about 1200 mg with a dosing frequency of once every 3 weeks;

[0408] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 6 mg / kg with a dosing frequency of once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 1200 mg with a dosing frequency of once every 3 weeks; or,

[0409] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 8 mg / kg with a dosing frequency of once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 1200 mg with a dosing frequency of once every 3 weeks.

[0410] In some embodiments, the dosing regimen of the anti-Nectin-4 antibody drug conjugate in combination with an anti-CTLA-4 antibody is:

[0411] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 0.1-50 mg / kg with a dosing frequency of at least once every 2 weeks, at least once every 3 weeks, at least once every 4 weeks, at least once every 6 weeks, or at least once every 8 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of 1-1000 mg with a dosing frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, once every 12 weeks, once every 14 weeks, once every 16 weeks, or as a single dose;

[0412] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 1-20 mg / kg with a dosing frequency of once every 2 weeks, once every 3 weeks, twice every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of 1-1000 mg with a dosing frequency of once every 6 weeks or as a single dose;

[0413] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 1-10 mg / kg with a dosing frequency of twice every 3 weeks or once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of 1-1000 mg with a dosing frequency of once every 6 weeks or as a single dose;

[0414] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, or about 10 mg / kg; the frequency of administration is twice every 3 weeks or once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of 1-1000 mg, the frequency of administration is once every 6 weeks or single administration;

[0415] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg; the frequency of administration is once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of 1-1000 mg, the frequency of administration is once every 6 weeks or single administration;

[0416] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 1 mg / kg, about 2 mg / kg, about 3 mg / kg, or about 4 mg / kg; the frequency of administration is twice every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of 1-1000 mg, the frequency of administration is once every 6 weeks or single administration;

[0417] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 1-10 mg / kg, the frequency of administration is twice every 3 weeks or once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 500 mg, or about 700 mg, the frequency of administration is once every 6 weeks or single administration;

[0418] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg, with a dosing frequency of twice every 3 weeks or once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 500 mg, or about 700 mg, with a dosing frequency of once every 6 weeks or a single dose;

[0419] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 3 mg / kg, or about 4 mg / kg, with a dosing frequency of twice every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 500 mg, or about 700 mg, with a dosing frequency of once every 6 weeks or a single dose;

[0420] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg, with a dosing frequency of once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 500 mg, or about 700 mg, with a dosing frequency of once every 6 weeks or a single dose;

[0421] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 4 mg / kg with a dosing frequency of twice every 3 weeks, on D1, D8 of each cycle; b2) the anti-CTLA-4 antibody is administered at a dose of about 280 mg or 210 mg as a single dose at week 1, no dose from week 2-12, and a dose of about 70 mg with a dosing frequency of once every 6 weeks starting from week 13;

[0422] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 6 mg / kg with a dosing frequency of once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of about 280 mg or 210 mg as a single dose at week 1, no dose from week 2-12, and a dose of about 70 mg with a dosing frequency of once every 6 weeks starting from week 13; or,

[0423] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 8 mg / kg with a dosing frequency of once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of about 280 mg or 210 mg as a single dose at week 1, no dose from week 2-12, and a dose of about 70 mg with a dosing frequency of once every 6 weeks starting from week 13.

[0424] In some embodiments, the dosing regimen of the anti-Nectin-4 antibody drug conjugate in combination with an anti-PD-L1 antibody and an anti-CTLA-4 antibody is:

[0425] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 0.1-50 mg / kg with a dosing frequency of at least once every 2 weeks, at least once every 3 weeks, at least once every 4 weeks, at least once every 6 weeks, or at least once every 8 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg with a dosing frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of 1-1000 mg with a dosing frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, once every 12 weeks, once every 14 weeks, once every 16 weeks, or as a single dose;

[0426] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 1-20 mg / kg with a dosing frequency of once every 2 weeks, once every 3 weeks, twice every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg with a dosing frequency of once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of 1-1000 mg with a dosing frequency of once every 6 weeks or as a single dose;

[0427] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 1-10 mg / kg with a dosing frequency of twice every 3 weeks or once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg with a dosing frequency of once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of 1-1000 mg with a dosing frequency of once every 6 weeks or a single dose;

[0428] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, or about 10 mg / kg; with a dosing frequency of twice every 3 weeks or once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg with a dosing frequency of once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of 1-1000 mg with a dosing frequency of once every 6 weeks or a single dose;

[0429] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg; with a dosing frequency of once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg with a dosing frequency of once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of 1-1000 mg with a dosing frequency of once every 6 weeks or a single dose;

[0430] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 1 mg / kg, about 2 mg / kg, about 3 mg / kg, or about 4 mg / kg; with a dosing frequency of twice every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg with a dosing frequency of once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of 1-1000 mg with a dosing frequency of once every 6 weeks or a single dose;

[0431] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 1-10 mg / kg with a dosing frequency of twice every 3 weeks or once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 100 mg, about 500 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, about 2500 mg, about 3000 mg with a dosing frequency of once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 500 mg, or about 700 mg with a dosing frequency of once every 6 weeks or a single dose;

[0432] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg with a dosing frequency of twice every 3 weeks or once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 100 mg, about 500 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, about 2500 mg, about 3000 mg with a dosing frequency of once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 500 mg, or about 700 mg with a dosing frequency of once every 6 weeks or a single dose;

[0433] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 3 mg / kg, or about 4 mg / kg, with a dosing frequency of twice every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 100 mg, about 500 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, about 2500 mg, about 3000 mg, with a dosing frequency of once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 500 mg, or about 700 mg, with a dosing frequency of once every 6 weeks or a single dose;

[0434] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg, with a dosing frequency of once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 100 mg, about 500 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, about 2500 mg, about 3000 mg, with a dosing frequency of once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 500 mg, or about 700 mg, with a dosing frequency of once every 6 weeks or a single dose;

[0435] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 4 mg / kg with a dosing frequency of twice every 3 weeks, on D1, D8 of each cycle; b1) the anti-PD-L1 antibody is administered at a dose of about 1200 mg with a dosing frequency of once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of about 280 mg or 210 mg once in week 1, no administration in weeks 2-12, and a dose of about 70 mg with a dosing frequency of once every 6 weeks starting from week 13;

[0436] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 6 mg / kg with a dosing frequency of once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 1200 mg with a dosing frequency of once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of about 280 mg or 210 mg once in week 1, no administration in weeks 2-12, and a dose of about 70 mg with a dosing frequency of once every 6 weeks starting from week 13; or,

[0437] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 8 mg / kg with a dosing frequency of once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 1200 mg with a dosing frequency of once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of about 280 mg or 210 mg once in week 1, no administration in weeks 2-12, and a dose of about 70 mg with a dosing frequency of once every 6 weeks starting from week 13.

[0438] In some embodiments, the dosing regimen of the anti-Nectin-4 antibody drug conjugate in combination with an anti-PD-L1 antibody and an anti-VEGF antibody is:

[0439] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 0.1-50 mg / kg with a dosing frequency of at least once every 2 weeks, at least once every 3 weeks, at least once every 4 weeks, at least once every 6 weeks, or at least once every 8 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg with a dosing frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks; b2) the anti-VEGF antibody is administered at a dose of 1 mg / kg-30 mg / kg with a dosing frequency of once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks;

[0440] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 0.1-20 mg / kg with a dosing frequency of once every 2 weeks, once every 3 weeks, twice every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg with a dosing frequency of once every 3 weeks; b2) the anti-VEGF antibody is administered at a dose of 1 mg / kg-30 mg / kg with a dosing frequency of once every 3 weeks;

[0441] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 1-10 mg / kg with a dosing frequency of twice every 3 weeks or once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg with a dosing frequency of once every 3 weeks; b2) the anti-VEGF antibody is administered at a dose of 1 mg / kg-30 mg / kg with a dosing frequency of once every 3 weeks;

[0442] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, or about 10 mg / kg; with a dosing frequency of twice every 3 weeks or once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg with a dosing frequency of once every 3 weeks; b2) the anti-VEGF antibody is administered at a dose of 1 mg / kg-30 mg / kg with a dosing frequency of once every 3 weeks;

[0443] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg; with a dosing frequency of once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg with a dosing frequency of once every 3 weeks; b2) the anti-VEGF antibody is administered at a dose of 1 mg / kg-30 mg / kg with a dosing frequency of once every 3 weeks;

[0444] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 1 mg / kg, about 2 mg / kg, about 3 mg / kg, or about 4 mg / kg; with a dosing frequency of twice every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg with a dosing frequency of once every 3 weeks; b2) the anti-VEGF antibody is administered at a dose of 1 mg / kg-30 mg / kg with a dosing frequency of once every 3 weeks;

[0445] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 1-10 mg / kg with a dosing frequency of twice every 3 weeks or once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 100 mg, about 500 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, about 2500 mg, about 3000 mg with a dosing frequency of once every 3 weeks; b2) the anti-VEGF antibody is administered at a dose of about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5 mg / kg, about 6.0 mg / kg, about 7.5 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, or about 25.0 mg / kg with a dosing frequency of once every 3 weeks;

[0446] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg with a dosing frequency of twice every 3 weeks or once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 100 mg, about 500 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, about 2500 mg, about 3000 mg with a dosing frequency of once every 3 weeks; b2) the anti-VEGF antibody is administered at a dose of about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5 mg / kg, about 6.0 mg / kg, about 7.5 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, or about 25.0 mg / kg with a dosing frequency of once every 3 weeks;

[0447] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 3 mg / kg, or about 4 mg / kg, with a dosing frequency of twice every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 100 mg, about 500 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, about 2500 mg, about 3000 mg, with a dosing frequency of once every 3 weeks; b2) the anti-VEGF antibody is administered at a dose of about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5 mg / kg, about 6.0 mg / kg, about 7.5 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, or about 25.0 mg / kg, with a dosing frequency of once every 3 weeks;

[0448] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 3 mg / kg, or about 4 mg / kg, with a dosing frequency of twice every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 1200 mg, with a dosing frequency of once every 3 weeks; b2) the anti-VEGF antibody is administered at a dose of about 7.5 mg / kg or about 15 mg / kg, with a dosing frequency of once every 3 weeks;

[0449] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg with a dosing frequency of once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 100 mg, about 500 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, about 2500 mg, about 3000 mg with a dosing frequency of once every 3 weeks; b2) the anti-VEGF antibody is administered at a dose of about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5 mg / kg, about 6.0 mg / kg, about 7.5 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, or about 25.0 mg / kg with a dosing frequency of once every 3 weeks;

[0450] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg with a dosing frequency of once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 1200 mg with a dosing frequency of once every 3 weeks; b2) the anti-VEGF antibody is administered at a dose of about 7.5 mg / kg with a dosing frequency of once every 3 weeks;

[0451] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg with a dosing frequency of once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 1200 mg with a dosing frequency of once every 3 weeks; b2) the anti-VEGF antibody is administered at a dose of about 15 mg / kg with a dosing frequency of once every 3 weeks;

[0452] a) the dosing regimen of the anti-Nectin-4 antibody drug conjugate is about 4 mg / kg, with a dosing frequency of twice every 3 weeks, administered on D1, D8 of each cycle; b1) the dosing regimen of the anti-PD-L1 antibody is about 1200 mg, with a dosing frequency of once every 3 weeks; b2) the dosing regimen of the anti-VEGF antibody is about 7.5 mg / kg, with a dosing frequency of once every 3 weeks;

[0453] a) the dosing regimen of the anti-Nectin-4 antibody drug conjugate is about 4 mg / kg, with a dosing frequency of twice every 3 weeks, administered on D1, D8 of each cycle; b1) the dosing regimen of the anti-PD-L1 antibody is about 1200 mg, with a dosing frequency of once every 3 weeks; b2) the dosing regimen of the anti-VEGF antibody is about 15 mg / kg, with a dosing frequency of once every 3 weeks;

[0454] a) the dosing regimen of the anti-Nectin-4 antibody drug conjugate is about 6 mg / kg, with a dosing frequency of once every 3 weeks; b1) the dosing regimen of the anti-PD-L1 antibody is about 1200 mg, with a dosing frequency of once every 3 weeks; b2) the dosing regimen of the anti-VEGF antibody is about 7.5 mg / kg, with a dosing frequency of once every 3 weeks;

[0455] a) the dosing regimen of the anti-Nectin-4 antibody drug conjugate is about 6 mg / kg, with a dosing frequency of once every 3 weeks; b1) the dosing regimen of the anti-PD-L1 antibody is about 1200 mg, with a dosing frequency of once every 3 weeks; b2) the dosing regimen of the anti-VEGF antibody is about 15 mg / kg, with a dosing frequency of once every 3 weeks;

[0456] a) the dosing regimen of the anti-Nectin-4 antibody drug conjugate is about 8 mg / kg, with a dosing frequency of once every 3 weeks; b1) the dosing regimen of the anti-PD-L1 antibody is about 1200 mg, with a dosing frequency of once every 3 weeks; b2) the dosing regimen of the anti-VEGF antibody is about 7.5 mg / kg, with a dosing frequency of once every 3 weeks;

[0457] a) the dosing regimen of the anti-Nectin-4 antibody drug conjugate is about 8 mg / kg, with a dosing frequency of once every 3 weeks; b1) the dosing regimen of the anti-PD-L1 antibody is about 1200 mg, with a dosing frequency of once every 3 weeks; b2) the dosing regimen of the anti-VEGF antibody is about 15 mg / kg, with a dosing frequency of once every 3 weeks.

[0458] In some embodiments, the dosing regimen of the anti-Nectin-4 antibody drug conjugate in combination with an anti-PD-L1 antibody, an anti-CTLA-4 antibody, and an anti-VEGF antibody is:

[0459] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 0.1-50 mg / kg with a frequency of at least once every 2 weeks, at least once every 3 weeks, at least once every 4 weeks, at least once every 6 weeks, or at least once every 8 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg with a frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of 1-1000 mg with a frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, once every 12 weeks, once every 14 weeks, once every 16 weeks, or as a single dose; b3) the anti-VEGF antibody is administered at a dose of 1 mg / kg-30 mg / kg with a frequency of once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks;

[0460] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 1-20 mg / kg with a frequency of once every 2 weeks, once every 3 weeks, twice every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg with a frequency of once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of 1-1000 mg with a frequency of once every 6 weeks or as a single dose; b3) the anti-VEGF antibody is administered at a dose of 1 mg / kg-30 mg / kg with a frequency of once every 3 weeks;

[0461] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 1-10 mg / kg with a frequency of twice every 3 weeks or once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg with a frequency of once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of 1-1000 mg with a frequency of once every 6 weeks or as a single dose; b3) the anti-VEGF antibody is administered at a dose of 1 mg / kg-30 mg / kg with a frequency of once every 3 weeks;

[0462] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, or about 10 mg / kg; the frequency of administration is twice every 3 weeks or once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg, the frequency of administration is once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of 1-1000 mg, the frequency of administration is once every 6 weeks or single administration; b3) the anti-VEGF antibody is administered at a dose of 1 mg / kg-30 mg / kg, the frequency of administration is once every 3 weeks;

[0463] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg; the frequency of administration is once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg, the frequency of administration is once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of 1-1000 mg, the frequency of administration is once every 6 weeks or single administration; b3) the anti-VEGF antibody is administered at a dose of 1 mg / kg-30 mg / kg, the frequency of administration is once every 3 weeks;

[0464] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 1 mg / kg, about 2 mg / kg, about 3 mg / kg, or about 4 mg / kg; the frequency of administration is twice every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg, the frequency of administration is once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of 1-1000 mg, the frequency of administration is once every 6 weeks or single administration; b3) the anti-VEGF antibody is administered at a dose of 1 mg / kg-30 mg / kg, the frequency of administration is once every 3 weeks;

[0465] a) the dosing amount of the anti-Nectin-4 antibody drug conjugate is 1-10 mg / kg, and the dosing frequency is 2 times per 3 weeks or 1 time per 3 weeks; b1) the dosing amount of the anti-PD-L1 antibody is about 100 mg, about 500 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, about 2500 mg, about 3000 mg, and the dosing frequency is 1 time per 3 weeks; b2) the dosing amount of the anti-CTLA-4 antibody is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 500 mg, or about 700 mg, and the dosing frequency is 1 time per 6 weeks or single dosing; b3) the dosing amount of the anti-VEGF antibody is 1 mg / kg-30 mg / kg, and the dosing frequency is 1 time per 3 weeks;

[0466] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg, with a dosing frequency of twice every 3 weeks or once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 100 mg, about 500 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, about 2500 mg, about 3000 mg, with a dosing frequency of once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 500 mg, or about 700 mg, with a dosing frequency of once every 6 weeks or a single dose; b3) the anti-VEGF antibody is administered at a dose of about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5 mg / kg, about 6.0 mg / kg, about 7.5 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, or about 25.0 mg / kg, with a dosing frequency of once every 3 weeks;

[0467] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 3 mg / kg, or about 4 mg / kg, with a dosing frequency of twice every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 100 mg, about 500 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, about 2500 mg, about 3000 mg, with a dosing frequency of once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 500 mg, or about 700 mg, with a dosing frequency of once every 6 weeks or a single dose; b3) the anti-VEGF antibody is administered at a dose of about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5 mg / kg, about 6.0 mg / kg, about 7.5 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, or about 25.0 mg / kg, with a dosing frequency of once every 3 weeks;

[0468] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg with a dosing frequency of once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 100 mg, about 500 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, about 2500 mg, about 3000 mg with a dosing frequency of once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 500 mg, or about 700 mg with a dosing frequency of once every 6 weeks or a single dose; b3) the anti-VEGF antibody is administered at a dose of about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5 mg / kg, about 6.0 mg / kg, about 7.5 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, or about 25.0 mg / kg with a dosing frequency of once every 3 weeks;

[0469] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 4 mg / kg with a dosing frequency of twice every 3 weeks, on D1, D8 of each cycle; b1) the anti-PD-L1 antibody is administered at a dose of about 1200 mg with a dosing frequency of once every 3 weeks; b2) the anti-CTLA-4 antibody is administered as a single dose in week 1 at a dose of about 280 mg or 210 mg, no dose from week 2 to week 12, and from week 13, the dose is about 70 mg with a dosing frequency of once every 6 weeks; b3) the anti-VEGF antibody is administered at a dose of about 7.5 mg / kg with a dosing frequency of once every 3 weeks;

[0470] a) the dosing amount of the anti-Nectin-4 antibody drug conjugate is about 4 mg / kg, the dosing frequency is 2 times per 3 weeks, and the drug is administered on D1, D8 of each cycle; b1) the dosing amount of the anti-PD-L1 antibody is about 1200 mg, the dosing frequency is 1 time per 3 weeks; b2) the anti-CTLA-4 antibody is administered once at the first week, the dosing amount is about 280 mg or 210 mg, no drug is administered from the second week to the twelfth week, and the dosing amount is about 70 mg, the dosing frequency is 1 time per 6 weeks, starting from the thirteenth week; b3) the dosing amount of the anti-VEGF antibody is about 15 mg / kg, the dosing frequency is 1 time per 3 weeks;

[0471] a) the dosing amount of the anti-Nectin-4 antibody drug conjugate is about 6 mg / kg, the dosing frequency is 1 time per 3 weeks; b1) the dosing amount of the anti-PD-L1 antibody is about 1200 mg, the dosing frequency is 1 time per 3 weeks; b2) the anti-CTLA-4 antibody is administered once at the first week, the dosing amount is about 280 mg or 210 mg, no drug is administered from the second week to the twelfth week, and the dosing amount is about 70 mg, the dosing frequency is 1 time per 6 weeks, starting from the thirteenth week; b3) the dosing amount of the anti-VEGF antibody is about 7.5 mg / kg, the dosing frequency is 1 time per 3 weeks;

[0472] a) the dosing amount of the anti-Nectin-4 antibody drug conjugate is about 6 mg / kg, the dosing frequency is 1 time per 3 weeks; b1) the dosing amount of the anti-PD-L1 antibody is about 1200 mg, the dosing frequency is 1 time per 3 weeks; b2) the anti-CTLA-4 antibody is administered once at the first week, the dosing amount is about 280 mg or 210 mg, no drug is administered from the second week to the twelfth week, and the dosing amount is about 70 mg, the dosing frequency is 1 time per 6 weeks, starting from the thirteenth week; b3) the dosing amount of the anti-VEGF antibody is about 15 mg / kg, the dosing frequency is 1 time per 3 weeks;

[0473] a) the dosing amount of the anti-Nectin-4 antibody drug conjugate is about 8 mg / kg, the dosing frequency is 1 time per 3 weeks; b1) the dosing amount of the anti-PD-L1 antibody is about 1200 mg, the dosing frequency is 1 time per 3 weeks; b2) the anti-CTLA-4 antibody is administered once at the first week, the dosing amount is about 280 mg or 210 mg, no drug is administered from the second week to the twelfth week, and the dosing amount is about 70 mg, the dosing frequency is 1 time per 6 weeks, starting from the thirteenth week; b3) the dosing amount of the anti-VEGF antibody is about 7.5 mg / kg, the dosing frequency is 1 time per 3 weeks; or

[0474] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 8 mg / kg with a dosing frequency of once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 1200 mg with a dosing frequency of once every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of about 280 mg or 210 mg as a single dose at week 1, no dose from week 2 to week 12, and a dose of about 70 mg with a dosing frequency of once every 6 weeks starting from week 13; b3) the anti-VEGF antibody is administered at a dose of about 15 mg / kg with a dosing frequency of once every 3 weeks.

[0475] In some embodiments, the dosing regimen of the anti-Nectin-4 antibody drug conjugate in combination with an anti-PD-L1 antibody and carboplatin is:

[0476] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 0.1-50 mg / kg with a dosing frequency of at least once every 2 weeks, at least once every 3 weeks, at least once every 4 weeks, at least once every 6 weeks, or at least once every 8 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg with a dosing frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks; b2) the carboplatin is administered at a dose (as AUC) of about 0.1 mg / mL / min to about 50 mg / mL / min with a dosing frequency of once every 3 weeks;

[0477] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 0.1-20 mg / kg with a dosing frequency of once every 2 weeks, once every 3 weeks, twice every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg with a dosing frequency of once every 3 weeks; b2) the carboplatin is administered at a dose (as AUC) of about 0.1 mg / mL / min to about 50 mg / mL / min with a dosing frequency of once every 3 weeks;

[0478] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 1-10 mg / kg with a dosing frequency of twice every 3 weeks or once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg with a dosing frequency of once every 3 weeks; b2) the carboplatin is administered at a dose (as AUC) of about 0.1 mg / mL / min to about 50 mg / mL / min with a dosing frequency of once every 3 weeks;

[0479] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, or about 10 mg / kg; the frequency of administration is twice every 3 weeks or once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg, the frequency of administration is once every 3 weeks; b2) the carboplatin is administered at a dose (as AUC) of about 0.1 mg / mL / min to about 50 mg / mL / min, the frequency of administration is once every 3 weeks;

[0480] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg; the frequency of administration is once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg, the frequency of administration is once every 3 weeks; b2) the carboplatin is administered at a dose (as AUC) of about 0.1 mg / mL / min to about 50 mg / mL / min, the frequency of administration is once every 3 weeks;

[0481] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 1 mg / kg, about 2 mg / kg, about 3 mg / kg, or about 4 mg / kg; the frequency of administration is twice every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg, the frequency of administration is once every 3 weeks; b2) the carboplatin is administered at a dose (as AUC) of about 0.1 mg / mL / min to about 50 mg / mL / min, the frequency of administration is once every 3 weeks;

[0482] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 1-10 mg / kg, the frequency of administration is twice every 3 weeks or once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 100 mg, about 500 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, about 2500 mg, about 3000 mg, the frequency of administration is once every 3 weeks; b2) the carboplatin is administered at a dose (as AUC) of about 1 mg / mL / min, about 2 mg / mL / min, about 3 mg / mL / min, about 4 mg / mL / min, about 5 mg / mL / min, about 6 mg / mL / min, about 7 mg / mL / min, about 8 mg / mL / min, about 9 mg / mL / min, about 10 mg / mL / min, the frequency of administration is once every 3 weeks;

[0483] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg, with a dosing frequency of twice every 3 weeks or once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 100 mg, about 500 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, about 2500 mg, about 3000 mg, with a dosing frequency of once every 3 weeks; b2) the carboplatin is administered at a dose (as AUC) of about 1 mg / mL / min, about 2 mg / mL / min, about 3 mg / mL / min, about 4 mg / mL / min, about 5 mg / mL / min, about 6 mg / mL / min, about 7 mg / mL / min, about 8 mg / mL / min, about 9 mg / mL / min, about 10 mg / mL / min, with a dosing frequency of once every 3 weeks;

[0484] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 3 mg / kg, or about 4 mg / kg, with a dosing frequency of twice every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 100 mg, about 500 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, about 2500 mg, about 3000 mg, with a dosing frequency of once every 3 weeks; b2) the carboplatin is administered at a dose (as AUC) of about 1 mg / mL / min, about 2 mg / mL / min, about 3 mg / mL / min, about 4 mg / mL / min, about 5 mg / mL / min, about 6 mg / mL / min, about 7 mg / mL / min, about 8 mg / mL / min, about 9 mg / mL / min, about 10 mg / mL / min, with a dosing frequency of once every 3 weeks;

[0485] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 3 mg / kg, or about 4 mg / kg, with a dosing frequency of twice every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 1200 mg, with a dosing frequency of once every 3 weeks; b2) the carboplatin is administered at a dose (as AUC) of about 4 mg / mL / min or 5 mg / mL / min, with a dosing frequency of once every 3 weeks;

[0486] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg with a dosing frequency of once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 1200 mg with a dosing frequency of once every 3 weeks; b2) the carboplatin is administered at a dose (as AUC) of about 4 mg / mL / min or 5 mg / mL / min with a dosing frequency of once every 3 weeks;

[0487] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg with a dosing frequency of once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 1200 m with a dosing frequency of once every 3 weeks; b2) the carboplatin is administered at a dose (as AUC) of about 4 mg / mL / min or 5 mg / mL / min with a dosing frequency of once every 3 weeks;

[0488] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 4 mg / kg with a dosing frequency of twice every 3 weeks, administered on D1, D8 of each cycle; b1) the anti-PD-L1 antibody is administered at a dose of about 1200 mg with a dosing frequency of once every 3 weeks; b2) the carboplatin is administered at a dose (as AUC) of about 4 mg / mL / min with a dosing frequency of once every 3 weeks;

[0489] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 4 mg / kg with a dosing frequency of twice every 3 weeks, administered on D1, D8 of each cycle; b1) the anti-PD-L1 antibody is administered at a dose of about 1200 mg with a dosing frequency of once every 3 weeks; b2) the carboplatin is administered at a dose (as AUC) of about 5 mg / mL / min with a dosing frequency of once every 3 weeks;

[0490] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 6 mg / kg with a dosing frequency of once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 1200 mg with a dosing frequency of once every 3 weeks; b2) the carboplatin is administered at a dose (on an AUC scale) of about 4 mg / mL / min with a dosing frequency of once every 3 weeks;

[0491] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 6 mg / kg with a dosing frequency of once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 1200 mg with a dosing frequency of once every 3 weeks; b2) the carboplatin is administered at a dose (on an AUC scale) of about 5 mg / mL / min with a dosing frequency of once every 3 weeks;

[0492] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 8 mg / kg with a dosing frequency of once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 1200 mg with a dosing frequency of once every 3 weeks; b2) the carboplatin is administered at a dose (on an AUC scale) of about 4 mg / mL / min with a dosing frequency of once every 3 weeks; or,

[0493] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 8 mg / kg with a dosing frequency of once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 1200 mg with a dosing frequency of once every 3 weeks; b2) the carboplatin is administered at a dose (on an AUC scale) of about 5 mg / mL / min with a dosing frequency of once every 3 weeks.

[0494] In some embodiments, the dosing regimen for the anti-Nectin-4 antibody drug conjugate in combination with an anti-PD-L1 antibody and cisplatin is:

[0495] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 0.1-50 mg / kg with a dosing frequency of at least once every 2 weeks, at least once every 3 weeks, at least once every 4 weeks, at least once every 6 weeks, or at least once every 8 weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg with a dosing frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks; b2) the cisplatin is administered at a dose of about 1 mg / m 2 to about 500 mg / m 2 with a dosing frequency of once every 3 weeks;

[0496] a) the dosing amount of the anti-Nectin-4 antibody drug conjugate is 0.1-20 mg / kg, and the dosing frequency is once every 2 weeks, once every 3 weeks, twice every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks; b1) the dosing amount of the anti-PD-L1 antibody is 5-5000 mg, and the dosing frequency is once every 3 weeks; b2) the dosing amount of cisplatin is about 1 mg / m 2 to about 500 mg / m 2 , and the dosing frequency is once every 3 weeks;

[0497] a) the dosing amount of the anti-Nectin-4 antibody drug conjugate is 1-10 mg / kg, and the dosing frequency is twice every 3 weeks or once every 3 weeks; b1) the dosing amount of the anti-PD-L1 antibody is 5-5000 mg, and the dosing frequency is once every 3 weeks; b2) the dosing amount of cisplatin is about 1 mg / m 2 to about 500 mg / m 2 , and the dosing frequency is once every 3 weeks;

[0498] a) the dosing amount of the anti-Nectin-4 antibody drug conjugate is about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, or about 10 mg / kg; and the dosing frequency is twice every 3 weeks or once every 3 weeks; b1) the dosing amount of the anti-PD-L1 antibody is 5-5000 mg, and the dosing frequency is once every 3 weeks; b2) the dosing amount of cisplatin is about 1 mg / m 2 to about 500 mg / m 2 , and the dosing frequency is once every 3 weeks;

[0499] a) the dosing amount of the anti-Nectin-4 antibody drug conjugate is about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg; and the dosing frequency is once every 3 weeks; b1) the dosing amount of the anti-PD-L1 antibody is 5-5000 mg, and the dosing frequency is once every 3 weeks; b2) the dosing amount of cisplatin is about 1 mg / m 2 to about 500 mg / m 2 , and the dosing frequency is once every 3 weeks;

[0500] a) the dosing amount of the anti-Nectin-4 antibody drug conjugate is 1 mg / kg, about 2 mg / kg, about 3 mg / kg, or about 4 mg / kg; and the dosing frequency is twice every 3 weeks; b1) the dosing amount of the anti-PD-L1 antibody is 5-5000 mg, and the dosing frequency is once every 3 weeks; b2) the dosing amount of cisplatin is about 1 mg / m 2 to about 500 mg / m 2at a dose of 1-10 mg / kg once every 3 weeks;

[0501] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 1-10 mg / kg twice every 3 weeks or once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 100 mg, about 500 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, about 2500 mg, about 3000 mg once every 3 weeks; b2) the cisplatin is administered at a dose of about 50 mg / m 2 , about 51 mg / m 2 , about 52 mg / m 2 , about 53 mg / m 2 , about 55 mg / m 2 , about 57 mg / m 2 , about 58 mg / m 2 , about 60 mg / m 2 , about 61 mg / m 2 , about 62 mg / m 2 , about 63 mg / m 2 , about 64 mg / m 2 , about 65 mg / m 2 , about 66 mg / m 2 , about 67 mg / m 2 , about 68 mg / m 2 , about 69 mg / m 2 , about 70 mg / m 2 , about 71 mg / m 2 , about 72 mg / m 2 , about 73 mg / m 2 , about 74 mg / m 2 , about 75 mg / m 2 , about 76 mg / m 2 , about 77 mg / m 2 , about 78 mg / m 2 , about 79 mg / m 2 , about 80 mg / m 2 , about 81 mg / m 2 , about 82 mg / m 2 , about 83 mg / m 2 , about 84 mg / m 2 , about 85 mg / m 2 , about 86 mg / m 2 , about 87 mg / m 2 , about 88 mg / m2 about 89 mg / m 2 about 90 mg / m 2 about 95 mg / m 2 about 100 mg / m 2 about 150 mg / m 2 with a dosing frequency of once every 3 weeks;

[0502] a) the dosing amount of the anti-Nectin-4 antibody drug conjugate is about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg or about 10 mg / kg, with a dosing frequency of twice every 3 weeks or once every 3 weeks; b1) the dosing amount of the anti-PD-L1 antibody is about 100 mg, about 500 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, about 2500 mg, about 3000 mg, with a dosing frequency of once every 3 weeks; b2) the dosing amount of cisplatin is about 50 mg / m 2 about 51 mg / m 2 about 52 mg / m 2 about 53 mg / m 2 about 55 mg / m 2 about 57 mg / m 2 about 58 mg / m 2 about 60 mg / m 2 about 61 mg / m 2 about 62 mg / m 2 about 63 mg / m 2 about 64 mg / m 2 about 65 mg / m 2 about 66 mg / m 2 about 67 mg / m 2 about 68 mg / m 2 about 69 mg / m 2 about 70 mg / m 2 about 71 mg / m 2 about 72 mg / m 2 about 73 mg / m 2 about 74 mg / m 2 about 75 mg / m 2 about 76 mg / m 2 about 77 mg / m 2 about 78 mg / m 2 about 79 mg / m2 about 80 mg / m 2 about 81 mg / m 2 about 82 mg / m 2 about 83 mg / m 2 about 84 mg / m 2 about 85 mg / m 2 about 86 mg / m 2 about 87 mg / m 2 about 88 mg / m 2 about 89 mg / m 2 about 90 mg / m 2 about 95 mg / m 2 about 100 mg / m 2 about 150 mg / m 2 at a dosing frequency of once every 3 weeks;

[0503] a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 3 mg / kg, or about 4 mg / kg, at a dosing frequency of twice every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 100 mg, about 500 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, about 2500 mg, about 3000 mg, at a dosing frequency of once every 3 weeks; b2) the cisplatin is administered at a dose of about 50 mg / m 2 about 51 mg / m 2 about 52 mg / m 2 about 53 mg / m 2 about 55 mg / m 2 about 57 mg / m 2 about 58 mg / m 2 about 60 mg / m 2 about 61 mg / m 2 about 62 mg / m 2 about 63 mg / m 2 about 64 mg / m 2 about 65 mg / m 2 about 66 mg / m 2 about 67 mg / m 2 about 68 mg / m 2 about 69 mg / m 2 about 70 mg / m 2 about 71 mg / m 2 about 72 mg / m 2 about 73 mg / m 2about 74 mg / m 2 about 75 mg / m 2 about 76 mg / m 2 about 77 mg / m 2 about 78 mg / m 2 about 79 mg / m 2 about 80 mg / m 2 about 81 mg / m 2 about 82 mg / m 2 about 83 mg / m 2 about 84 mg / m 2 about 85 mg / m 2 about 86 mg / m 2 about 87 mg / m 2 about 88 mg / m 2 about 89 mg / m 2 about 90 mg / m 2 about 95 mg / m 2 about 100 mg / m 2 about 150 mg / m 2 at a dosing frequency of once every 3 weeks;

[0504] a) the anti-Nectin-4 antibody drug conjugate is administered at a dosage of about 3 mg / kg, or about 4 mg / kg, at a dosing frequency of twice every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dosage of about 1200 mg, at a dosing frequency of once every 3 weeks; b2) the cisplatin is administered at a dosage of about 75 mg / m 2 at a dosing frequency of once every 3 weeks;

[0505] a) the anti-Nectin-4 antibody drug conjugate is administered at a dosage of about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg, at a dosing frequency of once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dosage of about 100 mg, about 500 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, about 2500 mg, about 3000 mg, at a dosing frequency of once every 3 weeks; b2) the cisplatin is administered at a dosage of about 50 mg / m 2 about 51 mg / m 2 about 52 mg / m 2 about 53 mg / m 2 about 55 mg / m 2 about 57 mg / m 2 about 58 mg / m2 about 60 mg / m 2 about 61 mg / m 2 about 62 mg / m 2 about 63 mg / m 2 about 64 mg / m 2 about 65 mg / m 2 about 66 mg / m 2 about 67 mg / m 2 about 68 mg / m 2 about 69 mg / m 2 about 70 mg / m 2 about 71 mg / m 2 about 72 mg / m 2 about 73 mg / m 2 about 74 mg / m 2 about 75 mg / m 2 about 76 mg / m 2 about 77 mg / m 2 about 78 mg / m 2 about 79 mg / m 2 about 80 mg / m 2 about 81 mg / m 2 about 82 mg / m 2 about 83 mg / m 2 about 84 mg / m 2 about 85 mg / m 2 about 86 mg / m 2 about 87 mg / m 2 about 88 mg / m 2 about 89 mg / m 2 about 90 mg / m 2 about 95 mg / m 2 about 100 mg / m 2 about 150 mg / m 2 at a dosing frequency of once every 3 weeks;

[0506] a) the anti-Nectin-4 antibody drug conjugate is administered at a dosage of about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg at a dosing frequency of once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dosage of about 1200 mg at a dosing frequency of once every 3 weeks; b2) the cisplatin is administered at a dosage of about 75 mg / m 2 at a dosing frequency of once every 3 weeks;

[0507] a) the dosing amount of the anti-Nectin-4 antibody drug conjugate is about 4 mg / kg, and the dosing frequency is twice every 3 weeks, and the dosing is performed on D1, D8 of each cycle; b1) the dosing amount of the anti-PD-L1 antibody is about 1200 mg, and the dosing frequency is once every 3 weeks; b2) the dosing amount of cisplatin is about 75 mg / m 2 , and the dosing frequency is once every 3 weeks;

[0508] a) the dosing amount of the anti-Nectin-4 antibody drug conjugate is about 6 mg / kg, and the dosing frequency is once every 3 weeks; b1) the dosing amount of the anti-PD-L1 antibody is about 1200 mg, and the dosing frequency is once every 3 weeks; b2) the dosing amount of cisplatin is about 75 mg / m 2 , and the dosing frequency is once every 3 weeks; or,

[0509] a) the dosing amount of the anti-Nectin-4 antibody drug conjugate is about 8 mg / kg, and the dosing frequency is once every 3 weeks; b1) the dosing amount of the anti-PD-L1 antibody is about 1200 mg, and the dosing frequency is once every 3 weeks; b2) the dosing amount of cisplatin is about 75 mg / m 2 , and the dosing frequency is once every 3 weeks.

[0510] In some embodiments, the dosing sequence of the anti-Nectin-4 antibody drug conjugate in combination with the anti-PD-L1 antibody is: it is recommended to administer the anti-Nectin-4 antibody drug conjugate first, and then administer the anti-PD-L1 antibody. The time interval between the administration of the two drugs should be > 30 minutes, and the administration of the two drugs should be completed on the same day as much as possible.

[0511] In some embodiments, the dosing sequence of the anti-Nectin-4 antibody drug conjugate in combination with the anti-PD-L1 antibody, the anti-VEGF antibody is: it is recommended to administer the anti-Nectin-4 antibody drug conjugate first, then administer the anti-PD-L1 antibody, and finally administer the anti-VEGF antibody. The time interval between the administration of the two drugs should be > 30 minutes, and the administration of the two drugs should be completed on the same day as much as possible.

[0512] In some embodiments, the dosing sequence of the anti-Nectin-4 antibody drug conjugate in combination with the anti-PD-L1 antibody, the platinum drug is: it is recommended to administer the anti-Nectin-4 antibody drug conjugate first, then administer the anti-PD-L1 antibody, and finally administer the platinum drug. The time interval between the administration of the two drugs should be > 30 minutes, and the administration of the two drugs should be completed on the same day as much as possible.

[0513] In some embodiments, the dosing sequence of the anti-Nectin-4 antibody drug conjugate in combination with an anti-PD-L1 antibody, an anti-CTLA-4 antibody: it is recommended to give the anti-Nectin-4 antibody drug conjugate first, then give the anti-PD-L1 antibody, and finally give the anti-CTLA-4 antibody. The interval between the administration of the two drugs should be > 30 minutes, and the administration should be completed as much as possible on the same day.

[0514] In some embodiments, the dosing sequence of the anti-Nectin-4 antibody drug conjugate in combination with an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-VEGF antibody: it is recommended to give the anti-Nectin-4 antibody drug conjugate first, then give the anti-PD-L1 antibody, then give the anti-CTLA-4 antibody, and finally give the anti-VEGF antibody. The interval between the administration of the two drugs should be > 30 minutes, and the administration should be completed as much as possible on the same day.

[0515] The anti-Nectin-4 antibody drug conjugate and its combination with other therapeutic agents show certain clinical benefits in the targeted treatment of non-small cell lung cancer and esophageal cancer, bringing better clinical benefits than existing treatments for patients, and the disease condition is controlled or relieved.

[0516] The terms

[0517] For easier understanding of the present disclosure, certain technical and scientific terms are defined below. Unless otherwise defined herein, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which the present disclosure belongs.

[0518] Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise", "comprising", "include", "including", and the like are to be construed in an inclusive sense, as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to".

[0519] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0520] "About," "approximately," or "substantially" means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend on how the value is measured or assessed (i.e., the limitations of the measurement system or method as well as the limits of the physical per se). For example, "about" can mean within 1 or more than 1 standard deviation, or by ranges in conventional everyday measurements used to describe amounts, lengths, or sizes. For example, "about" can mean ranges within 20% of an expected value, e.g., within 10% of an expected value, within 1% of an expected value, within 0.5% of an expected value, within 0.1% of an expected value, and the like. Each instance of a number or a numerical range in this disclosure that is preceded by the term "about" or "approximately," also includes an implementation of that given number. Unless otherwise indicated, the use of "about" or "substantially" in connection with a specific value should be assumed to mean that the value is within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend on how the value is measured or assessed.

[0521] The term "and / or," e.g., "X and / or Y" shall be understood to mean either "X and Y" or, in the alternative, "X or Y" and shall be used to provide explicit support for both usages.

[0522] In some embodiments, the present disclosure is defined as follows:

[0523] An "antibody drug conjugate" (ADC) is a compound that links an antibody or antibody fragment to a cytotoxic or cell-killing small molecule drug through a stable linker compound, taking advantage of the specificity of the antibody for binding to a specific or highly expressed antigen on a tumor cell and the high potency of the cytotoxic agent, while avoiding toxic side effects on normal cells. Compared to traditional chemotherapy drugs, ADCs can precisely bind to tumor cells and reduce the impact on normal cells.

[0524] An antibody retains its chemical stability in a pharmaceutical formulation if the antibody drug conjugate does not show significant chemical changes. Chemical stability can be assessed by detecting and quantifying chemically altered forms of the protein. Degradation processes that frequently alter the chemical structure of a protein include hydrolysis or truncation (evaluated by methods such as size exclusion chromatography and CE-SDS), oxidation (evaluated by methods such as peptide mapping in conjunction with mass spectrometry or MALDI / TOF / MS), deamidation (evaluated by methods such as ion exchange chromatography, capillary isoelectric focusing, peptide mapping, isoaspartate measurement), and isomerization (evaluated by measuring isoaspartate content, peptide mapping, etc.).

[0525] An antibody drug conjugate retains its biological activity in a pharmaceutical formulation if the biological activity of the antibody drug conjugate at a given time is within a predetermined range of the biological activity exhibited at the time of preparation of the pharmaceutical formulation.

[0526] The three letter and one letter codes for amino acids used herein are in accord with the IUPAC-IUB Commission on Biochemical Nomenclature, Biochem. 7, 4389-4392 (1968).

[0527] As used herein, the term "antibody" is used in the broadest sense, and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies; monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), full-length antibodies and antibody fragments (or antigen binding fragments, or antigen binding portions), so long as they exhibit the desired antigen-binding activity. An antibody can refer to an immunoglobulin, which is a four polypeptide chain structure consisting of two identical heavy chains and two identical light chains connected by interchain disulfide bonds. The amino acid composition and arrangement order of the constant region of immunoglobulin heavy chain are different, so its antigenicity is also different. Accordingly, immunoglobulins can be divided into five types, or called isotypes of immunoglobulins, namely IgM, IgD, IgG, IgA and IgE, and the corresponding heavy chains are μ chain, δ chain, γ chain, α chain and ε chain, respectively. The same type of Ig can be divided into different subtypes according to the difference in amino acid composition of the hinge region and the number and position of heavy chain disulfide bonds, such as IgG can be divided into IgG1, IgG2, IgG3, IgG4. The light chain is divided into κ chain or λ chain by the constant region. Each of the five types of Ig can have κ chain or λ chain. The sequence of about 110 amino acids near the N-terminus of the heavy chain and light chain of the antibody is highly variable, which is the variable region (V region); the remaining amino acid sequence near the C-terminus is relatively stable, which is the constant region (C region). The variable region includes three hypervariable regions (CDRs) and four relatively conserved framework regions (FRs). The three hypervariable regions determine the specificity of the antibody, also known as the complementarity determining region (CDR). Each light chain variable region (VL) and heavy chain variable region (VH) is composed of 3 CDR regions and 4 FR regions, arranged in the order from amino terminal to carboxyl terminal: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The three CDR regions of the light chain are LCDR1, LCDR2, and LCDR3; the three CDR regions of the heavy chain are HCDR1, HCDR2, and HCDR3.

[0528] For determination or definition of CDRs, the determination of CDRs and the identification of residues comprising the binding site of an antibody can be accomplished by resolving the structure of the antibody and / or resolving the structure of the antibody-ligand complex. This can be achieved by any of a variety of techniques known to those skilled in the art, such as X-ray crystallography. Various analytical methods can be used to identify CDRs, including but not limited to the Kabat numbering system, the Chothia numbering system, the AbM numbering system, the IMGT numbering system, contact definition, conformational definition.

[0529] The boundaries of the CDRs can be determined by various known schemes, such as the "Kabat" numbering convention (see Kabat et al. (1991), "Sequences of Proteins of Immunological Interest", 5th Ed., Public Health Service, National Institutes of Health, Bethesda, MD), the "Chothia" numbering convention, the "ABM" numbering convention, the "contact" numbering convention (see Martin, ACR. Protein Sequence and Structure Analysis of Antibody Variable Domains [J]. 2001), and the ImMunoGenTics (IMGT) numbering convention (Lefranc, M.P. et al., Dev. Comp. Immunol., 27, 55-77 (2003); Front Immunol. 2018 Oct 16;9:2278), among others.

[0530] The term "antigen-binding fragment" or "functional fragment" or "antigen-binding portion" refers to one or more fragments of an intact antibody that retain the ability to specifically bind to an antigen. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Illustrative examples of binding fragments encompassed by the term "antigen-binding fragment" include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region, (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VH and VL domains of a single arm of an antibody; (v) a dsFv, a stable antigen-binding fragment formed by the VH and VL domains of a single arm of an antibody via an interchain disulfide bond; (vi) a scFv; (vii) diabodies, bispecific antibodies, and multispecific antibodies comprising a scFv, a dsFv, a Fab, and the like fragments.

[0531] The terms "specifically binds," "selectively binds," "selectively binds to," and "binds specifically to" refer to the binding of an antibody to an epitope on a predetermined antigen. Typically, an antibody will bind to an antigen with an affinity of about less than 10 -8 M, for example, about less than 10 -9 M, 10 -10 M, 10 -11 M or less.

[0532] The term "KD" refers to the dissociation equilibrium constant of a particular antibody-antigen interaction. Generally, the antibodies of the present disclosure bind IL-5 with a dissociation equilibrium constant (KD) of less than about 10"7M, e.g., less than about 10"8M, 10"9M, 10"10M, 10"11M, or 10"12M or less, e.g., as determined using a surface plasmon resonance (SPR) technique in a BIACORE instrument. -8 M, 10 -9 M or 10 -10 M or less, e.g., as determined using a surface plasmon resonance (SPR) technique in a BIACORE instrument.

[0533] "Homology" refers to the sequence similarity between two polynucleotide sequences or between two polypeptides. When a position in both of the compared sequences is occupied by the same base or amino acid monomer subunit, e.g., if a position in each of two DNA molecules is occupied by adenine, then the molecules are homologous at that position. The percent of homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences divided by the number of positions in the comparison times 100. For example, if 6 of 10 positions in two sequences are matched or homologous, then the two sequences are 60% homologous; if 95 of 100 positions in two sequences are matched or homologous, then the two sequences are 95% homologous. Typically, comparisons are made to give the largest percent homology when aligning two sequences. For example, a comparison can be made by the BLAST algorithm, where the parameters of the algorithm are selected to give the largest match between the sequences over their entire length. The following references are directed to the BLAST algorithm, which is frequently used for sequence analysis: BLAST ALGORITHMS: Altschul, S.F. et al. (1990) J. Mol. Biol. 215:403-410; Gish, W. et al. (1993) Nature Genet. 3:266-272; Madden, T.L. et al. (1996) Meth. Enzymol. 266:131-141; Altschul, S.F. et al. (1997) Nucleic Acids Res. 25:3389-3402; Zhang, J. et al. (1997) Genome Res. 7:649-656. Other routine BLAST algorithms, such as those provided by NCBI BLAST, are also well known to those skilled in the art.

[0534] "Administering" and "treatment" when applied to an animal, human, experimental subject, cell, tissue, organ or biological fluid means the contact of an exogenous drug, therapeutic agent, diagnostic agent or composition with the animal, human, subject, cell, tissue, organ or biological fluid. "Administering" and "treatment" can refer to, for example, therapeutic, pharmacokinetic, diagnostic, research and experimental methods. Treatment of a cell includes contact of the agent with the cell, as well as contact of the agent with a fluid which is in contact with the cell. "Administering" and "treatment" also mean in vitro and ex vivo treatment of, for example, a cell by an agent, diagnostic, binding composition or by another cell. "Treatment" when applied to a human, veterinary or research subject means therapeutic treatment, prophylactic or preventative measures, research and diagnostic applications.

[0535] "Treatment" means the administration of an internal or external therapeutic agent, such as a composition comprising any of the binding compounds of the disclosure, to a patient having one or more symptoms of a disease, where the therapeutic agent is known to have a therapeutic effect on those symptoms. Typically, the therapeutic agent is administered in an amount effective to alleviate one or more symptoms of the disease in the treated patient or population to induce regression of such symptoms or to inhibit the development of such symptoms to any clinically measurable extent. The amount of therapeutic agent effective to alleviate any particular symptom of a disease (also referred to as "therapeutically effective amount") can vary depending on factors such as the disease state, age, and weight of the patient, and the ability of the drug to elicit a desired effect in the patient. Whether a disease symptom has been alleviated can be assessed by any clinical detection method typically used by a physician or other professional health care provider to assess the severity or progression of the symptom. While embodiments of the disclosure (e.g., therapeutic methods or articles of manufacture) can not be effective in alleviating every symptom of a target disease, it is determined that a statistically significant number of patients should have alleviation of the target disease symptoms according to any statistical test known in the art, such as Student's t-test, chi-square test, U-test according to Mann and Whitney, Kruskal-Wallis test (H-test), Jonckheere-Terpstra test, and Wilcoxon test.

[0536] "Effective amount" includes an amount which is enough to ameliorate or prevent the symptoms or conditions of a medical disease. Effective amount also means an amount which is enough to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject can vary depending on factors such as the condition to be treated, the overall health status of the patient, the method route and dosage of administration, and the severity of side effects. The effective amount can be the maximum dose or administration regimen which avoids significant side effects or toxic effects.

[0537] The term "subject," "patient" means a mammal, especially a primate, and especially a human.

[0538] The disclosure "Nectin-4 positive" refers to the detection of cell membrane or cytoplasmic nectin-4 expression by immunohistochemical methods, and if the expression value is ≥1, it is nectin-4 positive.

[0539] The disclosure "driver gene" includes but is not limited to EGFR mutation, ALK fusion, ROS1 fusion, BRAF V600E mutation, NTRK fusion, MET14 exon skipping mutation, RET fusion, KRAS G12C mutation, HER-2 mutation, etc., EGFR sensitive mutation, EGFR T790M mutation, EGFR 20 exon insertion, etc. The disclosure "driver gene positive" refers to the detection of specific gene mutations of non-small cell lung cancer by gene detection or immunohistochemical methods, etc. The "driver gene positive" includes but is not limited to EGFR mutation, EGFR sensitive mutation, EGFR T790M mutation, EGFR 20 exon insertion, ALK fusion, ROS1 fusion, BRAF V600E mutation, NTRK fusion, MET14 exon skipping mutation, RET fusion, KRAS G12C mutation, HER-2 mutation, etc. The disclosure "driver gene positive" also includes other specific gene mutations of non-small cell lung cancer to be discovered.

[0540] The disclosure "driver gene negative" refers to the non-detection of "driver gene" of non-small cell lung cancer by gene detection or immunohistochemical methods, etc. The patient population in the disclosure "driver gene positive but no approved targeted drug therapy" is treated with reference to the patient population of "driver gene negative".

[0541] The disclosure "immunotherapy" refers to tumor immunotherapy represented by immune checkpoint inhibitors (ICIs), including but not limited to Programmed cell death receptor 1 (PD-1), Programmed cell death ligand 1 (PD-L1), and Cytotoxic T lymphocyte associated antigen 4 (CTLA-4), etc.

[0542] The disclosure "platinum chemotherapy" includes the treatment of platinum drugs such as cisplatin and carboplatin.

[0543] The present disclosure“targeted drug therapy” refers to approved or future newly approved targeted drug therapy for“driver gene positive”, including but not limited to approved targeted drug therapy for EGFR mutation, KRAS G12C mutation, HER-2 mutation, EGFR sensitive mutation, EGFR T790M mutation, EGFR 20 exon insertion, ALK fusion, ROS1 fusion, NTRK fusion, BRAF V600E mutation, MET 14 exon skipping mutation, RET fusion, etc.

[0544] In the antibody drug conjugate of the present disclosure, “n” refers to the average number of cytotoxic drugs loaded on each antibody or antigen binding fragment thereof in the antibody drug conjugate molecule, which can also be expressed as the ratio of drug amount to antibody amount, which is the average number of drugs per ADC molecule after the coupling reaction identified by hydrophobic chromatography (HIC) mass spectrometry.

[0545] “Pharmaceutical composition” means a mixture containing one or more compounds described herein or physiologically / pharmaceutically acceptable salts or prodrugs thereof with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient, and thereby exert a biological activity. DETAILED DESCRIPTION

[0546] The present disclosure will be further described in conjunction with the following examples, but these examples are not a limitation on the scope of the present disclosure. The experimental methods in the present disclosure examples not specified are generally carried out under conventional conditions, such as referring to the Antibody Technology Experimental Manual published by Cold Spring Harbor Laboratory, Molecular Cloning Manual, or according to the conditions recommended by the manufacturer of the raw materials or products. Reagents not specified by the source are conventional reagents purchased on the market.

[0547] Example 1. Preparation of anti-Nectin-4 antibody drug conjugate

[0548] The anti-Nectin-4 antibody drug conjugate is ADC-4 prepared in Examples 3-4 of WO2023221971A (incorporated by reference in its entirety into the present disclosure), the structure of which is as follows:

[0549] Reverse phase chromatography average: n = 3.5-4.7.

[0550] The anti-Nectin-4 antibody is derived from antibody NEC49, the CDR sequences of which are shown in Table 1. The full length of the heavy chain of antibody NEC49 is shown in SEQ ID NO: 9, and the full length of the light chain is shown in SEQ ID NO: 10.

[0551] Example 2. An open, single-arm, multi-center phase I clinical study of safety, tolerability, efficacy and pharmacokinetics of ADC-4 in patients with advanced solid tumors

[0552] 1. Test drug

[0553] 1. Test drug

[0554] 2. Enrolled subjects

[0555] 1) Age ≥ 18 years old, gender unrestricted;

[0556] 2) Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1;

[0557] 3) Life expectancy ≥ 3 months;

[0558] 4) Patients with histologically confirmed unresectable locally advanced or advanced solid tumors who failed or were intolerant to standard treatment, had no standard treatment or refused standard treatment. The enrollment criteria for each cohort are as follows:

[0559] Cohort A: Pathologically confirmed unresectable locally advanced / metastatic non-small cell lung cancer: i) NSCLC subjects who are negative for driver genes must have received treatment based on PD-(L)1 and platinum chemotherapy, unless they are not suitable or refuse to receive the treatment; ii) NSCLC subjects who are known to be positive for driver genes must have received at least 1 targeted drug therapy for the positive driver gene mutation if a targeted drug has been approved; iii) If receiving chemotherapy, the number of previous lines of chemotherapy is ≤ 2 lines.

[0560] Cohort D: Pathologically confirmed unresectable locally advanced / metastatic esophageal squamous carcinoma; subjects must have received treatment based on PD-(L)1 and platinum chemotherapy for locally advanced / metastatic disease, and the number of previous lines of chemotherapy is ≤ 2 lines;

[0561] The enrollment criteria for each cohort in the efficacy expansion phase are as follows:

[0562] Cohort A1 enrolls EGFR mutant non-squamous non-small cell lung cancer (NSCLC);

[0563] Cohort A2 enrolls driver gene negative non-squamous non-small cell lung cancer (NSCLC);

[0564] Cohort A3 enrolls other driver gene positive non-squamous non-small cell lung cancer (NSCLC);

[0565] Cohort A4 enrolls squamous non-small cell lung cancer;

[0566] Cohort A5 enrolls non-small cell lung cancer with negative expression of Nectin-4.

[0567] Non-squamous (non-squamous non-small cell lung cancer) subjects in Cohorts A1, A2, A3 must undergo driver mutation testing, including but not limited to EGFR gene testing and other driver gene (refers to driver genes other than EGFR gene) testing and / or immunohistochemistry testing, and will be enrolled in different cohorts according to the test results.

[0568] 5) The subject enrolled in Cohorts A1, A2, A3, A4 can provide archived or fresh tumor tissue, and the tumor tissue of the subject is positive for Nectin-4 expression. For subjects who cannot provide tumor tissue samples that meet the above requirements, the subject will be discussed with the sponsor to determine whether to enroll.

[0569] 6) At least one measurable lesion according to RECIST v1.1 criteria.

[0570] 3. Clinical Protocol

[0571] 3.1 Study Design

[0572] Dose Escalation Phase

[0573] The starting dose of ADC-4 is 1 mg / kg, administered by intravenous infusion, intravenous infusion, once every 3 weeks (Q3W), and 21 days as a treatment cycle.

[0574] The Bayesian Optimal Interval (BOIN) design is used to start the dose escalation study with a starting dose of 1 mg / kg. BOIN design phase: 5 dose groups (2 mg / kg, 4 mg / kg, 6 mg / kg, 8 mg / kg, 10 mg / kg) are preset. Subjects are enrolled starting from the starting dose of the trial, and subjects are enrolled to receive treatment in each cohort with 3-6 subjects. After the safety evaluation of each cohort of subjects completes the DLT observation period (i.e., the first cycle of study drug administration), the next cohort of subjects is determined according to the BOIN design dose escalation decision table, until the maximum sample size of a single dose group (12 cases) or the total maximum sample size (36 cases) specified in the protocol or the safety monitoring committee (SMC) decides to terminate the dose escalation early. If necessary, the principal investigator and the sponsor will jointly discuss whether to increase other dose groups (higher doses or intermediate doses or lower doses) and / or adjust the dosing frequency (such as once a week, QW) based on the safety, tolerability, PK, immunogenicity data and efficacy information obtained.

[0575] PK Expansion Phase

[0576] According to the safety, tolerability, PK and other data of different dose groups in the dose escalation phase, about 3 dose groups are selected for PK expansion. It is planned to expand each dose group to 8-12 subjects (including all PK blood sampling subjects before the completion of the second cycle of the same dose group in the dose escalation phase). At the same time, if the safety evaluation of the dose escalation phase is completed, the subjects of the PK expansion of the same dose group can be enrolled simultaneously.

[0577] Efficacy expansion phase

[0578] The efficacy expansion phase will be divided into 6 main cohorts according to the types of tumors, namely:

[0579] Cohort A1: subjects with EGFR mutant non-squamous non-small cell lung cancer (NSCLC) treated with 6 mg / kg or 8 mg / kg Q3W ADC-4;

[0580] Cohort A2: subjects with driver gene negative (e.g. EGFR driver gene negative, etc.) non-squamous non-small cell lung cancer (NSCLC) treated with 6 mg / kg or 8 mg / kg Q3W ADC-4;

[0581] Cohort A3: subjects with other driver gene positive (driver gene positive other than EGFR gene) non-squamous non-small cell lung cancer (NSCLC) treated with 6 mg / kg or 8 mg / kg Q3W ADC-4;

[0582] Cohort A4: subjects with squamous non-small cell lung cancer treated with 6 mg / kg or 8 mg / kg Q3W ADC-4;

[0583] Cohort A5: subjects with Nectin-4 negative non-small cell lung cancer (squamous non-small cell lung cancer and non-squamous non-small cell lung cancer) treated with 6 mg / kg or 8 mg / kg Q3W ADC-4.

[0584] 3.2 Administration method

[0585] ADC-4: intravenous infusion, 2 mg / kg, 4 mg / kg, 6 mg / kg, 8 mg / kg, 10 mg / kg, Q3W or other doses determined by exploration.

[0586] 4. Outcome evaluation

[0587] 4.1 Effectiveness index

[0588] Tumor evaluation adopts the RECIST v1.1 standard, and all subjects are subjected to baseline tumor imaging evaluation in the screening period. The efficacy evaluation adopts the RECIST v1.1 standard, and the efficacy evaluation indexes include: ORR, DCR, DoR, PFS and OS assessed by researchers.

[0589] A total of 395 subjects were enrolled, including 197 subjects with non-small cell lung cancer and 77 subjects with esophageal squamous cell carcinoma.

[0590] The baseline characteristics of some of the enrolled subjects are shown in Table 5: the median age of all enrolled subjects among the 165 enrolled subjects (including 83 subjects with non-small cell lung cancer) was 60 years old, 86.1% had an ECOG score of 1, and 65.5% of the patients had received systemic anti-tumor therapy for ≥2 lines; for the non-small cell lung cancer population, the median age was 61 years old, 95.2% had an ECOG score of 1, and 78.3% of the patients had received systemic anti-tumor therapy for ≥2 lines.

[0591] Table 5. Baseline characteristics of subjects

[0592] In the dose escalation phase, 17 patients received 2 to 10 mg / kg of ADC-4 drug treatment. Only 1 case of DLT (grade 4 reduction in platelet count) occurred in the 10 mg / kg group, and the MTD has not been reached. 6 mg / kg and 8 mg / kg were selected for PK expansion and efficacy expansion.

[0593] 4.1.1 Evaluation of effectiveness against non-small cell lung cancer

[0594] The statistical results of the evaluation of the therapeutic efficacy of the enrolled subjects against non-small cell lung cancer are shown in Tables 2-4.

[0595] As shown in Table 6, among the 46 non-small cell lung cancer patients who completed at least one tumor evaluation, the ORR was 30.4% (36.7% for non-squamous carcinoma and 18.8% for squamous carcinoma), the DCR was 89.1% (83.3% for non-squamous carcinoma and 100% for squamous carcinoma), 14 patients (30.4%) had PR, 27 patients (58.7%) had SD, and 4 patients (8.7%) had PD: among them, 11 patients (36.7%) with non-squamous carcinoma had PR, 14 patients (46.7%) had SD, and 4 patients (13.3%) had PD; 3 patients (18.8%) with squamous carcinoma had PR, 13 patients (81.3%) had SD, and 0 patient had PD.

[0596] Table 6. Evaluation of efficacy * ORR, objective response rate; DCR, disease control rate

[0597] As shown in Table 7, in 69 EGFR mutant non-squamous non-small cell lung cancer patients, the ORR was 43.5%, the DCR was 84.1%, and the mPFS was 5.7 months (as of December 20, 2024, the mPFS was 8.5 months at a dose of 6 mg / kg and 5.7 months at a dose of 8 mg / kg). In 44 EGFR wild-type (EGFR driver gene negative) non-squamous non-small cell lung cancer patients, the ORR was 25.0%, the DCR was 72.7%, and 1 patient had a complete remission (CR) (2.3%), and the mPFS was 4.3 months (as of December 20, 2024, the mPFS was 2.6 months at a dose of 6 mg / kg and 4.3 months at a dose of 8 mg / kg, and as of May 2025, the mPFS was 5.7 months at a dose of 8 mg / kg). In 44 squamous non-small cell lung cancer patients, the ORR was 25%, the DCR was 100%, and the mPFS was 4.5 months (as of December 20, 2024, the mPFS was 4.4 months at a dose of 6 mg / kg and 6.0 months at a dose of 8 mg / kg).

[0598] Table 7. Efficacy evaluation * Includes unconfirmed ORR * EGFR driver gene negative non-squamous NSCLC: also referred to as “EGFR wild-type non-squamous NSCLC”, includes non-squamous NSCLC that is driver gene negative as well as other driver gene positive non-squamous NSCLC that is not EGFR mutant

[0599] As shown in Table 8 below, in 105 non-squamous non-small cell lung cancer subjects, EGFR mutant non-squamous non-small cell lung cancer subjects had an ORR of 48.6% at a dose of 6 mg / kg, a DCR of 80%, and a mPFS of 8.5 months (data as of May 2025); and an ORR of 43.8% at a dose of 8 mg / kg, a DCR of 90.6%, and a mPFS of 8.5 months (data as of May 2025). Driver gene negative non-squamous non-small cell lung cancer subjects had an ORR of 21.1% at a dose of 8 mg / kg, a DCR of 68.4%, and a mPFS of 5.7 months (data as of May 2025).

[0600] Table 8. Efficacy evaluation * Includes unconfirmed ORR * EGFR driver gene negative non-squamous NSCLC: also referred to as “EGFR wild-type non-squamous NSCLC”, includes non-squamous NSCLC that is driver gene negative as well as other driver gene positive non-squamous NSCLC that is not EGFR mutant

[0601] 4.1.2 Evaluation of effectiveness against esophageal squamous carcinoma

[0602] In 76 subjects with esophageal squamous cell carcinoma (ESCC), the ORR at the dose of 6 mg / kg was 25%, the DCR was 77.5%, the mPFS was 4.1 months (as of May 2025), and the mOS was 9.1 months (as of May 2025).

[0603] 4.2 Safety Evaluation

[0604] Safety evaluation will be performed for all subjects after enrollment in the study, every treatment cycle. It includes the incidence and severity of AEs, serious adverse events (SAEs) (judged according to the NCI-CTCAE v5.0 standard), changes in vital signs, abnormal laboratory test indicators, and the incidence of dose suspension, dose reduction, and dose termination due to study drug-related toxicity during the trial.

[0605] The safety evaluation results of some subjects (165 subjects) are shown in Table 9. Among them, 35.2% (58 / 165) of the patients had ≥ grade 3 TRAEs, and the most common (≥ 10%) TRAEs included neutrophil count decrease (16.4%) and leukocyte count decrease (13.3%). The safety evaluation results of all enrolled subjects (395 subjects) showed that the ADC-4 antibody conjugate was well tolerated, the incidence of interstitial lung disease (ILD) and ≥ grade 3 skin toxicity was very low (both 0.3%), and no new safety issues were found.

[0606] Table 9. Safety evaluation results

[0607] In summary, the ADC-4 antibody conjugate showed tolerable and controllable safety, and showed promising antitumor activity in non-small cell lung cancer.

[0608] Example 3. A multicenter, open IB / II phase clinical study on the safety, tolerability and effectiveness of ADC-4 combined with immunotherapeutic agents with or without other antitumor treatments in subjects with locally advanced or metastatic non-small cell lung cancer

[0609] 1. Test drug

[0610] (1) ADC-4 prepared in Example 1. The dosage form is injection (lyophilized powder).

[0611] (2) Anti-PD-L1 antibody, the heavy chain of which is shown in SEQ ID NO: 19, and the light chain of which is shown in SEQ ID NO: 20. The dosage form is injection.

[0612] (3) Carboplatin injection for injection and cisplatin injection are marketed drugs.

[0613] (4) Anti-VEGF antibody, the heavy chain is shown as SEQ ID NO: 39, and the light chain is shown as SEQ ID NO: 40. The dosage form is injection.

[0614] 2. Enrolled subjects

[0615] 1) Age ≥ 18 years old, gender unrestricted;

[0616] 2) Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1;

[0617] 3) Life expectancy ≥ 12 weeks;

[0618] 4) Patients with locally advanced unresectable or metastatic non-small cell lung cancer diagnosed by pathology:

[0619] - Subjects at stage IB who have failed or are intolerant to standard treatment or refuse standard treatment must meet the following conditions: subjects with negative driver genes must have received immunotherapy and platinum-based chemotherapy, and the number of previous systemic antitumor treatment lines ≤ 2; subjects with positive driver genes must have received targeted therapy and platinum-based chemotherapy, and the number of previous systemic antitumor treatment lines ≤ 2.

[0620] - Squamous cell carcinoma (squamous non-small cell lung cancer) subjects are included in cohort A and cohort C of stage II, and non-squamous cell carcinoma (non-squamous non-small cell lung cancer) subjects are included in cohort B and cohort D. All subjects must not have received systemic antitumor treatment for locally advanced unresectable or metastatic non-small cell lung cancer, including systemic treatment of clinical research drugs for solid tumor indications. Subjects who have previously received neoadjuvant / adjuvant chemotherapy, radical surgery, radiotherapy or chemoradiotherapy for non-metastatic tumors for curative purposes can be enrolled, but must meet the following conditions: at least 6 months from the end of the last chemotherapy, radical surgery, radiotherapy or chemoradiotherapy treatment to the first drug administration; at least 12 months from the end of the last immunotherapy treatment to the first drug administration.

[0621] Non-squamous cell carcinoma (non-squamous non-small cell lung cancer) subjects in cohort B and cohort D must undergo EGFR gene detection and ALK gene and / or immunohistochemical detection. Subjects with EGFR mutation positive or ALK fusion positive cannot be enrolled. At the same time, subjects with other driver gene mutations (except EGFR or ALK gene) and approved targeted drug therapy for the driver gene mutation cannot be enrolled.

[0622] 5) Subjects with tumor tissue available for archival or fresh tumor tissue, and tumor tissue Nectin-4 expression positive, and PD-L1 TPS > 1% (both based on central laboratory immunohistochemistry [IHC] testing) at Phase II stage. For subjects who cannot provide tumor tissue samples that meet the above requirements, it needs to be discussed with the sponsor to determine whether to enroll.

[0623] 6) At least one measurable lesion according to RECIST vl.l criteria.

[0624] 3. Clinical Protocol

[0625] 3.1 Study Design

[0626] Phase Ib

[0627] (1) IB-Part 1, ADC-4 in combination with anti-PD-L1 antibody exploration:

[0628] o Dose Level 1: ADC-4 6 mg / kg Q3W + anti-PD-L1 antibody 1200 mg Q3W,

[0629] o Dose Level 2: ADC-4 8 mg / kg Q3W + anti-PD-L1 antibody 1200 mg Q3W.

[0630] (2) IB-Part 2, ADC-4 in combination with anti-PD-L1 antibody and platinum (carboplatin or cisplatin) exploration:

[0631] o Dose Level 1:

[0632] ADC-4 4 mg / kg Q3W + anti-PD-L1 antibody 1200 mg Q3W + cisplatin 75 mg / m 2 Q3W; or

[0633] ADC-4 4 mg / kg Q3W + anti-PD-L1 antibody 1200 mg Q3W + carboplatin AUC4 Q3W; or

[0634] ADC-4 4 mg / kg Q3W + anti-PD-L1 antibody 1200 mg Q3W + carboplatin AUC5 Q3W.

[0635] o Dose Level 2:

[0636] ADC-4 6 mg / kg Q3W + anti-PD-L1 antibody 1200 mg Q3W + cisplatin 75 mg / m 2 Q3W; or

[0637] ADC-4 6 mg / kg Q3W + anti-PD-Ll antibody 1200 mg Q3W + carboplatin AUC4 Q3W; or

[0638] ADC-4 6 mg / kg Q3W + anti-PD-Ll antibody 1200 mg Q3W + carboplatin AUC5 Q3W.

[0639] (3) IB Phase Third Part (IB-Part 3), ADC-4 in combination with anti-PD-Ll antibody and anti-VEGF antibody exploration:

[0640] o Dose Level 1 : ADC-4 8 mg / kg Q3W + anti-PD-Ll antibody 1200 mg Q3W + anti-VEGF antibody 7.5 mg / kg Q3W;

[0641] o Dose Level 2: ADC-4 8 mg / kg Q3W + anti-PD-Ll antibody 1200 mg Q3W + anti-VEGF antibody 15 mg / kg Q3W.

[0642] Phase II (efficacy expansion)

[0643] Cohort A: subjects with squamous carcinoma (squamous non-small cell lung cancer) treated with ADC-4 (selected dose, Q3W) + anti-PD-Ll antibody (1200 mg, Q3W);

[0644] Cohort B: subjects with non-squamous carcinoma (non-squamous non-small cell lung cancer) treated with ADC-4 (selected dose, Q3W) + anti-PD-Ll antibody (1200 mg, Q3W);

[0645] Cohort C: subjects with squamous carcinoma (squamous non-small cell lung cancer) treated with ADC-4 (selected dose, Q3W) + anti-PD-Ll antibody (1200 mg, Q3W) + carboplatin (AUC4 or AUC5, Q3W); or

[0646] subjects with squamous carcinoma (squamous non-small cell lung cancer) treated with ADC-4 (selected dose, Q3W) + anti-PD-Ll antibody (1200 mg, Q3W) + cisplatin (75 mg / m 2 , Q3W);

[0647] Cohort D: subjects with non-squamous carcinoma (non-squamous non-small cell lung cancer) treated with ADC-4 (selected dose, Q3W) + anti-PD-Ll antibody (1200 mg, Q3W) + carboplatin (AUC4 or AUC5, Q3W); or

[0648] subjects with non-squamous carcinoma (non-squamous non-small cell lung cancer) treated with ADC-4 (selected dose, Q3W) + anti-PD-Ll antibody (1200 mg, Q3W) + cisplatin (75 mg / m 2Treatment of non-squamous (non-squamous non-small cell lung cancer) subjects with ADC-4 (8 mg / kg, Q3W) + anti-PD-Ll antibody (1200 mg, Q3W) + anti-VEGF antibody (selected dose, Q3W).

[0649] Cohort E: Treatment of non-small cell lung cancer subjects with ADC-4 (8 mg / kg, Q3W) + anti-PD-Ll antibody (1200 mg, Q3W) + anti-VEGF antibody (selected dose, Q3W).

[0650] 3.2 Administration method

[0651] ADC-4: Intravenous infusion, 4 mg / kg, 6 mg / kg, 8 mg / kg, Q3W or other doses determined in exploration.

[0652] Anti-PD-Ll antibody: Intravenous infusion, 1200 mg, once every 3 weeks, with infusion time of 30-60 minutes each time, 21 days as a cycle (Q3W).

[0653] Carboplatin (dosed according to Calvert formula): Intravenous infusion, dosed according to AUC 4 or AUC 5, once every 3 weeks, and the specific drug can be infused according to the prescription information or the infusion method according to the routine diagnosis and treatment of the research center. Calvert formula: Carboplatin dose (mg) = set AUC (mg / mL·min) x [endogenous creatinine clearance (mL / min) + 25]. The calculation of endogenous creatinine clearance uses the Cockcroft-Gault formula:

[0654] Serum creatinine concentration: mg / dL

[0655] Serum creatinine concentration: μmol / L

[0656] Age is in years, and body weight is in kilograms (kg).

[0657] Cisplatin: Intravenous infusion, 75 mg / m 2 , once every 3 weeks, with recommended infusion time of 1-2 hours each time.

[0658] Anti-VEGF antibody: Intravenous infusion, 7.5 mg / kg, 15 mg / kg, once every 3 weeks as a dosing cycle.

[0659] Dosing sequence: 1) Two-drug combination recommends giving ADC-4 first, and then anti-PD-Ll antibody; 2) Three-drug combination recommends giving ADC-4 first, then anti-PD-Ll antibody, and finally carboplatin or cisplatin or anti-VEGF antibody. The time interval between the administration of the two drugs should be > 30 minutes. The administration should be completed on the same day as much as possible. Different drugs require separate infusion bags and filters.

[0660] Maximum treatment course: Anti-PD-L1 antibody cumulative medication for 35 times needs to terminate the medication. Carboplatin / cisplatin is used for 2-4 cycles. If a study drug is prematurely terminated due to toxicity, other study drugs can be considered for continued use.

[0661] 4. Results evaluation

[0662] 4.1 Effectiveness indicators

[0663] Tumor evaluation uses the RECIST v1.1 standard, and all subjects undergo baseline tumor imaging evaluation during the screening period. Effectiveness indicators include: ORR, DCR, DoR, PFS, and OS assessed by researchers.

[0664] The clinical trial is still ongoing, and among the 103 non-small cell lung cancer subjects who completed at least one tumor evaluation, the subjects enrolled in phase IB (including non-squamous cancer subjects and squamous cancer subjects): the ORR at IB-Part1 dose level 1 was 30%, and the DCR was 80%; the ORR at IB-Part1 dose level 2 was 29.7%, and the DCR was 91.9%; the subjects enrolled in phase II (including 30 non-squamous cancer subjects and 26 squamous cancer subjects): the ORR reached 69.6% and the DCR reached 96.4% at the ADC-4 (8 mg / kg, Q3W) + anti-PD-L1 antibody (1200 mg, Q3W) dose level (as shown in Table 2).

[0665] Table 10. Efficacy evaluation * Includes unconfirmed ORR

[0666] 4.2 Safety evaluation

[0667] All subjects will undergo safety evaluation every treatment cycle after enrolling in the study. This includes the incidence of AEs, serious adverse events (SAEs), and grades (judged according to the NCI-CTCAE v5.0 standard), changes in vital signs, laboratory test abnormalities, and the incidence of dose suspension, dose reduction, and dose termination due to study drug-related toxicity during the trial.

[0668] Safety evaluation of enrolled subjects showed that the proportion of subjects with ≥ grade 3 TRAEs among subjects enrolled in phase IB was 38%, and the most common (≥ 10%) TRAEs included neutrophil count decrease (24%) and anemia (14%). The proportion of subjects with ≥ grade 3 TRAEs among subjects enrolled in phase II was 26.3%, and the most common (≥ 10%) TRAEs included neutrophil count decrease (22.8%) and leukocyte count decrease (10.5%).

[0669] In summary, ADC-4 antibody conjugate combined with other therapeutic agents (e.g. immunotherapeutic agents) showed tolerable and controllable safety, and promising antitumor activity in the second-line and first-line treatment of non-small cell lung cancer.

[0670] Example 4. Multicenter, open IB / II phase clinical study on safety, tolerability and efficacy of ADC-4 in combination with immunotherapeutic agents with or without other antitumor therapies in subjects with advanced solid tumors

[0671] 1. Test drug

[0672] (1) ADC-4 prepared in Example 1. The dosage form is injection (lyophilized powder).

[0673] (2) Anti-PD-L1 antibody, the heavy chain of which is shown in SEQ ID NO: 19, and the light chain of which is shown in SEQ ID NO: 20. The dosage form is injection.

[0674] (3) Anti-CTLA-4 antibody, the heavy chain of which is shown in SEQ ID NO: 29, and the light chain of which is shown in SEQ ID NO: 30. The dosage form is injection.

[0675] (4) Anti-VEGF antibody, the heavy chain of which is shown in SEQ ID NO: 39, and the light chain of which is shown in SEQ ID NO: 40. The dosage form is injection.

[0676] 2. Enrolled subjects

[0677] 1) Aged 18 years or older, gender unrestricted;

[0678] 2) Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1;

[0679] 3) Life expectancy ≥ 12 weeks;

[0680] 4) Patients with histologically confirmed unresectable locally advanced or metastatic non-small cell lung cancer,

[0681] - Subjects in phase Ib, patients with locally advanced or metastatic non-small cell lung cancer who failed or were intolerant to or refused standard treatment. The number of previously received systemic antitumor treatment lines was not more than 2. If the subject was a non-squamous carcinoma, it was required to have obtained the results of genetic testing.

[0682] - Phase II: Cohort A included subjects with squamous carcinoma, cohort B included subjects with non-squamous carcinoma, cohort C included subjects with non-small cell lung cancer with STK11 single mutation, KEAP1 single mutation, or STK11 / KEAP1 co-mutation, and cohort D included subjects with non-small cell lung cancer.

[0683] All subjects must not have received systemic anti-neoplastic therapy for locally advanced unresectable or metastatic non-small cell lung cancer, including systemic therapy with a clinical study drug for solid tumors. Subjects who received neoadjuvant / adjuvant therapy for non-metastatic tumor can be enrolled (the last neoadjuvant or adjuvant therapy must be > 6 months from the first dose of this study; if the neoadjuvant or adjuvant contained immunotherapy, the last immunotherapy must be > 12 months from the first dose of this study).

[0684] NSCLC non-squamous subjects must have EGFR gene testing and ALK gene and / or immunohistochemistry testing; subjects with EGFR mutation-positive or ALK-positive cannot be enrolled. Also, subjects with other driver gene mutations (in addition to EGFR or ALK gene-positive mutations) for which there is an approved targeted drug therapy cannot be enrolled.

[0685] 5) Ability to provide archival or fresh tumor tissue for testing of Nectin-4 and PD-L1 TPS expression levels. For subjects who are unable to provide tumor tissue samples that meet the above requirements, a discussion with the Sponsor is required to determine if the subject can be enrolled.

[0686] 6) At least one measurable lesion according to RECIST vl.l criteria.

[0687] 3. Clinical Protocol

[0688] 3.1 Study Design

[0689] Phase lb (Part A)

[0690] Dose Cohort 1 : ADC-4 (6 mg / kg, Q3W) + anti-PD-Ll antibody (1200 mg, Q3W) + anti- CTLA-4 antibody (280 mg given once for C1D1, no dosing for C2-C4, 70 mg Q6W for C5 and subsequent cycles)

[0691] Dose Cohort 2: ADC-4 (8 mg / kg, Q3W) + anti-PD-Ll antibody (1200 mg, Q3W) + anti- CTLA-4 antibody (280 mg given once for C1D1, no dosing for C2-C4, 70 mg Q6W for C5 and subsequent cycles).

[0692] Phase lb (Part B)

[0693] ADC-4 (8 mg / kg, Q3W) + anti-PD-Ll antibody (1200 mg, Q3W) + anti-CTLA-4 antibody (280 mg given once for C1D1, no dosing for C2-C4, 70 mg Q6W for C5 and subsequent cycles) + anti-VEGF antibody (15 mg / kg, Q3W).

[0694] SMC will decide whether to explore ADC-4 or anti-VEGF antibody or anti-CTLA-4 antibody down-titration combination therapy based on the acquired safety and efficacy data, or to proceed to Phase II with the current regimen.

[0695] Phase II stage (efficacy expansion)

[0696] Cohort A: Subjects with squamous non-small cell lung cancer treated with ADC-4 (selected dose, Q3W) + anti-PD-Ll antibody (1200 mg, Q3W) + anti-CTLA-4 antibody (C1D1 280 mg as a single dose, C2-C4 no dose, C5 and beyond 70 mg Q6W);

[0697] Cohort B: Subjects with non-squamous non-small cell lung cancer treated with ADC-4 (selected dose, Q3W) + anti-PD-Ll antibody (1200 mg, Q3W) + anti-CTLA-4 antibody (C1D1 280 mg as a single dose, C2-C4 no dose, C5 and beyond 70 mg Q6W);

[0698] Cohort C: Subjects with STK11 single mutation, KEAP1 single mutation, or STK11 / KEAP1 co-mutation non-small cell lung cancer treated with ADC-4 (selected dose, Q3W) + anti-PD-Ll antibody (1200 mg, Q3W) + anti-CTLA-4 antibody (C1D1 280 mg as a single dose, C2-C4 no dose, C5 and beyond 70 mg Q6W);

[0699] Cohort D: Subjects with non-small cell lung cancer treated with ADC-4 (selected dose, Q3W) + anti-PD-Ll antibody (1200 mg, Q3W) + anti-CTLA-4 antibody (C1D1 280 mg as a single dose, C2-C4 no dose, C5 and beyond 70 mg Q6W) + bevacizumab 15 mg / kg Q3W.

[0700] The administration mode of the anti-CTLA-4 antibody “C1D1 280 mg as a single dose, C2-C4 no dose, C5 and beyond 70 mg Q6W” means “a single dose of 280 mg on day 1 of cycle 1, no dose for cycles 2-4, and a dose of 70 mg every 6 weeks (also known as “every other cycle”) from day 1 of cycle 5 onwards”.

[0701] 3.2 Administration mode

[0702] ADC-4: intravenous infusion, 6 mg / kg, 8 mg / kg, Q3W; or other doses to be explored / determined. The first intravenous infusion is 90 ± 10 min, and if no infusion-related reactions occur after the first dose, each subsequent infusion can be shortened to about 30 min (no less than 20 min, no more than 60 min, including the flushing phase).

[0703] Anti-PD-L1 antibody: intravenous infusion, 1200 mg, once every 3 weeks, with each infusion lasting 30-60 minutes, and 21 days as a cycle (Q3W). The cumulative medication is not more than 35 times.

[0704] Anti-CTLA-4 antibody: intravenous infusion, C1D1 280 mg, once, C2-C4 no administration, C5 and subsequent cycles 70 mg Q6W (280 mg of single dose on the first day of the first cycle, no administration from the second to the fourth cycle, and administration according to the frequency of 70 mg every 6 weeks from the first day of the fifth cycle). Each intravenous infusion lasts 30 ± 10 min, and 21 days as a cycle. The cumulative medication is not more than 2 years.

[0705] Anti-VEGF antibody: intravenous infusion, 15 mg / kg or other doses to be explored / determined, with each cycle being 3 weeks, and administration on the first day of each cycle.

[0706] Dosing sequence: It is recommended to administer ADC-4 first, then anti-PD-L1 antibody, then anti-CTLA-4 antibody, and finally anti-VEGF antibody (if necessary). The interval between the administration of two drugs should be > 30 minutes. The administration should be completed on the same day as much as possible. Different drug infusions require separate infusion bags and filters.

[0707] Maximum medication course: The anti-PD-L1 antibody should be terminated if the cumulative medication is 35 times. The cumulative medication of the anti-CTLA-4 antibody should not exceed 2 years. If a study drug is terminated prematurely due to toxicity intolerance, the use of other study drugs can be considered.

[0708] 4. Results evaluation

[0709] 4.1 Evaluation of effectiveness

[0710] Tumor evaluation adopts the RECIST v1.1 standard, and all subjects undergo baseline tumor imaging evaluation during the screening period. The effectiveness indicators include: the objective response rate (ORR) of the standard evaluation by the investigator, the disease control rate (DCR), the duration of remission (DoR), the progression-free survival (PFS), and the overall survival (OS).

[0711] Clinical trials are also ongoing, and in Phase II, the ORR of 6 subjects (including 1 non-squamous cancer subject and 5 squamous cancer subjects) reached 50% at the dose of ADC-4 (8 mg / kg, Q3W) + anti-PD-L1 antibody (1200 mg, Q3W) + anti-CTLA-4 antibody (C1D1 280 mg, once, C2-C4 no administration, C5 and subsequent cycles 70 mg Q6W), and the DCR reached 100%.

[0712] 4.2 Safety Evaluation

[0713] Safety evaluation will be performed for all subjects enrolled in the study every treatment cycle. It includes the incidence and severity of AEs, serious adverse events (SAEs) (judged according to the NCI-CTCAE v5.0 standard), changes in vital signs, abnormal laboratory test indicators, and the incidence of dose suspension, dose reduction, and dose termination due to study drug-related toxicity during the trial.

[0714] Safety evaluation of the enrolled subjects showed that the most common (≥10%) TRAEs in the subjects included hyponatremia (15.8%), weakness (15.8%), decreased white blood cell count (10.5%), decreased neutrophil count (10.5%), and anemia (10.5%). The proportion of subjects with ≥ grade 3 TRAEs among the 17 subjects enrolled in Phase II was 11.8%.

[0715] In summary, the ADC-4 antibody conjugate combined with other therapeutic agents (such as immunotherapeutic agents) showed tolerable and controllable safety, and showed promising antitumor activity in the frontline and first-line treatment of non-small cell lung cancer.

[0716] Example 5. Multicenter, open IB / II phase clinical study on safety, tolerability, and effectiveness of ADC-4 combined or not combined with other antitumor treatments in subjects with locally advanced or metastatic esophageal cancer

[0717] 1. Test drug

[0718] (1) ADC-4 prepared in Example 1. The dosage form is an injection (lyophilized powder).

[0719] (2) Anti-PD-L1 antibody, the heavy chain of which is shown in SEQ ID NO: 19, and the light chain of which is shown in SEQ ID NO: 20. The dosage form is an injection.

[0720] (3) Anti-CTLA-4 antibody, the heavy chain of which is shown in SEQ ID NO: 29, and the light chain of which is shown in SEQ ID NO: 30. The dosage form is an injection.

[0721] (4) Cisplatin injection for injection is a marketed drug.

[0722] 2. Enrolled subjects

[0723] 1) Age 18-70 years, gender unrestricted;

[0724] 2) Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1;

[0725] 3) Life expectancy > 12 weeks;

[0726] 4) Patients with locally advanced unresectable or metastatic esophageal squamous cell carcinoma confirmed by pathology, subjects at stage Ib failed or were intolerant to or refused standard treatment, subjects must have received treatment based on PD-(L)1 and platinum chemotherapy, and the number of previous treatment lines was < 2 lines. Subjects who have received neoadjuvant / adjuvant chemotherapy, radical radiotherapy or radiotherapy for non-metastatic tumors can be considered as first-line treatment if disease recurrence or metastasis occurs < 6 months after treatment.

[0727] Subjects at stage II have not received systemic anti-tumor treatment for locally advanced unresectable or metastatic esophageal cancer, including systemic treatment of clinical research drugs for solid tumors; if subjects have received neoadjuvant / adjuvant chemotherapy, immunotherapy, radical surgery or radiotherapy or radiotherapy for non-metastatic tumors for curative purposes, at least 6 months have elapsed since the last chemotherapy, radical surgery, radiotherapy or radiotherapy course and before the first drug use; at least 12 months have elapsed since the last immunotherapy course and before the first drug use.

[0728] 5) Ability to provide archived or fresh tumor tissue for Nectin-4 and PD-L1 expression detection.

[0729] 6) At least one measurable lesion according to RECIST v1.1 criteria.

[0730] 3. Clinical protocol

[0731] 3.1 Study design

[0732] Stage Ib

[0733] (1) IB-Part 1, ADC-4 combined with anti-PD-L1 antibody exploration:

[0734] o Part 1 Dose Level 1: ADC-4 6 mg / kg Q3W + anti-PD-L1 antibody 1200 mg Q3W,

[0735] o Part 1 Dose Level 2: ADC-4 8 mg / kg Q3W + anti-PD-L1 antibody 1200 mg Q3W.

[0736] (2) IB Phase Part 2 (IB-Part2), ADC-4 in combination with anti-PD-L1 antibody and cisplatin exploration:

[0737] o Part2 Dose Level 1: ADC-4 4mg / kg Q3W + anti-PD-L1 antibody 1200mg Q3W + cisplatin 75mg / m 2 Q3W,

[0738] o Part2 Dose Level 2: ADC-4 6mg / kg Q3W + anti-PD-L1 antibody 1200mg Q3W + cisplatin 75mg / m 2 Q3W.

[0739] (3) IB Phase Part 3 (IB-Part3), ADC-4 in combination with anti-PD-L1 antibody and anti-CTLA-4 antibody exploration:

[0740] Part3 Dose Level 1: ADC-4 (6mg / kg, Q3W) + anti-PD-L1 antibody (1200mg, Q3W) + anti-CTLA-4 antibody (C1D1 280mg once, C2-C4 no dose, C5 and subsequent cycles 70mg Q6W).

[0741] Part3 Dose Level 2: ADC-4 (8mg / kg, Q3W) + anti-PD-L1 antibody (1200mg, Q3W) + anti-CTLA-4 antibody (C1D1 280mg once, C2-C4 no dose, C5 and subsequent cycles 70mg Q6W).

[0742] The administration mode of the anti-CTLA-4 antibody “C1D1 280mg once, C2-C4 no dose, C5 and subsequent cycles 70mg Q6W” means “with 21 days as one cycle, single dose of 280mg on the first day of the first cycle, no dose for the second to fourth cycles, and from the first day of the fifth cycle, the dose is administered according to the frequency of 70mg, once every 6 weeks (also known as “every other cycle”).

[0743] Phase II (efficacy expansion)

[0744] Cohort A: esophageal squamous carcinoma treated with ADC-4 (selected dose, Q3W) + anti-PD-L1 antibody (1200mg, Q3W);

[0745] Cohort B: esophageal squamous carcinoma treated with ADC-4 (selected dose, Q3W) + anti-PD-L1 antibody (1200mg, Q3W) + cisplatin (75mg / m 2 , Q3W).

[0746] Cohort C: Patients with esophageal squamous cell carcinoma treated with ADC-4 (selected dose, Q3W) + anti-PD-L1 antibody (1200 mg, Q3W) + anti-CTLA-4 antibody (C1D1 280 mg given once, C2-C4 no administration, C5 and subsequent cycles 70 mg Q6W).

[0747] 3.2 Administration method

[0748] ADC-4: Intravenous infusion, 4 mg / kg, 6 mg / kg, 8 mg / kg, Q3W or other doses determined in exploration.

[0749] Anti-PD-L1 antibody: Intravenous infusion, 1200 mg, once every 3 weeks, each infusion time 30-60 minutes, 21 days as a cycle (Q3W).

[0750] Cisplatin: Intravenous infusion, 75 mg / m 2 , once every 3 weeks, each infusion time about 60 min, chemotherapy for a maximum of 4 cycles.

[0751] Anti-CTLA-4 antibody: Intravenous infusion, C1D1 280 mg given once, C2-C4 no administration, C5 and subsequent cycles 70 mg Q6W (280 mg given once on the first day of the first cycle, no administration for the second to fourth cycles, and then given once every 6 weeks (also known as "every other cycle") starting from the first day of the fifth cycle). Each intravenous infusion lasts 30±10 min, and 21 days as a cycle. The cumulative administration does not exceed 2 years.

[0752] Administration sequence: 1) Two-drug combination, ADC-4 is given first, followed by anti-PD-L1 antibody; 2) Three-drug combination, ADC-4 is given first, followed by anti-PD-L1 antibody, and then cisplatin or anti-CTLA-4 antibody. The administration time interval of the two drugs should be > 30 minutes. The administration should be completed on the same day as far as possible. Different drugs require separate infusion bags and filters.

[0753] Maximum administration course: Anti-PD-L1 antibody cumulative administration for a maximum of 35 times, and anti-CTLA-4 antibody administration for a maximum of 2 years from the first administration time. If a study drug is terminated early due to toxicity intolerance, the other study drug can be considered for continued use.

[0754] 4. Outcome evaluation

[0755] 4.1 Effectiveness index

[0756] Tumor evaluation uses the RECIST v1.1 standard, and all subjects undergo baseline tumor imaging evaluation during the screening period. The effectiveness indicators include: ORR, DCR, DoR, PFS, and OS assessed by the investigator.

[0757] Clinical trials are also ongoing, as shown in Table 11, subjects enrolled in IB: ORR was 30% and DCR was 90% at Part 1-dose level 1 (part 1-1), ORR was 46.4% and DCR was 92.9% at Part 1-dose level 2 (part 1-2). Subjects enrolled in II: ORR was 64.7% and DCR was 91.2% at Cohort A (II-A, where the dose of ADC-4 was 8 mg / kg), ORR was 61.9% and DCR was 95.2% at Cohort C (II-C, where the dose of ADC-4 was 8 mg / kg).

[0758] In addition, there were 8 subjects in IB-part 3 who completed at least 1 tumor assessment, of which 4 were at part 3-dose level 1, including 3 with SD (stable disease) and 1 with PD (progressive disease), and 4 were at part 3-dose level 2, including 2 with PR (partial remission) and 2 with SD (stable disease).

[0759] Table 11. Efficacy evaluation *ORR: objective response rate, including unconfirmed ORR

[0760] 4.2 Safety evaluation

[0761] Safety evaluation will be performed for all subjects enrolled in the study every treatment cycle. It includes the incidence and grade of AE, serious adverse events (SAE) (judged according to NCI-CTCAE v5.0 standard), changes in vital signs, abnormal laboratory test indicators, and the incidence of dose suspension, dose reduction and dose termination due to study drug-related toxicity during the trial.

[0762] Safety evaluation of enrolled subjects showed that the most common (≥20%) TRAEs in enrolled subjects included anemia, loss of appetite, nausea, decreased white blood cell count, decreased neutrophil count, hypoalbuminemia, decreased lymphocyte count, decreased platelet count, hair loss, weakness, and vomiting. The proportion of subjects who experienced grade 3 TRAEs during first-line treatment was 18.8% in subjects enrolled in phase II.

[0763] In summary, ADC-4 antibody conjugate combined with immunotherapeutic agents showed tolerable and controllable safety, and showed promising antitumor activity in the second-line treatment and first-line treatment of esophageal squamous cell carcinoma.

Claims

1. Use of an anti-Nectin-4 antibody drug conjugate in the manufacture of a medicament for treating a tumor, the anti-Nectin-4 antibody drug conjugate comprising the structure shown below: wherein: n is a decimal or integer from 1 to 10, preferably from 1 to 8, more preferably from 3 to 5; NEC49 is an anti-Nectin-4 antibody; the tumor is non-small cell lung cancer or esophageal cancer.

2. Use according to claim 1, wherein, The non-small cell lung cancer is advanced non-small cell lung cancer; preferably locally advanced or metastatic non-small cell lung cancer.

3. Use according to claim 1 or 2, wherein, The non-small cell lung cancer is squamous non-small cell lung cancer or non-squamous non-small cell lung cancer; Preferably, the non-squamous non-small cell lung cancer is EGFR-mutant non-squamous non-small cell lung cancer or EGFR-wild-type non-squamous non-small cell lung cancer; preferably EGFR-mutant non-squamous non-small cell lung cancer or driver gene-negative non-squamous non-small cell lung cancer.

4. The use according to claim 1, wherein, The esophageal cancer is esophageal squamous cell carcinoma, preferably advanced esophageal squamous cell carcinoma, more preferably locally advanced or metastatic esophageal squamous cell carcinoma.

5. Use according to any one of claims 1 to 4, wherein, The subject with the non-small cell lung cancer or esophageal cancer has previously received an anti-tumor standard treatment selected from chemotherapy, immunotherapy, and / or targeted drug therapy, the chemotherapy comprising platinum-based chemotherapy.

6. Use according to any one of claims 1 to 5, wherein, The subject with the non-small cell lung cancer or esophageal cancer has previously failed or is intolerant to an anti-tumor standard treatment, preferably a subject who has failed or is intolerant to treatment with chemotherapy, immunotherapy, and / or targeted drug therapy, the chemotherapy comprising platinum-based chemotherapy.

7. Use according to any one of claims 1 to 6, wherein, The anti-Nectin-4 antibody comprises a heavy chain variable region (VH) comprising HCDR1, HCDR2, and HCDR3 as set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively; and a light chain variable region (VL) comprising LCDR1, LCDR2, and LCDR3 as set forth in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively; Preferably, the anti-Nectin-4 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence as set forth in SEQ ID NO: 7 or having at least 80%, 90% identity thereto; and a light chain variable region (VL) comprising an amino acid sequence as set forth in SEQ ID NO: 8 or having at least 80%, 90% identity thereto; More preferably, the anti-Nectin-4 antibody comprises a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 9 or having at least 80%, 90% identity thereto; and a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 10 or having at least 80%, 90% identity thereto.

8. Use according to any one of claims 1 to 7, wherein, The anti-Nectin-4 antibody drug conjugate is administered at a dose of 0.1-20 mg / kg, preferably 1-10 mg / kg, more preferably about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, or about 10 mg / kg; and / or The anti-Nectin-4 ADC is administered at a dose of about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg once every 3 weeks; or, the anti-Nectin-4 ADC is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg twice every 3 weeks. The anti-Nectin-4 ADC is administered at a dose of about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg once every 3 weeks; or, the anti-Nectin-4 ADC is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg twice every 3 weeks.

9. Use of an anti-Nectin-4 antibody drug conjugate in combination with an immunotherapeutic agent in the manufacture of a medicament for the treatment of non-small cell lung cancer or esophageal cancer; the anti-Nectin-4 antibody drug conjugate comprises the structure shown below: wherein: n is a number or an integer from 1 to 10, preferably from 1 to 8, more preferably from 3 to 5; NEC49 is an anti-Nectin-4 antibody; The immunotherapeutic agent is preferably an anti-PD-L1 antibody, and / or an anti- CTLA-4 antibody. The anti-Nectin-4 antibody is preferably as defined in claim 7, and the anti-Nectin-4 ADC is administered at a dose and frequency as defined in claim 8.

10. Use according to claim 9, wherein, The non-small cell lung cancer is preferably locally advanced or metastatic non- small cell lung cancer.

11. Use according to claim 9 or 10, wherein, The non-small cell lung cancer is preferably squamous non-small cell lung cancer or non-squamous non-small cell lung cancer.

12. The use according to claim 9, wherein, The esophageal cancer is preferably esophageal squamous cell carcinoma, preferably locally advanced or metastatic esophageal squamous cell carcinoma.

13. Use according to any one of claims 9-12, wherein, The subject with the non-small cell lung cancer or esophageal cancer has not been previously treated, or has been previously treated with an anti-neoplastic therapy. The subject has failed or is intolerant to the previous anti-neoplastic therapy. The subject has failed or is intolerant to the previous anti-neoplastic therapy, which is preferably chemotherapy, immunotherapy, and / or targeted drug therapy, more preferably chemotherapy comprising platinum-based chemotherapy.

14. The use according to any one of claims 9-13, wherein the anti-PD-L1 antibody comprises a heavy chain variable region (VH) comprising HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13, respectively, and a light chain variable region (VL) comprising LCDR1, LCDR2 and LCDR3 as set forth in SEQ ID NO: 14, SEQ ID NO: 15 and SEQ ID NO: 16, respectively. The heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO: 17 or at least 80%, 90% identical thereto, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO: 18 or at least 80%, 90% identical thereto. More preferably, the anti-PD-L1 antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 19 or having at least 80%, 90% identity thereto, and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 20 or having at least 80%, 90% identity thereto.

15. Use according to any one of claims 9 to 14, wherein, The anti-PD-L1 antibody is administered at a dose of 5-5000 mg, preferably about 100 mg, about 500 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, about 2500 mg, about 3000 mg; and / or, the anti-PD-L1 antibody is administered at a frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks, preferably once every 3 weeks; Preferably, the anti-PD-L1 antibody is administered at a dose of about 100 mg, about 500 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, about 2500 mg, about 3000 mg; the anti-PD-L1 antibody is administered at a frequency of once every 3 weeks. More preferably, the anti-PD-L1 antibody is administered at a dose of about 1200 mg, at a frequency of once every 3 weeks.

16. Use according to any one of claims 9-15, wherein, The anti-CTLA-4 antibody comprises a heavy chain variable region (VH) comprising HCDR1, HCDR2 and HCDR3 set forth in SEQ ID NO: 21, SEQ ID NO: 22 and SEQ ID NO: 23, respectively, and a light chain variable region (VL) comprising LCDR1, LCDR2 and LCDR3 set forth in SEQ ID NO: 24, SEQ ID NO: 25 and SEQ ID NO: 26, respectively; Preferably, the heavy chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 27 or having at least 90% identity thereto, and the light chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 28 or having at least 90% identity thereto; More preferably, the anti-CTLA-4 antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 29 or having at least 80%, 90% identity thereto, and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 30 or having at least 80%, 90% identity thereto.

17. Use according to any one of claims 9-16, wherein the anti-CTLA-4 antibody is administered at a dose of 1 mg to 1000 mg, preferably about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 500 mg, or about 700 mg; and / or the anti-CTLA-4 antibody is administered at a frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, once every 12 weeks, once every 14 weeks, once every 16 weeks, or as a single administration, preferably once every 6 weeks or as a single administration; preferably, the anti-CTLA-4 antibody is administered at a dose of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 500 mg, or about 700 mg; and the anti-CTLA-4 antibody is administered at a frequency of once every 6 weeks or as a single administration; more preferably, the anti-CTLA-4 antibody is administered as a single administration at a dose of about 280 mg or 210 mg at week 1, no administration at weeks 2-12, and a dose of about 70 mg at a frequency of once every 6 weeks starting from week 13.

18. The use according to any one of claims 9-17, which is selected from any one of the following combinations: (1) an anti-Nectin-4 antibody drug conjugate in combination with an anti-PD-L1 antibody, (2) an anti-Nectin-4 antibody drug conjugate in combination with an anti-PD-L1 antibody and an anti-CTLA-4 antibody; preferably, the administration regimen of (1) an anti-Nectin-4 antibody drug conjugate in combination with an anti-PD-L1 antibody is: (a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of 1-10 mg / kg at a frequency of once every 3 weeks or twice every three weeks; and (b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg at a frequency of once every 3 weeks; or, (a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg, with a dosing frequency of once every 3 weeks or twice every 3 weeks; (b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg, with a dosing frequency of once every 3 weeks; (a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg, with a dosing frequency of once every 3 weeks or twice every 3 weeks; (b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg, with a dosing frequency of once every 3 weeks; (a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg, with a dosing frequency of once every 3 weeks or twice every 3 weeks; (b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg, with a dosing frequency of once every 3 weeks; (a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg, with a dosing frequency of once every 3 weeks or twice every 3 weeks; (b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg, with a dosing frequency of once every 3 weeks; (a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg, with a dosing frequency of once every 3 weeks or twice every 3 weeks; (b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg, with a dosing frequency of once every 3 weeks; Preferably, the dosing regimen of (2) the anti-Nectin-4 antibody drug conjugate in combination with an anti-PD-L1 antibody and an anti-CTLA-4 antibody is: (a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg, with a dosing frequency of once every 3 weeks or twice every 3 weeks; (b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg, with a dosing frequency of once every 3 weeks; (b2) the anti-CTLA-4 antibody is administered at a dose of 1 mg-1000 mg, with a dosing frequency of once every 6 weeks or single dosing; (a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg, with a dosing frequency of once every 3 weeks or twice every 3 weeks; (b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg, with a dosing frequency of once every 3 weeks; (b2) the anti-CTLA-4 antibody is administered at a dose of 1 mg-1000 mg, with a dosing frequency of once every 6 weeks or single dosing; (a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg with a dosing frequency of once every 3 weeks; (b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg with a dosing frequency of once every 3 weeks; (b2) the anti-CTLA-4 antibody is administered at a dose of 1 mg-1000 mg with a dosing frequency of once every 6 weeks or a single dose; (a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, or about 4 mg / kg with a dosing frequency of twice every 3 weeks; (b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg with a dosing frequency of once every 3 weeks; (b2) the anti-CTLA-4 antibody is administered at a dose of 1 mg-1000 mg with a dosing frequency of once every 6 weeks or a single dose; (a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 6 mg / kg or about 8 mg / kg with a dosing frequency of once every 3 weeks; (b1) the anti-PD-L1 antibody is administered at a dose of 1200 mg with a dosing frequency of once every 3 weeks; (b2) the anti-CTLA-4 antibody is administered as a single dose at about 210 mg or 280 mg at week 1, no dose from week 2 to week 12, and a dose of about 70 mg with a dosing frequency of once every 6 weeks starting from week 13; or (a) the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 4 mg / kg with a dosing frequency of twice every 3 weeks; (b1) the anti-PD-L1 antibody is administered at a dose of 1200 mg with a dosing frequency of once every 3 weeks; (b2) the anti-CTLA-4 antibody is administered as a single dose at about 210 mg or 280 mg at week 1, no dose from week 2 to week 12, and a dose of about 70 mg with a dosing frequency of once every 6 weeks starting from week 13.

19. Use according to any one of claims 9-18, wherein, The use is the use of an anti-Nectin-4 antibody drug conjugate in combination with an immunotherapeutic agent and a VEGF signaling pathway inhibitor in the manufacture of a medicament for treating non-small cell lung cancer or esophageal cancer.

20. The use according to claim 19, wherein, The VEGF signaling pathway inhibitor is an anti-VEGF antibody; preferably, the anti-VEGF antibody comprises a heavy chain variable region (VH) comprising HCDR1, HCDR2, and HCDR3 as set forth in SEQ ID NO: 31, SEQ ID NO: 32, and SEQ ID NO: 33, respectively, and a light chain variable region (VL) comprising LCDR1, LCDR2, and LCDR3 as set forth in SEQ ID NO: 34, SEQ ID NO: 35, and SEQ ID NO: 36, respectively; More preferably, the VH comprises an amino acid sequence as set forth in SEQ ID NO: 37 or at least 80% identical thereto, and the VL comprises an amino acid sequence as set forth in SEQ ID NO: 38 or at least 80% identical thereto; Most preferably, the anti-VEGF antibody comprises a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 39 or at least 80% identical thereto, and a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 40 or at least 80% identical thereto.

21. The use of claim 19 or 20, wherein the anti-VEGF antibody is administered at a dose of about 1 mg / kg to about 30 mg / kg; preferably about 3.0 mg / kg, about 4.0 mg / kg, about 5 mg / kg, about 6.0 mg / kg, about 7.5 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg; and / or the anti-VEGF antibody is administered at a frequency of once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks; preferably once every 3 weeks; Preferably, the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 6 mg / kg or about 8 mg / kg, at a frequency of once every 3 weeks; the anti-PD-L1 antibody is administered at a dose of 1200 mg, at a frequency of once every 3 weeks; the anti-VEGF antibody is administered at a dose of about 7.5 mg / kg, at a frequency of once every 3 weeks; the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 6 mg / kg or about 8 mg / kg, at a frequency of once every 3 weeks; the anti-PD-L1 antibody is administered at a dose of 1200 mg, at a frequency of once every 3 weeks; the anti-VEGF antibody is administered at a dose of about 15 mg / kg, at a frequency of once every 3 weeks; the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 6 mg / kg or about 8 mg / kg, at a frequency of once every 3 weeks; the anti-PD-L1 antibody is administered at a dose of 1200 mg, at a frequency of once every 3 weeks; the anti-CTLA-4 antibody is administered at a dose of about 210 mg or 280 mg once at week 1, no administration from week 2 to week 12, and a dose of about 70 mg at a frequency of once every 6 weeks from week 13; the anti-VEGF antibody is administered at a dose of about 7.5 mg / kg, at a frequency of once every 3 weeks; or the anti-Nectin-4 antibody drug conjugate is administered at a dose of about 6 mg / kg or about 8 mg / kg, at a frequency of once every 3 weeks; the anti-PD-L1 antibody is administered at a dose of 1200 mg, at a frequency of once every 3 weeks; the anti-VEGF antibody is administered at a dose of about 7.5 mg / kg, at a frequency of once every 3 weeks; or The anti-Nectin-4 antibody drug conjugate is administered at a dosage of about 6 mg / kg or about 8 mg / kg, with a frequency of once every 3 weeks; the anti-PD-L1 antibody is administered at a dosage of 1200 mg, with a frequency of once every 3 weeks; the anti-CTLA-4 antibody is administered at a dosage of about 210 mg or 280 mg at week 1, with no administration from week 2 to week 12, and a dosage of about 70 mg from week 13, with a frequency of once every 6 weeks; and the anti-VEGF antibody is administered at a dosage of about 15 mg / kg, with a frequency of once every 3 weeks.

22. The use according to any one of claims 9-18, wherein, The use is the use of an anti-Nectin-4 antibody drug conjugate in combination with an immunotherapeutic agent and a platinum-based drug in the preparation of a medicament for treating non-small cell lung cancer or esophageal cancer.

23. The use according to claim 22, wherein the platinum-based drug is carboplatin or cisplatin.

24. The use according to claim 23, wherein the carboplatin is administered at a dosage (in terms of AUC) of about 0.1 mg / mL / min to about 50 mg / mL / min, or about 1 mg / mL / min to 10 mg / mL / min; preferably about 1 mg / mL / min, about 2 mg / mL / min, about 3 mg / mL / min, about 4 mg / mL / min, about 5 mg / mL / min, about 6 mg / mL / min, about 7 mg / mL / min, about 8 mg / mL / min, about 9 mg / mL / min, about 10 mg / mL / min; with a frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks, preferably once every 3 weeks. Preferably, The anti-Nectin-4 antibody drug conjugate is administered at a dosage of about 4 mg / kg or about 6 mg / kg, with a frequency of once every 3 weeks; the anti-PD-L1 antibody is administered at a dosage of 1200 mg, with a frequency of once every 3 weeks; the anti-CTLA-4 antibody is administered at a dosage of about 210 mg or 280 mg at week 1, with no administration from week 2 to week 12, and a dosage of about 70 mg from week 13, with a frequency of once every 6 weeks; and the anti-VEGF antibody is administered at a dosage of about 15 mg / kg, with a frequency of once every 3 weeks. Preferably, 25. The use according to claim 23, wherein cisplatin is administered at a dose of 1 mg / m2 to 500 mg / m2, or 50 mg / m2 to 150 mg / m2; preferably about 10 mg / m2, about 20 mg / m2, about 30 mg / m2, about 50 mg / m2, about 65 mg / m2, about 70 mg / m2, about 75 mg / m2, about 80 mg / m2, about 85 mg / m2, about 90 mg / m2, about 100 mg / m2, about 150 mg / m2; with a frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks, preferably once every 3 weeks. 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 ​​​​​​​​​​​​​​​​ 26. A kit or article of manufacture comprising an anti-Nectin-4 antibody drug conjugate as defined in any one of claims 1, 7-8 and 18, an immunotherapeutic agent as defined in any one of claims 9, 14-18, a VEGF signaling pathway inhibitor as defined in any one of claims 20-21, and / or a platinum-based drug as defined in any one of claims 23-25. The anti-Nectin-4 antibody drug conjugate is administered at a dose of about 4 mg / kg or about 6 mg / kg with a frequency of once every 3 weeks; the anti-PD-L1 antibody is administered at a dose of 1200 mg with a frequency of once every 3 weeks; and the cisplatin is administered at a dose of about 75 mg / m 2 with a frequency of once every 3 weeks. ​ Preferably, the kit or article of manufacture comprises an anti-Nectin-4 antibody drug conjugate, an anti-Nectin-4 antibody drug conjugate and an anti-PD-L1 antibody, an anti-Nectin-4 antibody drug conjugate, an anti-PD-L1 antibody and an anti-VEGF antibody, an anti-Nectin-4 antibody drug conjugate, an anti-PD-L1 antibody and carboplatin, an anti-Nectin-4 antibody drug conjugate, an anti-PD-L1 antibody and cisplatin, an anti-Nectin-4 antibody drug conjugate, an anti-PD-L1 antibody and an anti-CTLA-4 antibody, an anti-Nectin-4 antibody drug conjugate, an anti-PD-L1 antibody, an anti-CTLA-4 antibody and an anti-VEGF antibody.

27. A pharmaceutical composition comprising an anti-Nectin-4 antibody drug conjugate as defined in any one of claims 1, 7-8 and 18, an immunotherapeutic agent as defined in any one of claims 9, 14-18, a VEGF signaling pathway inhibitor as defined in any one of claims 20-21, and / or a platinum-based drug as defined in any one of claims 23-25; Preferably, the pharmaceutical composition comprises an anti-Nectin-4 antibody drug conjugate, an anti-Nectin-4 antibody drug conjugate and an anti-PD-L1 antibody, an anti-Nectin-4 antibody drug conjugate, an anti-PD-L1 antibody and an anti-VEGF antibody, an anti-Nectin-4 antibody drug conjugate, an anti-PD-L1 antibody and carboplatin, an anti-Nectin-4 antibody drug conjugate, an anti-PD-L1 antibody and cisplatin, an anti-Nectin-4 antibody drug conjugate, an anti-PD-L1 antibody and an anti-CTLA-4 antibody, an anti-Nectin-4 antibody drug conjugate, an anti-PD-L1 antibody, an anti-CTLA-4 antibody and an anti-VEGF antibody.

28. Use of the kit or article of manufacture of claim 26, or the pharmaceutical composition of claim 27, for the manufacture of a medicament for treating a tumor; Preferably, the tumor is as defined in any one of claims 2-6 and 13.

29. A method of preventing or treating a tumor, comprising administering to a subject in need thereof: 1) an anti-Nectin-4 antibody drug conjugate, 2) an anti-Nectin-4 antibody drug conjugate and an immunotherapeutic agent, 3) an anti-Nectin-4 antibody drug conjugate, an immunotherapeutic agent and a VEGF signaling pathway inhibitor, or 4) an anti-Nectin-4 antibody drug conjugate, an immunotherapeutic agent and a platinum-based drug; the anti-Nectin-4 antibody drug conjugate is administered at a dose of 0.1-20 mg / kg, preferably 1-10 mg / kg. The anti-Nectin-4 antibody drug conjugate comprises the structure shown below: wherein: n is a number or an integer from 1 to 10, preferably from 1 to 8, more preferably from 3 to 5; NEC49 is an anti-Nectin-4 antibody; Preferably, the anti-Nectin-4 antibody drug conjugate is as defined in any one of claims 1, 7-8 and 18, the immunotherapeutic agent is as defined in any one of claims 9, 14-18, the VEGF signaling pathway inhibitor is as defined in any one of claims 20-21, the platinum-based drug is as defined in any one of claims 23-25. The tumor is as defined in any one of claims 2-6 and 13.

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